Cycloolefin-substituted heteroaromatic compounds and their uses

Abstract

To provide cycloolefin substituted heteroaromatic compounds that are useful for treating hematologic malignancies, particularly acute myeloid leukemia, gliomas and other IDH mutation associated tumors.SOLUTION: The present invention discloses compounds represented by the formula (II-1) or a pharmaceutically acceptable salt thereof, and / or solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof (where, X is halo; and p, m, and n independently represent 0, 1 or 2).SELECTED DRAWING: None

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to cycloolefin-substituted heteroaromatic compounds and their use in the treatment of diseases caused by IDH mutations.

[0002] 2. Background of the Invention Tumor cells differ from normal cells in the way they survive, as well as in their energy intake and utilization. A common metabolic pathway in aerobic organisms is the tricarboxylic acid cycle, in which isocitrate dehydrogenase (IDH), which catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG), is the rate-limiting step. The known IDH family comprises three isozymes, IDH1, IDH2 and IDH3, which reside in different organelles and perform the same biological function, i.e., catalyzing the formation of α-KG. Recent studies have shown that heterozygous IDH1 / 2 mutations were present in a proportion of various tumors, including gliomas (60-80%), chondrosarcomas (55%) and acute myeloid leukemias (15-25%). Mutant IDH1 or IDH2 lack the ability to catalyze the conversion of isocitrate to α-KG, but have the ability to catalyze the reaction of α-KG with α-hydroxyglutarate (2-HG). The structure of 2-HG is similar to that of α-KG, and when 2-HG accumulates to a certain extent, it competitively inhibits the activity of many α-KG-dependent enzymes (e.g., TET family histone demethylases and methylcytosine hydroxylases), thus effecting the demethylation of histones and DNA, interfering with normal cell differentiation and resulting in the proliferation of immature cells.

[0003] Agios Pharmaceuticals published the results of its research in the journal Science in 2013: The mutant IDH1 enzyme inhibitor AGI-5198 (Science, 2013, 340, 626-630) and mutant IDH2 enzyme inhibitor AGI-6780 (Science, 2013, 340, 622-626) developed by the company can effectively inhibit the production of 2HG mediated by mutant IDH1 / IDH2 in cells and induce the differentiation of abnormally proliferating cancer cells. Treatment of glioma cells with mutant IDH1 gene and leukemia cells with mutant IDH2 gene both with AGI-5198 resulted in enhanced expression of maturation markers in the cells.

[0004] A phase I clinical trial of AG-120, a mutant IDH1 inhibitor developed by Agios Pharmaceuticals, showed that in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who harbored IDH1 mutations, 98% of patients had reduced alpha-hydroxyglutarate (2HG) levels.

[0005] Acute myeloid leukemia (AML) is one of the most difficult to control among common hematological malignancies. Its relapse rate is high. The development of new drugs for this disease has been slow, leading to a lack of effective drug therapy. Several studies have shown that approximately 15% of patients with AML have IDH2 gene mutations. Enasidenib (formerly known as AG-221), a mutant IDH2 inhibitor developed by Agios Pharmaceuticals and Celgene, has shown significant efficacy against relapsed and refractory AML with IDH2 gene mutations in clinical trials.

[0006] There is a need to develop new IDH mutant inhibitors to meet the needs of treating patients with hematological malignancies, particularly acute myeloid leukemia, gliomas and other IDH mutation-associated tumors. The present invention addresses these needs. Summary of the Invention

[0007] The present invention relates to compounds of formula (I): [ka] and / or a soluble salt thereof, and / or solvates, racemic mixtures, enantiomers, diasteromers, 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.

[0008] Also provided are pharmaceutical compositions comprising at least one compound of Formula (I) (e.g., any of the compounds described herein) and / or a pharma- ceutically acceptable salt thereof, and optionally including at least one pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable carrier).

[0009] Also provided is a method of treating a disease caused by an IDH mutation, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I) (e.g., any of the compounds described herein) and / or at least one pharma- ceutically acceptable salt thereof.

[0010] Also provided is the use of at least one compound of formula (I) (e.g., any of the compounds described herein) and / or at least one pharma- ceutically acceptable salt thereof for treating a disease caused by an IDH mutation.

[0011] Also provided is the use of at least one compound of Formula (I) (e.g., any of the compounds described herein) and / or at least one pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease caused by an IDH mutation. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows general synthetic route I for the preparation of the compounds described herein. [Diagram 2] FIG. 2 shows general synthetic route II for the preparation of the compounds described herein. [Diagram 3] FIG. 3 shows general synthetic route III for the preparation of compounds described herein. [Figure 4] FIG. 4 shows general synthetic route IV for the preparation of compounds described herein. [Diagram 5] FIG. 5 shows general synthetic route V for the preparation of compounds described herein. [Figure 6] FIG. 6 shows general synthetic route VI for the preparation of compounds described herein.

[0013] Detailed Description of the Invention definition As used in this application, the following words, phrases and symbols generally are intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0014] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -OR4 is attached through the oxygen. However, if the point of attachment of the group is obvious to one of ordinary skill in the art, for example a halo substituent, the "-" sign may be omitted.

[0015] Unless expressly stated to the contrary, use of the terms "a," "an," etc. refers to one or more.

[0016] The term "alkyl" as used herein refers to a linear or branched saturated hydrocarbon group containing 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. For example, "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), i-propyl ("i-Pr"), n-butyl ("n-Bu"), i-butyl ("i-Bu"), s-butyl ("s-Bu"), and t-butyl ("t-Bu").

[0017] The term "alkenyl," as used herein, refers to a linear or branched hydrocarbon group containing one or more, e.g., one, two, or three, carbon-carbon double bonds (C=C) and 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms. 2-6 "Alkenyl" refers to an alkenyl containing 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment of the alkenyl may or may not be on a double bond.

[0018] The term "alkynyl" as used herein refers to a linear or branched hydrocarbon group containing one or more, e.g., one, two, or three, carbon-carbon triple bonds (C≡C) and 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. 2-6 "Alkynyl" refers to an alkynyl containing 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment of the alkynyl may or may not be on the triple bond.

[0019] The term "halogen" or "halo" as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.

[0020] The term "haloalkyl" as used herein refers to an alkyl radical as defined herein in which one or more, e.g., 1, 2, 3, 4, or 5, hydrogen atoms are replaced by halogen atoms, and in the case where two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other. In certain embodiments, the term "haloalkyl" as used herein refers to an alkyl radical as defined herein in which two or more, e.g., 2, 3, 4, or 5, hydrogen atoms are replaced by halogen atoms, and the halogen atoms may be the same or different from each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl radical as defined herein in which two or more, e.g., 2, 3, 4, or 5, hydrogen atoms are replaced by halogen atoms, and the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, and the like.

[0021] The term "alkoxy" as used herein refers to an -O-alkyl group, where alkyl is defined above. Examples of alkoxy groups include, but are not limited to, C 1-6 Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, and hexyloxy, including their isomers.

[0022] The term "cycloalkyl," as used herein, refers to a saturated or partially unsaturated cyclic hydrocarbon group having 3 to 12 ring carbon atoms, e.g., 3 to 8 ring carbon atoms, 5 to 7 ring carbon atoms, 4 to 7 ring carbon atoms, or 3 to 6 ring carbon atoms, and may have one or more rings, e.g., 1, 2, or 3 rings, preferably 1 or 2 rings. For example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl containing 3 to 12 carbon atoms in the ring. "Cycloalkyl" also includes fused or bridged rings, or spirocyclic rings. The rings of the cyclic groups may be saturated or have one or more, e.g., one or two, double bonds (i.e., partially unsaturated), but are not fully conjugated and are not aryl as defined herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[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.

[0023] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used herein refers to a monocyclic, bicyclic or tricyclic saturated or partially unsaturated ring radical having 3 to 12 ring atoms, e.g., 3 to 8 ring atoms, 5 to 7 ring atoms, 4 to 7 ring atoms or 3 to 6 ring atoms, containing one or more, e.g., 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S in the ring, with the remaining ring atoms being carbon. Heterocyclic groups also include those in which the N or S heteroatoms may be oxidized to various oxidation states. The point of attachment of the heterocyclyl may be on the N heteroatom or on the carbon. For example, "3-8 membered heterocyclyl" refers to a heterocyclyl containing 3 to 8 ring atoms and containing at least one heteroatom independently selected from N, O and S.

[0024] Heterocyclic groups also include fused or bridged rings, or spirocyclic rings, in which at least one ring contains at least one heteroatom selected from O, S, and N, and none of the other rings is an aryl or heteroaryl as defined herein. The rings of the heterocyclic groups may be saturated or have one or more, e.g., one or two, double bonds (i.e., partially unsaturated), but are not fully conjugated and are not heteroaryl as defined herein. Examples of heterocycly groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.

[0025] The term "aryl" as used herein refers to a carbocyclic hydrocarbon group of 6 to 14 carbon atoms consisting of one ring or two or more fused rings, at least one of which is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.

[0026] The term "heteroaryl" as used herein means monocyclic aromatic hydrocarbon groups having 5, 6 or 7 ring atoms, preferably 6 ring atoms, and containing one or more, e.g. 1, 2 or 3, preferably 1 or 2 heteroatoms independently selected from N, O and S (preferably N) in the ring, the remaining ring atoms being carbon; and Bicyclic aromatic hydrocarbon groups having 8-12 ring atoms, preferably 9 or 10 ring atoms, and containing one or more, e.g., 1, 2, 3 or 4, preferably 2, 3 or 4, heteroatoms independently selected from N, O and S (preferably N) in the ring, the remaining ring atoms being carbon, and at least one of the rings being aromatic. For example, bicyclic heteroaryls include those in which a 5- or 6-membered heteroaromatic ring is fused to a 5- or 6-membered cycloalkyl ring.

[0027] When the total number of S and O atoms in the heteroaryl group exceeds 1, said S and O heteroatoms are not adjacent to one another.

[0028] Heteroaryl groups also include those in which the N heteroatom is present as an N-oxide, for example, pyridyl N-oxide.

[0029] Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, benzodioxolyl, benzoxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (e.g., imidazo[1,2 [1,2,4]triazolo[1,5-a]pyridyl), pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridyl), pyrazolopyrimidinyl, triazolopyridinyl (e.g., [1,2,4]triazolo[1,5-a]pyridyl), tetrazolopyridinyl, tetrahydropyrazolopyridyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, benzofuryl, benzimidazolinyl, indolyl, indazolyl, purinyl, quinolinyl, and isoquinolinyl.

[0030] "Hydroxyl" as used herein refers to the -OH radical.

[0031] "Mercapto" as used herein refers to the -SH radical.

[0032] "Oxo" as used herein refers to the =O radical.

[0033] The structures herein are marked with an asterisk " * ", it is " * " means that the chiral center of the compound marked with " is either R-configuration or S-configuration. * The content of the compound having a single configuration marked with " 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 the recited values). The configuration of a compound can be determined by one of skill in the art using various analytical techniques, such as single crystal X-ray crystallography and / or optical rotation measurements, following routine protocols.

[0034] When a structure herein contains "(RS)," it is meant that the chiral center of the compound with "(RS)" includes both the R- and S-configuration.

[0035] The terms "optional" or "optionally" as used herein mean that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and nonoccurrence of the event or circumstance. For example, "optionally substituted alkyl" encompasses "unsubstituted alkyl" and "substituted alkyl" as defined herein. With respect to any group that contains one or more substituents, it will be understood by those of skill in the art that such groups are not intended to introduce any substitutions or substitution patterns that are sterically infeasible, chemically impractical, synthetically infeasible, and / or inherently unstable.

[0036] The term "substituted" or "substituted with" as used herein means that one or more hydrogens of the designated atom or group are replaced with one or more choices from the group of indicated substituents (but not exceeding the valence of the designated atom). If the substituent is oxo (i.e. =O), then two hydrogens of a single atom are replaced with oxo. Combinations of substituents and / or variables are permissible only if such combinations result in chemically plausible and stable compounds. Chemically plausible and stable compounds are meant to imply compounds that are sufficiently robust to remain isolated from a reaction mixture to allow identification of the compound's chemical structure, and are sufficiently robust to allow subsequent formulation as a pharmaceutical agent having at least one practical utility.

