Cycloalkene-substituted heteroaromatic compounds and uses thereof

Abstract

The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof, and / or solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof, wherein: A, R1, R2, R3, R3', R4, R4', R5, R6, R7, R8, m and n are as defined in the detailed description of the invention.

Description

[0001] This application is a divisional application of the international application filed on September 7, 2018, with application number PCT / CN2018 / 104531 and the invention title "Cycloolefin-substituted heteroaromatic compounds and their uses". The international application entered the Chinese national phase on March 3, 2020, with application number 201880057118.4. Technical Field

[0002] This invention relates to cyclic olefin-substituted heterocyclic compounds and their use in treating diseases induced by IDH mutations. Background Technology

[0003] Tumor cells differ from normal cells in their survival strategies, energy uptake, and utilization. The tricarboxylic acid cycle (TCA cycle) is a ubiquitous metabolic pathway in aerobic organisms, with isocitrate dehydrogenase (IDH) catalyzing the conversion of isocitrate to α-ketoglutarate (α-KG), which is the rate-limiting step in the TCA cycle. Currently known members of the IDH family include three subtypes: IDH1, IDH2, and IDH3. They are located in different organelles but perform the same biological function: catalyzing the production of α-KG. Recent studies have found a certain proportion of heterozygous mutations in the IDH1 / 2 gene in various tumors, such as glioma (60–80%), chondrosarcoma (55%), and acute myeloid leukemia (15–25%). Mutated IDH1 or IDH2 genes lose their normal function of catalyzing the conversion of isocitrate to α-KG but gain the ability to catalyze the conversion of α-KG to α-hydroxyglutarate (2HG). Because 2HG and α-KG have very similar structures, when α-KG accumulates to a certain extent, it will competitively inhibit the activity of many α-KG-dependent enzymes (such as histone demethylases, TET family methylpyrimidine hydroxylases, etc.), affecting the demethylation of histones and DNA, interfering with normal cell differentiation, and thus leading to the proliferation of immature cells.

[0004] In 2013, Agios Pharmaceuticals published its research findings in the journal Science: The company's mutant IDH1 enzyme inhibitor AGI-5198 (Science, 2013, 340, 626-630) and mutant IDH2 enzyme inhibitor AGI-6780 (Science, 2013, 340, 622-626) effectively inhibited the production of 2HG mediated by mutant IDH1 / IDH2 in cells, inducing the differentiation of abnormally proliferating cancer cells. Treatment of glioma cells carrying IDH1 gene mutations with AGI-5198 and leukemia cells carrying IDH2 gene mutations with AG-6780 both resulted in increased expression of maturation markers in the cells.

[0005] Agios Pharmaceuticals' mutant IDH1 inhibitor AG-120 showed in its Phase I clinical trial that a decrease in α-hydroxyglutarate (2HG) levels was observed in 98% of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with IDH1 gene mutations.

[0006] Acute myeloid leukemia (AML) is one of the most difficult-to-control hematologic malignancies, characterized by a high relapse rate, slow progress in new drug development, and a lack of effective treatments. Studies show that approximately 15% of AML patients have IDH2 gene mutations. The mutant IDH2 inhibitor enasidenib (formerly known as AG-221), developed by Agios Pharmaceuticals and Celgene, has shown significant efficacy in clinical trials for relapsed, refractory AML with IDH2 gene mutations.

[0007] To meet the treatment needs of patients with hematologic malignancies, particularly acute myeloid leukemia, glioma, and other IDH gene mutation-related tumors, there remains a need to research and develop novel mutant IDH enzyme inhibitors. This invention addresses these needs. Invention Summary

[0008] This invention provides compounds of formula (I):

[0009]

[0010] And / or its pharmaceutically acceptable salts, and / or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, wherein: A, R1, R2, R3, R3', R4, R4', R5, R6, R7, R8, m and n are as defined in the detailed description of the invention.

[0011] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0012] The present invention also provides a method for treating a disease induced by an IDH mutation, comprising administering to an individual in need an effective amount of at least one compound of formula (I) of the present invention (e.g., any compound herein) and / or at least one of its pharmaceutically acceptable salts.

[0013] The present invention also provides the use of compounds of formula (I) of the present invention (e.g., any of the compounds herein) and / or pharmaceutically acceptable salts thereof in the treatment of diseases induced by IDH mutations.

[0014] The present invention also provides the use of compounds of formula (I) of the present invention (e.g., any compound herein) and / or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases induced by IDH mutations. Attached Figure Description

[0015] Figure 1 A general synthetic route I for preparing the compounds of the present invention is shown.

[0016] Figure 2 A general synthetic route II for preparing the compounds of the present invention is shown.

[0017] Figure 3 A general synthetic route III for preparing the compounds of the present invention is shown.

[0018] Figure 4 IV shows a general synthetic route for preparing the compounds of the present invention.

[0019] Figure 5 A general synthetic route V for preparing the compounds of the present invention is shown.

[0020] Figure 6 A general synthetic route VI for preparing the compounds of the present invention is shown. Invention Details

[0021] definition

[0022] The following words, phrases and symbols used in this application have the meanings described below, unless otherwise stated in the context.

[0023] A hyphen ("-") not between two letters or symbols indicates the linking site of a substituent. For example, -OR4 indicates a link to the rest of the molecule via an oxygen atom. The hyphen may be omitted when the linking site of the substituent is well known to those skilled in the art, such as halogen substituents.

[0024] Unless otherwise specified, the term "one" and similar terms used in this document refer to one or more.

[0025] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms, and even more preferably 1-4 carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), and tert-butyl ("t-Bu").

[0026] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon double bonds (C=C), and containing 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. For example, "C 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The alkenyl group may or may not be attached to a double bond.

[0027] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon triple bonds (C≡C), and containing 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. For example, "C 2-6 "Alynyl" indicates an alkynyl group having 2-6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The alkynyl group may or may not be attached to a triple bond.

[0028] As used herein, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine, and more preferably fluorine and chlorine.

[0029] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms, such as 1, 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein, in which two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein, in which two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, etc.

[0030] As used herein, the term "alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined above. Examples of alkoxy groups include, but are not limited to, C-alkyl groups. 1-6 Alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy, including their isomers.

[0031] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3-12 ring carbon atoms (e.g., 3-8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms, or 3-6 ring carbon atoms); it may have one or more rings, such as 1, 2, or 3, preferably 1 or 2 rings. For example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms. Cycloalkyl groups may include fused or bridged rings and spirocyclic rings. The ring of a cycloalkyl group may be saturated and may contain one or more double bonds, such as one or two (i.e., partially unsaturated), but it is not fully conjugated and is not an "aryl" group as defined in this invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bis[4.1.0]heptyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and bicyclo[3.1.1]hept-2-ene.

[0032] As used herein, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring having 3-12 ring atoms (e.g., 3-8, 5-7, 4-7, or 3-6 ring atoms), wherein the ring contains one or more (e.g., 1, 2, or 3, preferably 1 or 2) cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms. N and S may optionally be oxidized to various oxidation states, and the alkyl group may be attached to either an N heteroatom or a carbon atom. For example, "3-8 membered heterocyclic alkyl" indicates a heterocyclic alkyl group having 3-8 ring atoms, containing at least one heteroatom selected from N, O, and S.

[0033] Heterocyclic alkyl groups may include fused or bridged rings and spirocyclic groups, wherein at least one ring contains at least one cyclic heteroatom independently selected from N, O, and S, and the remaining rings are not “aryl” or “heteroaryl” as defined in this invention. The rings of heterocyclic alkyl groups may be saturated and may contain one or more double bonds, such as one or two double bonds (i.e., partially unsaturated), but they are not fully conjugated and are not “heteroaryl” as defined in this invention. Examples of heterocyclic alkyl groups include, but are not limited to: oxobutyranyl, azabutyranyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanecycloyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrazolyl, and oxaspiro[3.3]heptyl.

[0034] As used herein, the term "aryl" refers to a carbocyclic hydrocarbon group containing 6-14 carbon atoms, consisting of one or more fused rings, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indenyl, azulel, with phenyl and naphthyl being preferred.

[0035] The term "heteroaryl" as used in this article refers to:

[0036] A monocyclic aromatic hydrocarbon group having 5, 6, or 7 ring atoms (preferably 6 ring atoms), wherein the ring contains one or more, for example 1, 2, or 3, more preferably 1 or 2 cyclic heteroatoms independently selected from N, O, and S (preferably N), and the remaining ring atoms are carbon atoms; and

[0037] A bicyclic aromatic hydrocarbon group having 8-12 ring atoms (preferably 9 or 10 ring atoms), comprising one or more, for example 1, 2, 3 or 4, preferably 2, 3 or 4, cyclic heteroatoms independently selected from N, O and S (preferably N), with the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring. For example, a bicyclic heteroaryl group comprises a 5-6 membered heteroaryl ring fused to a 5-6 membered alkyl ring.

[0038] When the total number of S and O atoms in a heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

[0039] Heteroaryl groups also include those in which the N-ring atom is in the form of an N-oxide, such as N-pyridine oxide.

[0040] Examples of heteroaryl groups include, but are not limited to: pyridyl, N-pyridyl oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazoleyl, etc. azole group, iso Azolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thiophenyl, furanyl, pyranyl, pyrroleyl, pyridazinyl, benzo[a]dioxanepentenyl, benzo[a] azole group, benzo[a] Azolyl, benzothiophenyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl), pyrrolopyridyl, pyrrolopyrimidyl, pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridyl), pyrazolopyrimidyl, triazololopyridyl (e.g., [1,2,4]triazololo[1,5-a]pyridyl), tetraazololopyridyl, tetrahydropyrazololopyridyl (e.g., 4,5,6,7-tetrahydropyrazololo[1,5-a]pyridyl), benzofuranyl, benzimidazolinyl, indoleyl, indazoleyl, purinyl, quinolinyl, and isoquinolinyl.

[0041] The term "hydroxyl group" as used in this article refers to the -OH group.

[0042] The term "thiol" as used in this article refers to the -SH group.

[0043] The term "oxo" as used in this article refers to the =O group.

[0044] If a structural formula herein contains an asterisk “*”, it indicates that the chiral center at the * mark in the compound is a single configuration of either (R) or (S) configuration; wherein the content of the single configuration marked “*” is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these listed values). The configuration of the compound can be determined by those skilled in the art using various analytical techniques, such as single-crystal X-ray crystallography and / or optical rotation determination, and according to conventional protocols.

[0045] If a structural formula in this article contains “(RS)”, it means that the chiral center at the “(Rv)” mark in the compound contains both (R) and (S) configurations.

[0046] As used herein, the terms “optional,” “optional,” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur. For example, “optionally substituted alkyl” includes both “unsubstituted alkyl” and “substituted alkyl” as defined herein. Those skilled in the art will understand that, for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0047] As used herein, the terms "substituted" or "replaced by" mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the substitution does not exceed the normal valence of the given atom. When the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced. Such combinations are permitted only if the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be isolated from the reaction mixture and subsequently formulated into an agent with at least practical utility.

[0048] Unless otherwise stated, substituents are named within the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, it indicates that the substituent is attached to the core structure at the alkyl moiety.

[0049] As used herein, the term "substituted by one or more substituents" means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group. In some embodiments, "substituted by one or more substituents" means that a given atom or group is replaced by 1, 2, 3 or 4 substituents independently selected from the given group.

[0050] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Racemic mixtures of these isomers, mixtures of single isomers and enantiomer-enriched mixtures, and mixtures of diastereomers and specific diastereomer-enriched mixtures when there are two chiral centers are all within the scope of this invention. Those skilled in the art will also understand that this invention includes all single stereoisomers (e.g., enantiomers), racemic mixtures, or partially separated mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.

[0051] In other words, in some embodiments, the present invention provides compounds containing multiple stereoisomeric purities, i.e., enantiomeric or diastereomeric purities expressed in different "ee" or "de" values. In some embodiments, the compound of formula (I) (e.g., as described herein) has an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these listed values). In some embodiments, the compound of formula (I) (e.g., as described herein) has an enantiomeric purity greater than 99.9% ee, reaching 100% ee. In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between these listed values). In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity greater than 99.9% de.

[0052] The term "enantiomer excess" or "ee" indicates the amount of one enantiomer relative to another. For a mixture of R and S enantiomers, the percentage of enantiomer excess is defined as |RS|*100, where R and S are the molar or weight fractions of their respective enantiomers in the mixture, and R+S=1. If the optical rotation of a chiral substance is known, the percentage of enantiomer excess is defined as ([a]obs / [a]max)*100, where [a]obs is the optical rotation of the enantiomer mixture, and [a]max is the optical rotation of the pure enantiomer.

[0053] The term "diasteresome excess" or "de" indicates the amount of one diastereomer relative to another, and is defined by analogy based on enantiomer excess. Therefore, for a mixture of diastereomers D1 and D2, the percentage of diastereomer excess is defined as |D1-D2|*100, where D1 and D2 are the molar or weight fractions of their respective diastereomers in the mixture, and D1+D2=1.

[0054] The determination of diastereomers and / or enantiomer excesses can be performed using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography, and / or optical rotation determination, according to conventional procedures familiar to those skilled in the art.

[0055] Racemic mixtures can be used in their original form or can be resolved into their individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral forms can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonate, camphorate, α-bromocamphorate, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.). The salt is then fractionally crystallized, and one or both of the separated bases are released. Optionally, this process is repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., isomers with an optical purity of at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%. Alternatively, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer, which can be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary compound to obtain a pure enantiomer.

[0056] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in two positions within a molecule. Tautomers can interconvert; for example, enol and keto forms are typical tautomers. Furthermore, some compounds of this invention may also exist in structural forms such as a, b, c, d, e, and f as shown in the figure below; that is, compounds a, b, c, d, e, and f may be tautomers of the compounds of formula (I) of this invention. These individual tautomers and mixtures of these tautomers in any proportion are all compounds of this invention.

