EA044101B1

EA044101B1 - CYCLOOLEFIN SUBSTITUTED HETEROAROMATIC COMPOUNDS AND THEIR APPLICATION

Info

Publication number: EA044101B1
Application number: EA202090653
Authority: EA
Inventors: Вей-Гуо СУ; Гуансю Дай; Кун Сяо
Original assignee: Хатчисон Медифарма Лимитед
Priority date: 2017-09-07
Filing date: 2018-09-07
Publication date: 2023-07-24

Description

Field of technology to which the present invention relates

The present invention relates to cycloolefin substituted heteroaromatic compounds and their use in the treatment of diseases caused by IDH mutations.

State of the art

The way tumor cells survive differs from the way normal cells survive, as does energy consumption and energy use. A common metabolic pathway in aerobic organisms is the tricarboxylic acid cycle, in which isocitrate dehydrogenase (IDH), catalyzing the conversion of isocitrate to α-ketoglutaric acid (α-KG), is the rate-limiting step. The well-known IDH family consists of three isozymes IDH1, IDH2 and IDH3, which are located in different organelles and perform the same biological functions, i.e. catalyze the formation of α-KG. Recent studies have shown that heterozygous IDH1/2 mutations were present in a certain proportion in various tumors, such as glioma (60-80%), chondrosarcoma (55%), acute myeloid leukemia (15-25%), etc. The IDH1 or IDH2 mutant loses the ability to catalyze the conversion of isocitrate to α-KG, while it has the ability to catalyze the conversion of α-KG to α-hydroxyglutaric acid (2-HG). Since the structure of 2-HG is similar to the structure of α-KG, 2-HG can competitively inhibit the activity of many α-KG-dependent enzymes (for example, histone demethylase and methylcytosine hydroxylase of the TET family, etc.) when it accumulates in a certain degree and thus affects histone and DNA demethylation, interferes with normal cell differentiation and leads to the proliferation of immature cells.

Agios Pharmaceuticals published the results of their research in the journal Science in 2013: the mutant IDH1 enzyme inhibitor AGI-5198 (Science, 2013, 340, 626-630) and the mutant IDH2 enzyme inhibitor AGI-6780 (Science, 2013, 340, 622-626 ) developed by the company can effectively inhibit the formation of 2-HG mediated by the IDH1/IDG2 mutant in cells, and can induce the differentiation of abnormally proliferating cancer cells. Treatment of glioma cells carrying the mutant IDH1 gene with the compound AGI-5198, and treatment of leukemia cells carrying the mutant IDH2 gene with the compound AG-6780 lead to an increase in the expression of mature markers in the cells.

A phase I clinical trial of AG-120, a mutant IDH1 inhibitor developed by Agios Pharmaceuticals, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who have IDH1 mutations found that 98% of patients had decreased α-hydroxyglutaric acid levels (2 -GG).

Acute myeloid leukemia (AML) is one of the most challenging diseases to control in common hematologic malignancies. Its repetition rate is high. The development of new drugs for this disease is slow, resulting in a lack of effective drug therapy. Some studies have shown that about 15% of patients with acute myeloid leukemia have IDH2 gene mutations. Enasidenib (formerly AG-221), a mutant IDH2 inhibitor developed by Agios Pharmaceuticals and Celgene, showed significant results in relapsed and refractory acute myelogenous leukemia with IDH2 mutations in clinical trials.

New mutant IDH inhibitors need to be developed to meet the need for the treatment of patients with hematological tumors, especially acute myeloid leukemia, glioma and other tumors associated with IDH mutation. The present invention meets these needs.

Brief description of the invention

According to the present invention there is provided a compound of formula (I) nr ₃ r ₃ '

NR4R4'

V (I) and/or its pharmaceutically acceptable salt, and/or solvates, racemic mixtures, their enantiomers, diastereomers and tautomers, wherein A, R _b R ₂ , R ₃ , R ₃ ', R4, R4', R5, R ₆ , R ₇ , R ₈ , m and n are radicals which are specified in the detailed description of the present invention.

Also provided is a pharmaceutical composition containing at least one compound of Formula (I) (for example, any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (for example, a pharmaceutically acceptable carrier) .

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

- 1 044101 of one of its pharmaceutically acceptable salts.

Also provided is the use of at least one compound of formula (I) (for example, any of the compounds described herein) and/or at least one pharmaceutically acceptable salt thereof for the treatment of a disease caused by an IDH mutation.

Also provided is the use of at least one compound of formula (I) (for example, any of the compounds described herein) and/or at least one pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease caused by an IDH mutation.

Brief description of drawings

In fig. 1 depicts a general synthesis method for preparing the compounds described herein.

In fig. 2 depicts a general synthesis method II for preparing the compounds described herein.

In fig. 3 depicts the general synthesis method III for preparing the compounds described herein.

In fig. 4 depicts a general synthesis method for IV to produce the compounds described herein.

In fig. 5 depicts a general method for synthesizing V to produce the compounds described herein.

In fig. 6 depicts a general synthesis method for VI to produce the compounds described herein.

Detailed Description of the Invention Definitions

The following words, phrases and symbols used in this application generally have the meanings set forth below, except that the context in which they are used indicates otherwise.

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 added via oxygen. However, when the site of attachment of the group is obvious to those skilled in the art, such as a halogen substituent, the - sign may be omitted.

Unless explicitly stated otherwise, the use of the singular and the like refers to one or more.

The term alkyl as used herein refers to a straight or branched saturated hydrocarbon radical containing 1-18 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, and even more preferably 1-4 carbon atoms. For example, C ₁ . ₆ alkyl refers to an alkyl containing 1-6 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s- Bu) and tert-butyl (t-Bu), but are not limited to them.

The term alkenyl as used herein refers to a straight or branched hydrocarbon radical containing one or more, for example 1, 2 or 3 carbon-carbon (C=C) double bonds and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2- 4 carbon atoms. For example, C _{2_6} alkenyl refers to alkenyl containing 2-6 carbon atoms _. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl and 2-butenyl. The attachment site for said alkenyl may be a carbon atom with a double bond or another carbon atom.

The term alkynyl as used herein refers to a straight or branched hydrocarbon radical containing one or more, for example 1, 2 or 3 carbon-carbon (C=C) triple bonds and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2- 4 carbon atoms. For example, C ₂ - ₆ alkynyl refers to an alkynyl containing 2-6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl. The attachment site for said alkynyl may be a carbon atom with a triple bond or another carbon atom.

The term halogen or halo as used herein means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

The term haloalkyl as used herein refers to an alkyl radical as defined herein in which one or more, for example, 1, 2, 3, 4 or 5 hydrogen atoms are replaced by a halogen atom, and when more than one hydrogen atom is replaced by halogen atoms, These halogen atoms may be the same or different. In a specific embodiment, the term haloalkyl as used herein refers to an alkyl radical as defined herein in which two or more, for example 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein said halogen atoms are the same. In another embodiment, the term haloalkyl as used herein refers to an alkyl radical as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein said halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to -CF ₃ , -CHF ₂ , -CH2CF3 and the like.

The term alkoxy as used herein refers to the group -O-alkyl, wherein said alkyl is an alkyl as defined above. Examples of alkoxy groups include C ₁ . ₆ alkoxy, such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, pentyloxy and hexyloxy, including but not limited to their isomers.

The term cycloalkyl as used herein refers to a saturated or partially unsaturated cyclic hydrocarbon radical having 3 to 12 ring carbons, such as 3 to 8 ring carbons, 5 to 7 ring carbons, 4 to 7 ring carbons, or 3 to 6 ring carbon atoms, which may have one or more rings, for example 1, 2 or 3 rings, preferably 1 or 2 rings. For example, C ₃ . ₁₂ cycloalkyl refers to a cycloalkyl radical containing 3-12 carbon atoms in the ring. Cycloalkyl also includes a fused or bridged ring or a spirocyclic ring. Said rings of said cyclic group may be saturated or have one or more, for example one or two, double bonds (i.e., partially unsaturated), but not fully conjugated and not aryl as defined herein. Examples of cycloalkyl groups include 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]hepta-2-ene, but are not limited to.

The term heterocycle, heterocyclyl or heterocyclic as used herein refers to monocyclic, bicyclic or tricyclic saturated or partially unsaturated cyclic radicals having 3-12 ring atoms, for example 3-8 ring atoms, 5-7 ring atoms, 4-7 ring atoms in a ring or 3-6 atoms in a ring, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms, independently selected from N, O and S, in said rings, with the remaining atoms in the ring being atoms carbon. Said heterocyclic group also includes a heteroatom N or S, which are optionally oxidized to different oxidation states. The site of attachment of the heterocyclic group may be the specified N-heteroatom or carbon. For example, 3-8 membered heterocyclyl refers to a heterocyclyl containing 3-8 ring atoms and at least one heteroatom independently selected from N, O and S.

Said heterocyclic group also includes a fused or bridged ring or a spirocyclic ring, wherein at least one ring contains at least one heteroatom selected from O, S, and N and none of the remaining rings is aryl or heteroaryl such as defined in this document. Said rings of said heterocyclyl group may be saturated or have one or more, for example one or two, double bonds (ie, partially unsaturated), but not fully conjugated, and not heteroaryls as defined herein. Examples of heterocyclic groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.

The term aryl as used herein refers to a carbocyclic hydrocarbon radical containing from 6 to 14 carbon atoms, consisting of one ring or more fused rings, at least one ring being an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.

The term heteroaryl as used herein refers to a monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring atoms, preferably having 6 ring atoms, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms, independently selected of N, O and S (preferably N) in said ring, with the remaining atoms in the ring being carbon; and a bicyclic aromatic hydrocarbon radical having 8-12 ring atoms, preferably having 9 or 10 ring atoms, and containing one or more, for example 1, 2, 3 or 4, preferably 2, 3 or 4 heteroatoms, independently selected from N, O, and S (preferably N) on said rings, with the remaining ring atoms being carbon, wherein at least one of said rings is aromatic. For example, said bicyclic heteroaryl includes a 5- or 6-membered heterocyclic aromatic ring fused to a 5- or 6-membered cycloalkyl ring.

When the total number of S and O atoms in said heteroaryl group exceeds 1, said S and O heteroatoms are not adjacent to each other.

Said heteroaryl group also includes groups wherein said N-heteroatom is an N-oxide, such as pyridyl-N-oxides.

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

Hydroxyl as used herein refers to the radical -OH. Mercapto as used herein refers to the radical -SH. Oxo as used herein refers to the =O radical.

When a structure herein contains an asterisk *, it means that the chiral center of the compound marked with an asterisk * has either the R configuration or the S configuration, and the content of the compound marked * in one configuration is at least 90% ( e.g. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100% or any value in between). The configuration of these compounds can be determined using a variety of analytical techniques, for example, single crystal x-ray crystallography and/or optical polarimetry in accordance with standard protocols known to those skilled in the art.

When the structure herein contains 2(RS), this means that the specified chiral center of the compound, designated (RS), contains both the R configuration and the S configuration.

The term optional or optional as used herein means that the sequentially described event or circumstance may or may not occur, and the present description includes examples in which the specified event or circumstance occurred and examples in which the specified event or circumstance did not occur. For example, optionally substituted alkyl includes both unsubstituted alkyl and substituted alkyl as defined herein. One skilled in the art will understand, with respect to any of the groups containing one or more substituents, that such groups do not involve the introduction of any substitution or set of substitutions that is sterically infeasible, chemically incorrect, unsynthetically infeasible, and/or essentially unstable.

The term substituted or substituted by ......, as used herein means that one or more hydrogens on a specified atom or group are replaced by one or more substituents selected from a specified group of substituents, provided that the normal valency of the specified atom is not exceeded. When the substituent is an oxo group (ie, =O), 2 hydrogen atoms per atom are replaced by said oxo group. Combinations of substituents and/or variable substitutions are permitted only if such combinations result in a chemically correct and stable compound. By chemically correct and stable compound is meant a compound that is stable enough to withstand the process of isolation from the reaction mixture to be able to identify the chemical structure of the said compound, and is also stable enough to allow subsequent preparation as an agent having at least one practical use.

Unless otherwise noted, substituents are named in the main structure. For example, it should be understood that when (cycloalkyl)alkyl is indicated as a possible substituent, the site of attachment of this substituent to the main structure is at the specified alkyl moiety.

The term substituted with one or more substituents as used herein means that one or more hydrogens on a specified atom or group are independently substituted with one or more substituents selected from the specified group of substituents. In some embodiments, substituted with one or more substituents means that the specified atom or group is substituted with 1, 2, 3, or 4 substituents independently selected from the specified group of substituents.

One skilled in the art will appreciate that certain 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 when there are two chiral centers, and mixtures partially enriched in certain diastereomers are within the scope of the present invention. In addition, one skilled in the art will understand that the present invention includes all individual stereoisomers (eg, enantiomers), racemic mixtures or partially dissolved mixtures of the compounds of formula (I) and, if necessary, their individual tautomeric forms.