[0037] Unless otherwise noted, substituents are named relative to the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it is to be understood that the point of attachment of this substituent to the core structure is the alkyl moiety.

[0038] The term "substituted with one or more substitutents," as used herein, means that one or more hydrogens of a specified atom or group are independently replaced with one or more options selected from the group of substituents indicated. In some embodiments, "substituted with one or more substitutents" means that a specified atom or group is substituted with 1, 2, 3, or 4 substitutents independently selected from the group of substituents indicated.

[0039] Those skilled in the art ("POSITA") will recognize that some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms. Racemates of these isomers, individual isomers and mixtures enriched in one enantiomer, as well as diastereomers where two chiral centers are present, and mixtures partially enriched in a particular diastereomer are included within the scope of the present invention. Additionally, POSITA will recognize that the present invention includes all of the individual stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where applicable, their individual tautomers.

[0040] In other words, in some embodiments, the present invention provides compounds of various stereoisomeric purity, i.e., diastereomeric purity or enantiomeric purity, expressed as various "ee" or "de" values. In some embodiments, the compounds of formula (I) (e.g., as described herein) have 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 those recited values). In some embodiments, the compounds of formula (I) (e.g., as described herein) have an enantiomeric purity of greater than 99.9% ee, ranging up to 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 recited values). In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of greater than 99.9% de.

[0041] The term "enantiomeric excess" or "ee" refers to how much of one enantiomer is present relative to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is |RS| * The enantiomeric excess percent of the optical rotation of a chiral substance is defined as ([a]obs / [a]max) = 100, where R and S are the moles or weight fractions of each enantiomer in the mixture such that R+S=1. * It is defined as 100, where [a]obs is the optical rotation of the mixture of enantiomers and [a]max is the optical rotation of the pure enantiomer.

[0042] The term "diastereomeric excess" or "de" refers to how much of one diastereomer is present relative to the other and is defined similarly to enantiomeric excess. Thus, for a mixture of diastereomers D1 and D2, the percent diastereomeric excess is |D1-D2| * 100, where D1 and D2 are the moles or weight fractions of each of the diastereomers in the mixture such that D1+D2=1.

[0043] Determination of diastereomeric and / or enantiomeric excess can be accomplished using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, and / or optical rotation measurements following routine protocols well known to those skilled in the art.

[0044] Racemates can be used as is or can be resolved into their individual isomers. Resolution can provide stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, fractional crystallization of the salts, and then repeating the process to obtain one or both of the resolved bases, which may be substantially free of the other, i.e., in a form containing the desired stereoisomer with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, the racemic compound can be covalently bound to a chiral compound (auxiliary group) to produce diastereomers separable by chromatography or fractional crystallization, which can then be chemically removed to obtain the pure enantiomers, as known in POSITA.

[0045] The term "tautomer" as used herein refers to a structural isomer of a compound that is produced by the rapid movement of atoms at two locations in a molecule. Tautomers are easily interconverted with each other, for example, enol form and ketone form are typical tautomers. For example, some compounds disclosed herein can exist in the form a, b, c, d, e, f, etc., as shown in the diagram below, i.e., compounds in the form a, b, c, d, e, f may be tautomers of the compound of formula (I). All single tautomers and mixtures of these tautomers in any ratio are included in the compounds described herein. [ka]

[0046] "Pharmaceutically acceptable salt" is intended to mean a non-toxic, biologically tolerable, or otherwise biologically suitable acid or base salt of the free form of a compound of formula (I) for administration to a subject. See generally, for example, SM Berge, 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.

[0047] In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharma- ceutically acceptable acid addition salt, can be prepared by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. POSITA will recognize various synthetic methods that can be used to prepare non-toxic pharma-ceutically acceptable acid addition salts without undue experimentation.

[0048] The term "solvate" refers to a solvent addition form that contains a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance in which water retains its molecular state as H2O, and such a combination can form one or more hydrates, such as hemihydrate, monohydrate, and dihydrate, as well as various hydrates.

[0049] As used herein, the terms "group," "radical," and "moiety" are synonymous and are intended to refer to a functional group or fragment of a molecule capable of bonding with another fragment of the molecule.

[0050] The term "active ingredient" is used to indicate a chemical entity having biological activity. In some embodiments, an "active ingredient" is a chemical entity having pharmaceutical utility. In the United States, practical drug activity can be established by suitable preclinical assays, whether in vitro or in vivo. Drug activity sufficient to be approved by a regulatory agency, e.g., the FDA in the United States, is a higher standard than preclinical assays. Such higher standards of drug activity, the success of which is generally not reasonably predictable from preclinical results, can be established by suitable and successful randomized double-blind controlled clinical trials in humans.

[0051] The terms "treating", "treat," or "treatment" of a disease or disorder, in the context of achieving a therapeutic benefit, refer to the administration of one or more pharmaceutical agents, particularly compounds of Formula (I) as described herein and / or pharma- ceutically acceptable salts thereof, to a subject having the disease or disorder, having a symptom of the disease or disorder, or having a predisposition to the disease or disorder, with the intent to cure, ameliorate, alleviate, relieve, alter, remedy, modify, ameliorate, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition to the disease or disorder. In some embodiments, the disease or disorder is cancer.

[0052] The terms "treating," "contacting," and "reacting," in reference to a chemical reaction, refer to the addition or mixing of two or more reagents under conditions appropriate to produce the indicated and / or desired product. It will be appreciated that the reaction that produces the indicated and / or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., it may be one or more intermediates produced in the mixture that ultimately results in the formation of the indicated and / or desired product.

[0053] The term "effective amount" as used herein refers to an amount or dosage of an IDH mutation inhibitor sufficient to generally provide therapeutic benefit to patients who need treatment for a disease or disorder caused by an IDH mutation. The effective amount or dosage of the active ingredient of the present disclosure can be determined by methods such as modeling, dose escalation studies or clinical trials, and by considering factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to the drug, and the judgment of the attending physician. In the United States, the determination of effective dosage is generally difficult to predict from preclinical studies. In practice, dosage is not completely predictable, and dosage will evolve into new and unpredictable dosing schedules after initial use in randomized double-blind controlled clinical trials.

[0054] Exemplary doses are from about 0.0001 to about 200 mg of active agent per kg of subject body weight per day, e.g., from about 0.001 to 100 mg / kg / day, or from about 0.01 to 35 mg / kg / day, or from about 0.1 to 10 mg / kg, administered once daily or in divided dose units (e.g., BID, TID, QID). For a 70 kg human, exemplary ranges of suitable doses are from about 0.05 to about 7 g / day, or from about 0.2 to about 5 g / day. Once improvement of the patient's disease or disorder has occurred, the dose can be adjusted to maintain treatment. For example, the dose or frequency of administration, or both, can be reduced to a level at which the desired therapeutic effect is maintained as a function of the symptoms. Of course, once the symptoms have been alleviated to an appropriate level, treatment may be stopped. However, the patient may require intermittent treatment for an extended period of time upon recurrence of symptoms.

[0055] The term "subject" as used herein means mammals and non-mammals. Mammals means any member of the class Mammalia, including, but not limited to, humans; non-human primates and monkey species, such as chimpanzees and other apes; farm animals, such as cows, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex. In some embodiments, the subject is a human.

[0056] In general, the term "about" is used herein to modify numerical values ​​above and below a variance of 20% of the values ​​set forth herein.

[0057] Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by POSITA to which this disclosure pertains.

[0058] Compounds of formula (I): [ka] and / or pharma- ceutically acceptable salts thereof, and / or solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein A is, [ka] where R7 is selected from H, halo, -CN, -OH, or -NH2; R8 is selected from halo, -CN, -OH, or -NH2; q is 1 or 2; R1 is H, -OH, halo, C 1-6 Alkyl, C 1-6 Alkoxyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, oxo, or C 3-8 cycloalkyl; Each R2 is independently H, deuterium, halo, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, oxo, -OR5, -OCOR5, -NHR5, -N(R5)(C 1-4 alkyl), -COR5, -NHCOR5, or 3- to 8-membered heterocyclyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Each of cycloalkyl and 3- to 8-membered heterocyclyl is selected from the group consisting of deuterium, halo, -CN, -OH, -SH, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, or C 1-6 or two R2 attached to the same carbon atom together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl which may be substituted with one or more groups selected from halo or deuterium; R3, R3', R4 and R4' are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -C(O)R5, -OR5, or -NHR5, wherein 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Each of cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with one or more R6; wherein R3, R3', R4, and R4' are not simultaneously H; provided that when one of R3 and R4 is an optionally substituted phenyl or an optionally substituted 5- to 6-membered heteroaryl, the other is -OR5 or -NHR5; or R3 and R3' are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -C(O)R5, -OR5, or -NHR5, wherein 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Each of cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be optionally substituted with one or more R6; R4 and R4' together with the N atom to which they are attached form a 3- to 8-membered heterocyclic ring which may be optionally substituted with one or more R6; R5 is C 1-6 Alkyl or C 3-8 cycloalkyl, each of which is selected from halo, -CN, -OH, -SH, -NH2, or C 1-6 may be substituted with one or more groups independently selected from alkoxyl; Each R6 is independently selected from deuterium, halo, -CN, -OH, -SH, -NH2, C1-6 Alkoxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, 1-6 Alkoxyl, C 1-6 Alkyl, C 3-8 Each of cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl is selected from the group consisting of halo, -CN, -OH, -SH, -NH2, C 1-6 Alkoxyl, C 1-6 Alkynyl, or C 1-6 may be substituted with one or more groups independently selected from alkyl; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2.

[0059] In some embodiments of the compounds of Formula (I), R 1 is selected from H, —OH, or halo.

[0060] In some embodiments of the compounds of Formula (I), R 1 is selected from —OH or halo.

[0061] In some embodiments of the compound of Formula (I), R 1 is —OH.

[0062] In some embodiments of the compounds of Formula (I), R 1 is halo selected from F, Cl, or Br. In some embodiments of the compounds of Formula (I), R 1 is F.

[0063] In some embodiments of compounds of Formula (I), two R2 bonded to the same carbon atom together with the carbon atom to which they are bonded form a 3- to 5-membered cycloalkyl optionally substituted with one or more F.

[0064] In some embodiments of the compounds of Formula (I), two R2 attached to the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl.

[0065] In some embodiments of the compound of Formula (I), each R is independently H, deuterium, halo, -OH, -NH, -CN, -SH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, oxo, -OR5, -OCOR5, -NHR5, -N(R5)(C 1-4 alkyl), -NHCOR5, or 3- to 8-membered heterocyclyl.

[0066] In some embodiments of the compound of Formula (I), each R is independently H, deuterium, halo, -OH, -NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, -OR5, -NHR5, or -N(R5)(C 1-4 alkyl).

[0067] In some embodiments of the compound of Formula (I), each R2 is independently H, deuterium, halo, C 1-6 Alkyl, or C 1-6 haloalkyl.

[0068] In some embodiments of the compounds of Formula (I), each R2 is independently selected from halo, such as F, Cl, or Br.

[0069] In some embodiments of the compounds of Formula (I), R 2 is F.

[0070] In some embodiments of the compounds of Formula (I), m is 0, 1, 2, 3, or 4.

[0071] In some embodiments of the compounds of Formula (I), m is 0, 1, or 2.

[0072] 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.

[0073] In some embodiments of the compound of Formula (I), R and R are independently C 1-6 Alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -C(O)R5, -OR5, or -NHR5, wherein 1-6 Alkyl, C 3-12 Each of the cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with one or more R; R and R are independently H or C. 1-6 is selected from alkyl.

[0074] In some embodiments of the compound of Formula (I), R3' and R4' are both H.

[0075] In some embodiments of the compound of Formula (I), R and R are independently C 1-6 Alkyl, C 3-12 cycloalkyl, or 3- to 12-membered heterocyclyl, each of which is optionally substituted with one or more R6; R3' and R4' are both H.