[0057]

[0058] "Pharmaceutical acceptable salt" refers to a salt of a free acid or base of formula (I) that is nontoxic, biologically tolerable, or otherwise biologically suitable for administration to a therapeutic individual. See, for example: SMBerge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth eds., Wiley-VCH and VHCA, Zurich, 2002.

[0059] Furthermore, if the compound described herein is obtained as an acid addition salt, its free base form can be obtained by alkalizing the solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained by following the conventional procedure for preparing acid addition salts from basic compounds, by dissolving the free base in a suitable solvent and treating the solution with acid. Those skilled in the art can determine various synthetic methods for preparing non-toxic, pharmaceutically acceptable acid or base addition salts without extensive experimentation.

[0060] The term "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric solvents. Some compounds have a tendency to engulf solvent molecules in a fixed molar ratio in the solid state, thus forming solvates. If the solvent is water, the formed solvate is a hydrate; when the solvent is ethanol, the formed solvate is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance in which the water retains its H₂O molecular state. Such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates, as well as variable hydrates.

[0061] The terms “group” and “base” used in this article are synonyms and are used to refer to functional groups or molecular segments that can be linked to other molecular segments.

[0062] The term "active ingredient" is used to refer to a biologically active chemical substance. In some implementations, the "active ingredient" is a chemical substance intended for pharmaceutical use. In the United States, actual drug activity can be determined through appropriate preclinical trials, whether in vitro or in vivo. However, drug activity sufficient for acceptance by regulatory agencies (such as the FDA in the United States) requires a higher standard than that achieved through preclinical trials. The success of achieving such a higher standard of drug activity cannot generally be reasonably expected from preclinical trial results, but can be established through appropriate and effective randomized, double-blind, controlled clinical trials conducted in humans.

[0063] The term "treatment" or "treatment" of a disease or disorder refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) or pharmaceutically acceptable salts thereof, to an individual suffering from, or having symptoms of, the disease or disorder, or being susceptible to, the disease or disorder, in order to cure, heal, alleviate, reduce, alter, treat, improve, enhance, or influence the disease or disorder, its symptoms, or the individual's susceptibility to it. In some embodiments, the disease or disorder is cancer.

[0064] When referring to chemical reactions, the terms “treatment,” “contact,” and “reaction” mean the addition or mixing of two or more reagents under appropriate conditions to produce the shown and / or desired product. It should be understood that the reaction producing the shown and / or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the shown and / or desired product.

[0065] As used herein, the term "effective amount" refers to an amount or dose of an IDH mutation inhibitor that is generally sufficient to produce a beneficial therapeutic effect in patients requiring treatment of diseases or disorders induced by IDH mutations. The effective amount or dose of the active ingredient in this invention can be determined using conventional methods (e.g., modeling, dose-escalation studies, or clinical trials) combined with conventional influencing factors (e.g., the manner or route of administration, the pharmacokinetics of the drug component, the severity and duration of the disease or disorder, the individual's prior or ongoing treatments, the individual's health status and response to the drug, and the attending physician's judgment). In the United States, the determination of the effective dose is generally difficult to predict from preclinical trials. In fact, the dose is entirely unpredictable, and new, unpredictable dosing regimens may develop after the initial randomized, double-blind, controlled clinical trials.

[0066] Typical dosage ranges are from about 0.0001 to about 200 mg of active ingredient per kilogram of individual body weight per day, for example, from about 0.001 to 100 mg / kg / day, or about 0.01 to 35 mg / kg / day, or about 0.1 to 10 mg / kg, taken once daily or in divided doses (e.g., twice daily, three times daily, or four times daily). For a 70 kg person, an appropriate dosage range is typically from about 0.05 to about 7 g / day, or about 0.2 to about 5 g / day. Once the patient's condition or impairment improves, the dosage can be adjusted to maintain treatment. For example, the dosage or frequency of administration may be adjusted according to changes in symptoms, or the dosage and frequency may be reduced to maintain the desired therapeutic effect. Of course, treatment can be discontinued if symptoms have improved to an appropriate level. However, for recurrence of symptoms, patients may require intermittent long-term treatment.

[0067] As used herein, the term "individual" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds. The term "individual" is not limited to a specific age or sex. In some implementations, an individual is a human being.

[0068] Generally, the term "about" is used in this article to adjust the given value to be 20% higher or lower than that value.

[0069] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0070] This invention provides compounds of formula (I):

[0071]

[0072] and / or its pharmaceutically acceptable salts, and / or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, wherein:

[0073] A is selected from the following structures.

[0074]

[0075] Wherein: R7 is selected from hydrogen, halogen, -CN, hydroxyl or amino, R8 is selected from halogen, -CN, hydroxyl or amino, and q is 1 or 2;

[0076] R1 is selected from hydrogen, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, amino, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, oxo or C 3-8 cycloalkyl;

[0077] Each R2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -CN, mercapto, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, oxo, -OR5, -OCOR5, -NHR5, -N(R5)(C 1-4 Alkyl), -COR5, -NHCOR5 or 3-8 membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The cycloalkyl or 3-8 membered heterocycloalkyl group is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, -CN, hydroxyl, mercapto, amino, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2 or C 1-6 Alkyl group; or two R2 groups on the same carbon atom together with the carbon atom to which they are connected to form a 3- to 5-membered cycloalkyl group, optionally substituted with one or more halogens or deuterium;

[0078] R3, R3', R4, and R4' are each independently selected from hydrogen, C, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocycloalkyl, phenyl, 5-12-membered heteroaryl, -C(O)R5, -OR5 or -NHR5, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 The cycloalkyl, 3-12-membered heterocycloalkyl, phenyl, and 5-12-membered heteroaryl groups are each optionally substituted by one or more R6 groups; wherein R3, R3', R4, and R4' are not simultaneously hydrogen; provided that when one of R3 and R4 is an optionally substituted phenyl or an optionally substituted 5-6-membered heteroaryl group, the other is -OR5 or -NHR5.

[0079] Alternatively, R3 and R3' can be independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-12-membered heterocycloalkyl, phenyl, 5-12-membered heteroaryl, -C(O)R5, -OR5 or -NHR5, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 The cycloalkyl, 3-12-membered heterocycloalkyl, phenyl, and 5-12-membered heteroaryl groups are each optionally substituted by one or more R6 groups; R4 and R4' together with the N atom to which they are connected form a 3-8-membered heterocycloalkyl group optionally substituted by one or more R6 groups;

[0080] R5 is selected from C 1-6 Alkyl or C 3-8 cycloalkyl, the C 1-6 Alkyl or C 3-8Each cycloalkyl group may optionally be substituted by one or more substituents independently selected from the following: halogen, -CN, hydroxyl, mercapto, amino, or C. 1-6 Alkoxy;

[0081] Each R6 is independently selected from deuterium, halogen, -CN, hydroxyl, mercapto, amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 The cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -CN, hydroxyl, mercapto, amino, C 1-6 Alkoxy, C 2-6 alkynyl or C 1-6 alkyl;

[0082] m can be 0, 1, 2, 3, 4, 5, or 6;

[0083] n is 0, 1, or 2.

[0084] In some embodiments of the compound of formula (I), R1 is selected from hydrogen, hydroxyl, or halogen.

[0085] In some embodiments of the compound of formula (I), R1 is selected from hydroxyl or halogen.

[0086] In some embodiments of the compound of formula (I), R1 is a hydroxyl group.

[0087] In some embodiments of the compound of formula (I), R1 is a halogen selected from F, Cl, or Br. In some embodiments of the compound of formula (I), R1 is F.

[0088] In some embodiments of the compound of formula (I), the two R2 atoms on the same carbon atom together with the carbon atom to which they are connected form a 3-5 cyclic alkyl group optionally substituted with one or more F atoms.

[0089] In some embodiments of the compound of formula (I), the two R2 atoms on the same carbon atom together with the carbon atom to which they are connected form a cyclopropyl group.

[0090] In some embodiments of the compound of formula (I), each R2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -CN, mercapto, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C3-8 Cycloalkyl, oxo, -OR5, -OCOR5, -NHR5, -N(R5)(C 1-4 Alkyl), -NHCOR5 or 3-8 membered heterocyclic alkyl.

[0091] In some embodiments of the compound of formula (I), each R2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxo, -OR5, -NHR5 or -N(R5)(C 1-4 alkyl).

[0092] In some embodiments of the compound of formula (I), each R2 is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0093] In some embodiments of the compound of formula (I), each R2 is independently selected from halogens, such as F, Cl or Br.

[0094] In some embodiments of the compound of formula (I), R2 is F.

[0095] In some embodiments of the compound of formula (I), m is 0, 1, 2, 3 or 4.

[0096] In some embodiments of the compound of formula (I), m is 0, 1 or 2.

[0097] In some embodiments of the compound of formula (I), m is 1. In some embodiments of the compound of formula (I), m is 2. In some embodiments of the compound of formula (I), m is 3. In some embodiments of the compound of formula (I), m is 4.

[0098] In some embodiments of the compound of formula (I), R3 and R4 are each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12-membered heterocycloalkyl, phenyl, 5-12-membered heteroaryl, -C(O)R5, -OR5 or -NHR5, wherein C 1-6 Alkyl, C 3-12 The cycloalkyl, 3-12-membered heterocycloalkyl, phenyl, and 5-12-membered heteroaryl groups are each optionally substituted by one or more R6 groups; R3' and R4' are each independently selected from hydrogen or C6. 1-6 alkyl.

[0099] In some embodiments of the compound of formula (I), both R3' and R4' are hydrogen.

[0100] In some embodiments of the compound of formula (I), R3 and R4 are each independently selected from C1-6 Alkyl, C 3-12 Cycloalkyl or 3-12-membered heterocycloalkyl, each optionally substituted with one or more R6; R3' and R4' are both hydrogen.

[0101] In some embodiments of the compound of formula (I), R3 and R4 are each independently selected from C3 substituted with one or more halogens. 1-6 Alkyl, C 1-6 Halogenated alkyl-substituted 5-12-membered heteroaryl groups or -OR5; R3' and R4' are both hydrogen.

[0102] In some embodiments of the compound of formula (I), R3 and R4 are each independently selected from C3, which is optionally substituted with one or more halogens. 1-6 Alkyl group; both R3' and R4' are hydrogen.

[0103] In some embodiments of the compound of formula (I), R3 is C 1-6 5-12-membered heteroaryl groups substituted with haloalkyl groups, where R4 is C 1-6 Alkoxy group; R3' and R4' are both hydrogen.

[0104] In some embodiments of the compound of formula (I), R3 is a 5-7 membered heteroaryl group substituted with CF3, and R4 is a C 1-6 Alkoxy group; R3' and R4' are both hydrogen.

[0105] In some embodiments of the compound of formula (I), R3 is selected from hydrogen, optionally C. 1-6 Halogenated alkyl-substituted C 1-6 Alkyl, or optionally C 1-6 A 5-12-membered heteroaryl group substituted with a haloalkyl group; R3' is hydrogen; R4 and R4' together with the N atom they are attached to form a group optionally selected from one or more halogens, hydroxyls, or C. 1-6 3-8 membered heterocyclic alkyl groups substituted with haloalkyl groups.

[0106] In some embodiments of the compound of formula (I), R5 is C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0107] In some embodiments of the compound of formula (I), R5 is a C5 optionally substituted with one or more halogens. 1-6 alkyl.

[0108] In some embodiments of the compound of formula (I), each R6 is independently selected from deuterium, halogen, -CN, hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; the C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 The cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl groups are each optionally substituted with one or more halogens.

[0109] In some embodiments of the compound of formula (I), each R6 is independently selected from deuterium, halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl.

[0110] In some embodiments of the compound of formula (I), each R6 is independently selected from deuterium, halogen, -CN, hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl.

[0111] In some embodiments of the compound of formula (I), each R6 is independently selected from deuterium, halogen, or C. 1-6 Halogenated alkyl groups.

[0112] In some embodiments of the compound of formula (I), n is 1.

[0113] In some embodiments of the compound of formula (I), R7 and R8 are independently selected from halogens or -CN.

[0114] In some embodiments of the compound of formula (I), R7 and R8 are independently selected from F or -CN, respectively.

[0115] In some embodiments of the compound of formula (I), the compound of formula (I) is selected from...

[0116]

[0117] Where X is a halogen, and R1, R2, R3, R3', R4, R4', m and n are as defined in the compound of formula (I).

[0118] In some embodiments of the compound of formula (I), the compound of formula (I) has the structure of formula (I-1), wherein R1, R2, R3, R3', R4, R4', m and n are as defined in this invention.

[0119]

[0120] In some embodiments of the compound of formula (I), the compound of formula (I) has the structure of formula (I-1a), wherein R2, R3, R3', R4, R4', m and n are as defined in this invention.

[0121]

[0122] In some embodiments of the compound of formula (I), the compound of formula (I) has the structure of formula (I-1b), wherein R2, R3, R3', R4, R4', m and n are as defined in this invention.

[0123]

[0124] In some embodiments of the compound of formula (I), the compound of formula (I) has the structure of formula (II), wherein R1, R2, R3, R3', R4, R4', n and A are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, and m is 0, 1 or 2.

[0125]

[0126] In some embodiments of the compound of formula (II), X is F.

[0127] In some embodiments of the compound of formula (II), R1 is F.

[0128] In some embodiments of the compound of formula (II), R1 is a hydroxyl group.

[0129] In some embodiments of the compound of formula (II), p is 0.

[0130] In some embodiments of the compound of formula (II), p is 1.

[0131] In some embodiments of the compound of formula (II), p is 2.

[0132] In some embodiments of compounds of formula (I), formula (II) is selected from...

[0133]

[0134] R1, R2, R3, R3', R4, R4', m and n are defined as follows, X is a halogen, p is 0, 1 or 2, and m is 0, 1 or 2.

[0135] In some embodiments of the compound of formula (I), the compound of formula (II) has the structure of formula (II-1), wherein R1, R2, R3, R3', R4, R4', m and n are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, and m is 0, 1 or 2.

[0136]

[0137] In some embodiments of the compound of formula (I), the compound of formula (II) has the structure of formula (II-1a), wherein R2, R3, R3', R4, R4', m and n are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, and m is 0, 1 or 2.