In other words, in some embodiments, the present invention provides compounds of varying stereoisomeric purity, i.e., diastereomer or enantiomer purities are expressed by different ee values. (ee) or d.i. (de). In some embodiments, said compound of Formula (I) (eg, as described herein) has an enantiomeric purity of at least 60% ee. (e.g. 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% , 99.5%, 99.9% e.i. or any value between the specified numerical values). In some embodiments, said compound of formula (I) (e.g., described herein

- 4 044101 document) has an enantiomeric purity of more than 99.9% ee, up to 100% ee. In some embodiments, said compound of Formula (I) (eg, as described herein) has a diastereomeric purity of at least 60% d.i. (e.g. 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% , 99.5%, 99.9% d.i. or any value between the specified numerical values). In some embodiments, said compound of Formula (I) (eg, as described herein) has a diastereomeric purity greater than 99.9% d.i.

The term enantiomeric excess or e.i. denotes how much of one enantiomer is present compared to the other. For a mixture of R- and S-enantiomers, the percentage of enantiomeric excess is defined as |RS|*100, where R- and S are the respective molar or weight fractions of the enantiomers in the mixture such that R+S=1. Knowing the optical rotation of the chiral substance, the specified percentage of enantiomeric excess is determined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the specified mixture of enantiomers, and [a]max is the optical rotation of the pure enantiomer.

The term diastereomeric excess or d.i. denotes how much of one diastereomer is present compared to another and is determined by analogy with enantiomeric excess. Accordingly, for a mixture of diastereomers, D1 and D2, the specified percentage of diastereomer excess is defined as |D1-D2|*100, where D1 and D2 are the respective molar or weight fractions of the diastereomers in the mixture such that D1+D2=1.

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 polarimetry in accordance with conventional protocols known to those skilled in the art.

Racemates can be used as such or they can be separated into individual isomers. This separation may result in either stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (cf. Allinger NL and Eliel EL in Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using a chiral adsorbent. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be separated chemically from the mixture by forming diastereomeric salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid and the like, fractional crystallization of salts, after which one or both of the dissolved bases are released, optionally repeating the process to obtain one or both compounds essentially free from each other; those. in a form having an optical purity, for example, of at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight of the desired stereoisomer. Alternatively, said racemates may be covalently linked to a chiral auxiliary to produce diastereomers, which can be separated by chromatography or fractional crystallization, after which said chiral auxiliary is chemically removed to yield pure enantiomers, as is known in the art. specialists in this field of technology.

The term tautomer as used herein refers to constitutional isomers of compounds formed by the rapid movement of an atom between two positions in the molecule. Tautomers are easily interconvertible into each other, for example, the enol form and the ketone form are typical tautomers. For example, some of the compounds disclosed in this document may exist in forms a, b, c, d, e, f, etc., as shown in the figure below, i.e. compounds in forms a, b, c, d, e, f are possible tautomers of the compound of formula (I). A single tautomer and a mixture of these tautomers in any ratio are all included in the compounds described herein.

^'N R4-N ^R «'N

N^N Ν^ΝΗ ---HN^N

Pharmaceutically acceptable salt means a salt of the free acid or base compound of formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. For example, see S. M. 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.

- 5 044101

Additionally, if the compound described herein is prepared as an acid addition salt, the free base can be prepared by making the acid addition salt solution alkaline. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be prepared by dissolving the free base in a suitable solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from a base compound. Various synthetic methodologies are known to those skilled in the art that can be used without undue experimentation to produce non-toxic pharmaceutically acceptable acid addition salts.

The term solvates refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. When the solvent is water, the salt formed is a hydrate; when the solvent is alcohol, the salt formed is an alkoxide. Hydrates are formed by the combination of one or more molecules of water with one molecule of substances in which water retains its molecular state as H2O, and this combination is capable of forming one or more hydrates, such as hemihydrates, monohydrates and dihydrates, as well as variable hydrates.

In this text, the terms group, radical and residue are synonymous and denote functional groups or molecular fragments attached to other molecular fragments.

The term active ingredient is used to refer to a chemical substance that has biological activity. In some implementations, the active ingredient is a chemical substance having pharmaceutical value. In the United States, practical pharmaceutical activity can be established through appropriate preclinical assays, either in vitro or in vivo. Pharmaceutical activity sufficient to be recognized by a regulatory body such as the FDA in the US represents a higher standard than preclinical analysis. This higher standard of pharmaceutical activity, the success of which generally cannot be reasonably expected from preclinical results, can be established through appropriate and successful randomized, double-blind, controlled clinical trials in humans.

The terms treat or treat with respect to a disease or disorder in the context of achieving a therapeutic effect refer to the administration of one or more pharmaceutical substances, especially a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof described herein, to a subject who has the disease or disorder or who has a symptom of a disease or disorder or has a predisposition to a disease or disorder, for the purpose of treating, healing, alleviating, alleviating, altering, curing, ameliorating or influencing the disease or disorder, the symptoms of a disease or disorder or the predisposition to a disease or disorder. In some embodiments, the disease or disorder is cancer.

The terms processing, contacting and reacting in the context of a chemical reaction mean the addition or mixing of two or more reagents under appropriate conditions to obtain the specified and/or target product. It should be borne in mind that the reaction that leads to the indicated and/or target product may not necessarily be caused directly by the combination of the two reagents that were originally added, that is, one or more intermediates may be formed in the mixture, ultimately leading to to the formation of the specified and/or target product.

The term effective amount as used herein refers to an amount or dose of a mutant IDH inhibitor sufficient to generally provide therapeutic benefit to patients in need of treatment of a disease or disorder caused by an IDH mutation. Effective amounts or dosages of the active ingredient of the present invention may be determined by methods such as modeling, dose escalation studies, or clinical trials, and by taking into account factors such as the mode or route of administration or delivery of the drug, the pharmacokinetics of the agent, the severity and course of the drug. disease or disorder, the subject's previous or ongoing treatment, the patient's medical condition and response to medications, and the decisions of the treating physician. In the United States, determination of effective doses is generally difficult to predict from preclinical trials. In fact, such a dose is completely unpredictable and the specified dose develops a new unpredictable dosing regimen after initial use in a randomized, double-blind, controlled clinical trial.

An exemplary dose ranges from about 0.0001 to about 200 mg of active substance per kg of subject body weight per day, such as from about 0.001 to 100 mg/kg/day or about 0.01 to 35 mg/kg/day or approximately 0.1 to 10 mg/kg per day in single or divided doses (e.g., BID, TID, QID). For a 70 kg person, an approximate suitable dosage range is from about 0.05 to about 7 g/day or from about 0.2 to about 5 g/day. After the improvement

- 6 044101 depending on the patient's condition or disease, the dose may be adjusted for maintenance treatment. For example, the dosage or frequency of administration, or both, may be reduced depending on symptoms to a level that maintains the desired therapeutic effect. Of course, if symptoms have been mitigated to an appropriate level, treatment can be discontinued. However, patients may require intermittent treatment over a long period of time if symptoms recur.

The term subject as used herein means mammals and non-mammals. Mammals means any member of the class Mammals, including humans; non-human primates such as chimpanzees and other apes and apes; farm animals such as cattle, horses, sheep, goats and pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; and the like, but not limited to them. Non-mammal examples include, but are not limited to, birds and the like. The term subject does not designate a specific age or gender. In some embodiments, the subject is a human.

Generally, the term is roughly used in said document to change a numerical value above and below a stated value by an amount of 20%.

Technical and scientific terms used herein, when not specifically defined, have the meaning commonly understood by one skilled in the art to which this description relates.

Proposed compound of formula (I)

(I) and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein

l.

y and

A is selected from ^{Rt or n} >

wherein R ₇ is selected from H, halo, -CN, -OH or -NH ₂ ;

R1 is selected from H, -OH, halo, C _1-6 αlkyl, C ₁ . ₆ alkoxyl, -NH ₂ , -NH(C ₁ . ₄ alkyl), -N(C ₁ . ₄ alkyl) ₂ , oxo or C ₃ . ₈ cycloalkyl;

each of R2 is independently selected from 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(R ₅ )(C ₁ . ₄ alkyl), -COR5, -NHCOR5 or 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S; in which each of the specified C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl or 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, optionally containing as substituents one or more groups selected from deuterium, halo, -CN, -OH, -SH, -NH2, -NH(C ₁ . ₄ alkyl), -N(C ₁ . ₄ alkyl) ₂ or C ₁ . ₆ alkoxy; or two R2 which are attached to the same carbon atom, together with said carbon atom to which they are attached to form a 3-5 membered cycloalkyl which optionally contains one or more halo or deuterium as substituents;

R3' and _R4 ' are both H; and R3 and R4 are independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, -C( O)R ₅ , -OR ₅ or -NHR ₅ , in which each of the specified C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optional contains one or more R6 as substituents; provided that R3 and R4 are not both H; with the proviso that when one of R3 and R4 is an optionally substituted phenyl or, optionally, a substituted 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S the other is -OR5 or -NHR5 ;

or

R3 and R3' are independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl, 5-12 membered heteroaryl, -C(O)R ₅ , -OR5 or -NHR5, in which each indicated C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-12 membered heteroaryl,

- 7 044101 containing one or more heteroatoms independently selected from N, O and S, optionally containing one or more R ₆ as substituents; a

R ₄ and R ₄ ' together with the N atom to which they are attached to form a 3-8 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O and S, optionally substituted with one or more R ₆ ;

R5 is selected from C ₁ . ₆ αlkyl or C ₃ . ₈ cycloalkyl, each of which optionally contains as substituents one or more groups independently selected from halo, -CN, -OH, -SH, -NH2 or C ₁ . ₆ αlkoxylα;

each of R ₆ is independently selected from deuterium, halo, -CN, -OH, -SH, -NH2, C ₁ . ₆ alkoxyl, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₃ . ₈ cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, in which each of the above C ₁ . ₆ αlkoxyl, C ₁ . ₆ alkyl, C ₃ . ₈ cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optionally contains in as substituents one or more groups independently selected from halo, -CN, -OH, -SH, -NH2, C ₁ . ₆ alkoxyl, C ₁ . ₆ αlkynyl or C ₁ . ₆ alkyl;

m is 0, 1, 2, 3, 4, 5 or 6;

n is 0, 1 or 2.

In some embodiments of the compound of Formula (I), R ₁ is selected from H, -OH, or halogen.

In some embodiments of the compound of Formula (I), R ₁ is selected from -OH or halogen.

In some embodiments of the compound of formula (I), R ₁ is -OH.

In some embodiments of the compound of formula (I), R ₁ is a halogen selected from F, Cl, or Br. In some embodiments of the compound of Formula (I), R ₁ is F.

In some embodiments of a compound of formula (I), the two R ₂ that are attached to the same carbon atom, together with the carbon atom to which they are attached to form a 3- to 5-membered cycloalkyl, are optionally substituted with one or more Fs.

In some embodiments of the compound of formula (I), two R ₂ that are attached to the same carbon atom, together with the specified carbon atom to which they are attached, form cyclopropyl.

In some embodiments of the compound of formula (I), each of R2 is independently selected from H, deuterium, halogen, -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(R ₅ )(C ₁ . ₄ alkyl), -NHCOR5 or 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S.

In some embodiments of the compound of formula (I), each of R2 is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, oxo _, -OR5, -NHR5 or -N( _R5 )( _C1.4 αalkyl).

In some embodiments of the compound of formula (I), each of R ₂ is independently selected from H, deuterium, halogen, C ₁ . ₆ alkyl or C ₁ . ₆ haloalkyl.

In some embodiments of the compound of formula (I), each R ₂ is independently selected from a halogen such as F, Cl, or Br.

In some embodiments of a compound of formula (I), R2 is F. In some embodiments of a compound of formula (I), m is 0, 1, 2, 3, or 4. In some embodiments of a compound of formula (I), m is 0, 1, or 2.

In some embodiments of a compound of formula (I), m is equal to 1. In some embodiments of a compound of formula (I), m is equal to 2. In some embodiments of a compound of formula (I), m is equal to 3. In some embodiments of a compound of formula (I), m is equal to 4.

In some embodiments, the compounds of formula (I) R3 and R4 are independently selected from C ₁ . ₆ αlkyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, - C(O)R ₅ , -OR ₅ or -NHR ₅ , in which each of the specified C ₁ . ₆ alkyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optional contains one or more R6 as substituents.

In some embodiments of the compounds of formula (I), R3' and R4' are both H.

In some embodiments, the compounds of formula (I) R3 and R4 are independently selected from C ₁ . ₆ αlkyl, C ₃ . ₁₂ cycloalkyl or 3-12 membered heterocyclyl, each of which optionally contains one or more R ₆ as substituents; _R3 ' and R4' are both H.

In some embodiments, the compounds of Formula (I), R3 and _R4 are independently selected from _C1 . ₆ αlkyl substituted with one or more halogens, 5-12 membered heteroaryl containing one or

- 8 044101 more heteroatoms independently selected from N, O and S, substituted with C _1-6 haloalkyl or -OR5.

In some embodiments, compounds of formula (I) R ₃ and R 4 are independently selected from

C _1-6 alkyl, optionally substituted with one or more halogens; _R3 ' and _R4 ' are both H.

In some embodiments of the compound of formula (I), R ₃ is a 5-12 membered heteroaryl substituted with C _1-6 haloalkyl, R 4 is a C _1-6 alkoxy; _R3 ' and R4' are both H.

In some embodiments of the compound of formula (I), R ₃ is 5-7 heteroaryl substituted with CF ₃ , R 4 is C _1-6 alkoxy; _R3 ' and R4' are both H.