[0076] In some embodiments of the compound of Formula (I), R and R are independently selected from C substituted with one or more halo. 1-6 Alkyl, C 1-6 R3' and R4' are both H.

[0077] In some embodiments of the compound of Formula (I), R and R are independently C optionally substituted with one or more halo. 1-6alkyl; R3' and R4' are both H.

[0078] In some embodiments of the compound of Formula (I), R3 is C 1-6 R4 is a 5-12 membered heteroaryl substituted with haloalkyl; 1-6 R3' and R4' are both H.

[0079] In some embodiments of the compound of Formula (I), R3 is a 5-7 heteroaryl substituted with CF3, R4 is C 1-6 R3' and R4' are both H.

[0080] In some embodiments of the compounds of Formula (I), R3 is H, C 1-6 C optionally substituted with haloalkyl 1-6 Alkyl, or C 1-6 R3' is H; R4 and R4', together with the N atom to which they are attached, are selected from halo, -OH, or C. 1-6 It forms a 3- to 8-membered heterocyclic ring which may be substituted with one or more groups selected from haloalkyl.

[0081] In some embodiments of the compound of Formula (I), R5 is C 1-6 Alkyl or C 3-8 It is cycloalkyl.

[0082] In some embodiments of the compound of Formula (I), R5 is a C optionally substituted with one or more halo. 1-6 It is an alkyl.

[0083] In some embodiments of the compound of Formula (I), each R6 is independently deuterium, halo, -CN, -OH, -NH2, C 1-6 Alkoxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, 1-6 Alkoxyl, C 1-6 Alkyl, C 3-8 Each of the cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may be optionally substituted with one or more halo.

[0084] In some embodiments of the compound of Formula (I), each R6 is independently deuterium, halo, -OH, C 1-6 Alkoxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 It is selected from cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl.

[0085] In some embodiments of the compound of Formula (I), each R6 is independently deuterium, halo, -CN, -OH, -NH2, C 1-6 Alkoxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 3-8 cycloalkyl.

[0086] In some embodiments of the compound of Formula (I), each R6 is independently deuterium, halo, or C. 1-6 haloalkyl.

[0087] In some embodiments of the compounds of Formula (I), n is 1.

[0088] In some embodiments of the compounds of Formula (I), R7 and R8 are independently selected from halo or -CN.

[0089] In some embodiments of the compound of Formula (I), R7 and R8 are independently selected from F or -CN.

[0090] In some embodiments of the compound of Formula (I), the compound of Formula (I) is [ka] wherein X is halo; R1, R2, R3, R3', R4, R4', m and n are as defined for compounds of formula (I).

[0091] In some embodiments of the compound of formula (I), formula (I) is formula (I-1), wherein R1, R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I). [ka]

[0092] In some embodiments of the compound of formula (I), formula (I) is formula (I-1a), wherein R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I). [ka]

[0093] In some embodiments of the compound of formula (I), formula (I) is formula (I-1b), wherein R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I). [ka]

[0094] In some embodiments of the compound of formula (I), formula (I) is formula (II), wherein R1, R2, R3, R3', R4, R4', n and A are as defined for the compound of formula (I); X is halo; p is 0, 1, or 2; and m is 0, 1, or 2. [ka]

[0095] In some embodiments of the compound of Formula (II), X is F.

[0096] In some embodiments of the compound of Formula (II), R 1 is F.

[0097] In some embodiments of the compound of Formula (II), R 1 is —OH.

[0098] In some embodiments of the compound of Formula (II), p is 0.

[0099] In some embodiments of the compound of Formula (II), p is 1.

[0100] In some embodiments of the compound of Formula (II), p is 2.

[0101] In some embodiments of the compound of Formula (I), Formula (II) is [ka] wherein R1, R2, R3, R3', R4, R4', m and n are as defined for compounds of formula (I); X is halo; p is 0, 1, or 2; and m is 0, 1, or 2.

[0102] In some embodiments of the compound of formula (I), formula (II) is formula (II-1), wherein R1, R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I); X is halo; p is 0, 1, or 2; and m is 0, 1, or 2. [ka]

[0103] In some embodiments of the compound of formula (I), formula (II) is formula (II-1a), wherein R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I); X is halo; p is 0, 1, or 2; and m is 0, 1, or 2. [ka]

[0104] In some embodiments of the compound of formula (I), formula (II) is formula (II-1b), wherein R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I); X is halo; p is 0, 1, or 2; and m is 0, 1, or 2. [ka]

[0105] In some embodiments of the compounds of Formula (II-1) through Formula (II-5), X is F.

[0106] In some embodiments of the compounds of Formulae (II-1) through (II-5), R 1 is F.

[0107] In some embodiments of the compounds of Formula (II-1) through Formula (II-5), R 1 is —OH.

[0108] In some embodiments of the compounds of Formula (II-1) through Formula (II-5), p is 0.

[0109] In some embodiments of the compounds of Formula (II-1) through Formula (II-5), p is 1.

[0110] In some embodiments of the compounds of Formula (II-1) through Formula (II-5), p is 2.

[0111] In some embodiments of the compound of formula (I), formula (I) is formula (III), wherein R1, R2, R3, R3', R4, R4', n and A are as defined for the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; and v is 0, 1, or 2. [ka]

[0112] In some embodiments of the compound of Formula (III), X is F.

[0113] In some embodiments of the compound of Formula (III), R 1 is F.

[0114] In some embodiments of the compound of Formula (III), R 1 is —OH.

[0115] In some embodiments of the compound of Formula (III), p is 0.

[0116] In some embodiments of the compound of Formula (III), p is 1.

[0117] In some embodiments of the compound of Formula (III), p is 2.

[0118] In some embodiments of the compound of Formula (III), v is 0.

[0119] In some embodiments of the compound of Formula (III), v is 1.

[0120] In some embodiments of the compound of Formula (III), v is 2.

[0121] In some embodiments of the compound of Formula (I), Formula (III) is [ka] wherein R1, R2, R3, R3', R4, R4', m and n are as defined for compounds of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; and v is 0, 1, or 2.

[0122] In some embodiments of the compound of formula (I), formula (III) is formula (III-1), wherein R1, R2, R3, R3', R4, R4', m and n are as defined for the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; and v is 0, 1, or 2. [ka]

[0123] In some embodiments of the compounds of Formulae (III-1) through (III-5), X is F.

[0124] In some embodiments of the compounds of Formulae (III-1) through (III-5), R 1 is F.

[0125] In some embodiments of the compounds of Formulae (III-1) through (III-5), R 1 is —OH.

[0126] In some embodiments of the compounds of Formulae (III-1) through (III-5), p is 0.

[0127] In some embodiments of the compounds of Formulae (III-1) through (III-5), p is 1.

[0128] In some embodiments of the compounds of Formulae (III-1) through (III-5), p is 2.

[0129] In some embodiments of the compounds of Formulae (III-1) through (III-5), v is 0.

[0130] In some embodiments of the compounds of Formulae (III-1) through (III-5), v is 1.

[0131] In some embodiments of the compounds of Formulae (III-1) through (III-5), v is 2.

[0132] Also provided is a compound selected from compounds 1-87, 89-184, 186-301 as numbered in the Experimental Section, and / or a pharma- ceutically acceptable salt thereof.

[0133] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and / or a pharma- ceutically acceptable salt thereof, and optionally including at least one pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable carrier).

[0134] In another aspect, there is provided a method of treating a disease induced by an IDH mutation in a subject, comprising administering to a subject in need thereof a compound of Formula (I) (e.g., any of the compounds described herein) and / or a pharma- ceutically acceptable salt thereof in an amount effective to inhibit an increase in alpha-hydroxyglutarate (2HG) induced by an IDH mutation in said subject.

[0135] In another aspect, there is provided a method of treating a disease induced by an IDH mutation in a subject, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I) (e.g., any of the compounds described herein) and / or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable carrier) in an amount effective to inhibit an increase in alpha-hydroxyglutarate (2HG) induced by an IDH mutation in said subject.

[0136] In another aspect, there is provided a use of a compound of formula (I) as described herein (e.g., any of the compounds described herein) and / or a pharma- ceutically acceptable salt thereof for treating a disease induced by an IDH mutation in a subject by inhibiting an increase in α-hydroxyglutarate (2HG) induced by an IDH mutation.

[0137] In another aspect, there is provided the use of a compound of formula (I) as described herein (e.g., any of the compounds described herein) and / or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease caused by an IDH mutation.

[0138] In some embodiments, the IDH mutation is a mutation in the IDH1 gene.

[0139] In some embodiments, the IDH mutation is a mutation in the IDH2 gene.

[0140] In some embodiments, the IDH mutation is a mutation in the IDH1-R132H or IDH2-R140Q gene.

[0141] In some embodiments, the disease caused by an IDH mutation is cancer.

[0142] In some embodiments, the cancer is selected from a solid tumor, a glioma, or a hematological malignancy, such as leukemia, lymphoma, or myeloma.

[0143] In some embodiments, the cancer is selected from acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), cholangiocarcinoma, e.g., intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lung cancer, or non-Hodgkin's lymphoma (NHL).

[0144] In another aspect, there is provided a compound of formula (IV) and / or a salt thereof, and / or a racemic mixture or enantiomer thereof, which may be used in the manufacture of a compound of formula (I) (e.g., any of the compounds described herein), [ka] where R1, R2, m and n are as defined for compounds of formula (I); R aare halo, -OS(O)2CF3, -B(OH)2, -B(OC 1-6 alkyl)2, [ka] Selected from; R b is H or C 1-6 It is an alkyl.

[0145] In some embodiments of the compound of Formula (IV), R a -B(OH)2, -B(OC 1-6 alkyl)2, [ka] Selected from; R b is H or C 1-6 It is an alkyl.

[0146] In some embodiments of the compound of Formula (IV), R a are -B(OH)2, -B(OCH3)2, -B[OCH(CH3)2]2, [ka] is selected from.

[0147] In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-1): [ka]

[0148] In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-2), wherein X is halo; [ka]

[0149] In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-3), wherein X is halo; p is 0, 1, or 2; and m is 0, 1, or 2. [ka]

[0150] In some embodiments of the compound of Formula (IV), R 1 is —OH or oxo.

[0151] In some embodiments of the compound of Formula (IV), X is F.

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

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

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

[0155] In some embodiments of the compound of Formula (IV), the compound of Formula (IV) is selected from the following: [ka]

[0156] In some embodiments of the compound of Formula (IV), the compound of Formula (IV) is selected from the following: [ka]

[0157] General Synthetic Methods for Disclosed Embodiments The compounds of formula (I) described herein and / or their pharma- ceutically acceptable salts can be synthesized from commercially available starting materials by methods well known in the art in conjunction with the disclosure of this patent application. Figures 1-6 show general methods for the preparation of the compounds described herein.

[0158] As shown in Figure 1, the substitution reaction of 2,4,6-trichloro-1,3,5-triazine with an amine substituted with R3 and R3' gives a compound of formula 1-1. The substitution reaction of the compound of formula 1-1 with an amine substituted with R4 and R4' gives a compound of formula 1-2. The Suzuki coupling reaction of the compound of formula 1-2 with an intermediate of formula (IV) under the catalysis of a suitable palladium reagent gives a compound of formula (I-1) as described herein, where R1, R2, R3, R3', R4, R4', Ra, m, and n are as defined herein. The Pd catalyzed C-C coupling reaction can be carried out under suitable conditions, the solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF, a mixture of 1,4-dioxane and water, 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.

[0159] Suzuki coupling reaction of a compound of formula 1-1 with an intermediate of formula (IV) under the catalysis of a suitable palladium reagent provides a compound of formula 2-1, as shown in Scheme 2. Substitution reaction of a compound of formula 2-1 with an amine substituted with R4 and R4' provides a compound of formula (I-1) as described herein, where R1, R2, R3, R3', R4, R4', Ra, m, and n are as defined herein.