[0138]

[0139] In some embodiments of the compound of formula (I), the compound of formula (II) has the structure of formula (II-1b), wherein R2, R3, R3', R4, R4', m and n are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, and m is 0, 1 or 2.

[0140]

[0141] In some embodiments of compounds of formulas (II-1) to (II-5), X is F.

[0142] In some embodiments of compounds of formulas (III-1) to (III-5), R1 is F.

[0143] In some embodiments of compounds of formulas (III-1) to (III-5), R1 is a hydroxyl group.

[0144] In some embodiments of compounds of formulas (II-1) to (II-5), p is 0.

[0145] In some embodiments of compounds of formulas (II-1) to (II-5), p is 1.

[0146] In some embodiments of compounds of formulas (II-1) to (II-5), p is 2.

[0147] In some embodiments of the compound of formula (I), the compound has the structure of formula (III), wherein R1, R2, R3, R3', R4, R4', n and A are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, m is 0, 1 or 2, and v is 0, 1 or 2.

[0148]

[0149] In some embodiments of compounds of formula (III), X is F.

[0150] In some embodiments of the compound of formula (III), R1 is F.

[0151] In some embodiments of the compound of formula (III), R1 is a hydroxyl group.

[0152] In some embodiments of the compound of formula (III), p is 0.

[0153] In some embodiments of the compound of formula (III), p is 1.

[0154] In some embodiments of the compound of formula (III), p is 2.

[0155] In some embodiments of the compound of formula (III), v is 0.

[0156] In some embodiments of the compound of formula (III), v is 1.

[0157] In some embodiments of the compound of formula (III), v is 2.

[0158] In some embodiments of the compound of formula (I), the compound of formula (III) is selected from...

[0159]

[0160] R1, R2, R3, R3', R4, R4', m and n are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, m is 0, 1 or 2, and v is 0, 1 or 2.

[0161] In some embodiments of the compound of formula (I), the compound of formula (III) has the structure of formula (III-1), wherein R1, R2, R3, R3', R4, R4', m and n are as defined in the compound of formula (I), X is a halogen, p is 0, 1 or 2, m is 0, 1 or 2, and v is 0, 1 or 2.

[0162]

[0163] In some embodiments of compounds of formulas (III-1) to (III-5), X is F.

[0164] In some embodiments of compounds of formulas (III-1) to (III-5), R1 is F.

[0165] In some embodiments of compounds of formulas (III-1) to (III-5), R1 is OH.

[0166] In some embodiments of compounds of formulas (III-1) to (III-5), p is 0.

[0167] In some embodiments of compounds of formulas (III-1) to (III-5), p is 1.

[0168] In some embodiments of compounds of formulas (III-1) to (III-5), p is 2.

[0169] In some embodiments of compounds of formulas (III-1) to (III-5), v is 0.

[0170] In some embodiments of compounds of formulas (III-1) to (III-5), v is 1.

[0171] In some embodiments of compounds of formulas (III-1) to (III-5), v is 2.

[0172] The present invention also provides compounds selected from compounds numbered 1-87, 89-184, 186-301 in the experimental section, and / or their pharmaceutically acceptable salts.

[0173] On the other hand, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0174] On the other hand, the present invention also provides a method for treating a disease induced by an IDH mutation in an individual, comprising administering to the individual in need an amount of a compound of formula (I) (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof that can effectively inhibit the increase in α-hydroxyglutaric acid (2HG) levels in the individual due to the IDH mutation.

[0175] On the other hand, the present invention also provides a method for treating a disease induced by an IDH mutation in an individual, comprising administering to the individual in need an amount of a pharmaceutical composition capable of effectively inhibiting the increase in α-hydroxyglutaric acid (2HG) levels in the individual due to the IDH mutation, the pharmaceutical composition comprising a compound of formula (I) (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0176] On the other hand, the present invention also provides the use of a compound of formula (I) described herein (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof in treating diseases induced by IDH mutations by inhibiting the increase in α-hydroxyglutarate (2HG) levels in said individuals due to IDH mutations.

[0177] On the other hand, the present invention also provides the use of a compound of formula (I) described herein (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease induced by IDH mutations.

[0178] In some implementations, the IDH mutation refers to an IDH1 gene mutation.

[0179] In some implementations, the IDH mutation refers to an IDH2 gene mutation.

[0180] In some implementations, the IDH mutation refers to the IDH1-R132H or IDH2-R140Q gene mutation.

[0181] In some implementations, the disease induced by IDH mutations is cancer.

[0182] In some implementations, the cancer is selected from solid tumors, gliomas, or hematologic malignancies, such as leukemia, lymphoma, or myeloma.

[0183] In some implementations, the cancer is selected from acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), cholangiocarcinoma such as intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, giant cell tumor of bone, colorectal cancer, melanoma, lung cancer, or non-Hodgkin lymphoma (NHL).

[0184] On the other hand, the present invention also provides compounds of formula (IV), and / or their salts, racemic mixtures or enantiomers, for the preparation of compounds of formula (I) of the present invention (e.g., any compound herein):

[0185]

[0186] Wherein: R1, R2, m, and n are as defined in the compound of formula (I); Ra is selected from halogens, -OS(O)2CF3, -B(OH)2, -B(OC)2, -OS(O)2CF3, -B(OH)2, -B(OC)2CF3, -OS(O)2CF3, -B(OH)2CF3, -B(OC ... 1-6 Alkyl)2, R b It is hydrogen or C 1-6 alkyl.

[0187] In some embodiments of the compound of formula (IV), R a Selected from -B(OH)2, -B(OC) 1-6 Alkyl)2, R b It is hydrogen or C 1-6 alkyl.

[0188] In some embodiments of the compound of formula (IV), R a For -B(OH)2, -B(OCH3)2, -B[OCH(CH3)2]2,

[0189] In some embodiments of the compound of formula (IV), the compound of formula (IV) has the structure of formula (IV-1), wherein m is 0, 1 or 2;

[0190]

[0191] In some embodiments of the compound of formula (IV), the compound of formula (IV) has the structure of formula (IV-2), wherein X is a halogen and m is 0, 1 or 2;

[0192]

[0193] In some embodiments of the compound of formula (IV), the compound of formula (IV) has the structure of formula (IV-3), wherein X is a halogen, p is 0, 1 or 2, and m is 0, 1 or 2;

[0194]

[0195] In some embodiments of the compound of formula (IV), R1 is a hydroxyl group or an oxo group.

[0196] In some embodiments of compounds of formula (IV), X is F.

[0197] In some embodiments of the compound of formula (IV), p is 0.

[0198] In some embodiments of the compound of formula (IV), p is 1.

[0199] In some embodiments of the compound of formula (IV), p is 2.

[0200] In some embodiments of the compound of formula (IV), the compound of formula (IV) has the following structure:

[0201]

[0202] In some embodiments of the compound of formula (IV), the compound of formula (IV) is selected from:

[0203]

[0204] General synthesis method of publicly disclosed implementation scheme

[0205] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts may be synthesized from commercially available raw materials, by methods known in the art, or by methods disclosed in this patent application. Figure 1-6 The synthetic routes shown illustrate a general synthetic method for the compounds of the present invention.

[0206] like Figure 1 As shown, 2,4,6-trichloro-1,3,5-triazine undergoes a substitution reaction with an amine substituted with R3 and R3' groups to give the compound of formula 1-1. The compound of formula 1-1 undergoes a substitution reaction with an amine substituted with R4 and R4' groups to give the compound of formula 1-2. The compound of formula 1-2, under suitable palladium reagent catalysis, reacts with the intermediate shown in formula (IV) via a Suzuki coupling reaction to give the compound of formula (I-1) of this invention. Wherein: R1, R2, R3, R3', R4, R4', R... a m and n are as defined in this invention. The palladium-catalyzed carbon-carbon coupling reaction is carried out under suitable conditions. The solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF, or a mixed solvent of 1,4-dioxane and water, etc. The base used can be selected from Cs2CO3, Na2CO3, K3PO4, etc., and the catalyst used can be selected from Pd(dppf)Cl2·CH2Cl2, Pd(PPh3)4, Pd(OAc)2, etc.

[0207] like Figure 2 As shown, the compound of formula 1-1, under the catalysis of a suitable palladium reagent, reacts with the intermediate shown in formula (IV) via a Suzuki coupling reaction to give the compound of formula 2-1. The compound of formula 2-1 then undergoes a substitution reaction with an amine substituted with R4, R4' groups to give the compound of formula (I-1) of this invention. Wherein: R1, R2, R3, R3', R4, R4', R... a m and n are as defined in this invention.

[0208] like Figure 3 As shown, the compounds of formula 1-2, under appropriate palladium reagent catalysis, undergo a Suzuki coupling reaction with the intermediate shown in formula (IV-1) to yield the compound of formula 3-1. The palladium-catalyzed carbon-carbon coupling reaction is carried out under suitable conditions. The solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF, or a mixture of 1,4-dioxane and water, etc. The base used can be selected from Cs₂CO₃, Na₂CO₃, K₃PO₄, etc., and the catalyst can be selected from Pd(dppf)Cl₂·CH₂Cl₂, Pd(PPh₃)₄, Pd(OAc)₂, etc. The compound of formula 3-1 is reduced to yield the compound of formula (I-1a) of this invention.

[0209] like Figure 4As shown, the compound of formula 1-1, under the catalysis of a suitable palladium reagent, reacts with the intermediate shown in formula (IV-1) via a Suzuki coupling reaction to give the compound of formula 4-1. The compound of formula 4-1 is reduced to give the compound of formula 4-2. The compound of formula 4-2 undergoes a substitution reaction with R4- and R4'-substituted amines to give the compound of formula (I-1a) of the present invention.

[0210] like Figure 5 As shown, the compounds of formula 1-2, under the catalysis of a suitable palladium reagent, undergo a Suzuki coupling reaction with the intermediate shown in formula (IV-2) to give the compound of formula 5-1. The compound of formula 5-1 undergoes a substitution reaction with a halogenating reagent under basic conditions to give the compound of formula 5-2. The halogenating reagent can be NFSI, the solvent can be a polar solvent such as THF, DCM, etc., and the base can be a LiHMDS, KHMDS, LDA, etc. The compound of formula 5-2 is reduced to give the compound of formula (II-1a) of this invention.

[0211] like Figure 6 As shown, the compound of formula 3-1 reacts with a deuterating reagent to obtain the compound of formula (I-1b) of the present invention. The deuterating reagent used can be selected from sodium borodeuteride, deuterated borane, etc.

[0212] The substituents of the compounds obtained by the above methods can be further modified to obtain other desired compounds. For synthetic chemical transformation methods, see, for example: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0213] Prior to use, the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

[0214] Pharmaceutical Compositions and Practical Uses

[0215] Compounds of formula (I) described herein (e.g., any compound described herein) and / or their pharmaceutically acceptable salts may be formulated into pharmaceutical compositions, alone or in combination with one or more other active ingredients. A pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) described herein and / or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0216] A pharmaceutically acceptable carrier is one that is compatible with (and in some embodiments, stabilizes) the active ingredient in the composition and is harmless to the individual being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with compounds of formula (I) described herein and / or their pharmaceutically acceptable salts) can be used as pharmaceutical excipients to deliver the active ingredient. Other examples of carriers include colloidal silica, magnesium stearate, cellulose, sodium dodecyl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in a standard reference book in the art (Remington's Pharmaceutical Sciences, A.Osol).

[0217] Pharmaceutical compositions comprising compounds of formula (I) described herein (e.g., any compound described herein) and / or pharmaceutically acceptable salts thereof may be administered in a variety of known manners, such as oral, topical, rectal, parenteral, inhalation, or implantation. The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intravertebral, intra-affective, and intracranial injections or infusions.

[0218] The pharmaceutical compositions described herein may be prepared in the form of tablets, capsules, sachets, sugar-coated pills, powders, granules, lozenges, powder for injection, liquid preparations, or suppositories. In some embodiments, pharmaceutical compositions comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof may be formulated for intravenous infusion, topical administration, or oral administration.

[0219] Orally administered compositions can be in any orally acceptable dosage form, including but not limited to: tablets, capsules, emulsions, and aqueous suspensions, dispersants, and solutions. Common tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also frequently incorporated into tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspension or emulsion form, emulsifiers or suspending agents can be used to suspend or dissolve the active ingredient in the oil phase. If desired, certain sweeteners, flavoring agents, or colorings may be added.

[0220] In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt in the tablet may be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg. In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt in the capsule may be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0221] Sterile injectable compositions (such as aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable intermediates can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents, particularly mannitol, water, Ringer's solution, and physiological saline, are commonly used. Furthermore, sterile, non-volatile oils, such as synthetic mono- or diglycerides, are often used as solvents or suspension media. Fatty acids, such as oleic acid and its glyceride derivatives, and natural, pharmaceutically acceptable oils, such as olive oil or castor oil (especially in their polyoxyethylated forms), are commonly used as injectable intermediates. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

[0222] Inhalation compositions can be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers that improve bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art, according to techniques well known in the pharmaceutical formulation field, or they can be prepared as solutions in saline.

[0223] Topical compositions can be formulated as oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (i.e., alcohols with more than 12 carbon atoms). In some embodiments, pharmaceutically acceptable carriers are those in which the active ingredient can dissolve. If desired, the composition may also contain emulsifiers, stabilizers, wetting agents, and antioxidants, as well as substances that impart color or fragrance. Furthermore, transdermal penetration enhancers may be added to the topical formulation. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0224] Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, with an active ingredient dissolved in a small amount of oil, such as almond oil, incorporated therein. An example of a cream contains approximately 40 parts by weight of water, approximately 20 parts by weight of beeswax, approximately 40 parts by weight of mineral oil, and approximately 1 part by weight of almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm paraffin wax and then cooling the mixture. An example of an ointment contains approximately 30% by weight of almond oil and approximately 70% by weight of white paraffin wax.