In some embodiments of the compound of formula (I), R ₃ is selected from H, C _1-6 alkyl, optionally substituted with C _1-6 haloalkyl, or 5-12 membered heteroaryl, optionally substituted with C _1-6 haloalkyl; R ₃ ' represents H; R4 and R4', together with the N atom to which they are attached, form a 3-8 membered heterocyclic ring, optionally substituted with one or more groups selected from halogen, -OH or C _1-6 haloalkyl.

In some embodiments of the compound of formula (I), R5 is C _1-6 alkyl or C _3-8 cycloalkyl.

In some embodiments of the compound of formula (I), R5 is C _1-6 alkyl, optionally substituted with one or more halogens.

In some embodiments of the compound of formula (I), each of R6 is independently selected from deuterium, halogen, -CN, -OH, -NH2, _C1-6 alkoxyl, _C1-6 αalkylα, _C1-6 haloalkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, in which each of said C _1-6 alkoxyl, C _1-6 alkylα, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optionally contains one or more halogen atoms as substituents.

In some embodiments of the compound of formula (I), each of R ₆ is independently selected from deuterium, halogen, -OH, C _1-6 alkoxyα, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkylα, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.

In some embodiments of the compound of formula (I), each of R6 is independently selected from deuterium, halogen, -CN, -OH, -NH2, _C1-6 alkoxy, _C1-6 alkyl, _C1-6 haloalkyl, or _C3-8 cycloalkyl.

In some embodiments of the compound of formula (I), each R ₆ is independently selected from deuterium, halogen, or Ci-6 haloalkyl.

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

In some embodiments, the compounds of formula (I) R ₇ and R 8 are independently selected from halogen or -CN.

In some embodiments, the compounds of formula (I) R ₇ and R 8 are independently selected from F or -CN.

In some embodiments of a compound of formula (I), said compound of formula (I) is selected from

wherein X represents a halogen;

R1, _R2 , _R3 , _R3 ', R4, R4', m and n, as defined for the specified compound of formula (I).

In some embodiments of a compound of formula (I), said formula (I) is formula (I-1), wherein R1, _R2 , _R3 , _R3 ', R4, _R4 ', m, and n are as defined for said compound of formula (I)

- 9 044101

In some embodiments of a compound of formula (I), said formula (I) is formula (I-1a), wherein R2, _R3 , _R3 ', R4, R4', m, and n are as defined for said compound of Formula ( I)

In some embodiments of a compound of formula (I), said formula (I) is formula (I-1b), wherein R2, _R3 , _R3 ', _R4 , _R4 ', m, and n are as defined for said compound formula (I)

In some embodiments of a compound of formula (I), said formula (I) is formula (II), wherein R1, R2, _R3 , _R3 ', R4, R4', n, and A are as defined for said compound of formula ( I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2

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

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

In some embodiments of the compound of Formula (II), R1 is -OH.

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

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

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

In some embodiments of a compound of formula (I), formula (II) is selected from

wherein R1, R2, _R3 , _R3 ', R4, R4', m and n, as defined for the specified compound of formula (I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2.

In some embodiments of a compound of formula (I), formula (II) is formula (II-1), wherein R1, R2, _R3 , _R3 ', R4, R4', m, and n are as defined for said compound of formula (I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2

- 10 044101

In some embodiments of a compound of formula (I), formula (II) is formula (II-1a), wherein R2, _R3 , _R3 ', _R4 , _R4 ', m, and n are as defined for said compound of formula (I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2

In some embodiments of a compound of formula (I), formula (II) is formula (II-1b), wherein R2, _R3 , _R3 ', _R4 , R4', m, and n are as defined for said compound of formula ( I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2

In some embodiments of the compound of formula (II-1), in formula (II-5) X is F.

In some embodiments of the compound of formula (II-1), in formula (II-5), R1 is F.

In some embodiments of the compound of formula (II-1), in formula (II-5), R1 is -OH.

In some embodiments of the compound of formula (II-1), in formula (II-5), p is 0.

In some embodiments of the compound of formula (II-1), in formula (II-5), p is 1.

In some embodiments of the compound of formula (II-1), in formula (II-5), p is 2.

In some embodiments of a compound of formula (I), formula (I) is formula (III), wherein R1, R2, _R3 , _R3 ', _R4 , R4', n, and A are as defined for said compound of formula ( I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2; v is 0, 1 or 2

In some embodiments of the compound of formula (III), X is F.

In some embodiments of the compound of Formula (III), R1 is F.

In some embodiments of the compound of Formula (III), R1 is -OH.

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

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

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

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

In some embodiments of the compound of Formula (III), v is equal to 1.

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

In some embodiments of a compound of formula (I), formula (III) is selected from

- 11 044101

(HM) d"-5) wherein R _b R2, R ₃ , R ₃ ', R4, R4', m and n, as defined for the specified compound of formula (I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2; v is 0, 1 or 2.

In some embodiments of a compound of formula (I), formula (III) is formula (III-1), wherein R1, _R2 , _R3 , _R3 ', R4, R4', m, and n are as defined for said compound formula (I); X represents halogen; p is 0, 1 or 2; m is 0, 1 or 2; v is 0, 1 or 2

Wp Il'S /U ¹ r ₃ ·

V>v ^P (^2)t (111-1)

In some embodiments of the compound of formula (III-1), in formula (III-5), X is F.

In some embodiments of the compound of formula (III-1), in formula (III-5), R1 is F.

In some embodiments of the compound of formula (III-1), in formula (III-5), R1 is -OH.

In some embodiments of the compound of formula (III-1), in formula (III-5), p is 0.

In some embodiments of the compound of formula (III-1), in formula (III-5), p is 1.

In some embodiments of the compound of formula (III-1), in formula (III-5), p is 2.

In some embodiments of the compound of formula (III-1), in formula (III-5), v is 0.

In some embodiments of the compound of formula (III-1), in formula (III-5), v is equal to 1.

In some embodiments of the compound of formula (III-1), in formula (III-5), v is 2.

Also provided is a compound selected from Compounds 1-87, 89-184, 186-301, numbered in the experimental part, and/or a pharmaceutically acceptable salt thereof.

In another aspect, a pharmaceutical composition is provided containing a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and optionally containing at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

In another aspect, there is provided a method of treating a disease caused by an IDH mutation in a subject, comprising administering to the subject in need thereof an amount of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, effective for inhibiting the increase in α-hydroxyglutaric acid (2-HG) caused by an IDH mutation in the subject.

In another aspect, there is provided a method of treating a disease caused by an IDH mutation in a subject, comprising administering to the subject in need thereof an amount of a pharmaceutical composition containing a compound of formula (I) (e.g., any of the compounds described herein) and/or its a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient (eg, a pharmaceutically acceptable carrier) effective for inhibiting the increase in α-hydroxyglutaric acid (2-HG) caused by an IDH mutation in the subject.

Another aspect provides the use of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof described herein for the treatment of a disease caused by an IDH mutation by inhibiting the increase in α-hydroxyglutaric acid. (2-GG) caused by an IDH mutation in the specified subject.

Another aspect provides the use of a compound of formula (I) (eg, any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof as described herein for the manufacture of a medicament for the treatment of a disease caused by an IDH mutation.

In some embodiments, said IDH mutation is a mutation in the IDH1 gene. In some embodiments, said IDH mutation is a mutation in the IDH2 gene.

In some embodiments, the IDH mutation is the IDH1-R132H or IDH2-R140Q gene mutation.

In some embodiments, the disease caused by the IDH mutation is cancer.

In some embodiments, the cancer is selected from a solid cancer, a neurogliocytoma, or a hematologic malignancy such as leukemia, lymphoma, or myeloma.

In some embodiments, said cancer is selected from acute myeloid leukemia (AML), acute promyeloid leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), cholangiocarcinoma, chondrosarcoma, giant cell tumor, gastrointestinal cancer tract, melanoma, lung cancer or non-Hodgkin lymphoma (NHL).

In some embodiments, said cancer is intrahepatic cholangiocarcinoma (IHCC).

In another aspect, there is provided a compound of formula (IV) and/or a salt thereof, and/or racemic mixtures or enantiomers thereof, which can be used to prepare compounds of formula (I) (for example, any of the compounds described herein)

(IV) wherein R1 represents -OH or oxo, R2 and m as defined for the specified compound of formula (I); n is 1 or 2; Ra selected from halogen, -OS(O)2CF ₃ , -B(OH) ₂ , -B(OC _1-6 alkyl) ₂

R _b represents H or C _1-6 alkyl.

In some embodiments of the compound of formula (IV), Ra is selected from -B(OH) ₂ , -B(OC _1-6 alkyl) ₂ ,

R _b represents H or C _1-6 alkyl.

In some embodiments of the compound of formula (IV), Ra is selected from -B(OH) ₂ , -B( _OSH3 ) ₂ , -B[OSH(CH3)2]2,

In some embodiments of a compound of formula (IV), formula (IV) 1), wherein m is 0, 1, or 2, is formula (IV-

In some embodiments, the compound of formula (IV) has formula (IV) 2), wherein X is halogen; m is 0, 1 or 2

Ch?n G is the formula (IV ^x (IV-2)

In some embodiments of the compound of formula (IV), formula (IV) is formula (IV3), wherein X is halogen; p is 0, 1 or 2; m is 0, 1 or 2

- 13 044101

In some embodiments of the compound of Formula (IV), R1 is -OH or oxo.

In some embodiments of a compound of formula (IV), X is F. In some embodiments of a compound of formula (IV), p is 0. In some embodiments of a compound of formula (IV), p is 1. In some embodiments of a compound of formula (IV) p equals 2.

In some embodiments of a compound of formula (IV), said compound of formula (IV) is selected from χ\Λ ^ΟΗ /\L ^OH pc, φ; ςχ, ςχ,

Ra Ra Ra or Ra.

In some embodiments of a compound of formula (IV), said compound of formula (IV) is selected from

Basic methods for synthesizing the disclosed implementation options

Said compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be synthesized from commercially available starting materials by methods well known in the art, taken in conjunction with the disclosures in this patent application. Fig. 1-6 illustrate general methods for preparing the compounds described herein.

As shown in FIG. 1, the substitution reaction of 2,4,6-trichloro-1,3,5-triazine with an amine substituted with R ₃ and R ₃ ' gives the compound of formula 1-1. The substitution reaction of a compound of formula 1-1 with an amine substituted with R ₄ and R ₄ ' results in a compound of formula 1-2. The Suzuki addition reaction of a compound of formula 1-2 with an intermediate represented by formula (IV), under catalytic conditions with a suitable palladium reagent, produces a compound of formula (I-1) described herein, wherein R1, _R2 , _R3 , R ₃ ', R4, R4', Ra, m, and n as defined herein. The palladium-catalyzed C-C addition 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 and the like, the base used can be selected from Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ and the like, and the catalyst used may be selected from Pd(dppf)Cl ₂ -CH ₂ Cl ₂ , Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ and similar connections.

As shown in Scheme 2, the Suzuki addition reaction of a compound of formula 1-1 with the intermediate represented by formula (IV), under catalysis conditions with a suitable palladium reagent, gives the compound of formula 2-1. The substitution reaction of a compound of formula 2-1 with an amine substituted with R4 and R4' results in a compound of formula (I-1) described herein, wherein R1, _R2 , _R3 , _R3 ', R4, R4', R _a , m , and n as defined herein.

As shown in Scheme 3, the Suzuki addition reaction of a compound of formula 1-2 with the intermediate represented by formula (IV-1), under catalysis conditions with a suitable palladium reagent, gives the compound of formula 3-1. The palladium-catalyzed C-C addition reaction can be carried out under suitable conditions, and the solvent used can be selected from polar solvents such as 1,4-dioxane, DMF, THF, a mixture of 1,4-dioxane and water and the like, the base used can be selected from Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ and the like, the catalyst used may be selected from Pd(dppf)Cl ₂ -CH ₂ Cl ₂ , Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ and similar connections. Reduction of the compound of formula 3-1 results in the compound of formula (I-1α) described herein.

As shown in Scheme 4, the Suzuki addition reaction of a compound of formula 1-1 with the intermediate represented by formula (IV-1), under catalysis conditions with a suitable palladium reagent, gives the compound of formula 4-1. Reduction of the compound of formula 4-1 gives the compound of formula 4-2. The substitution reaction of a compound of formula 4-2 with an amine substituted with R4 and R4' results in the compound of formula (I-1a) described herein.

As shown in Scheme 5, the Suzuki addition reaction of the compound of formula 1-2 with the intermediate represented by formula (IV-2), under catalysis conditions with a suitable palladium reagent, gives the compound of formula 5-1. Halogenation of a compound of Formula 5-1 using a halogenating reagent such as NFSI and similar compounds in the presence of a base such

- 14 044101 as LiHMDS, KHMDS, LDA and similar compounds, and in a suitable polar solvent such as

THF, DCM and similar compounds give the compound of formula 5-2. Reduction of the compound of formula 5-2 results in the compound of formula (P-1a) described herein.

As shown in Scheme 6, the compound of formula 3-1 reacts with a deuterating agent such as NaBD ₄ , deuterated borane and the like to produce the compound of formula (I-1b) described herein.

The substituents of the compounds thus obtained can be further modified to yield other desired compounds. Synthetic chemistry 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 their subsequent editions.

Before use, the specified compound of formula (I) and/or its pharmaceutically acceptable salt described herein can be purified using column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

Pharmaceutical compositions and practical use

Said compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof as described herein is used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions. The pharmaceutical composition includes: (a) an effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof as described herein; and (b) a pharmaceutically acceptable excipient (eg, a pharmaceutically acceptable carrier).