[0160] Suzuki coupling reaction of compound of formula 1-2 with intermediate of formula (IV-1) under the catalysis of suitable palladium reagent gives compound of formula 3-1, as shown in Scheme 3. Pd-catalyzed CC coupling reaction can be carried out under suitable conditions, the solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF, mixture of 1,4-dioxane and water, 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. Reduction of compound of formula 3-1 gives compound of formula (I-1a) as described herein.

[0161] As shown in Scheme 4, Suzuki coupling reaction of a compound of formula 1-1 with an intermediate of formula (IV-1) under the catalysis of a suitable palladium reagent gives a compound of formula 4-1. Reduction of a compound of formula 4-1 gives a compound of formula 4-2. Substitution reaction of a compound of formula 4-2 with an amine substituted with R4 and R4' gives a compound of formula (I-1a) as described herein.

[0162] Suzuki coupling reaction of a compound of formula 1-2 with an intermediate of formula (IV-2) under the catalysis of a suitable palladium reagent, as shown in Scheme 5, gives a compound of formula 5-1. Halogenation of a compound of formula 5-1 with a halogenating reagent such as NFSI in the presence of a base such as LiHMDS, KHMDS, LDA in a suitable polar solvent such as THF, DCM, gives a compound of formula 5-2. Reduction of a compound of formula 5-2 gives a compound of formula (II-1a) as described herein.

[0163] As shown in Scheme 6, reaction of a compound of formula 3-1 with a deuteration reagent, such as NaBD4, deuterated borane, etc., provides a compound of formula (I-1b) as described herein.

[0164] The substituents of the compounds thus obtained can be further modified to obtain other desired compounds.Synthetic chemical transformations are described, for example, in 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 its successors.

[0165] Prior to use, the compounds of formula (I) described herein and / or their pharma- ceutically acceptable salts may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

[0166] Pharmaceutical Compositions and Practical Usefulness A compound of formula (I) described herein (e.g., any of those described herein) and / or a pharma- ceutically acceptable salt thereof is used alone or in combination with one or more additional active ingredients to formulate a pharmaceutical composition. The pharmaceutical composition comprises (a) an effective amount of a compound of formula (I) described herein and / or a pharma- ceutically acceptable salt thereof, and (b) a pharma- ceutically acceptable excipient (e.g., a pharma- ceutically acceptable carrier).

[0167] A pharma- ceutically acceptable carrier refers to a carrier that is compatible with the active ingredients of the composition (and in some embodiments, can stabilize these active ingredients) and is not harmful to the subject being treated. For example, solubilizers such as cyclodextrins (which form specific, more soluble complexes with the compounds of formula (I) and / or their pharma-ceutically acceptable salts described herein) can be used as pharmaceutical excipients to deliver the active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and dyes such as D&C Yellow #10. Suitable pharma-ceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0168] Pharmaceutical compositions comprising a compound of formula (I) described herein (e.g., any of those described herein) and / or a pharma- ceutically acceptable salt thereof can be administered in a variety of known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0169] The pharmaceutical compositions described herein can be prepared in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. In some embodiments, the pharmaceutical compositions comprising the compound of formula (I) and / or its pharma- ceutically acceptable salts are formulated for intravenous infusion, topical administration, or oral administration.

[0170] Oral compositions can be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Conventional carriers for tablets include lactose and cornstarch. Tablets generally contain lubricants such as magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For oral administration in aqueous suspension or emulsion, active ingredient can be suspended or dissolved in oil phase combined with emulsifier or suspending agent. If desired, certain sweeteners, flavors or colorants can be added.

[0171] In some embodiments, the compound of formula (I) and / or its pharma- ceutically acceptable salt may be present in a tablet in an amount of 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 compound of formula (I) and / or its pharma- ceutically acceptable salt may be present in a capsule in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0172] Sterile injectable compositions (e.g., aqueous or oily suspensions) can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable intermediates can also be injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Pharmaceutically acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile hardened oils are conventionally used as solvents or suspending media (e.g., synthetic mono- or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives are also useful as intermediates for injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

[0173] Inhalation compositions can be prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0174] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (greater than C12). In some embodiments, the pharma- ceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants, as well as agents that impart color or fragrance, may also be included as desired. In addition, transdermal penetration enhancers may be used in these topical formulations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0175] Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, into which is mixed the active ingredient dissolved in a small amount of oil, such as almond oil. An example of such a cream contains, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. An example of such an ointment contains about 30% by weight almond oil and about 70% by weight white soft paraffin.

[0176] Suitable in vitro assays can be used to evaluate the practical utility of the compound of formula (I) described herein and / or its pharmaceutically acceptable salt in inhibiting IDH mutation. The compound of formula (I) described herein and / or its pharmaceutically acceptable salt can be further examined for further practical utility in cancer treatment by in vivo assay. For example, the compound of formula (I) described herein and / or its pharmaceutically acceptable salt can be administered to animals (e.g., mouse models) with cancer, and its therapeutic effect can be evaluated. If preclinical results show success, the administration range and route for animals, such as humans, can be predicted.

[0177] The compounds of formula (I) and / or pharma- ceutically acceptable salts thereof described herein may be shown to have sufficient preclinical practical utility to merit clinical trials that seek to demonstrate beneficial therapeutic or prophylactic effects, for example, in subjects with cancer.

[0178] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies. The term "cancer" encompasses diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term "cancer" further encompasses primary and metastatic cancers.

[0179] 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, advanced epithelial 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.

[0180] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including aggressive CML and blastic phase CML (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; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and accelerated RAEB (RAEB-T); and myeloproliferative syndromes.

[0181] In some embodiments, exemplary hematological malignancies include leukemias such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); multiple myeloma (MM); and lymphomas such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0182] The compounds of formula (I) and / or pharma- ceutically acceptable salts described herein can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in a subject with cancer.

[0183] In addition, the compounds of formula (I) described herein (e.g., any of those described herein) and / or pharma- ceutically acceptable salts thereof may be used in combination with additional active ingredients in the treatment of cancer. The additional active ingredients may be co-administered separately from the compounds of formula (I) described herein and / or pharma- ceutically acceptable salts thereof, or may be included with such ingredients in a pharmaceutical composition according to the present disclosure, such as a fixed-dose combination product. In an exemplary embodiment, the additional active ingredient is a compound known or found to be effective in treating diseases caused by IDH mutations, such as another mutant IDH inhibitor, or an effective compound against another target related to a particular disease. This combination may serve to increase efficacy (e.g., by including in combination a compound that enhances the potency or efficacy of the compounds of formula (I) described herein and / or pharma- ceutically acceptable salts thereof), reduce one or more side effects, or reduce the required dose of the compounds of formula (I) described herein and / or pharma- ceutically acceptable salts thereof.

[0184] In some embodiments, the compound of formula (I) described herein (e.g., any of those described herein) and / or its pharmaceutically acceptable salt is administered in combination with antineoplastic agent.As used herein, the term "antineoplastic agent" refers to any agent that is administered to a subject with cancer for the purpose of treating cancer.Non-limiting examples of antineoplastic agents include radiation therapy; immunotherapy; DNA-damaging chemotherapy agents; and chemotherapy agents that interrupt cell replication.

[0185] Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, , methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalator-free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, azacitidine (VIDAZA®); mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

[0186] Chemotherapeutic agents that disrupt cell replication include paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (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 inhibitors of IκB kinase; antibodies that bind to proteins overexpressed in cancer, thereby downregulating cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be downregulated, overexpressed or activated in cancer, and whose inhibition downregulates cell replication. EXAMPLES

[0187] The following examples are intended to be illustrative and should not be considered as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation must be accounted for. Unless otherwise noted, parts are parts by weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. All MS data were determined on an Agilent 6120 or Agilent 1100. All NMR data were obtained using a Varian 400-MR machine. All reagents used herein, except intermediates, are commercially available. All compound names, except reagents, were obtained by Chemdraw 12.0.

[0188] Where an atom with an open valence is present in any of the structures disclosed herein, the balance is a hydrogen atom which has been omitted for convenience.

[0189] In this application, in the event of a discrepancy between a structure and a name of a compound, where both are given for that compound, the structure of the compound shall prevail unless the context indicates that the structure of the compound is inappropriate and the name is appropriate.

[0190] In the examples below, the following abbreviations are used:

[0191] [Table 1] TIFF0007603740000027.tif104150

[0192] Example 1 Preparation of intermediates Intermediate I-1 3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-ol and Intermediate I-61 ( * ) 3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol [ka]

[0193] (A) 2-Fluoro-3-hydroxycyclohex-2-en-1-one (A1) A mixture of cyclohexane-1,3-dione (30 g, 268 mmol) and Selectfluor™ (94.8 g, 268 mmol) in MeCN (1.2 L) was stirred at 70° C. under nitrogen atmosphere for 96 h. The mixture was then concentrated in vacuo. The residue was dissolved in DCM (1.2 L) and filtered. The filtrate was concentrated in vacuo and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound A1 as a white solid (7.7 g, yield: 22%). MS(m / z): 131.1 [M+H] +

[0194] (B) 2-fluoro-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate (A2) Compound A1 (208 mg, 1.6 mmol) was dissolved in DCM under nitrogen atmosphere and cooled to 0° C. Then, DIEA (415 mg, 3.2 mmol) and Tf2O (540 mg, 1.92 mmol) were added at 0° C., and the mixture was stirred at 0° C. under nitrogen atmosphere for 2 h. After the reaction was completed, it was quenched by adding water and extracted with DCM. The organic layer was collected, concentrated, and purified by flash column chromatography (eluted with PE / EA) to give compound A2 as a yellow oil (220 mg, yield: 52.5%). MS (m / z): 263.0 [M+H] +

[0195] (C) (R)-4,6-dichloro-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine (A3) A solution of 2,4,6-trichloro-1,3,5-triazine (9.1 g, 49.3 mmol) in dry THF was cooled to 0° C., and (R)-1,1,1-trifluoropropan-2-amine hydrochloride (7.37 g, 49.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was adjusted to pH=7 by adding saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was collected, concentrated, and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound A3 as a colorless oil (7.8 g, yield: 60.6%). MS(m / z): 260.9[M+H] +

[0196] (D) (R)-3-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one (A4) A mixture of compound A2 (4.0 g, 15.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.3 g, 16.8 mmol), AcOK (3.8 g, 38.3 mmol), Pd(dppf)Cl2 (0.63 g, 0.77 mmol) in 1,4-dioxane (40 mL) was stirred under reflux for 2 h under nitrogen atmosphere. The reaction mixture was then cooled to room temperature, and compound A3 (4.0 g, 15.3 mmol), Cs2CO3 (14.4 g, 38.3 mmol), Pd(PPh3)4 (0.89 g, 0.77 mmol) and water (8 mL) were added in that order. The reaction was stirred at 80 °C for another 2 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound A4 as a white solid (0.8 g, yield: 15.4%). MS(m / z): 339.0[M+H] +

[0197] (E) 3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol (I-1) A flask was charged with compound A4 (1150 mg, 3.41 mmol), CeCl3·7H2O (1269 mg, 3.41 mmol) and EtOH (20 mL). The mixture was cooled to 0 °C, NaBH4 (130 mg, 3.41 mmol) was added and the mixture was stirred at 0 °C for 2 h. After the reaction was completed, the mixture was quenched by the addition of saturated aqueous NH4Cl (10 mL) and water (50 mL) and extracted with EtOAc. The organic layer was collected, concentrated and purified by flash column chromatography (eluted with gradient PE / EA = 100:0-0:100) to give I-1 as a white solid (800 mg, yield: 68.9%). MS (m / z): 341.2 [M+H] +

[0198] (F)( * ) 3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol (I-61) Under nitrogen atmosphere, 1 mol / L (S)-CBS / THF solution (2.4 mL, 2.4 mmol) was added to dry THF (5 mL) under ice bath cooling ℃, and then 2 mol / L BH3·Me2S / THF solution (2.4 mL, 4.8 mmol) was added in one portion. After stirring for 2 min, compound A4 (800 mg, 2.4 mmol) in THF (3 mL) was added dropwise to the above solution. After stirring for 1 h under ice bath cooling ℃, MeOH (0.5 mL), EtOAc (10 mL) and water (20 mL) were added to the reaction mixture. The organic layer was collected. The aqueous phase was extracted with EtOAc (10 mL). The organic layers were combined, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by flash column chromatography (eluted with a gradient PE / EA=100:0-0:100) to give intermediate I-61 as a white solid (360 mg). MS(m / z): 341.2 [M+H] +