[0225] Appropriate in vitro studies can be used to evaluate the practical use of compounds of formula (I) described herein and / or their pharmaceutically acceptable salts in inhibiting IDH mutations. Further in vivo studies can be conducted to investigate additional practical use of compounds of formula (I) described herein and / or their pharmaceutically acceptable salts in the treatment of cancer. For example, compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be administered to animals with cancer (e.g., mouse models), and their therapeutic effects can then be evaluated. If the preclinical trial results are successful, the dosage range and route of administration in animals, such as humans, can also be predicted.

[0226] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts have shown sufficient preclinical practical use to warrant clinical trials and are expected to demonstrate beneficial therapeutic or preventative effects, for example, in individuals with cancer.

[0227] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disordered cell proliferation, reduced cell differentiation, inappropriate invasion of surrounding tissues, and / or the ability to establish new growth sites in other locations. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary and metastatic cancers.

[0228] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal carcinoma; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancer, including, for example, malignant melanoma; neuroendocrine carcinoma, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid cancer.

[0229] Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast crisis (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; and myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), and refractory anemia with excess bud cells. RAEB and refractory anemia with excess blast in transformation (RAEB-T); as well as myeloproliferative syndrome.

[0230] In some implementations, typical hematologic malignancies include leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); multiple myeloma (MM); and lymphomas such as Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0231] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts may be used to achieve beneficial therapeutic or preventive effects, for example, in individuals with cancer.

[0232] Furthermore, compounds of formula (I) described herein (e.g., any of the compounds described herein) and / or their pharmaceutically acceptable salts may be used in combination with additional active ingredients for the treatment of cancer. The additional active ingredient may be administered separately from the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts, or may be included in a pharmaceutical composition, such as a fixed-dose combination drug, in accordance with this disclosure. In some embodiments, the additional active ingredient is one that is known or has been found to be effective in treating diseases induced by IDH mutations, such as another IDH mutation inhibitor or a compound that effectively antagonizes another target associated with that particular disease. Combination therapy can be used to improve efficacy (e.g., by including a compound that enhances the potency or effectiveness of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts in the combination therapy), reduce one or more side effects, or reduce the required dose of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts.

[0233] In some embodiments, compounds of formula (I) described herein (e.g., any compounds herein) and / or pharmaceutically acceptable salts thereof may be used in combination with antitumor agents. As used herein, the term "antitumor agent" refers to any agent administered to a subject suffering from cancer for the purpose of treating cancer, including but not limited to radiotherapy agents, immunotherapy agents, chemotherapeutic agents that damage DNA, and chemotherapeutic agents that interfere with cell replication.

[0234] Non-limiting examples of chemotherapeutic agents that damage DNA include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogues or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, demethoxydaunorubicin, and donomycin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard, cyclohexanenitrosourea, methylcyclohexanenitrosourea, streptozotocin, aminoimidamine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalating agents (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalating agents and free radical generating agents such as bleomycin; and nucleoside analogues (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine). Mercaptopurine, thioguanine, pentostatin, and hydroxyurea.

[0235] Chemotherapy agents that interfere with cell replication include: paclitaxel, taxanes and related analogues; vincristine, vinblastine and related analogues; sedatives and related analogues (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including IκB kinase inhibitors; antibodies that bind to proteins overexpressed in cancer and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other protein or enzyme inhibitors known to be upregulated, overexpressed, or activated in cancer, and whose inhibition can downregulate cell replication. Example

[0236] The following examples are illustrative of the invention and do not limit the invention in any way. The data given (e.g., quantities, temperatures, etc.) are intended to be accurate; however, those skilled in the art will understand that some experimental errors and biases may occur. Unless otherwise stated, all parts are by weight, temperatures are in Celsius, and pressures are at or near atmospheric pressure. All mass spectrometry data were obtained using Agilent 6120 and 1100. Except for synthetic intermediates, all reagents used in this invention were commercially available. The names of all compounds, except for reagents, were generated using Chemdraw 12.0.

[0237] In any structural formula of this application, if there is a vacant valence on any atom, the vacant valence is actually for the sake of simplicity and is not specifically described for the hydrogen atom.

[0238] In this application, if both the name and structural formula of a compound are given, and the two are inconsistent, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect while the name is correct.

[0239] The following table of abbreviations is used in the embodiments:

[0240] AcOK Potassium Acetate

[0241] BAST bis(2-methoxyethyl)aminosulfuric acid

[0242] BINAP 1,1'-Binaphthyl-2,2'-bis(diphenylphosphine)

[0243] t-BuONa sodium tert-butoxide

[0244] (n-Bu3Sn)2 1,1,1,2,2,2-hexadecylditin

[0245] (S)-CBS (S)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazolidineborane

[0246] CD3OD Deuterated Methanol

[0247] DAST diethylaminosulfuric acid

[0248] DCM dichloromethane

[0249] DIEA N,N-Diisopropylethylamine

[0250] DMF N,N-dimethylformamide

[0251] DMSO-d6 Deuterated dimethyl sulfoxide

[0252] EtOAc / EA (ethyl acetate)

[0253] Et3N Triethylamine

[0254] EtvH ethanol

[0255] Et2Zn - Diethylzinc

[0256] g gram

[0257] HC(vMe)3 trimethyl orthoformate

[0258] L rise

[0259] LiHMDS (Lithium Bistrimethylsilylamino)

[0260] M moles / liter

[0261] MevH (methanol)

[0262] MeCN Acetonitrile

[0263] mg

[0264] mL

[0265] mmol millimole

[0266] mol

[0267] NaBH(OAc)3 sodium triacetoxyborohydride

[0268] NaOMe (sodium methoxide)

[0269] Sodium ethanol (NaOEt)

[0270] NCS N-chlorosuccinimide

[0271] NFSI N-Fluorobisbenzenesulfonamide

[0272] PdCl2(PPh3)2 bis(triphenylphosphine)palladium dichloride

[0273] Pd2(dba)3 Tris(dibenzylacetone)dipalladium

[0274] Pd(dppf)Cl2[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride

[0275] Pd(dppf))Cl2·CH2Cl2 [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex

[0276] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium

[0277] PE petroleum ether

[0278] Fluorine reagent, 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octanebis(tetrafluoroboronic acid) salt

[0279] TBAF Butyl Ammonium Fluoride

[0280] TBSOTf tert-butyldimethylsilyltrifluoromethanesulfonate

[0281] TFA (trifluoroacetic acid)

[0282] Tf2O trifluoromethanesulfonic anhydride

[0283] THF Tetrahydrofuran

[0284] TsOH·H2O p-Toluenesulfonic Acid Monohydrate

[0285] Example 1

[0286] Preparation of intermediates

[0287] Intermediate I-1

[0288] 3-(4-chloro-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-ol and intermediate I-61

[0289] (*)3-(4-chloro-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-ol

[0290]

[0291] (A) 2-Fluoro-3-hydroxycyclohexane-2-en-1-one (A1)

[0292] MeCN (1.2 L) and 1,3-cyclohexanedione (30 g, 268 mmol) were added sequentially to the reaction flask at room temperature. (94.8 g, 268 mmol). The reaction was carried out under nitrogen protection at 70 °C with stirring for 96 hours. After the reaction was completed, the product was evaporated to dryness under reduced pressure, and DCM (1.2 L) was added. The mixture was filtered, the filtrate was concentrated, and purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to give compound A1 (7.7 g, yield 22%) as a white solid. MS (m / z): 131.1 [M+H] +

[0293] (B) 2-Fluoro-3-oxocyclohexyl-1-en-1-yltrifluoromethanesulfonate (A2)

[0294] Compound A1 (208 mg, 1.6 mmol) was dissolved in DCM and cooled to 0 °C. DIEA (415 mg, 3.2 mmol) and Tf₂O (540 mg, 1.92 mmol) were added sequentially. The reaction was stirred at 0 °C for 2 hours under nitrogen protection. After the reaction was complete, water was added, and the mixture was extracted with DCM, concentrated, and purified by flash column chromatography (PE / EA) to give a yellow oily product, compound A2 (220 mg, yield 52.5%). MS (m / z): 263.0 [M+H] +

[0295] (C)(R)-4,6-dichloro-N-(1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2-amine (A3)

[0296] 2,4,6-Trichloro-1,3,5-triazine (9.1 g, 49.3 mmol) was dissolved in dry THF and cooled to 0 °C. (R)-1,1,1-trifluoropropane-2-amine hydrochloride (7.37 g, 49.3 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the pH was adjusted to 7 with aqueous sodium bicarbonate solution, and the mixture was extracted with EtOAc. The organic phase was collected, concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a colorless oily product, compound A3 (7.8 g, yield 60.6%). MS (m / z): 260.9 [M+H] +

[0297] (D)(R)-3-(4-chloro-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-one (A4)

[0298] Under nitrogen protection, compound A2 (4.0 g, 15.3 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxoboronylcyclopentane) (4.3 g, 16.8 mmol), AcOK (3.8 g, 38.3 mmol), Pd(dppf)Cl2 (0.63 g, 0.77 mmol), and 1,4-dioxane (40 mL) were added sequentially to a reaction flask. The mixture was heated to reflux and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and compound A3 (4.0 g, 15.3 mmol), cesium carbonate (14.4 g, 38.3 mmol), Pd(PPh3)4 (0.89 g, 0.77 mmol), and water (8 mL) were added sequentially. The mixture was heated to 80 °C and stirred for 2 hours. The solution was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give compound A4 (0.8 g, yield 15.4%) as a white solid. MS (m / z): 339.0 [M+H] +

[0299] (E)3-(4-chloro-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-ol (I-1)

[0300] Compound A4 (150 mg, 3.41 mmol), cerium trichloride heptahydrate (1269 mg, 3.41 mmol), and ethanol (20 mL) were added to a reaction flask. The reaction mixture was cooled to 0 °C, and sodium borohydride (130 mg, 3.41 mmol) was added. The reaction was stirred at 0 °C for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (10 mL) and water (50 mL) were added, and the mixture was extracted with EtOAc. The organic phase was collected, concentrated, and purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to give a white solid intermediate I-1 (800 mg, yield 68.9%). MS (m / z): 341.2 [M+H] +

[0301] (F)(*)3-(4-chloro-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-ol (I-61)

[0302] Under nitrogen protection and ice bath cooling, 1 mol / L (S)-CBS / THF solution (2.4 mL, 2.4 mmol) was added to anhydrous THF (5 mL), followed by rapid addition of 2 mol / L borane dimethyl sulfide / THF solution (2.4 mL, 4.8 mmol). After stirring for 2 minutes, compound A4 (800 mg, 2.4 mmol) / THF (3 mL) solution was added dropwise. The mixture was stirred in an ice bath for one hour, then methanol (0.5 mL), EtOAc (10 mL), and water (20 mL) were added. The organic phase was collected, and the aqueous phase was extracted with 10 mL of EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to obtain a white solid intermediate I-61 (360 mg). MS (m / z): 341.2 [M+H] +

[0303] The compounds in the table below were prepared using the same reagents and intermediates as intermediate I-1, under conditions deemed suitable by those skilled in the art.

[0304]

[0305] Intermediate I-2

[0306] (R)-6-chloro-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0307]

[0308] In a sealed tube, compound A3 (3.5 g, 13.4 mmol), isopropylamine (872 mg, 14.7 mmol), DIEA (3.5 g, 26.8 mmol), and THF (20 mL) were added sequentially. The mixture was heated to 50 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA) to give a white solid intermediate I-2 (3.8 g, 100% yield). MS (m / z): 284.0 [M+H] +

[0309] The compounds in the table below were prepared using the same reagents and intermediates as intermediate I-2, under conditions deemed suitable by those skilled in the art.

[0310]

[0311]

[0312]

[0313] Intermediate I-3

[0314] 6-Chloro-N 2 N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0315]

[0316] At 0 °C, 1,4-dioxane (50 mL), 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol), (R)-1,1,1-trifluoropropane-2-amine hydrochloride (2.99 g, 20 mmol), and DIEA (5.17 g, 40 mmol) were added sequentially to a reaction flask. The mixture was heated to 60 °C and stirred for 4 hours. After the reaction was complete, the mixture was concentrated and purified by flash column chromatography (water / methanol = 100:0–0:100 gradient elution) to give a yellow solid intermediate I-3 (2.50 g, yield 74%). MS (m / z): 338.0 [M+H] +

[0317] The compounds in the table below were prepared using the same reagents and intermediates as intermediate I-3, under conditions deemed suitable by those skilled in the art.

[0318]

[0319] Intermediate I-4

[0320] (R)-N-(4-chloro-6-((1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)isobutyramide

[0321]

[0322] 4,6-Dichloro-1,3,5-triazin-2-amine (1 g, 6.06 mmol) was added to isobutyryl chloride (5 mL), and the mixture was heated to 100 °C for two hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to give a yellow solid, N-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide. The obtained N-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide, (R)-1,1,1-trifluoropropane-2-amine hydrochloride (900 mg, 6.06 mmol), and DIEA (2.34 g, 18.18 mmol) were added to 1,4-dioxane (10 mL), and the mixture was heated to reflux for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with EtOAc (20 mL), the solvent was removed from the organic phase under reduced pressure, and the mixture was purified by flash column chromatography (PE / EA) to give intermediate I-4 (80 mg). MS(m / z): 312.1 [M+H]+

[0323] Intermediate I-26 & 1-27

[0324] 3-(4-chloro-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol optically pure diastereomer

[0325]

[0326] Intermediate I-25 was resolved by chiral HPLC to yield optically pure diastereomeric intermediates I-26 and I-27 (chiral HPLC conditions: column: AS-H; mobile phase: n-heptane / isopropanol = 80:20; flow rate: 0.5 mL / min; detection wavelength: UV 254 nm). The isomer obtained after evaporation of the first eluent (RT = 1.703 min) was named I-26, with a de value of 100% and MS (m / z): 400.1 [M+H]+. The isomer obtained after evaporation of the second eluent (RT = 2.067 min) was named I-27, with a de value of 99.4% and MS (m / z): 400.1 [M+H]+.