A pharmaceutically acceptable carrier refers to carriers that are compatible with the active ingredients of the composition (and in some embodiments, capable of stabilizing said active ingredients) and are not harmful to the subject being treated. For example, solubilizers such as cyclodextrins (which form specific, more soluble complexes with the specified compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein) can be used as pharmaceutical excipients for the delivery of these active ingredients. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a commonly cited text in the art.

A pharmaceutical composition containing a compound of formula (I) (for example, any compound described herein) and/or a pharmaceutically acceptable salt thereof described herein can be administered by various known routes, such as orally, topically, rectally, parenterally, inhalation by spray or using an implantable reservoir. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intrarenal, and intracranial injection or infusion techniques.

The pharmaceutical composition described herein may be in the form of a tablet, capsule, sachet, dragee, powder, granules, lozenge, preparation powder, liquid preparation or suppository. In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof is formulated for intravenous infusion, topical administration, or oral administration.

The oral composition may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added to these tablets. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase in combination with emulsifying or suspending agents. Certain sweeteners, flavors or colors may be added if desired.

In some embodiments, said compound of formula (I) and/or a pharmaceutically acceptable salt thereof 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, said compound of Formula (I) and/or a pharmaceutically acceptable salt thereof may be present in the 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.

A sterile injectable composition (eg, an aqueous or oleaginous suspension) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable intermediate may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, a fixed oil (eg, synthetic mono- or diglycerides) is usually used as a solvent or suspending medium. Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable intermediates, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant or carboxymethylcellulose or similar dispersing agents.

The inhalation composition may be prepared according to techniques well known in the pharmaceutical composition art and may be formulated as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other solubilizing or dispersing agents. agents known in the art.

The topical composition may be formulated as an oil, cream, lotion, ointment, or the like. Suitable carriers for this composition include vegetable or mineral oils, petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (containing more than 12 carbon atoms). In some embodiments, said active ingredient is soluble. Emulsifiers, stabilizers, wetting agents and antioxidants may also be included, as well as coloring or flavoring agents if desired. In addition, transdermal penetration enhancers may be used in these topical formulations. Examples of such amplifiers can be found in US patents 3989816 and 4444762.

Creams can be made from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredient is mixed, dissolved in a small amount of oil, such as almond oil. An example of such a cream includes a cream containing, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments can be prepared by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and then cooling the mixture. An example of such an ointment is an ointment that contains about 30% by weight almond oil and about 70% by weight white soft paraffin.

Suitable in vitro assay methods can be used to evaluate the utility of the compounds of Formula (I) and/or their pharmaceutically acceptable salts described herein for inhibiting IDH mutation. such a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein may be further investigated to explore additional practical utility in the treatment of cancer using in vivo assays. For example, a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be administered to an animal (eg, a mouse model) having cancer, and the results of studies of its therapeutic effect can be accessed. If preclinical results are successful, a dosage range and route of administration can be predicted for animals and humans.

The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein may be shown to have sufficient preclinical utility to merit clinical trials in which there is hope of demonstrating a beneficial therapeutic or prophylactic effect, e.g. , in patients with cancer.

As used herein, the term cancer refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, decreased cellular differentiation, inadequate ability to invade surrounding tissues, and/or the ability to form new lesions at ectopic sites. The term cancer includes, but is not limited to, solid tumors and hematologic malignancies. The term cancer includes diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term cancer also includes primary and metastatic cancer.

Examples of solid tumors include pancreatic cancer; colon and rectal 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 cancer; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar cancer (BAC) and lung adenocarcinoma; ovarian cancer, including, for example, advanced epithelial or primary peritoneal cancer; cervical cancer; stomach cancer; esophageal carcinoma; head and neck cancer, including e.g.

- 16 044101 squamous cell carcinoma of the head and neck; skin cancer, including, for example, malignant melanomas; neuroendocrine cancer, 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, but not limited to.

Examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (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); Waldenström's macroglobulinemia; myelodysplastic syndrome (MDS), including but not limited to refractory anemia (RA), refractory anemia with ring siderblasts (RARS), refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) and myeloproliferative syndromes.

In some embodiments, typical hematologic malignancies include leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); multiple myeloma (MM); Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma and Diffuse large cell lymphoma (DLBCL).

Said compound of formula (I) and/or a pharmaceutically acceptable salt described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in patients with cancer.

Also, a compound of formula (I) (eg, any of them described herein) and/or a pharmaceutically acceptable salt thereof described herein can be used in combination with additional active ingredients in the fight against cancer. Additional active ingredients may be administered separately concomitantly with a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein or included in a pharmaceutical composition with such ingredient as described herein as a fixed-dose combination drug product. In one embodiment, the additional active ingredients are ingredients already known or to be discovered that are effective in treating diseases caused by an IDH mutation, such as other IDH mutation inhibitors, or compounds active against another target associated with a specific disease. The combination may serve to increase efficacy (for example, by including in the combination a compound that enhances the activity or efficacy of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein), reduce one or more side effects, or reduce the required dose of the compound Formula (I) and/or a pharmaceutically acceptable salt thereof described herein.

In some embodiments, the specified compound of formula (I) (eg, any of them described herein) and/or a pharmaceutically acceptable salt thereof, which is described herein, is administered in combination with an antitumor agent. As used herein, the term antineoplastic agent refers to any agent that is administered to a subject with cancer to treat said cancer. Examples of antineoplastic agents include: radiation therapy; immunotherapy; DNA damaging chemotherapeutic agents; and, but not limited to, chemotherapeutic agents that interfere with cell replication.

Examples of DNA-damaging chemotherapeutic agents include topoisomerase I inhibitors (eg, irinotecan, topotecan, camptothecin and their analogs or metabolites, and doxorubicin); topoisomerase II inhibitors (eg, etoposide, teniposide, mitoxantrone, idarubicin and daunorubicin); alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C and cyclophosphamide); DNA intercalators (eg, cisplatin, oxaliplatin and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (eg, but not limited to, 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine (VIDAZA®); mercaptopurine, thioguanine, pentostatin and hydroxyurea).

Chemotherapeutic agents that interfere with cell replication include: paclitaxel, docetaxel and related analogs; vincristine, vinblastine and corresponding analogues; thalidomide and related analogues (eg CC-5013 and CC-4047); protein tyrosine kinase inhibitors (eg, imatinib, mesylate and gefitinib); proteasome inhibitors (eg, botrezomib); NF-kappa B inhibitors, including kappa B kinase I inhibitors; antibodies that bind to proteins overexpressed in cancer and thereby inhibit cell replication (for example, trastuzumab, rituximab, cetuximab and bevacizumab); and other inhibitors of proteins or enzymes known to be overexpressed or activated in cancer, the inhibition of which inhibits cell replication.

Examples

The examples below are intended to describe examples and should not be construed as limiting the scope of the present invention. Efforts have been made to ensure the accuracy of the numbers used (e.g. quantity, temperature, etc.), but some experimental errors and deviations should be taken into account. 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 acquired using an Agilent 6120 or Agilent 1100. All NMR data were acquired using a Varian 400-MR instrument. All reagents, except intermediates, used in this invention are commercially available. All compound names except reagents were generated by Chemdraw 12.0.

If any one of the structures disclosed herein contains any atom with empty valence(s), then the empty valence(s) is the hydrogen atom(s), which are omitted for convenience.

In this application, in the event of a discrepancy between the structure and the name of a compound when both options are given for the specified compounds, the structure of the specified compound should be used unless the context shows that the specified structure of the compound is incorrect and the name is correct.

The following examples use the abbreviations below:

AcOK - potassium acetate

BAST - bis(2-methoxyethyl)aminosulfotrifluoride

BINAP - (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene t-BuONa - sodium tert-butoxide (n-Bu ₃ Sn) ₂ - 1,1,1,2,2,2 -hexabutyldistannan (S)-CBS- - (S)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole

CD ₃ OD - methanol-d ₄

DAST - diethylaminosulfotrifluoride

DCM/DCM - dichloromethane

DIEA - K,K-diisopropylethylamine

DMF - N,N-dimethylformamide

DMSO-d ₆ - dimethyl sulfoxide-d ₆

EA/EtOAc/EA - ethyl acetate

Et ₃ N - triethylamine

EtOH - ethanol

Et ₂ Zn - diethylzinc g - gram

HC(OMe) ₃ - trimethyl orthoformate l - liter

LiHMDS - lithium bis(trimethylsilyl)amide

M - mol/l

MeOH - methanol

MeCN - acetonitrile mg - milligram ml - milliliter mmol - millimole mol - mol

NaBH(OAc)3 - sodium triacetoxyborohydride

NaOMe - sodium methoxide

NaOEt - sodium ethoxide

NCS - N-chlorosuccinimide

NFSI - N-fluorobenzenesulfonimide

PdCl ₂ (PPh ₃ ) ₂ - bis(triphenylphosphine) palladium(I) dichloride

Pd(dba) ₃ - tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)Cl ₂ - [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(P)

Pd(dppf)Cl ₂ -CH ₂ Cl ₂ - complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) + dichloromethane

Pd(PPh ₃ ) ₄ - tetrakis(triphenylphosphine)palladium(0)

RE/PE - petroleum ether

Selectfluor® - 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

TBAF - tetrabutylammonium fluoride

TBSOTf - tert-butyldimethylsilyltrifluoromethanesulfonate

TFA - trifluoroacetic acid

- 18 044101

Tf2O - trifluoromethanesulfonic anhydride

THF/THF - tetrahydrofuran

TsOH-H2O - 4-methylbenzenesulfonic acid monohydrate

Example 1.

Obtaining intermediate compounds

Intermediate I-1:

3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene -1-ol and intermediate I-61 (*)3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazine -2-yl)-2-fluorocyclohex-2-en-1 ol

(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 for 96 h under nitrogen atmosphere. 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 (PE/EA gradient elution=100:0-0:100), resulting in compound A1 as a white solid (7.7 g, yield: 22%). MS (m/z): 131.1 [M+H]+ (B) 2-fluoro-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate (A2)

Compound A1 (208 mg, 1.6 mmol) was dissolved under nitrogen in DCM and cooled to 0°C. DIEA (415 mg, 3.2 mmol) and Tf ₂ O (540 mg, 1.92 mmol) were then added at 0°C and the resulting mixture was stirred for 2 hours at 0°C under nitrogen. After completion of the reaction, it was stopped by adding water and extracted with dichloromethane. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA elution) to obtain compound A2 as a yellow oil (220 mg, yield: 52.5%). MS (m/z): 263.0 [M+H] ⁺ (C) (R)-4,6-dichloro-N-(1,1,1-trifluoropropan-2-yl)-1,3,5 -triazine-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-trifluoropropane-2 was added -amine hydrochloride (7.37 g, 49.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was adjusted to pH=7 by adding saturated aqueous NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100) to obtain compound A3 as a colorless oil (7.8 g, yield: 60.6%) . MS (m/z): 260.9 [M+H] ⁺ (D) (R)-3-(4-chloro-6-(( 1,1,1 -trifluoropropan-2-yl)amino)-1 ,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-1 he (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)Cl ₂ (0.63 g, 0.77 mmol) in 1,4-dioxane (40 ml) was stirred under nitrogen at reflux for 2 hours. The reaction mixture was then cooled to room temperature, and then compound A3 (4.0 g, 15.3 mmol), Cs ₂ CO ₃ (14.4 g, 38.3 mmol), Pd(PPh ₃ ) ₄ (0.89 g, 0.77 mmol) and water (8 ml). The reaction mixture was stirred at 80°C for an additional 2 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (elution with a gradient of PE/EA=100:0-0:100), resulting in the compound A4 as a white solid (0.8 g, yield: 15.4%). MS (m/z): 339.0 [M+H] ⁺ (E) 3-(4-chloro-6-(((R)-1,1,1 -trifluoropropan-2-yl)amino)-1 ,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-1

- 19 044101 ol (I-1)

Compound A4 (1150 mg, 3.41 mmol), CeCl ₃ ·7H ₂ O (1269 mg, 3.41 mmol) and EtOH (20 ml) were added to the flask. The mixture was cooled to 0°C, NaBH ₄ (130 mg, 3.41 mmol) was added and the resulting mixture was stirred at 0°C for 2 hours. After completion of the reaction, the mixture was stopped by adding a saturated aqueous solution of NH ₄ Cl (10 ml) and water (50 ml) and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in I-1 as a white solid (800 mg, yield: 68.9%) . MS (m/z): 341.2 [M+H]+ (F) (*)3-(4-chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino )-1,3,5-triazin-2-yl)-2-fluorocyclohex-2en-1-ol (I-61)

To dry THF (5 mL) under nitrogen, add 1 mol/L (S)-CBS/TFO solution (2.4 mL, 2.4 mmol) at ice bath temperature, then add 2 mol/L BH ₃ solution in one portion Me ₂ S/THF (2.4 ml, 4.8 mmol). After stirring for 2 minutes, compound A4 (800 mg, 2.4 mmol) in THF (3 ml) was added dropwise to the above solution. After stirring at ice bath temperature for 1 hour, 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 ethyl acetate (10 ml). The organic layers were combined, dried over Na ₂ SO ₄ , and filtered. The filtrate was condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in intermediate I-61 as a white solid (360 mg). MS (m/z): 341.2 [M+H]+