[0199] The compounds in the table below were prepared following the procedure for intermediate I-1 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0200] [Table 2]

[0201] Intermediate I-2 (R)-6-Chloro-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] Compound A3 (3.5 g, 13.4 mmol), propan-2-amine (872 mg, 14.7 mmol), DIEA (3.5 g, 26.8 mmol) and THF (20 mL) were added in sequence to a sealed tube, and the mixture was stirred at 50° C. overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give intermediate I-2 as a white solid (3.8 g, yield: 100%). MS (m / z): 284.0 [M+H] +

[0202] The compounds in the table below were prepared following the procedure for intermediate I-2 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0203] [Table 3] TIFF0007603740000032.tif216150 TIFF0007603740000033.tif45150

[0204] Intermediate I-3 6-Chloro-N 2 ,N 4 -Bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] At 0° C., a flask was charged with 1,4-dioxane (50 mL), 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.99 g, 20 mmol) and DIEA (5.17 g, 40 mmol). The reaction was heated to 60° C. and stirred for 4 h. After the reaction was complete, the mixture was concentrated and purified by flash column chromatography (eluted with gradient water / MeOH=100:0-0:100) to give intermediate I-3 as a yellow solid (2.50 g, yield: 74%). MS(m / z): 338.0 [M+H] +

[0205] The compounds in the table below were prepared following the procedure for intermediate I-3 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0206] [Table 4]

[0207] Intermediate I-4 (R)-N-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)isobutyramide [ka] A mixture of 4,6-dichloro-1,3,5-triazin-2-amine (1 g, 6.06 mmol) in isobutyryl chloride (5 mL) was stirred at 100° C. for 2 h. After the reaction was complete, the mixture was cooled to room temperature and concentrated to dryness in vacuum to obtain N-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide as a yellow solid. Then, in 1,4-dioxane (10 mL), N-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide obtained above, (R)-1,1,1-trifluoropropan-2-amine hydrochloride (900 mg, 6.06 mmol) and DIEA (2.34 g, 18.18 mmol) were added. The mixture was heated to reflux and stirred for 2 h. After the reaction was complete, the mixture was quenched by the addition of water and extracted with EtOAc (20 mL). The organic layer was collected, concentrated under reduced pressure, and purified by flash column chromatography (eluted with PE / EA) to give intermediate I-4 (80 mg). MS(m / z): 312.1 [M+H] +

[0208] Intermediates I-26 and I-27 Optically pure diastereoisomer, 3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka] Intermediates I-26 and I-27 were obtained by the resolution of intermediate I-25 using chiral HPLC (chiral HMPL 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 from the first eluent (RT = 1.703 min) was designated as I-26. de% = 100%, MS (m / z): 400.1 [M+H] + The isomer obtained from the second elution (RT=2.067 min) was designated I-27, de%=99.4%, MS(m / z): 400.1 [M+H] + ).

[0209] Intermediate I-41 6-Chloro-N 2 -(propan-2-yl-d7)-N 4 -(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine [ka]

[0210] (A) 4,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (A5) To a solution of 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol) and 2-(trifluoromethyl)pyridin-4-amine (1.62 g, 10 mmol) in dry THF (20 mL) at 0° C., NaHCO3 (1.68 g, 20 mmol) was added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound A5 as a white solid (2.68 g, yield: 86%). MS(m / z): 309.9 [M+H] +

[0211] (B) 6-Chloro-N 2 -(propan-2-yl-d7)-N 4 -(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine Compound A5 (465 mg, 1.5 mmol), propane-d7-2-amine hydrochloride (154 mg, 1.5 mmol), DIEA (388 mg, 3.0 mmol) and 1,4-dioxane (20 mL) were added in sequence to a sealed test tube. The mixture was heated to 60° C. and stirred for 5 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give intermediate I-41 as a white solid (485 mg, yield: 95%). MS(m / z): 340.0 [M+H] +

[0212] The compounds in the table below were prepared following the procedure for intermediate I-41 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0213] [Table 5]

[0214] Intermediate I-46 2-((4-(Tert-butoxyamino)-6-chloro-1,3,5-triazin-2-yl)amino)isonicotinonitrile [ka]

[0215] (A) O-(Tert-butyl)-N-(4,6-dichloro-1,3,5-triazin-2-yl)hydroxylamine (A6) To a solution of 2,4,6-trichloro-1,3,5-triazine (0.92 g, 5 mmol) and O-(tert-butyl)hydroxylamine hydrochloride (0.63 g, 5 mmol) in dry THF (50 mL) at 0° C., NaHCO3 (1.26 g, 15 mmol) was added. The mixture was stirred at 0° C. for 2 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound A6 as a colorless oil (0.83 g, yield: 80%). MS(m / z): 237.0 [M+H] +

[0216] (B) 2-((4-(Tert-butoxyamino)-6-chloro-1,3,5-triazin-2-yl)amino)isonicotinonitrile In a sealed tube, compound A6 (0.83 g, 4.0 mmol), 2-aminoisonicotinonitrile (0.48 g, 4.0 mmol), Pd(dppf)Cl2 (0.15 g, 0.2 mmol), t-BuONa (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 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give intermediate I-46 as a yellow solid (109 mg, yield: 8%). MS(m / z): 320.0 [M+H] +

[0217] The compounds in the table below were prepared following the procedure for intermediate I-46 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0218] [Table 6]

[0219] Intermediate I-88 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one [ka] Compound A2 (80 g, 305 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (80 g, 315 mmol), AcOK (74.8 g, 763 mmol), Pd(dppf)Cl2·CH2Cl2 (12.4 g, 15.3 mmol) and 1,4-dioxane (1.4 L) were added in sequence to a flask under nitrogen atmosphere. The mixture was stirred at 90 °C for 4 h, then cooled to room temperature and filtered. The filtrate was concentrated and purified by flash column chromatography (eluted with PE / EA=4 / 1) to give intermediate I-88 as a yellow solid (76 g, 100% yield). MS (m / z): 159.0 [M+H] + 1H NMR (400 MHz, DMSO-d6): δ 2.47- 2.36 (m, 4H), 1.91-1.82 (m, 2H), 1.22 (s, 12H).

[0220] Example 2 Synthesis of compounds 1-87, 89-184, and 186-301 compound 1 2-Fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka]

[0221] (A) (R)-2-Fluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B1) Compound A2 (220 mg, 0.84 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (234 mg, 0.92 mmol), AcOK (206 mg, 2.10 mmol), Pd(dppf)Cl2·CH2Cl2 (32 mg, 0.04 mmol) and 1,4-dioxane (20 mL) were added to a flask under a nitrogen atmosphere and stirred under reflux for 16 hours. Then, the mixture was cooled to room temperature and Intermediate I-2 (238 mg, 0.84 mmol), Cs2CO3 (682 mg, 2.1 mmol), Pd(PPh3)4 (46.2 mg, 0.04 mmol) and water (4 mL) were added in sequence and stirred at 80° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound B1 as a white solid (160 mg, yield: 52.8%). MS(m / z): 362.1 [M+H] +

[0222] (B) 2-Fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol A flask was charged with compound B1 (80 mg, 0.22 mmol), CeCl3·7H2O (107 mg, 0.29 mmol) and EtOH (5 mL). The mixture was cooled to 0 °C. Then NaBH4 (11 mg, 0.29 mmol) was added and the mixture was stirred at 0 °C for 2 h. After the reaction was completed, the mixture was quenched by the addition of saturated aqueous NH4Cl (2 mL) and water (20 mL) and extracted with EtOAc. The organic layer was collected, concentrated and purified by flash column chromatography (eluted with gradient PE / EA = 100:0-0:100) to give compound 1 as a white solid (61 mg, yield: 76.3%). MS (m / z): 364.1 [M+H] + 1 H NMR(400 MHz,CD3OD): δ 4.99-4.87(m,1H),4.33-4.23(m,1H),4.19-4.07(m,1H),2.61-2.47(m,1H),2.40-2.2 4(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).

[0223] The compounds in the table below were prepared following the procedure for Compound 1 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0224] [Table 7] TIFF0007603740000045.tif221150 TIFF0007603740000046.tif204150 TIFF0007603740000047.tif212150 TIFF0007603740000048.tif79150

[0225] compound 35 6-(2,3-difluorocyclohex-1-en-1-yl)-N 2 -Isopropyl-N 4 -((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka]

[0226] At 0° C., compound 1 (20 mg, 0.06 mmol) was dissolved in DCM (3 mL) and DAST (17 mg, 0.12 mmol) was added. The mixture was stirred at 0° C. for 2.5 h. After the reaction was completed, the mixture was quenched by the addition of saturated aqueous NH4Cl (5 mL) and water (5 mL) and extracted with EtOAc. The organic layer was collected, concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give the title compound as a white solid (14 mg, yield: 70%). MS(m / z): 366.2 [M+H] + 1 H NMR(400 MHz,CD3OD): δ 5.15-4.86(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).

[0227] The compounds in the table below were prepared following the procedure for Compound 35 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0228] [Table 8]

[0229] compound 39 ( * ) 3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept-2-en-1-ol [ka] Under nitrogen atmosphere, 1 mol / L (S)-CBS / THF solution (1.4 mL, 1.4 mmol) was added to dry THF (5 mL) under ice bath cooling °C, and then 2 mol / L BH3-Me2S / THF solution (1.4 mL, 2.8 mmol) was added to this solution in one portion. After stirring for 2 min, 3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept-2-en-1-one (prepared according to the procedure for compound 1 using intermediate I-10, 600 mg, 1.4 mmol) in THF (3 mL) was added dropwise, and the mixture was stirred in ice bath for 1 h. Then, MeOH (0.5 mL), EtOAc (10 mL), and water (20 mL) were added to the reaction mixture. The organic layer was collected. The aqueous layer was extracted with EtOAc (10 mL). The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give the title compound as a white solid (60 mg, yield: 10%). MS(m / z): 420.1 [M+H] + 1 H NMR(400MHz,CD3OD): δ 4.52-4.38(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).

[0230] The compounds in the table below were prepared following the procedure for compound 39 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0231] [Table 9] TIFF0007603740000053.tif207150 TIFF0007603740000054.tif209150 TIFF0007603740000055.tif208150 TIFF0007603740000056.tif212150 TIFF0007603740000057.tif195150

[0232] Compounds 82 and 83 ( * ) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-6,6-D 2 -1-ol and 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-1,6,6-D 3 -1-all [ka]

[0233] (A) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one-6,6-D 2 To a solution of 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (prepared according to the procedure for compound 1 using intermediate I-3, 114 mg, 0.27 mmol) in 1,4-dioxane (6 mL) was added DO (2 mL) and KCO (75 mg, 0.54 mmol). The mixture was stirred at 80° C. for 4.5 h. Then, the solvent was removed in vacuo and the residue was purified by flash column chromatography (eluted with a gradient PE / EA=100:0-0:100) to give the title compound as a yellow oil (64 mg, yield: 56%). MS(m / z): 418.0 [M+H] +

[0234] (B)( * ) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-6,6-D2-1-ol Compound 82 was prepared according to the procedure for compound 39. MS(m / z): 420.1 [M+H] + 1H NMR(400MHz,CD3OD): δ 5.00-4.87(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).

[0235] (C) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-1,6,6-D 3 -1-all Compound 83 was prepared according to the procedure of Compound 1, step (B) using NaBD4. MS(m / z): 421.1 [M+H] + 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).