[0327] Intermediate I-41

[0328] 6-Chloro-N 2 -(propyl-2-yl-d7)-N 4 -(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

[0329]

[0330] (A) 4,6-Dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine (A5)

[0331] 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol) and 2-(trifluoromethyl)pyridin-4-amine (1.62 g, 10 mmol) were dissolved in dry THF (20 mL), and sodium bicarbonate (1.68 g, 20 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give the white solid product compound A5 (2.68 g, yield 86%). MS (m / z): 309.9 [M+H] +

[0332] (B)6-Chloro-N 2 -(propyl-2-yl-d7)-N 4 -(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine

[0333] In a sealed tube, compound A5 (465 mg, 1.5 mmol), propan-d7-2-amine hydrochloride (154 mg, 1.5 mmol), diisopropylethylamine (388 mg, 3.0 mmol), and 1,4-dioxane (20 mL) were added sequentially. The mixture was heated to 60 °C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a white solid intermediate I-41 (485 mg, 95% yield). MS (m / z): 340.0 [M+H] +

[0334] The compounds in the table below were prepared using the same reagents and intermediates as intermediate I-41, under conditions deemed suitable by those skilled in the art.

[0335]

[0336]

[0337] Intermediate I-46

[0338] 2-((4-(tert-Butoxyamino-1-6-chloro-1,3,5-triazine-2-yl)amino)isonicotinonitrile

[0339]

[0340] (A)O-tert-butyl-N-(4,6-dichloro-1,3,5-triazin-2-yl)hydroxylamine (A6)

[0341] 2,4,6-trichloro-1,3,5-triazine (0.92 g, 5 mmol) and O-tert-butylhydroxylamine hydrochloride (0.63 g, 5 mmol) were dissolved in dry THF (50 mL), and sodium bicarbonate (1.26 g, 15 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a colorless oily product, compound A6 (0.83 g, 80% yield). MS (m / z): 237.0 [M+H] +

[0342] (B)2-((4-(tert-butoxyamino)-6-chloro-1,3,5-triazine-2-yl)amino)isonicotinonitrile

[0343] In a sealed tube, compound A6 (0.83 g, 4.0 mmol), 2-aminoisocyanonitrile (0.48 g, 4.0 mmol), Pd(dppf)Cl2 (0.15 g, 0.2 mmol), sodium tert-butoxide (0.77 g, 8.0 mmol), and 1,4-dioxane (10 mL) were added sequentially. The mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a yellow solid intermediate I-46 (109 mg, yield 8%). MS (m / z): 320.0 [M+H] +

[0344] The compounds in the table below were prepared using the same reagents and intermediates as intermediate I-46, under conditions deemed suitable by those skilled in the art.

[0345]

[0346] Intermediate I-88

[0347] 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)cyclohex-2-en-1-one

[0348]

[0349] Under nitrogen protection, compound A2 (80 g, 305 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxoborane) (80 g, 315 mmol), AcvK (74.8 g, 763 mmol), Pd(dppf)Cl2·CHCl2 (12.4 g, 15.3 mmol), and 1,4-dioxane (1.4 L) were added sequentially to a reaction flask. The reactants were stirred at 90 °C for 4 hours, cooled to room temperature, and filtered. The filtrate was concentrated and purified by flash column chromatography (PE / EA = 4 / 1 elution) to give a yellow solid intermediate I-88 (76 g, 100% yield). MS (m / z): 159.0 [M+H]+. 1H NMR (400MHz, DMSO-d6): δ2.47-2.36 (m, 4H), 1.91-1.82 (m, 2H), 1.22 (s, 12H).

[0350] Example 2

[0351] Synthesis of compounds 1-87, 89-184, and 186-301

[0352] Compound 1

[0353] 2-Fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0354]

[0355] (A)(R)-2-fluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one (B1)

[0356] Under nitrogen protection, compound A2 (220 mg, 0.84 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxoboronylcyclopentane) (234 mg, 0.92 mmol), AcOK (206 mg, 2.10 mmol), Pd(dppf)Cl2·CHCl2 (32 mg, 0.04 mmol), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask. The mixture was heated to reflux and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and intermediate I-2 (238 mg, 0.84 mmol), cesium carbonate (682 mg, 2.1 mmol), Pd(PPh3)4 (46.2 mg, 0.04 mmol), and water (4 mL) were added sequentially. The mixture was heated to 80 °C and stirred for 2 hours. The mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give compound B1 (160 mg, yield 52.8%) as a white solid. MS (m / z): 362.1 [M+H] +

[0357] (B) 2-Fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0358] Compound B1 (80 mg, 0.22 mmol) and cerium trichloride heptahydrate (107 mg, 0.29 mmol) were dissolved in ethanol (5 mL). The reaction solution was cooled to 0 °C, and sodium borohydride (11 mg, 0.29 mmol) was added. The reaction was stirred at 0 °C for 2 hours. After the reaction was complete, saturated ammonium chloride solution (2 mL) and water (20 mL) were added, and the mixture was extracted with EtOAc. The organic phase was concentrated and purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to give compound 1 (61 mg, yield 76.3%) as a white solid. MS (m / z): 364.1 [M+H]+

[0359] 1 H NMR (400MHz, CD3OD): δ4.99-4.87(m, 1H), 4.33-4.23(m, 1H), 4.19-4.07(m, 1H), 2.61-2.47(m, 1H ), 2.40-2.24(m, 1H), 1.89-1.73(m, 3H), 1.70-1.61(m, 1H), 1.38-1.31(m, 3H), 1.22-1.16(m, 6H).

[0360] The compounds in the table below were prepared using the same intermediates and reagents as Compound 1, under conditions deemed suitable by those skilled in the art.

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] Compound 35

[0368] 6-(2,3-Difluorocyclohexyl-1-en-1-yl)-N 2 -Isopropyl-N 4 -((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazin-2-yl)-2,4-diamine

[0369]

[0370] Compound 1 (20 mg, 0.06 mmol) was dissolved in DCM (3 mL) at 0 °C, and DAST (17 mg, 0.12 mmol) was added. The reaction was stirred at 0 °C for 2.5 h. After the reaction was complete, saturated ammonium chloride solution (5 mL) and water (5 mL) were added, and the mixture was extracted with EtOAc. The organic phase was collected, concentrated, and purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to give a white solid product (14 mg, 70% yield). MS (m / z): 366.2 [M+H] +

[0371] 1 H NMR (400MHz, CD3OD): δ5.15-4.86 (m, 2H), 4.21-4.08 (m, 1H), 2.70-2.51 (m, 1H), 2.42-2 .26(m, 1H), 2.20-2.08(m, 1H), 1.92-1.67(m, 3H), 1.37-1.31(m, 3H), 1.21-1.16(m, 6H).

[0372] The compounds in the table below were prepared using the same preparation process as compound 35, with appropriate intermediates and reagents, under conditions generally recognized as suitable by those skilled in the art.

[0373]

[0374] Compound 39

[0375] (*)3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocycloheptane-2-en-1-ol

[0376]

[0377] Under nitrogen protection and ice bath cooling, 1 mol / L (S)-CBS / THF solution (1.4 mL, 1.4 mmol) was added to anhydrous THF (5 mL), followed by rapid addition of 2 mol / L borane dimethyl sulfide / THF solution (1.4 mL, 2.8 mmol). After stirring for 2 minutes, 3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohepta-2-en-1-one (obtained using intermediate I-10, referring to the synthesis procedure of compound 1, 600 mg, 1.4 mmol) / THF (3 mL) solution was added dropwise. The mixture was stirred in an ice bath for one hour. Methanol (0.5 mL), EtOAc (10 mL), and water (20 mL) were added. The organic phase was collected, and the aqueous phase was extracted again with EtOAc (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to give a white solid product (60 mg, yield 10%). MS (m / z): 420.1 [M+H]+

[0378] 1 H NMR (400MHz, CD3OD): δ4.52-4.38(m, 1H), 4.33-4.17(m, 2H), 2.99-2.84(m, 4H ), 2.71-2.48(m, 5H), 2.37-2.23(m, 1H), 2.01-1.82(m, 3H), 1.74-1.60(m, 3H).

[0379] The compounds in the table below were prepared using the same preparation process as compound 39, with appropriate intermediates and reagents, under conditions generally recognized as suitable by those skilled in the art.

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388] Compounds 82 and 83

[0389] (*)3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-ene-6,6-bisdeuter-1-ol and

[0390] 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1,6,6-trideuter-1-ol

[0391]

[0392] (A) 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one-6,6-bisdeuterium

[0393] 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexane-2-en-1-one (114 mg, 0.27 mmol, obtained using intermediate I-3, reference compound 1) was dissolved in 1,4-dioxane (6 mL), and heavy water (2 mL) and potassium carbonate (75 mg, 0.54 mmol) were added. The mixture was stirred at 80 °C for 4.5 h. The solvent was evaporated to dryness, and the product was purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a yellow oily product (64 mg, 56% yield). MS (m / z): 418.0 [M+H] +

[0394] (B)(*)3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-ene-6,6-bisdeuter-1-ol

[0395] Following the synthesis of compound 39, compound 82 was obtained. MS (m / z): 420.1 [M+H] +

[0396] 1H NMR (400MHz, CD3OD): δ5.00-4.87(m, 2H), 4.32-4.23(m, 1H), 2.63-2.53(m, 1H ), 2.37-2.26(m, 1H), 1.81-1.69(m, 1H), 1.67-1.60(m, 1H), 1.37-1.31(m, 6H).

[0397] (C)3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1,6,6-trideuter-1-ol

[0398] Using NaBD4, following reaction step (B) of compound 1, compound 83 was obtained. MS (m / z): 421.1 [M+H] +

[0399] 1 H NMR (400MHz, CD3OD): δ 5.00-4.87 (m, 2H), 2.63-2.53 (m, 1H), 2.37-2.26 (m, 1H), 1.81-1.69 (m, 1H), 1.67-1.60 (m, 1H), 1.37-1.31 (m, 6H).

[0400] The compounds in the table below were prepared using the same preparation process as compound 82, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0401]

[0402]

[0403] The compounds in the table below were prepared using the same preparation process as compound 83, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0404]

[0405] Compound 93

[0406] (*)3-(4-amino-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-ol

[0407]

[0408] (A)(R)-2-fluoro-3-(4-((4-methoxybenzyl)amino)-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one (B2)

[0409] The title compound B2 was synthesized using intermediate I-55, following the method used for compound 1. MS (m / z): 440.1 [M+H] +

[0410] (B)3-(4-amino-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-ol (B3)

[0411] Compound B2 (1.1 g, 2.5 mmol) was dissolved in TFA (10 mL) and refluxed for 4 hours. The solvent was evaporated to dryness, and the mixture was washed with sodium bicarbonate solution. The residue was purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to give compound B3 as a pale yellow solid. MS (m / z): 320.0 [M+H]+

[0412] (C)(*)3-(4-amino-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-ol

[0413] Following the same synthetic procedure as compound 39, compound 93 was obtained. MS (m / z): 322.0 [M+H] +

[0414] 1 H NMR (400MHz, CD3OD): δ 5.01-4.89 (m, 1H), 4.38-4.19 (m, 1H), 2.62-2.47 (m, 1H), 2.38-2.24 (m, 1H), 1.89-1.61 (m, 4H), 1.36-1.29 (m, 3H).

[0415] Compounds 95 and 96

[0416] 2,6-Difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol optically pure diastereomer

[0417]

[0418] (A)(R)-2,6-Difluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one (B4)

[0419] Under nitrogen protection, at -78°C, a 20 mL solution of THF containing compound 123 (1.2 g, 3.30 mmol) was added dropwise to a 1 mol / L LiHMDS / THF solution (14.85 mL, 14.85 mmol). After the addition was complete, the reaction mixture was stirred at 0°C for 2 hours. Then, a 9.90 mmol THF solution of NFSI was slowly added dropwise to the reaction mixture, and the temperature was raised to room temperature and stirred for 3 hours. An aqueous solution of NH4Cl (30 mL) was added to the reaction mixture. The organic phase was collected, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the residue was purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a white solid product, compound B4 (190 mg, yield 15.2%). MS (m / z): 380.2 [M+H] +

[0420] (B) 2,6-Difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0421] Following the preparation process of compound 39, compounds 95 and 96 were obtained by separation and purification using preparative thin-layer chromatography (PE / EA = 2 / 1).

[0422] Compound 95, Rf≈0.55, MS (m / z): 382.1 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ4.97-4.90(m, 1H), 4.72-4.55(m, 1H), 4.38-4.03(m, 2H ), 2.63-2.46(m, 2H), 2.06-1.90(m, 2H), 1.38-1.31(m, 3H), 1.23-1.13(s, 6H).

[0423] Compound 96, Rf≈0.50, MS (m / z): 382.2 [M+H] + ; 1H NMR (400MHz, CD3OD): δ4.97-4.90 (m, 1H), 4.71-4.55 (m, 1H), 4.51-4.40 (m, 1H), 4.20-4.05 (m, 1H), 2.76-2 .58(m, 1H), 2.48-2.31(m, 1H), 2.15-2.01(m, 1H), 1.98-1.81(m, 1H), 1.40-1.30(m, 3H), 1.22-1.12(m, 6H).

[0424] The compounds in the table below were prepared using the same intermediates and reagents as compounds 95 and 96, under conditions deemed suitable by those skilled in the art.

[0425]

[0426]

[0427]

[0428] Note: Compounds 230 and 231 were obtained by flash column chromatography (H2O / MeOH = 100:0-0:100 gradient elution), wherein the compound obtained in the first eluent was named compound 230 and the compound obtained in the second eluent was named compound 231.

[0429] Compounds 242, 266-269

[0430] 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohexyl-2-en-1-deuter-1-ol optically pure diastereomer

[0431]

[0432] (A) 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one

[0433] Compound 242 was obtained using compound 295 and the corresponding reagents, following the preparation steps (A) of compounds 95 and 96. MS (m / z): 434.0 [M+H] + ; 1H NMR (400MHz, CD3OD): δ5.31-5.06 (m, 1H), 5.03-4.90 (m, 2H), 3.09-3.00 (br, 1H ), 2.90-2.74(m, 1H), 2.57-2.42(m, 1H), 2.31-2.12(m, 1H), 1.39-1.31(m, 6H).