The compounds listed in the table below were prepared in accordance with the specified procedure for preparing Intermediate I-1 using the appropriate Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Intermediate connection Structure MS (M+N) ⁺ Intermediate connection Structure MS (M+H) ⁺ 1-22 , 2 1 A A NN CI N 314.0 1-25 %γ ^ΟΗ CF ₃ A An^n^ci 323.0 1-23 9 , A A A A Ν XI 279.1 1-80 σ°CI^NH 285.0 1-24 2.A A vAn n ci V n 265.1

Intermediate I-2: (R)-6-chloro-N ² -isopropyl-N ⁴ -(1,1,1-trifluoropropan-2-yl)-1,3,5triazin-2,4-diamine

AZ 1-2

Compound A3 (3.5 g, 13.4 mmol), propan-2amine (872 mg, 14.7 mmol), DIEA (3.5 g, 26.8 mmol) and THF (20 ml) were added sequentially to a sealed tube. and stirred the mixture at 50°C overnight. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution) to obtain Intermediate I-2 as a white solid (3.8 g, yield: 100%). MS (m/z): 284.0 [M+H]+

The compounds listed in the table below were prepared in accordance with the procedure for preparing Intermediate I-2 using the Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

- 20 044101

Intermediate connection Structure MS (M+H) ⁺ Intermediate connection Structure MS (M+H) ⁺ 1-7 CI CF ₃ N^N A A A / Gan n nV, Η Η |όη 314.0 1-50 \J ^N ^ ^N I N\JI J 11 A 1 HH 318.0 1-8 CI CF ₃ Ν^Ν ι—\ A Α Α Χ/° Ga Ν ν N*fsr Η Η 312.0 1-51 ^ClN ^ ^N । \\D L aa 1 Η Η 321.0 1-9 CI AF CF ₃ Ν^ Ν ,-G AAA A/ ^F G ^N H 332.0 1-54 Cl AF CF ₃ N^ N rJ •WA ^F HH 332.0 1-11 AV CF ₃ N r-\ AAA A / Ga ν n nAt HH 346.0 1-55 Cl CF ₃ N^N AAA Άν ν νΑΑ ^HH II JL 362.1 1-12 Cl CF ₃ N^N g-L A A A A / An ν n HH 310.0 1-71 Cl CF ₃ N^NI ΆνΆΑνΆ HH 284.0 1-13 Cl CF ₃ N^N AAA Ga NN NA^ η h | 298.1 1-72 Cl CF ₃ N^N < ^F Ga'n'^n'^n'^ ^x ' ^f HH 320.4 1-14 Cl CF ₃ N^N AAA An n nG-t η h VA ^F F 346.0 1-73 Cl χΆ l Ga ν ν νΆ V 308.1 1-15 Cl ΐΆ G HH 296.0 1-74 ci ^F \AG Jb-y N^NG ^F VA AAA 'Ν Ν ΝΆ HH 296.1 1-16 Cl A'L A ΆινΑν'Ά'^ HH 282.0 1-75 Cl AAA An % JI J l AO η h 350.9 1-17 Cl CF ₃ N^N AAA o Ga ν n Η Η 300.0 1-76 Cl CF ₃ N^N AAA Ga NNN CF ₃ HH 323.9 1-18 Cl CF ₃ N^N AAA / GaN N HH 284.0 1-77 Cl CF ₃ N^N AAA Ga'n n nA η η V 296.0 1-19 Cl CF ₃ N^N AAA Ga nn n'^ HH 270.0 1-78 Cl CF ₃ N^N AAA / Ga ν n HH 284.0 1-20 Cl CF ₃ N^N AAA 1 J Ga NNN^^ HH 324.1 1-79 Cl ^zS A% n^n N\JI J II A η h | He 351.0 1-21 Cl n A ι n HH 333.0 1-81 ^Cln ^ ^niHH 321.0 1-30 Cl A ^F CF ₃ N^ NA _F HH 332.0 1-82 AV ^F CF ₃ N ^N A A A A/ Ga ν n nw ⁷ HH 346.0 1-31 Cl CF ₃ N^NAAAA 310.0 1-83 Cl CF ₃ N^N Gan ^x ^n^n' ^x ^ ^f HH 288.0 1-33 Cl QF ₃ N^N CF ₃ anAAnpA HH 352.2 1-84 Cl JL-y n^n ^F AA AA N^N^N^CF, 318.0 1-35 Cl Λ ι Ga'nAn'A'A ^H 1 298.1 1-85 Cl All GHH 282.2 1-36 Cl e A L-ι N^N _l AaaA Ν Ν NHH 276.0 1-86 Cl CF ₃ N^N -^N-^N^N^CF ₃ 324.0

-21 044101

1-37 CI F A 0. 1 ^^N^N^N^ N N 278.0 1-87 Cl CF ₃ NA AAA H ^H 333.0 1-38 CI A x Ν Ν N (RS>\ N N 290.0 1-89 Cl CF ₃ NA CF ₃ '^ΑιΑνΑ HH 338.0 1-39 CI CF ₃ N^N CD ₃ A?nAAAd ₃ 291.1 1-90 Cl cf ₃ nA A A A / W NNN HH 314.1 1-40 Cl CF ₃ nA _n CD ₃ ΑνΑΑνΑ^ H HD ³ 291.1 1-91 Cl cf ₃ nA x A A x / -^N Ν Ν X HH % 314.1 1-42 Cl EA _F N^N CD ₃ N Aj N AcD ₃ H HD ³ 285.1 1-101 Cl cf ₃ nA Atn'^n^ ^x n-^ _f F 318.0 1-49 ClnA. ^_ \AA aa 1 Ν Ν NHH 318.0 1-102 Cl Γ ³ JM Ahhd HA ^F F 318.1

Intermediate I-3: 6-chloro-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2,4diamine

1,4-dioxane (50 ml), 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol), (R)1,1,1 was added to the flask at 0°C -trifluoropropane-2-amine hydrochloride (2.99 g, 20 mmol) and DIEA (5.17 g, 40 mmol). The reaction mixture was heated to 60°C and stirred for 4 hours. After completion of the reaction, the mixture was condensed and purified by flash column chromatography (elution with a water/MeOH gradient of 100:0-0:100), resulting in Intermediate I-3 as a yellow solid (2.50 g, yield: 74%). MS (m/z): 338.0 [M+H]+

The compounds listed in the table below were prepared in accordance with the procedure for preparing Intermediate I-3 using the Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Intermediate connection Structure MS (M+H) ⁺ Intermediate connection Structure MS (M+H) ⁺ 1-6 Cl nA vXnnnXv V η η V 254.1 1-34 Cl 1 nA AA a A NNNHH 230.1 1-10 Cl FA ^F N^N ^f aX aa AA Ν Ν NHH 326.0 1-106 Cl N^N m ^HH A /° °\ 446.0 1-32 Cl cf ₃ n A cf ₃ D. JL χ ^(S) Ν Ν Ν (5Λ 338.0

Intermediate I-4: (R)-N-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin2-yl)isobutyramide

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 hours. After completion of the reaction, the mixture was cooled to room temperature temperature and concentrated to dryness in vacuo to obtain N-(4,6-dichloro-1,3,5-triazin-2yl)isobutyramide as a yellow solid. N-(4,6

- 22 044101 dichloro-1,3,5-triazin-2-yl)isobutyramide prepared above, (R)-1,1,1-trifluoropropan-2-amine hydrochloride (900 mg, 6.06 mmol) and DIEA ( 2.34 g, 18.18 mmol). The mixture was refluxed and stirred for 2 hours. After completion of the reaction, the mixture was stopped by adding water and extracted with ethyl acetate (20 ml). The organic layer was collected, concentrated under reduced pressure and purified by flash column chromatography (PE/EA elution) to give Intermediate I-4 (80 mg). MS (m/z): 312.1 [M+H]+

Intermediates I-26 and I-27.

Optically pure diastereomers 3-(4-chloro-6-(((K)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5triazin-2-yl)cyclohex-2-en-1 -ola

1-25 1-26 & 1-27

Intermediates I-26 and I-27 were prepared by resolving Intermediate I25 using chiral HPLC (chiral HPLC conditions: Column: AS-H; mobile phase: nheptane/isopropanol=80:20; flow rate: 0.5 ml/min ; detection at wavelength: UV 254 nm). The isomer obtained with the first eluent (RT = 1.703 min) was named I-26, de% = 100%, MS (m/z): 400.1 [M+H] ⁺ . The isomer obtained with the second eluent (RT=2.067 min) was named I-27, de%=99.4%, MS (m/z): 400.1 [M+H]+).

Intermediate I-41: 6-chloro-N ² -(propan-2-yl-d ₇ )-N ⁴ -(2-(trifluoromethyl)pyridin-4-yl)1,3,5-triazin-2,4 -diamine

A5 1-41 (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) NaHCO ₃ (1.68 g, 20 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was filtered. The filtrate was condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in compound A5 as a white solid (2.68 g, yield: 86%). MS (m/z): 309.9 [M+H]+ (B) 6-Chloro-N ² -(propan-2-yl-d ₇ )-N ⁴ -(2-(trifluoromethyl)pyridine-4- yl)-1,3,5-triazine-2,4-diamine

Compound A5 (465 mg, 1.5 mmol), propane-d ₇ -2amine hydrochloride (154 mg, 1.5 mmol), DIEA (388 mg, 3.0 mmol) and 1,4-dioxane were added sequentially to a sealed test tube. (20 ml). The mixture was heated to 60°C and stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (elution with a PE/EA gradient = 100:0-0:100), resulting in Intermediate compound I-41 as a white solid (485 mg, yield: 95%). MS (m/z): 340.0 [M+H]+

The compounds listed in the table below were prepared in accordance with the procedure for preparing Intermediate I-41 using the Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

- 23 044101

Intermediate connection Structure MS (M+H) ⁺ Intermediate connection Structure MS (M+H) ⁺ 1-43 CI XN^A 1 —ν \ ΐ ί[ 1 Ν Ν^ N N 268.0 1-94 Cl nX n^n _λ AND AA /△ CF ₃ ^^NNN ³ HH 361.1 1-44 CI νΛ n^nd s 1 1 FjC^NN NTd ³ Η HD 308.0 1-96 Cl nX nA aAL aa cr Ν Ν N HH 329.0 1-45 Cl XnX N^N 1 Vk AAAA ^^NNN^ HH 304.0 1-97 Cl nX nA aJL aa CF ₃ Ν Ν N HH 349.1 1-53 Cl XnX n^n VOL A A / ^^nnnXC , η h | oi 334.0 1-98 Cl nX nA aA aa /x _f CFf Ν NN%/ ^H Xf 381.1 1-59 Cl nX n^na^A. aa cr Ν Ν Ν X HHA 329.0 1-99 Cl n% nA Y <XAA\ 385.0 1-63 Cl N% N^N a. AL aa F ₃ C Ν Ν Ν X ³ HHA 363.0 I-100 Cl nX NA aA aa CF ₃ Ν N N-D H χ-F F 366.9 1-66 Cl _Ν χ n^n A aa F ₃ C^^NN NX ³ η η 1 OH 363.0 1-101 Cl CF ₃ nO Αν^ν^νλ h AA F 318.0 1-68 Cl n^nn^n AA AA -o. / FjC^N Ν Ν X ³ HH % 364.0 1-103 Cl NX, nA a 1 a a /X he CFX*^ NN nX ^uh ^H XcF ₃ 428.9 1-92 Cl nX nA /ALL aa -0. CFf Ν NN HH 321.1 1-104 Cl nX nA AAAA /x _F CF^^^NN NX ^F ^H Ac ^F T ^f 416.9 1-93 Cl N^ji nA cf ₃ - ^x ^A _N A _N A _N HH 335.1 1-105 Cl A QF ₃ Ν Χν ^λ ν^νΆ HH 362.1

Intermediate I-46:

2-((4-(tert-butoxyamino)-6-chloro-1,3,5-triazin-2yl)amino)isonicotinonitrile

(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) NaHCO ₃ (1.26 g, 15 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. After completion of the reaction, the mixture was filtered. The filtrate was condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in compound A6 as a colorless oil (0.83 g, yield: 80%). MS (m/z): 237.0 [M+H]+ (B) 2-((4-(tert-Butoxyamino)-6-chloro-1,3,5-triazin-2-yl)amino)isonicotinonitrile

Compound A6 (0.83 g, 4.0 mmol), 2-aminoisonicotinonitrile (0.48 g, 4.0 mmol), Pd(dppf)Cl ₂ (0.15 g, 0.2 mmol) were sequentially added to a sealed test tube. t-BuONa (0.77 g, 8.0 mmol) and 1,4-dioxane (10 ml). The mixture was heated to 90°C and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (elution with a PE/EA gradient of 100:0-0:100), resulting in Intermediate I -46 as a yellow solid (109 mg, yield: 8%). MS (m/z): 320.0 [M+H]+

The compounds listed in the table below were prepared in accordance with the procedure for preparing Intermediate I-46 using the Intermediates and reagents under suitable conditions that would be understood by one skilled in the art.