[0236] The compounds in the table below were prepared following the procedure for Compound 82 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0237] [Table 10]

[0238] The compounds in the table below were prepared following the procedure for Compound 83 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0239] [Table 11]

[0240] compound 93 ( * ) 3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol [ka]

[0241] (A) (R)-2-Fluoro-3-(4-((4-methoxybenzyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B2) The title compound B2 was prepared according to the procedure for compound 1 using intermediate I-55. MS(m / z): 440.1 [M+H] +

[0242] (B) (R)-3-(4-amino-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one (B3) A solution of compound B2 (1.1 g, 2.5 mmol) in TFA (10 mL) was stirred under reflux for 4 h. The solvent was removed. The residue was washed with saturated aqueous NaHCO3 and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound B3 as a pale yellow solid. MS(m / z): 320.0[M+H] +

[0243] (C)( * ) 3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol Compound 93 was prepared according to the procedure for compound 39. MS(m / z): 322.0 [M+H] + 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).

[0244] Compounds 95 and 96 Optically pure diastereoisomer, 2,6-difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka]

[0245] (A) 2,6-difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B4) Under nitrogen atmosphere, a solution of compound 123 (1.2 g, 3.30 mmol) in THF (20 mL) was added dropwise to 1 mol / L LiHMDS / THF solution (14.85 mL, 14.85 mmol) at -78°C. The mixture was stirred at 0°C for 2 h. A solution of NFSI (3.12 g, 9.90 mmol) in THF was slowly added dropwise, and then the mixture was warmed to room temperature and stirred for 3 h. After the reaction was completed, the mixture was quenched by the addition of saturated aqueous NH4Cl solution (30 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuum and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound B4 as a white solid (190 mg, yield: 15.2%). MS(m / z): 380.2 [M+H] +

[0246] (B) 2,6-difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol Compounds 95 and 96 were prepared according to the procedure for Compound 39 and purified by preparative TLC (eluted with PE / EA=2 / 1). Compound 95, Rf ≒ 0.55, MS(m / z): 382.1 [M+H] + ; 1 H NMR(400MHz,CD3OD): δ 4.97-4.90(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). Compound 96, Rf ≒ 0.50, MS(m / z): 382.2 [M+H] + ; 1 H NMR(400MHz,CD3OD): δ 4.97-4.90(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).

[0247] The compounds in the table below were prepared following the procedures for compounds 95 and 96 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0248] [Table 12] TIFF0007603740000064.tif203150 TIFF0007603740000065.tif100150 Note: Compounds 230 and 231 were obtained by flash column chromatography (eluted with a gradient of H2O / MeOH = 100:0-0:100). The compound obtained from the first elution was designated as compound 230, and the compound obtained from the second elution was designated as compound 231.

[0249] Compounds 242, 266~269 Optically pure diastereoisomer, 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-D-1-ol [ka]

[0250] (A) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-one Compound 242 was prepared using compound 295 and the corresponding reagents according to the procedure of step A of compounds 95 and 96. MS(m / z): 434.0 [M+H] + ; 1 H NMR(400 MHz,CD3OD): δ 5.31-5.06(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).

[0251] (B) Optically pure diastereoisomer, 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-one Compound 242 was separated by chiral HPLC to give compounds 246 and 247 as an optically pure diastereoisomeric pair (chiral HMPL conditions: column: AD-H (0.46 cm ID x 15 cm L); mobile phase: n-heptane / isopropanol = 80 / 20; flow rate: 0.5 mL / min; detection wavelength: UV 254 nm). The first elution (compound 246: RT = 2.025 min, de% = 100%, MS (m / z): 434.0 [M+H] + ). Second elution (compound 247: RT=2.083 min, de%=100%, MS(m / z): 434.0 [M+H] + ).

[0252] (C) Optically pure diastereoisomer, 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-D-1-ol Compounds 266 and 267 were prepared according to the procedure for compound 1 using compound 246 and NaBD4, and purified by flash column chromatography (eluted with PE / EA). Compound 266: Rf ≒ 0.55, MS(m / z): 437.2 [M+H] + ; 1 H NMR (400MHz, CD3OD): δ 4.93-4.80(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). Compound 267: Rf ≒ 0.50, MS(m / z): 437.2 [M+H] + ; 1 H NMR(400MHz,CD3OD): δ 4.95-4.79(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).

[0253] Compounds 268 and 269 were prepared according to the procedure for compound 1 using compound 247 and NaBD4, and purified by flash column chromatography (eluted with PE / EA). Compound 268: Rf ≒ 0.55, MS(m / z): 437.2 [M+H]+ ; 1 H NMR (400MHz, CD3OD): δ 4.93-4.80(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). Compound 269: Rf ≒ 0.50, MS (m / z): 437.2 [M+H] + ; 1 H NMR(400MHz,CD3OD): δ 4.95-4.79(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).

[0254] compound 94 2,6,6-trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka]

[0255] (A) (R)-2,6,6-trifluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B5) A solution of compound 123 (1.2 g, 3.30 mmol) in THF (20 mL) was added dropwise to a 1 mol / L LiHMDS solution in THF (14.85 mL, 14.85 mmol) at −78° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 2 h. A solution of NFSI (3.12 g, 9.90 mmol) in THF was then added dropwise to the mixture, and the reaction was then slowly warmed to room temperature and stirred for another 3 h. After the reaction was complete, the mixture was quenched by the addition of saturated aqueous NH4Cl solution (30 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuum and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give compound B5 as a white solid (25 mg, yield: 1.9%). MS(m / z): 398.1 [M+H] +

[0256] (B) 2,6,6-trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol Compound 94 was prepared according to the procedure for compound 39 using compound B5 and the corresponding reagents. MS(m / z): 400.2 [M+H] + 1 H NMR(400MHz,CD3OD): δ 4.97-4.88(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).

[0257] The compounds in the table below were prepared following the procedure for Compound 94 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0258] [Table 13]

[0259] compound 234 3-(4-((cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol [ka]

[0260] (A) (R)-3-(4-((cyclopropylmethyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B7) The title compound B7 was prepared using compound B6 (prepared according to the procedure for compound 1 using intermediate I-77) and the corresponding reagents according to the procedure of step A for compound 94.

[0261] (B) 3-(4-((cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol Compound 234 was prepared according to the procedure for Compound 1 using Compound B7 and the corresponding reagents. MS(m / z): 412.2 [M+H] + 1H NMR(400MHz,CD3OD): δ 4.99-4.90(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).

[0262] The compounds in the table below were prepared following the procedure for Compound 234 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0263] [Table 14]

[0264] compound 259 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol [ka]

[0265] (A) (R)-6-(3-((tert-butyldimethylsilyl)oxy)-2-fluorocyclohexa-1,3-dien-1-yl)-N 2 -(3,3-difluorocyclobutyl)-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (B9) To a mixture of compound B8 (prepared according to compound 39 using intermediate I-9: 750 mg, 1.83 mmol) and Et3N (371 mg, 3.66 mmol) in dry DCM (15 mL) under N2 at 0-5 °C, a solution of TBSOTf (726 mg, 2.75 mmol) in DCM (5 mL) was added. The mixture was stirred for 30 min. Then, it was poured into water and extracted with DCM. The organic layer was collected, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography (eluted with PE / EA) to give compound B9 as a yellow oil (958 mg, yield: 100%). MS (m / z): 524.1 [M+H] +

[0266] (B) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one (B10) A solution of compound B9 (958 mg, 1.83 mmol) in dry MeCN (20 mL) under N2 was added dropwise to a suspension of Selectfluor™ (778 mg, 2.20 mmol) in dry acetonitrile (20 mL) at 0-5° C. and stirred for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was collected, concentrated under reduced pressure, and purified by flash column chromatography (eluted with PE / EA) to give compound B10 as a white solid (512 mg, yield: 66%). MS (m / z): 428.0 [M+H] + .

[0267] (C) (R)-3-(4-((3,3-difluorocyclobutyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B11) To a solution of compound B10 (512 mg, 1.12 mmol) in dry THF (10 mL) under N2, 1M LiHMDS / THF solution (3.47 mL, 3.47 mmol) was added dropwise at -78 °C and stirred for 30 min. Then, NFSI (388 mg, 1.23 mmol) / THF solution (10 mL) was added dropwise at -78 °C and the reaction was stirred for 2 h. After the reaction was completed, the reaction was quenched by adding saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was collected, concentrated under reduced pressure and purified by flash column chromatography (eluted with PE / EA) to give compound B11 as a yellow solid (230 mg, yield: 46%). MS (m / z): 446.2 [M+H] +

[0268] (D) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol Compound 259 was prepared using compound B11 and the corresponding reagents according to the procedure for compound 39. MS(m / z): 448.0 [M+H] + 1 H NMR (400MHz, CD3OD): δ 4.91-4.81(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).

[0269] The compounds in the table below were prepared following the procedure for Compound 259 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0270] [Table 15]

[0271] compound 274 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-D-1-ol [ka]

[0272] (A) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one (B12) A mixture of 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) was stirred at 60 °C for 2 h under N2. After the reaction was completed, the mixture was poured into water and extracted with DCM. The organic layer was collected, concentrated and purified by flash column chromatography (eluted with PE / EA) to give compound B12 as a yellow solid (4.98 g, yield: 93%). MS (m / z): 356.1 [M+H] +

[0273] (B) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one (B13) The title compound B13 was prepared using compound B12 and the corresponding reagents according to the procedure of steps A and B of compound 259. MS(m / z): 374.1 [M+H] +

[0274] (C) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B14) The title compound B14 was prepared using compound B13 and the corresponding reagents according to the procedure of steps A and B of compound 259. MS(m / z): 392.0 [M+H] +

[0275] (D) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-D-1-ol Compound 274 was prepared according to the procedure of step B of compound 1 using compound B14, NaBD4 and the corresponding reagent. MS(m / z): 395.1 [M+H] +1 H NMR (400MHz, CD3OD): δ 4.33-4.20(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).

[0276] The compounds in the table below were prepared following the procedure for Compound 274 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0277] [Table 16] TIFF0007603740000075.tif158150

[0278] compound 297 2,6,6-trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka]

[0279] (A) (R)-3-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluoro-cyclohex-2-en-1-one (B16) The title compound B16 was prepared using intermediate A4 and the corresponding reagents according to the procedure of steps B and C of compound 274. MS(m / z): 375.1 [M+H] +

[0280] (B) (R)-2,6,6-trifluoro-3-(4-(methoxyamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B17) The title compound B17 was prepared using compound B16 and the corresponding reagents according to the procedure for compound 190. MS(m / z): 386.1 [M+H] +

[0281] (C) 2,6,6-trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol Compound 297 was prepared using compound B17 and the corresponding reagents according to the procedure of step B of compound 1. MS(m / z): 388.2 [M+H] + 1 H NMR(400MHz,CD3OD): δ 5.04-4.92(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).

[0282] compound 280 3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluoro-cyclohex-2-en-1-ol [ka]

[0283] (A) (R)-2-Fluoro-3-(4-((4-methoxyphenyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B18) The title compound B18 was prepared using intermediate I-105 and the corresponding reagents according to the procedure for compound 1. MS(m / z): 440.2 [M+H] +

[0284] (B) (R)-3-(4-amino-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one (B19) A mixture of compound B18 (1.4 g, 3.19 mmol) in TFA (10 mL) was stirred under reflux for 2 h. The solvent was removed under vacuum. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was collected and concentrated under reduced pressure to give the title compound B19 (800 mg, 79% yield) as a yellow solid, which was used in the next step without purification.

[0285] (C) 3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol Compound 280 was prepared using compound B19 and the corresponding reagents according to the procedure for compound 274. MS(m / z): 358.1 [M+H] + ; 1H 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).