[0434] (B)3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one diastereomer

[0435] Compound 242 was resolved by chiral HPLC to yield a pair of optically pure diastereomers, compounds 246 and 247 (chiral HPLC conditions: column: AD-H (0.46 cm ID × 15 cm L); mobile phase: n-heptane / isopropanol = 80 / 20; flow rate: 0.5 mL / min; detector: UV 254 nm). The first eluent (compound 246, RT = 2.025 min) had a de value of 100% and MS (m / z): 434.0 [M+H]. + The second eluent (compound 247, RT = 2.083 min) had a de value of 100% and MS (m / z) of 434.0 [M+H]. + .

[0436] (C)3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-deuter-1-ol, optically pure diastereomer

[0437] Following the preparation process of compound 1, compounds 246 and NaBD4 were purified by flash column chromatography (PE / EA elution) to obtain diastereomers 266 and 267.

[0438] Compound 266, Rf≈0.55, MS (m / z): 437.2 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ4.93-4.80 (m, 2H), 4.71-4.55 (m, 1H), 2.54-2.40 (m, 2H), 1.97-1.83 (m, 2H), 1.30-1.22 (m, 6H).

[0439] Compound 267, Rf≈0.50, MS (m / z): 437.2 [M+H] + ; 1H NMR (400MHz, CD3OD): δ4.95-4.79(m, 2H), 4.75-4.57(m, 1H), 2.68-2.52(m, 1H ), 2.45-2.27(m, 1H), 2.07-1.92(m, 1H), 1.90-1.75(m, 1H), 1.31-1.21(m, 6H).

[0440] Following the preparation process of compound 1, compounds 247 and NaBD4 were used to purify the diastereomers 268 and 269 by flash column chromatography (PE / EA elution).

[0441] Compound 268, Rf≈0.55, MS (m / z): 437.2 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ4.93-4.80 (m, 2H), 4.71-4.55 (m, 1H), 2.54-2.40 (m, 2H), 1.97-1.83 (m, 2H), 1.30-1.22 (m, 6H).

[0442] Compound 269, Rf≈0.50, MS (m / z): 437.2 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ4.95-4.79(m, 2H), 4.75-4.57(m, 1H), 2.68-2.52(m, 1H ), 2-45-2.27(m, 1H), 2.07-1.92(m, 1H), 1.90-1.75(m, 1H), 1.31-1.21(m, 6H).

[0443] Compound 94

[0444] 2,6,6-Trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0445]

[0446] (A)(R)-2,6,6-trifluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one

[0447] Under nitrogen protection, at -78°C, a 20 mL solution of THF containing compound 123 (1.2 g, 3.30 mmol) was added dropwise to a 1 mol / L LiHMDS / THF solution (14.85 mL, 14.85 mmol). After the addition was complete, the reaction mixture was stirred at 0°C for 2 hours. Then, a 3.12 g, 9.90 mmol) THF solution of NFSI was slowly added dropwise to the reaction mixture, and the temperature was raised to room temperature and stirred for 3 hours. An aqueous solution of NH4Cl (30 mL) was added to the reaction mixture. The organic phase was collected, and the aqueous phase was extracted with EtOAc. The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the residue was purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a white solid product, compound B5 (25 mg, yield 1.9%). MS (m / z): 398.1 [M+H] +

[0448] (B)2,6,6-trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0449] Following the preparation procedure of compound 39, compound 94 was obtained using compound B5 and corresponding reagents. MS (m / z): 400.2 [M+H] +

[0450] 1 H NMR (400MHz, CD3OD): δ4.97-4.88(m, 1H), 4.33-4.19(m, 1H), 4.19-4.07(m, 1H), 2.78-2 .61 (m, 1H), 2.59-2.40 (m, 1H), 2.21-2.00 (m, 2H), 1.37-1.30 (m, 3H), 1.21-1.12 (m, 6H).

[0451] The compounds in the table below were prepared using the same preparation process as compound 94, with appropriate intermediates and reagents, under conditions generally recognized as suitable by those skilled in the art.

[0452]

[0453]

[0454] Compound 234

[0455] 3-(4-((cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0456]

[0457] (A)(R)-3-(4-((cyclopropylmethyl)amino)-6-((1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexane-2-en-1-one (B7)

[0458] Following the preparation procedure (A) of compound 94, compound B6 (obtained using intermediate I-77, following the preparation procedure of compound 1) and the corresponding reagents were used to obtain the title compound B7.

[0459] (B)3-(4-((cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0460] Following the same preparation procedure as compound 1, compound 234 was obtained using compound B7 and corresponding reagents. MS (m / z): 412.2 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ4.99-4.90 (m, 1H), 4.31-4.20 (m, 1H), 3.25-3.16 (m, 2H), 2.79-2.63 (m, 1H), 2.59-2 .44 (m, 1H), 2.23-2.03 (m, 2H), 1.37-1.31 (m, 3H), 1.13-0.99 (m, 1H), 0.53-0.41 (m, 2H), 0.28-0.17 (m, 2H).

[0461] The compounds in the table below were prepared using the same preparation process as compound 234, with appropriate intermediates and reagents, under conditions generally recognized as suitable by those skilled in the art.

[0462]

[0463] Compound 259

[0464] 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0465]

[0466] (A)(R)-6-(3-((tert-butyldimethylsilyl)oxy)-2-fluorocyclohex-1,3-dien-1-yl)-N 2-(3,3-Difluorocyclobutyl)-N 4 -(1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine (B9)

[0467] At 0–5 °C, anhydrous DCM (15 mL), (R)-3-(4-((3,3-difluorocyclobutyl)-6-((1,1,1-trifluoroprop-2-yl)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-one (prepared using intermediate I-9, 750 mg, 1.83 mmol) and Et3N (371 mg, 3.66 mmol) were added sequentially to a reaction flask. Then, nitrogen gas was introduced, and anhydrous DCM (5 mL) solution of TBSOTf (726 mg, 2.75 mmol) was added dropwise while stirring for 30 minutes. After the reaction was complete, the reaction solution was poured into water, extracted with DCM, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (PE / EA elution) to give the yellow oily product compound B9 (958 mg, 100% yield). MS (m / z): 524.1 [M+H]+

[0468] (B)3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohexane-2-en-1-one (B10)

[0469] At 0–5°C, anhydrous acetonitrile (20 mL) and [other ingredients] were added sequentially to the reaction flask. (778 mg, 2.20 mmol) was added, then nitrogen was introduced, and a solution of compound B9 (958 mg, 1.83 mmol) in anhydrous acetonitrile (20 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was complete, the reaction solution was poured into water, extracted with EtOAc, and the organic phase was collected, concentrated under reduced pressure, and purified by flash column chromatography (PE / EA elution) to give a white solid product, compound B10 (512 mg, yield 66%). MS (m / z): 428.0 [M+H] + .

[0470] (C)(R)-3-(4-((3,3-difluorocyclobutyl)amino)-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-one (B11)

[0471] Under nitrogen protection, at -78°C, a 1 mol / L LiHMDS / THF solution (3.47 mL, 3.47 mmol) was added dropwise to a 10 mL solution of anhydrous tetrahydrofuran containing compound B10 (512 mg, 1.12 mmol) and stirred for 30 minutes. Then, at -78°C, a 10 mL solution of anhydrous tetrahydrofuran containing NFSI (388 mg, 1.23 mmol) was slowly added dropwise to the reaction mixture and stirred for 2 hours. After the reaction was complete, a saturated aqueous NH4Cl solution was added to the reaction mixture, and the mixture was extracted with EtOAc. The combined organic phases were collected, concentrated under reduced pressure, and purified by flash column chromatography (PE / EA elution) to give a yellow solid product, compound B11 (230 mg, yield 46%). MS (m / z): 446.2 [M+H] +

[0472] (D)3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0473] Following the preparation procedure for compound 39, compound B11 and corresponding reagents were used to obtain compound 259. MS (m / z): 448.0 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ4.91-4.81 (s, 1H), 4.26-4.09 (m, 2H), 2.92-2.76 (m, 2H), 2.72-2.33 (m, 4H), 2.18-1.96 (m, 2H), 1.30-1.22 (m, 3H).

[0474] The compounds in the table below were prepared using the same preparation process as compound 259, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0475]

[0476]

[0477] Compound 274

[0478] 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-deuter-1-ol

[0479]

[0480] (A) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (B12)

[0481] Intermediate I-37 (4.17 g, 15.0 mmol), intermediate I-88 (4.32 g, 18.0 mmol), Na₂PdCl₄ (221 mg, 0.75 mmol), DTBPPS (402 mg, 1.5 mmol), K₂CO₃ (5.18 g, 37.5 mmol), MeCN (40 mL), and H₂O (10 mL) were added sequentially to a reaction flask. The mixture was then purged with nitrogen, heated to 60 °C, and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, the organic phase was collected, concentrated under reduced pressure, and purified by flash column chromatography (PE / EA elution) to give a yellow solid product, compound B12 (4.98 g, 93% yield). MS (m / z): 356.1 [M+H]⁺.

[0482] (B)3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohexane-2-en-1-one (B13)

[0483] Following steps (A) and (B) of the preparation of compound 259, compound B12 and the corresponding reagents were used to obtain the title compound B13. MS (m / z): 374.1 [M+H] +

[0484] (C)3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexane-2-en-1-one (B14)

[0485] Following steps (A) and (B) of the preparation of compound 259, the title compound was obtained using compound B13 and the corresponding reagents. MS (m / z): 392.0 [M+H] +

[0486] (D)3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-deuter-1-ol

[0487] Following the preparation procedure (B) of compound 1, compound 274 was obtained using compound B14, NaBD4, and appropriate reagents. MS (m / z): 395.1 [M+H] + ; 1H NMR (400MHz, CD3OD): δ4.33-4.20 (m, 1H), 4.20-4.03 (m, 1H), 3.05-2.85 (m, 2H), 2.80-2.41 (m, 4H), 2.29-2.02 (m, 2H), 1.25-1.14 (m, 6H).

[0488] The compounds in the table below were prepared using the same preparation process as compound 274, with appropriate intermediates and reagents, under conditions generally recognized as suitable by those skilled in the art.

[0489]

[0490]

[0491] Compound 297

[0492] 2,6,6-Trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0493]

[0494] (A)(R)-3-(4-chloro-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexane-2-en-1-one (B16)

[0495] Following steps (B) and (C) of the preparation of compound 274, using intermediate A4 and the corresponding reagents, the title compound B16 was obtained. MS (m / z): 375.1 [M+H] +

[0496] (B)(R)-2,6,6-trifluoro-3-(4-(methoxyamino)-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one (B17)

[0497] Following the preparation procedure of compound 190, compound B16 and corresponding reagents were used to obtain the title compound B17. MS (m / z): 386.1 [M+H] +

[0498] (C)2,6,6-trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0499] Following the preparation procedure (B) of compound 1, compound 297 was obtained using compound B17 and the corresponding reagents. MS (m / z): 388.2 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ5.04-4.92(m, 1H), 4.34-4.20(m, 1H), 3.81-3.66(m, 3H ), 2.80-2.64(m, 1H), 2.59-2.44(m, 1H), 2.31-2.04(m, 2H), 1.41-1.32(m, 3H).

[0500] Compound 280

[0501] 3-(4-amino-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0502]

[0503] (A)(R)-2-fluoro-3-(4-((4-methoxyphenyl)amino)-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one (B18)

[0504] Following the preparation procedure of compound 1, using intermediate I-105 and appropriate reagents, the title compound B18 was obtained. MS (m / z): 440.2 [M+H] +

[0505] (B)(R)-3-(4-amino-6-((1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexane-2-en-1-one (B19)

[0506] Compound B18 (1.4 g, 3.19 mmol) was dissolved in TFA (10 mL), heated to reflux, and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc and washed with saturated NaHCO3 aqueous solution. The organic phase was collected and concentrated under reduced pressure to give a yellow solid product (800 mg, 79% yield), which was used directly in the next reaction.

[0507] (C)3-(4-amino-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0508] Following the preparation procedure of compound 274, compound 280 was obtained using compound B19 and corresponding reagents. MS (m / z): 358.1 [M+H]+ ; 1 H NMR (400MHz, CD3OD): δ 5.00-4.92 (m, 1H), 4.38-4.18 (m, 1H), 2.80-2.61 (m, 1H), 2.61-2.44 (m, 1H), 2.31-2.10 (m, 2H), 1.50-1.23 (m, 3H).

[0509] Compound 284

[0510] 3-(4,6-Diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0511]

[0512] (A) 3-(4,6-bis((3,5-dimethoxyphenyl)amino)-1,3,5-triazin-2-yl)-2-trifluorocyclohexyl-2-en-1-one (B20)

[0513] Following the preparation procedure of compound 1, using intermediate I-106 and corresponding reagents, the title compound B20 was obtained. MS (m / z): 542.1 [M+H] +

[0514] (B)3-(4,6-diamino-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-one (B21)

[0515] Following the preparation procedure (B) of compound 280, compound B20 and corresponding reagents were used to obtain the title compound B21. MS (m / z): 224.0 [M+H] +

[0516] (C)3-(4,6-bis((tert-butyldimethylsilyl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexane-2-en-1-one (B22)

[0517] Following steps (B) and (C) of the preparation of compound 274, compound B21 and the corresponding reagents were used to obtain the title compound B22. MS (m / z): 488.1 [M+H] +

[0518] (D)3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexane-2-en-1-one (B23)

[0519] Compound B22 (410 mg, 0.84 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and methanol (5 mL) and stirred at room temperature for 30 minutes. The reaction solution was diluted with EtOAc and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The organic phase was collected, concentrated under reduced pressure, and the residue was purified by flash column chromatography (methanol / water elution) to give the title compound B23 (150 mg, 69% yield) as a white solid. MS (m / z): 260.0 [M+H] +

[0520] (E)3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol

[0521] Following the preparation procedure (B) of compound 1, compound 284 was obtained using compound B23 and the corresponding reagents. MS (m / z): 262.0 [M+H] +

[0522] 1 H NMR (400MHz, CD3OD): δ4.33-4.20 (m, 1H), 2.73-2.60 (m, 1H), 2.56-2.43 (m, 1H), 2.29-2.04 (m, 2H).