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Intermediate connection Structure MS (M+H) ⁺ Intermediate connection Structure MS (M+H) ⁺ 1-47 CI AN^N X A A Cl Ν Ν N n Η Y 329.0 1-65 Cl nA n^X aUL a a yu^x F Ν NN H n I 313.0 1-48 CI AA νΑι ι UL JL a λ Λ Ν NNHH 315.0 1-67 Cl nA iAn ι AIAAX F Ν Ν Ν HH 283.0 1-52 Cl CH AA Λ HH 305.0 1-69 Cl. ^Ν χ nA _n uaa HH 304.0 1-56 Cl fA G ³ HH 358.0 1-70 ClXiNA. A, AAAA >An NN^ HH 308.0 1-57 Cl CQ A i νΑΑνΑΧΑ HH 304.1 1-5 Cl ΥγΑ nA n' ⁿ A _n A^ _n ^ H 304.0 1-58 Cl °XA nA I ^nAL AA xL X- ^^ N Ν N HH 295.0 1-28 Cl nA nA _n ХД AA .0^ Ν Ν Ν X HY 309.0 1-60 Cl ^X N% N^N ι 11 AA Λ Ν Ν NHH 295.1 1-29 Cl nA nA Х\ААХ HH % 310.0 1-62 Cl AA An cf ₃ ^nAYnA^nA HH 369.0 1-95 Cl P ύ o cf-An ν ν n X H Η Y 363.9 1-64 Cl n% n^n ay aJL aa XJ F ₃ C Ν NN ³ HH 385.0

Intermediate I-88: 2-fluoro-3-(4,4,5,5-tretramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one

Under a nitrogen atmosphere, 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)Cl ₂ -CH ₂ Cl ₂ (12.4 g, 15.3 mmol) and 1,4- dioxane (1.4 L). The mixture was stirred at 90°C for 4 hours, then cooled to room temperature and filtered. The filtrate was condensed and purified by flash column chromatography (elution PE/EA=4/1), resulting in Intermediate I-88 as a yellow solid (76 g, 100% yield). MS (m/z): 159.0 [M+H]+ ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 2.47-2.36 (m, 4H), 1.91-1, 82 (m, 2H), 1.22 (s, 12H).

Example 2. Synthesis of compounds 1-87, 89-184, 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

(R)-2-fluoro-3 -(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2(A)yl) cyclohex-2-en-1-one (B1)

- 25 044101

Under a nitrogen atmosphere, 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)Cl ₂ -CH ₂ Cl ₂ (32 mg, 0.04 mmol) and 1, 4-dioxane (20 ml) and stirred under reflux for 16 hours. The mixture was then cooled to room temperature and Intermediate I-2 (238 mg, 0.84 mmol), Cs ₂ CO ₃ (682 mg, 2.1 mmol), Pd(PPh ₃ ) ₄ (46.2 mg, 0.04 mmol) and water (4 ml), and stirred at 80°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in compound B1 as a white solid (160 mg, yield: 52.8%). MS (m/z): 362.1 [M+H]+ (B) 2-fluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropane-2- yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol

Compound B1 (80 mg, 0.22 mmol), CeCl ₃ ·7H ₂ O (107 mg, 0.29 mmol) and EtOH (5 ml) were added to the flask. The mixture was cooled to 0°C. NaBH4 (11 mg, 0.29 mmol) was then added and the resulting mixture was stirred at 0°C for 2 hours. After completion of the reaction, the mixture was quenched by adding saturated aqueous NH4Cl (2 ml) and water (20 ml) and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100) to obtain compound 1 as a white solid (61 mg, yield: 76.3%). MS (m/z): 364.1 [M+H]+

1H-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), 2.40-2.24 (m, 1H), 1.89-1.73 (m, 3H), 1.70-1.61 (m, 1H ), 1.38-1.31 (m, 3H), 1.22-1.16 (m, 6H).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 1 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 2 g^ ^on T ^F CF ₃ n+ n CF ₃ >> A. JL On) Ν Ν Ν HH 418.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.88 (m, 2H), 4.36-4.24 (m, 1H), 2.66-2.50 (m, 1H ), 2.41-2.31 (m, 1H), 1.97-1.60 (m, 4H), 1.381.30 (m, 6H). 1-3 3 a CF ₃ N^N ^T A- A 7° N Ν N isR ⁷ 392.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.06-4.90 (m, 1H), 4.61-4.46 (m, 1H), 4.37-4.21 (m, 1H ), 4.04-3.87 (m, 2H), 3.85-3.76 (m, 1H), 3.733.60 (m, 1H), 2.66-2.49 (m, 1H), 2.44-2.14 (m, 2H), 2.01-1.60 (m, 5H), 1.45-1.30 (m, 3H). 1-8

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4 ecg CF ₃ N^N r-L AMa ^F <rsjN Ν Ν 412.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.87 (m, 1H), 4.37-4.15 (m, 2H), 3.05-2.84 (m, 2H ), 2.77-2.49 (m, 3H), 2.42-2.24 (m, 1H), 1.961.56 (m, 4H), 1.44-1.31 (m, 3H). 1-30 5 ^f Ax λα aA ^f Η Η 406.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.37-4.22 (m, 3H), 3.02-2.86 (m, 4H), 2.73-2.50 (m, 5H ), 2.41-2.25 (m, 1H), 1.91-1.72 (m, 3H), 1.721.62 (m, 1H). 1-10 6 Γ iRsjl CF ₃ nA Г- \ ^F ΑΛΑ А/ Αν ν N'JrsT 426.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.00-4.90 (m, 1H), 4.51-4.41 (m, 1H), 4.34-4.25 (m, 1H ), 2.62-2.47 (m, 2H), 2.38-2.17 (m, 3H), 2.ΜΙ.96 (m, 2H), 1.90-1.75 (m, 4H ), 1.70-1.61 (m, 1H), 1.40-1.31 (m, 3H). 1-11 7 <v ^0H A XVA Η Η 376.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.89 (m, 1H), 4.33-4.24 (m, 1H), 4.19-4.06 (m, 1H ), 2.63-2.47 (m, 1H), 2.40-2.25 (m, 1H), 1.921.60 (m, 4H), 1.40-1.30 (m, 3H), 1.23-1.15 (m, 6H). 1-15 8 CF ₃ Ν^Ν . Α Λ Λ Λ MCn Ν NisA Η Η V 390.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.99-4.87 (m, 1H), 4.36-4.22 (m, 1H), 3.60-3.40 (m, 1H ), 2.66-2.47 (m, 1H), 2.40-2.26 (m, 1H), 1.911.62 (m, 4H), 1.37-1.31 (m, 3H), 1.27-1.21 (m, 3H), 1.01-0.85 (m, 1H), 0.55-0.15 (m, 4H). 1-31 9 Αα ^η —Г (W T ^F CF ₃ ΝΆ I HH 392.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.99-4.88 (m, 1H), 4.42-4.34 (m, 1H), 4.18-4.07 (m, 1H) , 2.40-2.17 (m, 2H), 1.91-1.80 (m, 1H), 1.621.53 (m, 1H), 1.38-1.31 (m, 3H), 1 .22-1.15 (m, 6H), 1.06 (s, 3H), 1.00 (s, 3H). 1-2 10 riA T ^F CF ₃ hr NM\ AAA A/ HH 390.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.03-4.89 (m, 1H), 4.37-4.16 (m, 2H), 2.64-2.47 (m, 1H ), 2.40-2.24 (m, 1H), 2.04-1.44 (m, 12H), 1.391.31 (m, 3H). 1-12 AND A A ^F ?F ₃ Ν' N QF ₃ Αν'ίΑν'Α HH 418.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.04-4.90 (m, 2H), 4.35-4.24 (m, 1H), 2.66-2.52 (m, 1H ), 2.43-2.27 (m, 1H), 1.95-1.60 (m, 4H), 1.431.31 (m, 6H). 1-3

- 27 044101

12 risr ^0H 1 ^F CF ₃ N^N χ to X η h | 378.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.00-4.89 (m, 1H), 4.35-4.23 (m, 1H), 3.26-3.05 (m, 2H ), 2.66-2.48 (m, 1H), 2.42-2.25 (m, 1H), 1.971.59 (m, 5H), 1.41-1.30 (m, 3H), 0.96-0.88 (m, 6H). 1-13 13 rir ⁰ 1 ^F CF ₃ N^N XX x Ν Ν'^ΤΛ η h LV ^F F 426.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.89 (m, 1H), 4.35-4.23 (m, 1H), 3.63-3.40 (m, 2H ), 2.65-2.51 (m, 3H), 2.47-2.21 (m, 4H), 1.891.61 (m, 4H), 1.39-1.31 (m, 3H). 1-14 14 x Q/g O u- Zi ΚγΛ o 418.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.03-4.90 (m, 2H), 4.36-4.23 (m, 1H), 2.67-2.49 (m, 1H ), 2.42-2.26 (m, 1H), 1.94-1.61 (m, 4H), 1.401.31 (m, 6H). 1-32 15 ? ^F F X ^N^N^NiRS)^ 432.3 Ή-NMR (400 MHz, CD ₃ OD): δ 5.04-4.93 (m, 1H), 4.82-4.70 (m, 1H), 4.34-4.23 (m, 1H ), 2.65-2.51 (m, 1H), 2.43-2.28 (m, 1H), 1.911.74 (m, 4H), 1.71-1.61 (br, 2H), 1.40-1.31 (m, 3H), 1.04-0.93 (m, 3H). 1-33 16 CF ₃ N^N _l XXX Afs; ^WN N N''fRJ ''F HH 380.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.12-4.92 (m, 1H), 4.80-4.53 (m, 1H), 4.37-4.26 (m, 1H ), 2.87-2.77 (m, 1H), 2.68-2.51 (m, 1H), 2.462.27 (m, 1H), 1.97-1.60 (m, 4H), 1.43-1.31 (m, 3H), 1.2-1.06 (m, 1H), 1.02-0.87 (m, 1H). 1-1 17 l ύ A HH 380.4 Ή-NMR (400 MHz, CD ₃ OD): δ 5.00-4.92 (m, 1H), 4.22-4.07 (m, 2H), 2.50-2.27 (m, 2H ), 1.95-1.81 (m, 3H), 1.76-1.66 (m, 1H), 1.411.32 (m, 3H), 1.23-1.18 (m, 6H). 1-2 18 <x< ^{is he} the one? ^F3 Xtp 419.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.87 (m, 2H), 2.68-2.51 (m, 1H), 2.44-2.28 (m, 1H ), 1.92-1.63 (m, 4H), 1.42-1.30 (m, 6H). 1-3 19 а^ои Г ί“ψΌ χ Χ'χ HH 407.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.38-4.15 (m, 2H), 3.05-2.85 (m, 4H), 2.72-2.48 (m, 5H ), 2.40-2.26 (m, 1H), 1.90-1.61 (m, 4H). 1-10 20 Q ^0H XA rA Η Η 420.2 Ή-NMR (400 MHz, CD ₃ OD): 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), 2.011.82 (m, 3H), 1.74-1.60 (m, 3H). 1-10

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21 Θζ ^0Η Т ^з Άν N 432.3 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.89 (m, 2H), 4.53-4.41 (m, 1H), 2.77-2.62 (m, 1H) , 2.40-2.27 (m, 1H), 2.02-1.83 (m, 3H), 1.741.61 (m, 3H), 1.39-1.32 (m, 6H). 1-3 22 (Χ A ΑΉ n n 421.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.36-4.16 (m, 2H), 3.00-2.84 (m, 4H), 2.73-2.50 (m, 5H ), 2.39-2.21 (m, 1H), 2.01-1.82 (m, 3H), 1.751.59 (m, 3H). 1-10 23 No. Λ An ν Η Η 365.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.99-4.86 (m, 1H), 4.20-4.07 (m, 1H), 2.61-2.47 (m, 1H ), 2.37-2.25 (m, 1H), 1.88-1.62 (m, 4H), 1.371.29 (m, 3H), 1.20-1.17 (m, 6H). 1-2 24 CF ₃ Ν^Ν ,—/ ΑΛΑ AT ^F Αν ν ν' Η Η 427.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.99-4.86 (m, 1H), 4.34-4.15 (m, 1H), 2.97-2.83 (m, 2H ), 2.73-2.51 (m, 3H), 2.37-2.25 (m, 1H), 2.011.82 (m, 3H), 1.72-1.60 (m, 3H), 1.39-1.13 (m, 3H). 1-9 25 g ("l 1 Ν^Ν ι Am'-CHDmA Η Η 310.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.36-4.24 (m, 1H), 4.24-4.00 (m, 2H), 2.62-2.43 (m, 1H ), 2.39-2.22 (m, 1H), 1.91-1.82 (m, 2H), 1.821.72 (m, 1H), 1.70-1.60 (m, 1H), 1.19(s, 12H). 1-34 26 ΘΓ А ΑΑ Λ Άν ^λ ν ^λ νΑ η 1 378.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.19-4.88 (m, 2H), 4.38-4.22 (m, 1H), 2.96 (s, 3H), 2. 68-2.49 (m, 1H), 2.43-2.28 (m, 1H), 1.91-1.83 (m, 2H), 1.83-1.70 (m, 1H), 1.701.59 (m, 1H), 1.35 (d, J = 5.3 Hz, ZN), 1.16 (d, J = 6.5 Hz, 6H). 1-35 27 <Α ^ΟΗ φζ ^F X^^ Η Η 356.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.42-4.13 (m, 2H), 3.02-2.86 (m, 2H), 2.83-2.46 (m, 4H ), 2.44-2.21 (m, 1H), 1.92-1.83 (m, 2H), 1.831.60 (m, 2H), 0.82-0.67 (m, 2H), 0.60-0.45 (m, 2H). 1-36 28 ^χ^ΟΗ GAG Vi Ν^Ν ι ^F ®^νΑΑν^ Η Η 358.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.36-4.20 (m, 2H), 4.20-4.04 (m, 1H), 3.01-2.84 (m, 2H ), 2.71-2.45 (m, 3H), 2.40-2.23 (m, 1H), 1.901.83 (m, 2H), 1.83-1.60 (m, 2H), 1.20(s, 6H). 1-37 29 Γ^6ο ^Η I ^F QF ₃ Ν^Ν CD ₃ -An ^A n ^A n^cd ₃ 372.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.98-4.88 (m, 1H), 2.65-2.43 (m, 1H), 2.41-2.23 (m, 1H ), 1.92-1.70 (m, 3H), 1.70-1.59 (m, 1H), 1.371.29 (m, 3H). 1-39