[0286] compound 284 3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol [ka]

[0287] (A) 3-(4,6-bis((3,5-dimethoxybenzyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (B20) The title compound B20 was prepared using intermediate I-106 and the corresponding reagents according to the procedure for compound 1. MS(m / z): 542.1 [M+H] +

[0288] (B) 3-(4,6-diamino-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (B21) The title compound B21 was prepared using compound B20 and the corresponding reagents according to the procedure of step B of compound 280. MS(m / z): 224.0 [M+H] +

[0289] (C) 3-(4,6-bis((tert-butyldimethylsilyl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B22) The title compound B22 was prepared using compound B21 and the corresponding reagents according to the procedures in steps B and C of compound 274. MS(m / z): 488.1 [M+H] +

[0290] (D) 3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B23) A solution of compound B22 (410 mg, 0.84 mmol) in concentrated aqueous HCl (1 mL) and MeOH (5 mL) was stirred at room temperature for 30 min. The mixture was diluted with EtOAc and adjusted to pH=8 with saturated aqueous NaHCO3. The organic layer was collected, concentrated to dryness under vacuum, and purified by flash column chromatography (eluted with MeOH and water) to give the title compound B23 as a white solid (150 mg, yield: 69%). MS (m / z): 260.0 [M+H] +

[0291] (E) 3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol Compound 284 was prepared according to the procedure of step B of compound 1 using compound B23 and the corresponding reagent. MS(m / z): 262.0 [M+H] + 1 H NMR (400MHz, CD3OD): δ 4.33-4.20(m,1H),2.73-2.60(m,1H),2.56-2.43(m,1H),2.29-2.04(m,2H).

[0292] compound 99 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-ol [ka]

[0293] (A) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-one (B24) In a sealed test tube, 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (prepared according to the procedure for compound 1 using intermediate I-3, 700 mg, 1.69 mmol), NCS (224 mg, 1.69 mmol), TsOH·HO (321 mg, 1.69 mmol) and MeCN (10 mL) were added in sequence. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with a gradient PE / EA = 100:0 to 0:100) to give the title compound B24 as a white solid (320 mg, 42.2% yield). MS(m / z): 450.1, 452.1 [M+H] +

[0294] (B) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-ol Compound 99 was prepared according to the procedure for compound 39 using compound B24 and the corresponding reagents. MS(m / z): 452.1 [M+H] + 1H NMR(400MHz,CD3OD): δ 5.02-4.90(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).

[0295] compound 122 (R)-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one [ka] A flask was charged with intermediate I-2 (500 mg, 1.76 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (391 mg, 1.76 mmol), Cs2CO3 (1144 mg, 3.52 mmol), Pd(PPh3)4 (101 mg, 0.09 mmol), 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (350 mg, 57.9% yield). MS(m / z): 344.1 [M+H] +1 H NMR(400 MHz,CD3OD): δ 7.00(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).

[0296] The compounds in the table below were prepared following the procedure for Compound 122 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0297] [Table 17]

[0298] compound 124 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka]

[0299] To a flask were added compound 122 (250 mg, 0.73 mmol), CeCl3·7H2O (353 mg, 0.95 mmol) and EtOH (10 mL). The mixture was cooled to 0 °C, NaBH4 (36 mg, 0.95 mmol) was added and the reaction was stirred at 0 °C for 2 h. After the reaction was complete, the mixture was quenched by the addition of saturated aqueous NH4Cl (3 mL) and water (20 mL) and extracted with EtOAc. The organic layer was collected, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (210 mg, yield: 83.3%). MS(m / z): 346.0 [M+H] + 1 H NMR(400 MHz,CD3OD): δ 7.19-6.92(m,1H),5.10-4.87(m,1H),4.37-4.26(m,1H),4.25-4.07(m,1H),2.51-2.3 0(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).

[0300] The compounds in the table below were prepared following the procedure for Compound 124 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0301] [Table 18] TIFF0007603740000084.tif221150 TIFF0007603740000085.tif82150

[0302] compound 138 (R)-6-(3,3-difluorocyclohex-1-en-1-yl)-N2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] In a sealed tube, compound 122 (100 mg, 0.29 mmol), DAST (1 mL), BAST (1 mL) and DCM (10 mL) were added. The mixture was stirred at 80° C. for 48 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (40 mg, yield: 38.1%). MS (m / z): 366.1 [M+H] +1 H NMR(400 MHz,CD3OD): δ 7.00-6.82(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).

[0303] Compound 139 in the table below was prepared following the procedure for compound 138 using the corresponding intermediates and reagents under appropriate conditions identified in POSITA.

[0304] [Table 19]

[0305] compound 140 6-(3-Methoxycyclohex-1-en-1-yl)-N 2 ,N 4 -Bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] A mixture of compound 126 (100 mg, 0.25 mmol) and Ag2O (115 mg, 0.5 mmol) in CH3I (4 mL) was stirred under reflux for 16 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (60 mg, yield: 58.3%). MS (m / z): 414.0 [M+H] + ; 1 H NMR(400MHz,CD3OD): δ 7.27-7.08(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).

[0306] compound 141 6-(3-(dimethylamino)cyclohex-1-en-1-yl)-N 2 ,N 4 -Bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] To a solution of compound 126 (50 mg, 0.125 mmol) in dry DCM (3 mL) was added SOCl2 (16 mg, 0.137 mmol) under ice bath cooling °C, and the mixture was stirred in ice bath for 30 min. Then the solution was loaded into a sealed test tube, dimethylamine hydrochloride (20 mg, 0.25 mmol) was added, and the mixture was stirred under reflux overnight. After the reaction was completed, the mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was collected, concentrated, and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (10 mg, yield: 18.9%). MS(m / z): 427.0 [M+H] + 1H NMR(400 MHz,CD3OD): δ 7.27-7.11(m,1H),5.06-4.89(m,2H),3.58-3.44(m,1H),2.64-2.53(m,1H),2.44-2.3 8(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).

[0307] Compound 142 in the table below was prepared following the procedure for compound 141 using the corresponding intermediates and reagents under appropriate conditions identified in POSITA.

[0308] [Table 20]

[0309] compound 143 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-1-(trifluoromethyl)-cyclohex-2-en-1-ol [ka] To a solution of 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (prepared according to the procedure of compound 122 using the corresponding intermediates and reagents, 100 mg, 0.25 mmol) and trimethyl(trifluoromethyl)silane (142 mg, 1.25 mmol) in dry THF (10 mL) under ice bath cooling °C, TBAF (1 M, 1.25 mL) was added. The mixture was stirred under reflux for 2 h, quenched by addition of saturated aqueous NH4Cl solution, and extracted with EtOAc. The organic layer was collected, concentrated, and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (10 mg, yield: 8.6%). MS(m / z): 468.0 [M+H] + ; 1H NMR (400 MHz, CD3OD): δ 7.10 (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).

[0310] compound 144 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-ol [ka]

[0311] (A)(R)-N 2 -Isopropyl-6-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (B25) Under nitrogen atmosphere, a flask was charged with 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-dioxaborolane (300 mg, 1.13 mmol), Cs2CO3 (734 mg, 2.26 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 80° C. for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound B25 as a white solid.

[0312] (B) (R)-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-one (B26) To a solution of compound B25 in dry DCM (3 mL) was added TFA (3 mL) and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was collected, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound B26 as a yellow solid (200 mg, yield: 51.5%). MS (m / z): 344.3 [M+H] +

[0313] (C) 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-ol Compound 144 was prepared according to the procedure for compound 124 using compound B26 and the corresponding reagents. MS(m / z): 346.3 [M+H] + 1 H NMR(400MHz,CD3OD): δ 7.27-6.96(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).

[0314] Compound 145 in the table below was prepared following the procedure for compound 144 using the corresponding intermediates and reagents under appropriate conditions identified in POSITA.

[0315] [Table 21]

[0316] compound 152 2-Fluoro-3-(4-(((R)-1-phenylethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol [ka] In a sealed test tube, intermediate I-1 (50 mg, 0.15 mmol), (R)-1-phenylethan-1-amine (36 mg, 0.30 mmol), DIEA (77 mg, 0.60 mmol) and 1,4-dioxane (3 mL) were added in sequence. The mixture was stirred at 100° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (15 mg, yield: 23.4%). MS(m / z): 426.3 [M+H] +1H NMR(400 MHz,CD3OD): δ 7.35-7.15(m,5H),5.22-4.60(m,2H),4.33-4.21(m,1H),2.62-2.23(m,2H),1.89-1.7 3(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).

[0317] The compounds in the table below were prepared following the procedure for Compound 152 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0318] [Table 22] TIFF0007603740000096.tif212150 TIFF0007603740000097.tif211150 TIFF0007603740000098.tif192150 TIFF0007603740000099.tif82150

[0319] compound 186 6-(Cyclohex-1-en-1-yl)-N 2 ,N 4 -Bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] Under nitrogen atmosphere, intermediate I-3 (150 mg, 0.44 mmol), cyclohex-1-en-1-ylboronic acid (85 mg, 0.66 mmol), Cs2CO3 (290 mg, 0.88 mmol), Pd(PPh3)4 (26 mg, 0.022 mmol), 1,4-dioxane (10 mL) and water (2 mL) were added in sequence to a flask. The mixture was stirred at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a white solid (154 mg, yield: 90.4%). MS(m / z): 384.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 7.84-7.60(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).

[0320] The compounds in the table below were prepared following the procedure for Compound 186 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0321] [Table 23]

[0322] compound 190 (R)-6-(cyclohex-1-en-1-yl)-N 2 -Isopropyl-N 4 -(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine [ka] A mixture of intermediate I-22 (85 mg, 0.33 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (201 mg, 1.34 mmol) and DIEA (0.47 mL, 2.69 mmol) in 1,4-dioxane (3 mL) was stirred at 150° C. for 3 h under microwave. After the reaction was complete, the mixture was cooled to room temperature, concentrated and purified by flash column chromatography (eluted with PE / EA) to give the title compound as a yellow solid (18 mg, 14% yield). MS (m / z): 330.1 [M+H] + 1 H NMR(400 MHz,CD3OD): δ 7.32-6.94(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).

[0323] The compounds in the table below were prepared following the procedure for Compound 190 using the corresponding intermediates and reagents under the appropriate conditions identified in POSITA.

[0324] [Table 24]

[0325] Compounds 206 and 207 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-ol and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-ol [ka]

[0326] (A) 2-Chloro-5-fluoro-N 4 ,N 6 -Bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-4,6-diamine and 6-chloro-5-fluoro-N 2 ,N 4 -Bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4-diamine mixture Under nitrogen atmosphere, a mixture of 2,4,6-trichloro-5-fluoropyrimidine (1.12 g, 5.6 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.51 g, 16.8 mmol), DIEA (4.22 g, 56 mmol) and N-methylpyrrolidone (5 mL) was stirred at 200° C. for 1 h under microwave. After cooling to room temperature, the mixture was directly loaded onto a RP-C18 column and purified by flash column chromatography (eluted with a gradient of water / MeOH=100:0-0:100) to give the product as a white solid (80 mg, 4.2% yield). MS(m / z): 354.9 [M+H] +

[0327] (B) A mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-one Under nitrogen atmosphere, a mixture of the product obtained in step (A) (80 mg, 0.23 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (50 mg, 0.23 mmol), Cs2CO3 (150 mg, 0.46 mmol), 1,4-dioxane (5 mL) and water (1.5 mL) was stirred at 130° C. for 40 minutes under microwave. After cooling to room temperature, the mixture was concentrated and purified by flash column chromatography (eluted with a gradient PE / EA=100:0-0:100) to give the product as a white solid (60 mg, yield: 63.2%). MS(m / z): 415.0 [M+H] +

[0328] (C) 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-ol and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-ol Compounds 206 and 207 were prepared according to the procedure for Compound 124 using the mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one obtained in step (B) and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-one obtained in step (B) and the corresponding reagents, and purified by flash column chromatography (eluted with a gradient PE / EA=100:0-0:100). Compound 206, MS(m / z): 417.0 [M+H] + . 1 H NMR(400 MHz,CD3OD): δ 6.97-6.89(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), Compound 207, MS(m / z): 417.0 [M+H] + . 1 H NMR(400 MHz,CD3OD): δ 6.47-6.40(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=7.1 Hz, 3H),1.32(d, J=7.0 Hz, 3H).

[0329] The compounds in the table below were prepared according to the procedures described above using the corresponding intermediates and reagents under the appropriate conditions recognized in POSITA.