[0523] Compound 99

[0524] 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluorocyclohexyl-2-en-1-ol

[0525]

[0526] (A) 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluorocyclohexane-2-en-1-one (B24)

[0527] In a sealed tube, 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohexyl-2-en-1-one (700 mg, 1.69 mmol, obtained using intermediate I-3 according to the synthetic procedure of compound 1), NCS (224 mg, 1.69 mmol), TsOH·H2O (321 mg, 1.69 mmol), and acetonitrile (10 mL) were added sequentially. The mixture was heated to 80 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give the title compound B24 (320 mg, 42.2% yield) as a white solid. MS (m / z): 450.1, 452.1 [M+H] +

[0528] (B) 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluorocyclohexyl-2-en-1-ol

[0529] Following the preparation procedure of compound 39, compound 99 was obtained using compound B24 and corresponding reagents. MS (m / z): 452.1 [M+H] +

[0530] 1 H NMR (400MHz, CD3OD): δ5.02-4.90(m, 2H), 4.40-4.33(m, 1H), 4.27-4.19(m, 1H ), 2.80-2.66(m, 1H), 2.52-2.38(m, 1H), 2.13-1.97(m, 2H), 1.36-1.30(m, 6H).

[0531] Compound 122

[0532] (R)-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-one

[0533]

[0534] In a reactor, intermediate I-2 (500 mg, 1.76 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)cyclohexyl-2-en-1-one (391 mg, 1.76 mmol), cesium carbonate (1144 mg, 3.52 mmol), Pd(PPh3)4 (101 mg, 0.09 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially. The mixture was heated to 80 °C and stirred for two hours. After cooling to room temperature, the mixture was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate) to give a white solid product (350 mg, yield 57.9%). MS (m / z): 344.1 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ7.00 (s, 1H), 5.05-4.86 (m, 1H), 4.26-4.04 (m, 1H), 2.87-2.74 (m, 2H), 2.48-2.41 (m, 2H), 2.11-2.02 (m, 2H), 1.39-1.32 (m, 3H), 1.23-1.17 (m, 6H).

[0535] The compounds in the table below were prepared using the same preparation process as compound 122, with appropriate intermediates and reagents, under conditions generally recognized as suitable by those skilled in the art.

[0536]

[0537] Compound 124

[0538] 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-2-en-1-ol

[0539]

[0540] Compound 122 (250 mg, 0.73 mmol) and cerium trichloride heptahydrate (353 mg, 0.95 mmol) were dissolved in ethanol (10 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (36 mg, 0.95 mmol) was added. The reaction was stirred at 0 °C for 2 hours. After the reaction was complete, saturated ammonium chloride solution (3 mL) and water (20 mL) were added, and the mixture was extracted with EtOAc. The organic phase was collected, concentrated, and purified by flash column chromatography (PE / EA) to give a white solid product (210 mg, yield 83.3%). MS (m / z): 346.0 [M+H] + ;

[0541] 1H NMR (400MHz, CD3OD): δ7.19-6.92(m, 1H), 5.10-4.87(m, 1H), 4.37-4.26(m, 1H), 4.25-4.07(m, 1H) ), 2.51-2.30(m, 2H), 2.01-1.82(m, 2H), 1.71-1.49(m, 2H), 1.38-1.30(m, 3H), 1.23-1.12(m, 6H).

[0542] The compounds in the table below were prepared using the same reagents as compound 124.

[0543]

[0544]

[0545] Compound 138

[0546] (R)-6-(3,3-difluorocyclohexyl-1-en-1-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0547]

[0548] Compound 122 (100 mg, 0.29 mmol), DAST (1 mL), and BAST (1 mL) were mixed in DCM (10 mL) and placed in a sealed tube. The mixture was heated to 80 °C and stirred for 48 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA) to give a white solid (40 mg, yield 38.1%). MS (m / z): 366.1 [M+H] +

[0549] 1 H NMR (400MHz, CD3OD): δ7.00-6.82 (m, 1H), 5.05-4.88 (m, 1H), 4.27-4.05 (m, 1H), 2.59-2 .47(m, 2H), 2.14-2.00(m, 2H), 1.91-1.83(m, 2H), 1.39-1.32(m, 3H), 1.22-1.17(m, 6H).

[0550] Compound 139 in the table below was prepared using the same intermediates and reagents as compound 138, under conditions deemed suitable by those skilled in the art.

[0551]

[0552] Compound 140

[0553] 6-(3-Methoxycyclohexyl-1-en-1-yl)-N 2 N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0554]

[0555] Compound 126 (100 mg, 0.25 mmol) and silver oxide (115 mg, 0.5 mmol) were added to iodomethane (4 mL), heated to reflux, and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA) to give a white solid (60 mg, yield 58.3%). MS (m / z): 414.0 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ7.27-7.08 (m, 1H), 5.05-4.87 (m, 2H), 4.03-3.91 (m, 1H), 3.42 (s, 3H), 2.51-2.34 (m, 2H), 1.98-1.80 (m, 2H), 1.69-1.56 (m, 2H), 1.38-1.29 (m, 6H).

[0556] Compound 141

[0557] 6-(3-(dimethylamino)cyclohexyl-1-en-1-yl)-N 2 N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0558]

[0559] Compound 126 (50 mg, 0.125 mmol) was dissolved in anhydrous DCM (3 mL). Thionyl chloride (16 mg, 0.137 mmol) was added under ice bath conditions. After stirring for 30 minutes under ice bath conditions, the reaction mixture was transferred to a sealed tube, and dimethylamine hydrochloride (20 mg, 0.25 mmol) was added. The mixture was heated to reflux and reacted overnight under sealed conditions. After the reaction was complete, the mixture was cooled to room temperature, extracted with water and EtOAc, concentrated by EtOAc layer, and purified by flash column chromatography (PE / EA) to give a white solid (10 mg, yield 18.9%). MS (m / z): 427.0 [M+H] + ; 1H NMR (400MHz, CD3OD): δ7.27-7.11(m, 1H), 5.06-4.89(m, 2H), 3.58-3.44(m, 1H), 2.64-2.53(m, 1H) ), 2.44-2.38(m, 6H), 2.38-2.25(m, 1H), 2.05-1.92(m, 2H), 1.66-1.53(m, 2H), 1.39-1.31(m, 6H).

[0560] The compounds in the table below were prepared using the same preparation process as compound 141, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0561]

[0562] Compound 143

[0563] 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-1-(trifluoromethyl)cyclohexyl-2-en-1-ol

[0564]

[0565] 3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one was prepared according to compound 122. 3-(4,6-bis((((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (100 mg, 0.25 mmol) and (trifluoromethyl)trimethylsilane (142 mg, 1.25 mmol) were added to anhydrous THF (10 mL). TBAF (1 M, 1.25 mL) was added under ice bath conditions, and the mixture was heated to reflux. After reacting for two hours, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with EtOAc, concentrated the organic phase, and purified by flash column chromatography (PE / EA) to give a white solid (10 mg, yield 8.6%). MS (m / z): 468.0 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ7.10 (s, 1H), 5.05-4.88 (m, 2H), 2.81-2.63 (m, 1H), 2.35-2.21 (m, 1H), 1.92-1.77 (m, 4H), 1.39-1.31 (m, 6H).

[0566] Compound 144

[0567] 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-3-en-1-ol

[0568]

[0569] (A)(R)-N 2 -Isopropyl-6-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-N 4 -(1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine (B25)

[0570] In a reaction flask under nitrogen protection, intermediate I-2 (320 mg, 1.13 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1,3,2-dioxaborane (300 mg, 1.13 mmol), cesium carbonate (734 mg, 2.26 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially. The mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA) to give the white solid title compound B25.

[0571] (B)(R)-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-3-en-1-one (B26)

[0572] Compound B25 was dissolved in DCM (3 mL), and TFA (3 mL) was added. The mixture was reacted overnight at room temperature. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with EtOAc. The EtOAc layer was concentrated, and the mixture was purified by flash column chromatography (PE / EA) to give a pale yellow solid, title compound B26 (200 mg, yield 51.5%). MS (m / z): 344.3 [M+H] +

[0573] (C)3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropyl-2-yl)amino)-1,3,5-triazin-2-yl)cyclohexyl-3-en-1-ol

[0574] Compound 144 was prepared using compound B26 and corresponding reagents, following the same procedure as compound 124. MS (m / z): 346.3 [M+H] +

[0575] 1H NMR (400MHz, CD3OD): δ7.27-6.96 (m, 1H),), 5.08-4.89 (m, 1H), 4.28-4.07 (m, 1H), 4.02-3.83 (m, 1H), 2.91- 2.72 (m, 1H), 2.47-2.20 (m, 3H), 1.93-1.80 (m, 1H), 1.65-1.53 ​​(m, 1H), 1.38-1.28 (m, 3H), 1.24-1.13 (m, 6H).

[0576] Compound 145 in the table below was prepared using the same intermediates and reagents as compound 144, under conditions deemed suitable by those skilled in the art.

[0577]

[0578] Compound 152

[0579] 2-Fluoro-3-(4-(((R)-1-phenylethyl)amino)-6-(((R)-1,1,1-trifluoroprop-2-yl)amino)-triazin-2-yl)cyclohexyl-2-en-1-ol

[0580]

[0581] In a sealed tube, intermediate I-1 (50 mg, 0.15 mmol), (R)-1-phenylethyl-1-amine (36 mg, 0.30 mmol), DIEA (77 mg, 0.60 mmol), and 1,4-dioxane (3 mL) were added sequentially. The mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA) to give a white solid product (15 mg, yield 23.4%). MS (m / z): 426.3 [M+H] +

[0582] 1 H NMR (400MHz, CD3OD): δ7.35-7.15(m, 5H), 5.22-4.60(m, 2H), 4.33-4.21(m, 1H), 2.62-2.23(m, 2H) ), 1.89-1.73(m, 3H), 1.67-1.58(m, 1H), 1.50-1.44(m, 3H), 1.34-1.28(m, 2H), 1.16-1.07(m, 1H).

[0583] The compounds in the table below were prepared using the same preparation process as compound 152, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590] Compound 186

[0591] 6-(cyclohexyl-1-en-1-yl)-N 2 N 4 -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0592]

[0593] In a reaction flask under nitrogen protection, intermediate I-3 (150 mg, 0.44 mmol), cyclohexyl-1-en-1-ylboronic acid (85 mg, 0.66 mmol), cesium carbonate (290 mg, 0.88 mmol), Pd(PPh3)4 (26 mg, 0.022 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially. The mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (PE / EA) to give a white solid (154 mg, yield 90.4%). MS (m / z): 384.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ7.84-7.60 (m, 2H), 7.18 (s, 1H), 5.07-4.76 (m, 2H), 2.40-2.28(m, 2H), 2.25-2.16(m, 2H), 1.68-1.52(m, 4H), 1.34-1.25(m, 6H).

[0594] The compounds in the table below were prepared using the same intermediates and reagents as compound 186, under conditions deemed suitable by those skilled in the art.

[0595]

[0596]

[0597] Compound 190

[0598] (R)-6-(cyclohexyl-1-en-1-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

[0599]

[0600] Intermediate I-22 (85 mg, 0.33 mmol), (R)-1,1,1-trifluoropropyl-2-amine hydrochloride (201 mg, 1.34 mmol), and DIEA (0.47 mL, 2.69 mmol) were added to 1,4-dioxane (3 mL), and the mixture was heated to 150 °C and microwaved for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and the residue was purified by flash column chromatography (PE / EA) to give a yellow solid (18 mg, yield 14%). MS (m / z): 330.1 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ7.32-6.94 (m, 1H), 4.66-4.52 (m, 1H), 4.32-4.02 (m, 1H), 2.52-2 .33(m, 2H), 2.29-2.16(m, 2H), 1.79-1.60(m, 4H), 1.40-1.29(m, 3H), 1.24-1.14(m, 6H).

[0601] The compounds in the table below were prepared using the same reagents as compound 190.

[0602]

[0603]

[0604] Compounds 206 and 207

[0605] 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-2-yl)cyclohexyl-2-en-1-ol and 3-(5-fluoro-2,6-bis((((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-4-yl)cyclohexyl-2-en-1-ol

[0606]

[0607] (A) 2-Chloro-5-fluoro-N4,N6-bis((R)-1,1,1-trifluoropropyl-2-yl)pyrimidin-4,6-diamine and 6-chloro-5-fluoro-N 2 N 4A mixture of bis((R)-1,1,1-trifluoropropyl-2-yl)pyrimidine-2,4-diamine

[0608] Under nitrogen protection, intermediates 2,4,6-trichloro-5-fluoropyrimidine (1.12 g, 5.6 mmol), (R)-1,1,1-trifluoropropane-2-amine hydrochloride (2.51 g, 16.8 mmol), DIEA (4.22 g, 56 mmol), and N-methylpyrrolidone (5 mL) were added sequentially to a microwave-safe reaction flask. The mixture was heated to 200 °C and stirred for 1 hour in a microwave reactor. After cooling to room temperature, the reaction solution was directly injected into an RP-C18 column (eluted with a water / methanol gradient of 100:0–0:100) to purify the product, yielding a white solid (80 mg, 4.2% yield). MS (m / z): 354.9 [M+H]+

[0609] (B) A mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-2-yl)cyclohexyl-2-en-1-one and 3-(5-fluoro-2,6-bis((((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-4-yl)cyclohexyl-2-en-1-one

[0610] Under nitrogen protection, in a microwave-safe reaction flask, the solid product obtained in step (A) (80 mg, 0.23 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)cyclohexyl-2-en-1-one (50 mg, 0.23 mmol), cesium carbonate (150 mg, 0.46 mmol), 1,4-dioxane (5 mL), and water (1.5 mL) were added sequentially. The mixture was heated to 130 °C and stirred for 40 minutes in the microwave reactor. After cooling to room temperature, the mixture was concentrated and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution) to give a white solid product (60 mg, yield 63.2%). MS (m / z): 415.0 [M+H]+

[0611] (C) 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-2-yl)cyclohexyl-2-en-1-ol and 3-(5-fluoro-2,6-bis((((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-4-yl)cyclohexyl-2-en-1-ol

[0612] Following the preparation process of compound 124, compound 206 and compound 207 were prepared using a mixture of 3-(5-fluoro-4,6-bis((((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one and 3-(5-fluoro-2,6-bis((((R)-1,1,1-trifluoroprop-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-one and the corresponding reagents, and purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to obtain white solid products compound 206 and compound 207.