- 29 044101

thirty φζο CF ₃ N^N CD ₃ ^nAAnAcd ₃ 372.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.97-4.89 (m, 1H), 2.70-2.42 (m, 1H), 2.41-2.21 (m, 1H ), 1.90-1.72 (m, 3H), 1.69-1.59 (m, 1H), 1.371.29 (m, 3H). 1-40 31 ΙΖ ω ¹ ιζ -π о У ¹ “Π 412.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.89 (m, 1H), 4.38-4.14 (m, 2H), 3.03-2.86 (m, 2H ), 2.80-2.49 (m, 3H), 2.44-2.26 (m, 1H), 1.951.59 (m, 4H), 1.41-1.31 (m, 3H). 1-9 32 0 ΙΖ ya ΙΖ -π ο ¹ -π 412.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.03-4.90 (m, 1H), 4.38-4.16 (m, 2H), 3.02-2.86 (m, 2H ), 2.82-2.50 (m, 3H), 2.43-2.25 (m, 1H), 1.941.60 (m, 4H), 1.42-1.32 (m, 3H). 1-54 33 CF ₃ N% ϊ Η Η 364.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.90 (m, 1H), 4.38-4.22 (m, 1H), 4.18-4.04 (m, 1H ), 2.66-2.49 (m, 1H), 2.39-2.20 (m, 1H), 2.031.58 (m, 4H), 1.42-1.29 (m, 3H), 1.23-1.10 (m, 6H). 1-71 34 ec Ν Ν Ν X Η Η | ^χ 431.0 Ή-NMR (400 MHz, CD ₃ OD) δ 8.93-8.75 (m, 2H), 7.98-7.93 (m, 1H), 7.83-8.77 (m, 1H) , 4.37-4.29 (m, 1H), 2.72-2.60 (m, 1H), 2.472.35 (m, 341H), 1.92-1.85 (m, 2H), 1 .84-1.75 (m, 1H), 1.73-1.65 (m, 1H), 1.32 (s, 9H). 1-75 200 IA OU- Ζ %</=<< £ У--(\ ζ ζι И 384.1 Ή-NMR (400 MHz, CD ₃ OD): δ 9.55 (s, 1H), 7.91-7.78 (m, 1H), 7.64-7.48 (m, 1H), 7. 33-7.13 (m, 1H), 6.62-6.47 (m, 1H), 4.41-4.14 (m, 2H), 2.72-2.32 (m, 2H), 1.911.63 (m, 4H), 1.29-1.20 (m, 6H). 1-5 205 Ή ΛΑ ΙΖ -η ο Ъ ¹ y 390.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.59-8.34 (m, 2H), 4.39-4.28 (m, 1H), 2.74-2.61 (m, 1H ), 2.55 (s, 3H), 2.51-2.37 (m, 1H), 1.98-1.66 (m, 4H), 1.31 (s, 9H). 1-29 219 CF ₃ N^N CF ₃ Ά?Ν Al MTU 444.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.05-4.86 (m, 2H), 3.49-3.39 (m, 1H), 2.73-2.58 (m, 1H ), 2.53-2.38 (m, 1H), 2.22-2.09 (m, 1H), 1.391.32 (m, 6H), 1.03-0.94 (m, 1H), 0.78-0.68 (m, 1H), 0.51-0.40 (m, 3H). 1-3 229 β U Zh TZ -PO G ¹ 401.0 Ή-NMR (400 MHz, CD ₃ OD): δ 9.34-9.19 (m, 1H), 8.60-8.36 (m, 1H), 7.73-7.54 (m, 2H ), 4.39-4.30 (m, 1H), 4.26-4.15 (m, 1H), 2.722.56 (m, 1H), 2.48-2.33 (m, 1H), 1.93-1.63 (m, 4H), 1.29-1.21 (m, 6H). 1-81

Compound 3 5: 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

Compound 1 (20 mg, 0.06 mmol) was dissolved at 0°C in DCM (3 ml) and DAST (17 mg, 0.12 mmol) was added. The mixture was stirred at 0°C for 2.5 hours. After completion of the reaction, the mixture was quenched by adding saturated aqueous NH ₄ Cl (5 ml) and water (5 ml) and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100) to obtain 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 35 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 36 ^f Г iRsY CF ₃ N^NI HH 348.0 Ή-NMR (400 MHz, CD ₃ OD): δ 7.166.94 (m, 1H), 5.25-5.06 (m, 1H), 5.054.89 (m, 1H), 4.27-4, 06 (m, 1H), 2.632.26 (m, 2H), 1.95-1.63 (m, 4H), 1.391.30 (d, J = 5.2 Hz, 3H), 1.24-1 .16 (m, 6H). Connection 124 37 CF ₃ N^NI HH 348.3 Ή-NMR (400 MHz, CD ₃ OD): δ 7.267.00 (m, 1H), 5.08-4.85 (m, 2H), 4.264.07 (m, 1H), 2.87-2. 70 (m, 1H), 2.682.53 (m, 1H), 2.44-2.26 (m, 2H), 1.951.80 (m, 2H), 1.36-1.30 (m, 3H) , 1.201.16 (m, 6H). Connection 144 38 F 6 CF ₃ N% I HH 348.3 Ή-NMR (400 MHz, CD ₃ OD): δ 7.136.85 (m, 1H), 5.03-4.85 (m, 2H), 4.244.07 (m, 1H), 2.63-2. 35 (m, 4H), 2.011.82 (m, 2H), 1.36-1.31 (m, 3H), 1.201.16 (m, 6H). Connection 145

Compound 39: (*)3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept2-en-1-ol

Under a nitrogen atmosphere, a mol/L solution of (S)-CBS/THF (1.4 mL, 1.4 mmol) was added to dry THF (5 ml) at ice bath temperature, then a 2 mol/L solution was added to this solution in one portion BH ₃ Me ₂ S/THF (1.4 ml, 2.8 mmol). After stirring for 2 minutes, 3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept-2-en-1 was added dropwise -one (prepared according to the procedure for preparation of compound 1 using Intermediate 110, 600 mg, 1.4 mmol) in THF (3 ml) and the resulting mixture was stirred in an ice bath for 1 hour. MeOH ( 0.5 ml), EtOAc (10 ml) and water (20 ml). The organic layer was collected. The aqueous layer was extracted with ethyl acetate (10 ml). The organic layers were combined, dried over Na ₂ SO ₄ and filtered. The filtrate was condensed and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100) to obtain the title compound as a white solid (60 mg, yield: 10%). MS (m/z): 420.1 [M+H]+ ¹ H-NMR (400 MHz, 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 39 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

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Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 40 Q, CF ₃ An /-J RALLS Η Η 426.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.87 (m, 1H), 4.51-4.41 (m, 1H), 4.314.16 (m, 1H), 2.97-2.84 (m, 2H), 2.732.49 (m, 3H), 2.37-2.23 (m, 1H), 2.001.81 (m, 3H), 1.72-1.58 (m, 3H), 1.391.30 (m, 3H). 1-9 41 ar CF ₃ Ν^Ν L Η Η 400.1 Ή-NMR (400 MHz, CD ₃ OD): 5 5.004.89 (m, 1H), 4.69-4.44 (m, 5H), 4.344.22 (m, 1H), 2.65-2. 50 (m, 1H), 2.40-2.25 (m, 1H), 1.89-1.57 (m, 4H), 1.38-1.29 (m, 3H). 1-72 42 GC Ν V 388.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.89 (m, 1H), 4.33-4.21 (m, 1H), 3.132.99 (m, 1H), 2.62-2. 47 (m, 1H), 2.37-2.18 (m, 1H), 1.87-1.61 (m, 4H), 1.37-1.30 (m, 3H), 1.25- 1.19 (m, 1H), 1.00-0.71 (m, 5H). 1-73 43 ώ V, Ν^Ν f ^FF νΧ l X Λ Η Η 376.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.514.18 (m, 5H), 3.01-2.82 (m, 2H), 2.712.45 (m, 3H), 2.38-2. 20 (m, 1H), 1.87-1.59 (m, 4H), 1.27-1.19 (m, 3H). 1-74 44 α; Ν^Ν CF ₃ Ν*Χλ _Ν Α _Ν Α _Ν ^ Η Η 438.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.478.11 (m, 2H), 7.66 (s, 1H), 7.49-7.37 (m, 1H), 7.18-7, 05 (m, 1H), 5.08-4.94 (m, 1H), 4.40- 4.27 (m, 1H), 2.75-2.61 (m, 1H), 2.51- 2.37 (m, 1H), 1.92-1.66 (m, 4H), 1.43-1.37 (m, 3H). 1-56 45 α: ΝΑ _ν Η Η 384.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.378.29 (br, 1H), 8.29-8.16 (m, 1H), 7.65 (s, 1H), 7.47-7, 38 (m, 1H), 7.15-6.99 (m, 1H), 4.37-4.18 (m, 2H), 2.74-2.56 (m, 1H), 2.51- 2.34 (m, 1H), 1.90-1.64 (m, 4H), 1.29-1.22 (m, 6H). 1-57 46 α: °Υ% Ν^Ν , / ⁿ ^A _n A _n A _n J\ Η Η 375.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.638.10 (m, 1H), 7.69-7.53 (m, 1H), 6.52 (d, J = 9.6 Hz, 1H) , 4.36-4.24 (m, 1H), 4.22-4.04 (m, 1H), 3.57 (s, 3H), 2.682.50 (m, 1H), 2.43-2 .28 (m, 1H), 1.891.61 (m, 4H), 1.23-1.16 (m, 6H). 1-58

- 32 044101

47 s. Ah ZI 0 o 409.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.488.19 (m, 1H), 8.14-8.04 (m, 1H), 7.657.46 (m, 1H), 4.38-4.26 (m, 1H), 2.732.58 (m, 1H), 2.49-2.34 (m, 1H), 1.911.64 (m, 4H), 1.32 (s, 9H). 1-59 48 α; ^X N% νΆ ϊ cAA^/A HH 375.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.507.42 (m, 1H), 7.26-7.20 (m, 1H), 6.8Ιό,68 (m, 1H), 4.36-4 .13 (m, 2H), 3.48 (s, 3H), 2.74-2.55 (m, 1H), 2.46-2.32 (m, 1H), 1.89-1.62 (m, 4H), 1.27-1.17 (m, 6H). 1-60 49 a ^H Уу n^n _l ^f aa k i l Η Η 356.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.394.18 (m, 2H), 2.99-2.86 (m, 2H), 2.802.46 (m, 4H), 2.39-2. 23 (m, 1H), 1.891.82 (m, 2H), 1.81-1.62 (m, 2H), 0.790.67 (m, 2H), 0.55-0.48 (m, 2H) . 1-36 50 370.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.454.14 (m, 2H), 3.05-2.82 (m, 2H), 2.792.23 (m, 5H), 1.91-1, 61 (m, 4H), 1,180.45 (m, 6H). 1-38 51 os А\ ^Ν< ^ ^Ν 1 ^р Х^лА n n 358.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.354.20 (m, 2H), 4.20-4.06 (m, 1H), 2.982.86 (m, 2H), 2.70-2, 45 (m, 3H), 2.382.23 (m, 1H), 1.89-1.82 (m, 2H), 1.811.60 (m, 2H), 1.19 (s, 6H). 1-37 52 A ?F ₃ N^N CD ₃ Н D ^С ° ³ 371.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.994.87 (m, 1H), 4.33-4.23 (m, 1H), 2.642.45 (m, 1H), 2.40-2. 21 (m, 1H), 1.891.71 (m, 3H), 1.70-1.58 (m, 1H), 1.361.30 (m, 3H). 1-39 53 A CF ₃ N^N CD ₃ 4ΛΑΉ H HD ³ 371.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.88 (m, 1H), 4.35-4.19 (m, 1H), 2.632.44 (m, 1H), 2.44-2. 21 (m, 1H), 1.931.70 (m, 3H), 1.70-1.53 (m, 1H), 1.391.29 (m, 3H). 1-40 54 ar ^N< AN^N CD ₃ СрзАа^ы^ы^СОз 420.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.608.22 (m, 2H), 8.09-7.74 (m, 1H), 4.384.27 (m, 1H), 2.75-2. 58 (m, 1H), 2.48-2.33 (m, 1H), 1.91-1.75 (m, 3H), 1.73-1.64 (m, 1H). 1-41 55 . A Ή-д N^N CD ₃ ^F '^'N'^N^N^CDa H HD ³ 365.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.364.15 (m, 2H), 3.02-2.81 (m, 2H), 2.732.41 (m, 3H), 2.40-2. 19 (m, 1H), 1.89-1.71 (m, 3H), 1.70-1.59 (m, 1H). 1-42