[0330] [Table 25] TIFF0007603740000106.tif213150 TIFF0007603740000107.tif30150

[0331] Compounds 197 and 198 Optically pure diastereoisomer, 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol [ka] Compound 196 was resolved by chiral HPLC to give compounds 197 and 1987 as an optically pure diastereoisomeric pair (Chiral HPLC conditions: Preparation equipment: Shimadzu LC-10AD vp; Column: Daicel AD-H (250 mm *30 mm, 5 um; mobile phase: n-heptane / isopropanol=90 / 10; flow rate: 40 mL / min; column temperature: 40° C.). The first eluate (RT=4.203 min) was concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give a compound designated as compound 197, de%=99.27%, MS(m / z): 454.1 [M+1]. + The second eluate (RT=5.906 min) was concentrated and purified by flash column chromatography (eluted with gradient PE / EA=100:0-0:100) to give a compound designated as compound 198, de%=97.82%, MS(m / z): 454.2 [M+1]. + . Compound 197: 1 H NMR (400 MHz, 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). Compound 198: 1 H NMR (400 MHz, 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).

[0332] The compounds in the following table were prepared according to the procedures for Compounds 197 and 198 using the corresponding compounds under appropriate HPLC conditions (flow rate: 0.5 mL / min; detection wavelength: UV 254 nm):

[0333] [Table 26] TIFF0007603740000110.tif214150 TIFF0007603740000111.tif232145 TIFF0007603740000112.tif227150 TIFF0007603740000113.tif231150 TIFF0007603740000114.tif220150 TIFF0007603740000115.tif231150 TIFF0007603740000116.tif214150 TIFF0007603740000117.tif232148

[0334] Example 3 Fluorescence measurement of IDH2-R140Q cell activity material: U87MG cells were purchased from the ATCC cell bank and then transfected with a plasmid containing the IDH2-R140Q mutation to isolate monoclonal cells stably expressing the R140Q mutation for the experiments. These cells were cultured in MEM medium containing 10% FBS.

[0335] 96-well plate a: Beckman Dickinson, catalog number 353072; 96-well plate b: Thermo, catalog number 249952; 96-well plate c: Greiner, catalog number 675076.

[0336] Solution preparation: Enzyme reaction solution: 1 mM nicotinamide adenine dinucleotide (NAD), 0.6 ng / μL D-2-hydroxyglutarate dehydrogenase (D2HGDH), 0.8 U / mL lipoamidase dehydrogenase (Diaphorase) and 60 μM resazurin in 40 mM Tris.HCl pH 8.8 assay buffer.

[0337] Standard curve stock solution: 2-HG sodium salt preparation was serially diluted with serum-free MEM medium to prepare standard curve stock solutions, with final gradient concentrations of 500 μM, 167 μM, 56 μM, 18.5 μM, 6 μM, 2 μM, 0.7 μM, and 0.2 μM.

[0338] method: Add 100 µL of U87MGR140Q cells to a 96-well plate, 6 × 10 cells per well. 4 The plate was incubated overnight at 37°C, 5% CO2, and then 10μL / well of test compound solution diluted in serum-free MEM (final concentrations of test compound: 10μM, 3.3μM, 1.1μM, 0.37μM, 0.12μM, 0.041μM, 0.014μM and 0.005μM, final DMSO concentration is 0.5%) or 10μL of control solution (serum-free MEM medium containing DMSO at a final concentration of 0.5%) was added and incubated for 72 hours.

[0339] From each well of 96-well plate a, 50 μL of culture supernatant was transferred to the corresponding well of 96-well plate b, and 50 μL of standard curve storage solution was added to the other wells of 96-well plate b at the same time. Then, 10 μl of 360 mM hydrochloric acid was added to all wells. After shaking and mixing, the plate was placed on ice for 10 minutes, and then 10 μl of 420 mM Tris base was added. After shaking and mixing, the plate was placed on ice for another 5 minutes. Then, the plate was centrifuged at 2500 rpm for 10 minutes.

[0340] After centrifugation, 20 μL of the supernatant from each well of 96-well plate b was transferred to 96-well plate c. Furthermore, 80 μL of the enzyme reaction solution was added to each well and incubated at 25° C. for 90 minutes.

[0341] detection: Plate c was measured on a Tecan Infinite F500 reader at excitation 544 nm and emission 590 nm. A standard curve of fluorescence values ​​against corresponding 2-HG concentrations was prepared, and the corresponding 2-HG concentrations of each compound concentration point were calculated. The inhibition rate was then calculated, and the data was analyzed using XLfit5 (ID Business Solutions Limited) software to obtain IC 50 Got the value.

[0342] The inhibition rate was calculated as follows: Inhibition rate (IH%) = (1 - 2-HG concentration in test compound-treated cells / 2-HG concentration in control cells) x 100%

[0343] Below are the activity values ​​of some compounds of the present invention measured in this example.

[0344] [Table 27] TIFF0007603740000119.tif208150 TIFF0007603740000120.tif91150

[0345] Example 4 Fluorescence measurement of IDH1-R132H cell activity The 2-HG inhibitory activity of the compounds of the present invention in U87MGR132H cells transfected with the IDH1-R132H mutant plasmid was measured according to the method of Example 3.

[0346] Below are the activity values ​​of some compounds of the present invention measured in this example.

[0347] [Table 28] TIFF0007603740000122.tif204150

[0348] Example 5 Metabolic stability test in liver microsomes material: Male CD1 mouse liver microsomes were provided by Research Institute for Liver Diseases (Shanghai) Co., Ltd. Male SD rat liver microsomes were provided by Bioreclamation IVT, USA.

[0349] Phenacetin, glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PD), and nicotinamide adenine dinucleotide phosphate (NADP) were supplied by Sigma-Aldrich (MO, USA).

[0350] Solution preparation: 10 mM stock solution of test compound: A fixed amount of test compound is weighed and dissolved in a fixed volume of dimethylsulfoxide (DMSO) to obtain a 10 mM stock solution of test compound.

[0351] Reaction termination solution: A fixed amount of phenacetin as an internal standard was weighed and dissolved in acetonitrile to obtain a 1000 ng / mL reaction termination solution, which was stored at room temperature until use.

[0352] Test Method: Stock solutions of test compounds were diluted to the indicated concentrations with organic solutions (usually mixtures of acetonitrile, methanol and water in various proportions depending on the compound solution) to a final concentration of 1 μM, with the organic solvent content being 1% or less in the final incubation system (for DMSO, the control margin was 0.1%). 100 mM NADP, 500 mM G-6-P and 100 U / mL G-6-PDH were mixed and diluted with ultrapure water to obtain an NADPH regenerating system containing 1 mM NADP, 5 mM G-6-P and 1 U / mL G-6-PD, which was preincubated in a 37°C water bath for 10 min and then cooled on ice until added to the reaction system. 20 mg / mL liver microsomes were mixed with 200 mM PBS and diluted with ultrapure water to give liver microsomes and PBS concentrations of 0.5 mg / mL and 50 mM, respectively, in the final incubation system. After the diluted liver microsomes were mixed with the NADPH regenerating solution, a volume of 100 mM EDTA and 300 mM MgCl2 (the concentrations of EDTA and MgCl2 in the final incubation system were 1 mM and 3 mM, respectively) was added, and the incubation system was placed in a water bath at 37°C. The incubation was started by adding the stock solution of the test compound and maintained for 30 minutes. The incubation was terminated by adding the reaction termination solution. The 0 min sample was prepared by adding the stock solution of the test compound immediately after adding the reaction termination solution to the incubation system and placing the system in a water bath. The terminated incubation mixture was vortexed and centrifuged at 4400 rpm for 10 minutes, and the supernatant was collected for LC-MS / MS analysis.

[0353] Analysis method: The concentration of the test compounds was measured using an LC-MS / MS method. The peak area ratio of the compound and the internal standard as an index was used to calculate the percentage of the compound remaining after 30 min of incubation compared to the 0 min sample to evaluate the metabolic stability of the compounds.

[0354] According to the above test, the compounds of the present invention showed good metabolic stability. The metabolic stability of some exemplary compounds of the present invention is as follows:

[0355] [Table 29]

[0356] Example 6 Solubility Measurement 1. Sample Solution Preparation Sample standard solution: Approximately 3-5mg of test compound was accurately weighed and added to a 5mL sample tube, followed by 5mL of DMSO. Shake and sonicate for 1 hour.

[0357] pH 2.1 sample solution: Approximately 1 mg of test compound was accurately weighed and added to a 1 mL sample tube, and 1 mL of pH 2.1 sodium phosphate buffer was added. Shake. If the solution was visually clear, add test compound to this solution until obvious insoluble matter was seen in the solution. Sonicate for 1 hour.

[0358] pH 7.4 sample solution: Approximately 1 mg of test compound was accurately weighed and added to a 1 mL sample tube, and 1 mL of pH 7.4 sodium phosphate buffer was added. Shake. If the solution was visually clear, add test compound to this solution until obvious insoluble matter was seen in the solution. Sonicate for 1 hour.

[0359] 2. Measurement 1 mL of sample standard solution was accurately pipetted into HPLC tubes. Peak areas were determined by HPLC.

[0360] 0.5mL of pH 2.1 sample solution was filtered through a syringe filter, accurately pipetted into an HPLC tube, and 0.5mL of pH 2.1 sodium phosphate buffer was accurately added. Shake. Peak area was determined by HPLC.

[0361] 0.5mL of pH 7.4 sample solution was filtered through a syringe filter, accurately pipetted into an HPLC tube, and 0.5mL of pH 7.4 sodium phosphate buffer was accurately added. Shake. Peak area was determined by HPLC.

[0362] HPLC conditions: Equipment: Agilent 1200 Column: Agilent SB-C18 5u 4.6 * 150mm Mobile phase: Phase A: Water (containing 0.1% formic acid) Phase B: MeOH (contains 0.1% formic acid) Gradient Table

[0363] [Table 30]

[0364] 3.Calculation The solubility of the test compound in pH 2.1 and pH 7.4 sodium phosphate buffers was calculated according to the following formula: Solubility of sample at pH 2.1 (mg / mL) = 2 x A x Y ÷ X Solubility of sample at pH 7.4 (mg / mL) = 2 x A x Z ÷ X Where: A: concentration of test compound in sample standard solution in mg / mL; X: peak area of ​​sample standard solution; Y: peak area of ​​pH 2.1 sample solution; Z: peak area of ​​pH 7.4 sample solution.

[0365] The solubilities of some exemplary compounds of the present invention are as follows:

[0366] [Table 31]

Claims

1. Formula (II-1): 【Chemistry 1】 where X is halo; m is 0, 1, or 2; R ２ each independently represents H, deuterium, halo, C １－６ Alkyl, or C １－６ haloalkyl; R ３ and R ４ C, which may be substituted with one or more halo groups, １－６ or a pharma- ceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein X is fluoro.

3. R ２ is H or deuterium, or a pharma- ceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof.

4. R ３ and R ４ C which is optionally substituted with one or more fluoro １－６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R is selected from the group consisting of alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ...

5. R ３ and R ４ are independently substituted with one or more fluoro groups. １－６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R is selected from the group consisting of alkyl, aryl, arylsulfates, arylalkyl, arylsulfates ... 【Request 6】 【Table 1】 2. The compound of claim 1, selected from:

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, and optionally including at least one pharma- ceutically acceptable excipient.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof for treating a disease induced by an IDH mutation.

9. 9. The pharmaceutical composition of claim 8, wherein the IDH mutation-induced disease is cancer, and the cancer is selected from solid tumors, gliomas, or hematological malignancies.

10. The pharmaceutical composition of claim 9, wherein the cancer is selected from leukemia, lymphoma, or myeloma.

11. 10. The pharmaceutical composition of claim 9, wherein the cancer is selected from acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), cholangiocarcinoma, chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lung cancer, or non-Hodgkin's lymphoma (NHL).

12. The pharmaceutical composition of claim 9, wherein the cancer is intrahepatic cholangiocarcinoma (IHCC).

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