[0613] Compound 206, MS (m / z): 417.0 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ6.97-6.89(m, 1H), 5.21-5.03(m, 2H), 4.38-4.26(m, 1H ), 2.55-2.34(m, 2H), 1.96-1.82(m, 2H), 1.68-1.52(m, 2H), 1.42-1.32(m, 6H).

[0614] Compound 207, MS (m / z): 417.0 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ6.47-6.40(m, 1H), 5.10-4.97(m, 1H), 4.82-4.72(m, 1H), 4.35-4.26(m, 1H), 2 .50-2.30 (m, 2H), 1.99-1.85 (m, 2H), 1.71-1.56 (m, 2H), 1.38 (d, J=7.1Hz, 3H), 1.32 (d, J=7.0Hz, 3H).

[0615] Following the method described above, the following compounds were also prepared using appropriate intermediates and related reagents.

[0616]

[0617]

[0618] Compounds 197 and 198

[0619] 3-(4,6-Di(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohexyl-2-en-1-ol, optically pure diastereomeric

[0620]

[0621] Racemic compound 196 was resolved by chiral HPLC to yield a pair of optically pure diastereomeric compounds 197 and 198 (chiral preparation conditions: instrument: Shimadzu LC-10AD vp; column: Daicel AD-H (250mm*30mm, 5µm); mobile phase: n-heptane / isopropanol = 90 / 10; flow rate: 40mL / min; column temperature: 40℃). The first eluent (RT = 4.203 min) was concentrated and purified by flash column chromatography (PE / EA = 100:0-0:100 gradient elution) to obtain compound 197, with a de value of 99.27% ​​and MS (m / z): 454.1 [M+H]. + The second eluent (RT = 5.906 min) was concentrated and purified by flash column chromatography (PE / EA = 100:0–0:100 gradient elution). The resulting compound was named compound 198, with a de value of 97.82% and MS (m / z) of 454.2 [M+H]. + .

[0622] Compound 197: 1 H NMR (400MHz, CD3OD): δ 5.00-4.86 (m, 2H), 4.36-4.17 (m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H), 1.37-1.31 (m, 6H).

[0623] Compound 198: 1 H NMR (400MHz, CD3OD): δ 5.00-4.86 (m, 2H), 4.36-4.17 (m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.25-2.05 (m, 2H), 1.37-1.31 (m, 6H).

[0624] Following the preparation methods of compounds 197 and 198, the compounds listed in the table below were prepared using the corresponding racemic compounds under suitable HPLC conditions:

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635] Example 3: Detection of IDH2-R140Q cell viability using fluorescence method

[0636] Material

[0637] U87MGR140Q cells: U87MG cells were purchased from the ATCC cell bank and transfected with a plasmid containing the IDH2-R140Q mutation. Cells stably expressing the R140Q mutation were selected by single-clone selection for experiments. These cells were cultured in MEM medium containing 10% FBS.

[0638] 96-well plate a: Beckman Dickinson, part number 353072;

[0639] 96-well plate b: Thermo, part number 249952;

[0640] 96-well plate c: Greiner, part number 675076.

[0641] Solution preparation

[0642] Enzyme reaction solution: The assay buffer, 40 mM Tris.HCl pH 8.8, contains 1 mM nicotinamide adenine dinucleotide (NAD), 0.6 ng / μL D-2-hydroxyglutarate dehydrogenase (D2HGDH), 0.8 U / mL lipoamide dehydrogenase (Diaphorase), and 60 μM resazurin.

[0643] Standard curve stock solutions: Prepare standard curve stock solutions by serially diluting 2-HG sodium salt standard with serum-free MEM medium. The final gradient concentrations are: 500 μM, 167 μM, 56 μM, 18.5 μM, 6 μM, 2 μM, 0.7 μM, and 0.2 μM.

[0644] method

[0645] In a 96-well plate (a), 100 μL of U87MGR140Q cells were seeded into each well at a density of 6 × 10⁴ / mL, with 6000 cells per well. After incubating overnight at 37°C and 5% CO₂, 10 μL of different concentrations of the test compound solution diluted in serum-free MEM medium (final concentrations of the test compound were: 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.041 μM, 0.014 μM, and 0.005 μM, with a final DMSO concentration of 0.5%) or 10 μL of control solution (serum-free MEM medium containing 0.5% DMSO) was added to each well, and the plate was incubated for 72 hours.

[0646] From each well of 96-well plate a, 50 μL of culture supernatant was transferred to the corresponding well of 96-well plate b; simultaneously, 50 μL of standard curve stock solution was added to the other wells. Then, 10 μL of 360 mM hydrochloric acid was added to all wells, vortexed to mix, and incubated on ice for 10 minutes; next, 10 μL of 420 mM Tris-base was added, vortexed to mix, and incubated on ice for 5 minutes. Finally, the plates were centrifuged at 2500 rpm for 10 minutes.

[0647] Take 20 μL of supernatant from each well of the centrifuged 96-well plate b and add it to each well of the 96-well plate c. Then add 80 μL of enzyme reaction solution to each well and incubate at 25°C for 90 minutes.

[0648] Detection

[0649] The fluorescence value at 590 nm under 544 nm excitation was detected using a Tecan Infinite F500 Reader instrument. A standard curve was plotted against the corresponding 2-HG concentration using the fluorescence value, and the 2-HG concentration corresponding to each concentration point of the compound was calculated. Then, the inhibition rate was calculated, and the data was analyzed using XLfit5 (ID Business Solutions Limited) software to obtain the IC50 value.

[0650] The inhibition rate was calculated as follows: Inhibition rate % (IH%) = (1 - 2-HG concentration in the cell pores of the test compound / 2-HG concentration in the control cells) × 100%.

[0651] The following are the activity values ​​of some compounds of the present invention measured in this embodiment.

[0652]

[0653]

[0654]

[0655] Example 4: Detection of IDH1-R132H cell viability using fluorescence method

[0656] Following the exact same method as in Example 3, the inhibitory activity of the compound of the present invention on 2-HG in U87MGR132H cells transfected with the IDH1-R132H mutant plasmid was determined.

[0657] The following are the activity values ​​of some compounds of the present invention measured in this embodiment.

[0658]

[0659]

[0660] Example 5: Liver Microsome Stability Test

[0661] Experimental materials:

[0662] Mixed liver microsomes from male CD-1 mice: purchased from Rede Liver Disease Research (Shanghai) Co., Ltd.; Mixed liver microsomes from male SD rats: purchased from Bioreclamation IVT, Inc., USA.

[0663] Phenacetin, glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PDH), and nicotinamide adenine dinucleotide phosphate (NADP) were all purchased from Sigma-Aldrich, USA.

[0664] Solution preparation:

[0665] 10mM Stock Solution of Test Compound: Weigh a certain amount of the test compound, dissolve it in an appropriate volume of DMSO, and prepare a stock solution with a concentration of 10mM for later use.

[0666] Reaction termination solution: Dissolve an appropriate amount of the internal standard compound phenacetin in acetonitrile to prepare a reaction termination solution with a concentration of 1000 ng / mL, and keep it at room temperature for later use.

[0667] Experimental methods:

[0668] The stock solution of the test compound is diluted to the target concentration with an organic solvent (usually a mixture of acetonitrile, methanol, and water in different proportions, depending on the solubility of the compound) to ensure that the final reaction system concentration is 1 μM and the concentration of the organic solvent in the incubation system does not exceed 1% (of which the proportion of DMSO should not exceed 0.1%). 100 mM NADP, 500 mM G-6-P, and 100 Unit / mL G-6-PDH are mixed and diluted with ultrapure water to ensure that the final system contains 1 mM NADP, 5 mM G-6-P, and 1 U / mL G-6-PDH. After preparation, it is pre-incubated in a 37°C water bath for 10 minutes and then placed on ice for later use as the NADPH regeneration solution. 20 mg / mL liver microsome solution is mixed with 200 mM phosphate buffer and diluted with ultrapure water to a final reaction system concentration of 0.5 mg / mL liver microsomes and 50 mM phosphate buffer. The diluted liver microsome solution was mixed with the prepared NADPH regeneration solution, and an appropriate volume of 100 mM EDTA and 300 mM MgCl2 solution was added (the final system consisted of 3 mM MgCl2 and 1 mM EDTA). The mixture was placed in a 37°C water bath, and the reaction was initiated by adding the stock solution of the analyte. The reaction was allowed to proceed for 30 minutes. The reaction was terminated by adding a stop solution. The stock solution of the analyte was added before placing the incubation system in the water bath, and the sample obtained after the reaction was terminated was taken as the 0-minute sample. After vortexing to mix the sample with the stop solution, the mixture was centrifuged at 4400 rpm for 10 minutes, and the supernatant was analyzed by LC-MS / MS.

[0669] Analysis method:

[0670] The concentrations of compounds in the samples were determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The percentage of remaining compounds after 30 minutes of incubation was calculated, using the peak area ratio of the compound to the internal standard as an indicator, compared to the sample at 0 minutes, to evaluate the metabolic stability of the compounds.

[0671] Based on the above tests, the compounds of the present invention exhibit good metabolic stability. The metabolic stability of some representative compounds of the present invention is as follows:

[0672]

[0673]

[0674] Example 6 Solubility Test

[0675] 1. Sample solution preparation

[0676] Sample standard solution: Accurately weigh approximately 3-5 mg of the test compound into a 5 mL sample tube, add 5 mL of DMSO, and shake well; sonicate for one hour and then set aside for use.

[0677] pH 2.1 sample solution: Accurately weigh approximately 1 mg of the test compound into a 1 mL sample tube, add 1 mL of pH 2.1 sodium phosphate buffer, and shake well; if the solution appears clear to the naked eye, add an appropriate amount of the test compound until there are obvious insoluble substances in the solution; sonicate for one hour before use;

[0678] pH 7.4 sample solution: Accurately weigh approximately 1 mg of the test compound into a 1 mL sample tube, add 1 mL of pH 7.4 sodium phosphate buffer, and shake well; if the solution appears clear to the naked eye, add an appropriate amount of the test compound until there are obvious insoluble substances in the solution; sonicate for one hour before use.

[0679] 2. Testing

[0680] Accurately pipette 1 mL of the sample standard solution into an HPLC sample vial and determine the peak area by HPLC. Filter the pH 2.1 sample solution using a syringe filter and accurately pipette 0.5 mL of the solution into an HPLC sample vial. Accurately add 0.5 mL of pH 2.1 sodium phosphate buffer and mix well; determine the peak area by HPLC.

[0681] The pH 7.4 sample solution was filtered using a syringe filter, and 0.5 mL of the solution was accurately pipetted into an HPLC sample vial. 0.5 mL of pH 7.4 sodium phosphate buffer was accurately added, and the solution was shaken well. The peak area was then determined by HPLC.

[0682] The HPLC test conditions are as follows:

[0683] Instrument: Agilent 1200

[0684] Column: Agilent SB-C18 5u 4.6*150mm

[0685] Mobile phase:

[0686] Mobile phase A: Water (containing 0.1% formic acid)

[0687] Mobile phase B: MeOH (containing 0.1% formic acid)

[0688] Gradient table:

[0689] Time (min) ％A ％B 0 95 5 10 5 95 13 5 95 14 95 5 16 95 5

[0690] 3. Calculate solubility

[0691] The solubility of the analyte in phosphate buffer solutions at pH 2.1 and pH 7.4 was calculated using the following method:

[0692] pH 2.1 Sample solubility (mg / mL) = 2 × A × Y ÷ X

[0693] Sample solubility at pH 7.4 (mg / mL) = 2 × A × Z ÷ X

[0694] Where: A is the concentration of the compound to be tested in the sample standard solution, mg / mL;

[0695] X represents the peak area of ​​the sample standard solution;

[0696] Y represents the peak area of ​​the sample solution at pH 2.1;

[0697] Z represents the peak area of ​​the sample solution at pH 7.4.

[0698] The metabolic stability of some representative compounds of this invention is as follows:

[0699]

Claims

1. Compounds of formula (I-1a): and / or its pharmaceutically acceptable salts, and / or its racemic mixtures, enantiomers, diastereomers and tautomers, wherein: Each R2 is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R3 ’ and R4 ’ Both are H; R3 and R4 are each independently selected from C3, which are optionally substituted with one or more halogens. 1-6 alkyl; m can be 0, 1, 2, 3, 4, 5, or 6; n is 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, and / or a racemic mixture thereof, enantiomer, diastereomer, and tautomer, wherein: R2 is selected from halogens.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, and / or a racemic mixture thereof, enantiomer, diastereomer, and tautomer, wherein: R2 is F.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, and / or a racemic mixture thereof, enantiomer, diastereomer, and tautomer, wherein: m is 3.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, and / or a racemic mixture thereof, enantiomer, diastereomer, and tautomer, wherein: m is 4.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, and / or a racemic mixture thereof, enantiomer, diastereomer, and tautomer, wherein: R3 and R4 are each independently selected from C, which are optionally replaced by one or more Fs. 1-6 alkyl.

7. A pharmaceutical composition comprising a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease induced by an IDH mutation in an individual, wherein: The diseases induced by IDH mutations are cancers, specifically acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

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