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56 D.D. J N^NI ^F HH 360.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 4.324.19 (m, 2H), 4.19-4.04 (m, 1H), 2.982.83 (m, 2H), 2.72-2, 43 (m, 3H), 2.39-2.21 (m, 1H), 1.80-1.70 (m, 1H), 1.68-1.58 (m, 1H), 1.25- 1.11(br,6H). 1-37 57 ar ,N^ N^N । -n J 1X1 HH 348.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 8.167.44 (m, 2H), 4.38-4.24 (m, 1H), 4.244.10 (m, 1H), 3.84 (s, 3H), 2.69-2.49 (m, 1H), 2.47-2.27 (m, 1H), 1.91-1.74 (m, 3H), 1.72-1.61 ( m, 1H), 1.29-1.18 (m, 6H). 1-43 58 ar νΉ| N^N CFj^Oafj-a -Ή _C D ₃ ³ HH 388.0 Ή-NMR (400 MHz, CD ₃ 0D): δ 8.618.24 (m, 2H), 8.04-7.81 (m, 1H), 4.394.27 (m, 1H), 2.75-2, 58 (m, 1H), 2.51-2.31 (m, 1H), 1.92-1.75 (m, 3H), 1.73-1.64 (m, 1H). 1-44 59 ar /'N^ N*4 । ^αα _Ν α _Ν Λ _Ν Α^ HH 348.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 8.398.25 (m, 2H), 7.86-7.79 (m, 1H), 7.137.02 (m, 1H), 6.42-6, 36 (m, 1H), 4.37-4.28 (m, 1H), 4.26-4.15 (m, 1H), 2.72-2.55 (m, 1H), 2.47- 2.34 (m, 1H), 1.91-1.85 (m, 2H), 1.85-1.74 (m, 1H), 1.73-1.64 (m, 1H), 1. 28-1.21 (m, 6H). 1-45 60 ar r^NN^N Ν Η HU 400.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 9.078.95 (m, 1H), 8.49-8.43 (m, 1H), 7.687.57 (m, 2H), 7.57-7, 52 (m, 1H), 7.30-7.25 (m, 1H), 4.39-4.28 (m, 1H), 2.75-2.59 (m, 1H), 2.48- 2.35 (m, 1H), 1.92-1.84 (m, 2H), 1.84-1.76 (m, 1H), 1.74-1.65 (m, 1H), 1, 33 (s, 9H). 1-46 61 ar r^N n1 _N CI^^N^N^N'°>< h n 409.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 8.918.64 (m, 1H), 8.27-8.16 (m, 1H), 7.1 Ιό.99 (m, 1H), 4.38 -4.28 (m, 1H), 2.742.56 (m, 1H), 2.48-2.33 (m, 1H), 1.921.84 (m, 2H), 1.84-1.76 (m , 1H), 1.731.64 (m, 1H), 1.33 (s, 9H). 1-47 62 o u- Ct κή ZI g 395.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 8.758.53 (m, 1H), 8.25-8.15 (m, 1H), 7.837.73 (m, 2H), 7.66-7, 59 (m, 1H), 7.457.36 (m, 1H), 4.39-4.28 (m, 1H), 4.264.15 (m, 1H), 2.73-2.56 (m, 1H) , 2.482.33 (m, 1H), 1.92-1.85 (m, 2H), 1.851.75 (m, 1H), 1.72-1.63 (m, 1H), 1.27-1 .20 (m, 6H). 1-48 63 0 IZ Ηπ Ohm IZ -no % ¹ 398.1 Ή-NMR (400 MHz, CD ₃ 0D): δ 8.188.11 (m, 1H), 8.09-8.01 (m, 1H), 7.527.46 (m, 1H), 7.46-7, 32 (m, 1H), 4.35-4.26 (m, 1H), 4.22-4.16 (m, 1H), 4.15 (s, 3H), 2.70-2.29 ( m, 2H), 1.901.84 (m, 2H), 1.84-1.74 (m, 1H), 1.711.63 (m, 1H), 1.25-1.18 (m, 6H). 1-49

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64 , dsg nx II J to ii 1 HH 398.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.258.10 (m, 1H), 7.94-7.86 (m, 1H), 7.667.39 (m, 2H), 4.35-4, 25 (br, 1H), 4.23-4.11 (m, 1H), 4.02 (s, 3H), 2.702.51 (m, 1H), 2.45-4.28 (m, 1H) , 1.911.83 (m, 2H), 1.83-1.74 (m, 1H), 1.711.62 (m, 1H), 1.26-1.17 (m, 6H). 1-50 65 cX ^ALAL HH 401.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.898.84 (m, 1H), 8.83-8.66 (m, 1H), 7.987.91 (m, 1H), 7.82-7. 70 (m, 1H), 4.36-4.28 (m, 1H), 4.25-4.18 (m, 1H), 2.71-2.56 (m, 1H), 2.47- 2.34 (m, 1H), 1.91-1.85 m, 2H), 1.85-1.77 (m, 1H), 1.72-1.64 (m, 1H), 1.28 -1.22 (m, 6H). 1-51 66 - A , ⁿ ~N hK ν I —4 ji k ii 1 ν ^α ^{ν λ} ν ^λ Χ Η Η 385.1 Ή-NMR (400 MHz, CD3OD/ CDCh = 2/1): δ 8.63-8.54 (m, 1H), 7.62-7.57 (m, 2H), 7.13-7.04 (m, 1H), 4.38-4.12 (m, 2H), 2.70-2.32 (m, 2H), 1.91-1.84 (m, 2H), 1.84-1 .74 (m, 1H), 1.73-1.63 (m, 1H), 1.25-1.20 (m, 6H). 1-52 67 ,β NxLD ¹ X 414.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.388.22 (m, 2H), 7.89-7.76 (m, 1H), 7.127.01 (m, 1H), 6.45-6, 34 (m, 1H), 4.38-4.27 (m, 1H), 3.51-3.42 (m, 2H), 2.70-2.56 (m, 1H), 2.46- 2.34 (m, 1H), 1.91-1.84 (m, 2H), 1.83-1.74 (m, 1H), 1.72-1.64 (m, 1H), 1, 26-1.18 (m, 6H). 1-53 68 X *Χν cf ₃ LL II 12 1 Ν ΝίκΧ Η Η 449.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.867.07 (m, 6H), 5.19-4.97 (m, 1H), 4.414.27 (m, 1H), 2.78-2. 60 (m, 1H), 2.53-2.37 (m, 1H), 1.94-1.78 (m, 3H), 1.76-1.65 (m, 1H), 1.45- 1.36 (m, 3H). 1-62 69 d ΡΓ1 ? ^Fs JsT N^N^nIsI Η Η 418.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.87 (m, 2H), 4.36-4.22 (m, 1H), 2.652.51 (m, 1H), 2.43-2. 29 (m, 1H), 1.89-1.60 (m, 4H), 1.38-1.29 (m, 6H). 1-32 70 X Ν^Ν Jk 1 Λ Λ CFo^^^N Ν Ν >Χ ³ Η Η rn 443.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.647.73 (m, 3N), 4.43-4.27 (m, 1H), 3.533.43 (m, 2H), 2.79-2. 61 (m, 1H), 2.52-2.36 (m, 1H), 1.92-1.67 (m, 4H), 1.24-1.16 (m, 6H). 1-66 71 χ νΛι ν^ν cf ₃ -XnXn'V Η Η D 443.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.558.36 (m, 2H), 8.01-7.90 (m, 1H), 4.414.30 (m, 1H), 2.77-2. 62 (m, 1H), 2.52-2.32 (m, 1H), 1.96-1.64 (m, 4H), 1.31 (s, 9H). 1-63 72 X Ν^Ν to 11 ii λ JL JJ CF ₃ ^^^NNN^^ Η Η 465.0 Ή-NMR (400 MHz, CD ₃ OD): δ 8.587.52 (m, 5H), 7.14-6.94 (m, 2H), 4.424.27 (m, 1H), 2.80-2. 65 (m, 1H), 2.56-2.37 (m, 1H), 1.94-1.66 (m, 4H). 1-64

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73 OS nA f''^^n^n^n'°>< HH 393.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.097.85 (m, 2H), 7.51-7.39 (m, 1H), 4.414.26 (m, 1H), 2.74-2. 57 (m, 1H), 2.49-2.32 (m, 1H), 1.96-1.64 (m, 4H), 1.32-1.29 (m, 9H). 1-65 74 (X*Chiral JO. AA Λ HH 363.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.027.88 (m, 1H), 7.85-7.72 (m, 1H), 7.527.39 (m, 1H), 4.39-4. 29 (m, 1H), 4.26-4.12 (m, 1H), 2.76-2.56 (m, 1H), 2.49-2.32 (m, 1H), 1.99- 1.61 (m, 4H), 1.28-1.20 (m, 6H). 1-67 75 OS N^NN^N CFsCOXAX^O^/ 444.1 Ή-NMR (400 MHz, CD ₃ OD): δ 9.188.77 (m, 2H), 4.45-4.24 (m, 1H), 2.812.64 (m, 1H), 2.53-2. 34 (m, 1H), 2.00-1.66 (m, 4H), 1.37-1.26 (m, 9H). 1-68 76 a; adi HH 384.1 Ή-NMR (400 MHz, CD ₃ OD): δ 9.639.01 (m, 1H), 7.74 (s, 1H), 7.54-7.48 (m, 1H), 7.47-7, 40 (m, 1H), 7.38-7.22 (m, 1H), 4.39- 4.29 (m, 1H), 4.25-4.12 (m, 1H), 2.73- 2.55 (m, 1H), 2.50-2.31 (m, 1H), 1.96-1.63 (m, 4H), 1.29-1.18 (m, 6H). 1-69 77 ar N^N 1 ^N XnA^n^ HH 388.1 Ή-NMR (400 MHz, CD ₃ OD): δ 6.596.32 (m, 1H), 4.36-4.27 (m, 1H), 4.234.10 (m, 1H), 4.03-3, 90 (m, 2H), 2.822.72 (m, 2H), 2.65-2.51 (m, 1H), 2.462.29 (m, 1H), 2.09-1.97 (m, 2H) , 1.901.63 (m, 6H), 1.25-1.16 (m, 6H). 1-70 78 ar CF ₃ N^N AAA / N NOT HH | 378.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.044.89 (m, 1H), 4.34-4.24 (m, 1H), 3.253.07 (m, 2H), 2.65-2. 48 (m, 1H), 2.402.20 (m, 1H), 1.96-1.59 (m, 5H), 1.381.30 (m, 3H), 0.95-0.87 (m, 6H) . 1-13 79 SG CF ₃ nO _N AAA '^NNN CFg HH 404.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.90 (m, 1H), 4.35-4.26 (m, 1H), 4.214.00 (m, 2H), 2.65-2. 49 (m, 1H), 2.43-2.24 (m, 1H), 1.93-1.59 (m, 4H), 1.42-1.30 (m, 3H). 1-76 80 « CF ₃ N^NAAAA An noa η η V 376.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.504.87 (m, 1H), 4.34-4.23 (m, 1H), 3.263.14 (m, 2H), 2.62-2. 47 (m, 1H), 2.39-2.22 (m, 1H), 1.89-1.82 (m, 2H), 1.82-1.73 (m, 1H), 1.71- 1.63 (br, 1H), 1.37-1.31 (m, 3H), 1.14-0.99 (m, 1H), 0.51-0.42 (m, 2H), 0. 26-0.19 (m, 2H). 1-77

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81 A; CF ₃ N^N Η Η 364.1 THMR (400 MHz, CD ₃ OD): δ 5.014.87 (m, 1H), 4.34-4.22 (m, 1H), 3.373.30 (m, 1H), 3.28-3.23 ( m, 1H), 2.62-2.48 (m, 1H), 2.38-2.22 (m, 1H), 1.88-1.82 (m, 2H), 1.82-1, 72 (m, 1H), 1.69-1.62 (m, 1H), 1.62-1.53 (m, 2H), 1.37-1.30 (m, 3H), 0.96- 0.89 (m, 3H). 1-78 199 a οί A ^Ν 431.0 'H-NMR (400 MHz, CD ₃ OD): δ 8.918.85 (m, 1H), 8.80-8.66 (m, 1H), 7.997.91 (m, 1H), 7.82-7 .72 (m, 1H), 4.384.28 (m, 1H), 3.53-3.40 (m, 2H), 2.722.58 (m, 1H), 2.48-4.34 (m, 1H ), 1.931.85 (m, 2H), 1.84-1.76 (m, 1H), 1.731.65 (m, 1H), 1.25-1.19 (m, 6H). 1-79 204 A; Ν^Ν 11 a a Ν Ν N XL n L 389.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.308.09 (m, 1H), 7.93 -7.58 (m, 2H), 4.40-4.28 (m, 1H), 2. 75-2.60 (m, 1H), 2.52-2.36 (m, 4H), 1.95-1.65 (m, 4H), 1.32 (s, 9H). 1-28 224 «Г У ³ VX А ^й ^Н й 362.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.124.89 (m, 1H), 4.36-4.21 (m, 1H), 2.812.66 (m, 1H), 2.65-2. 46 (m, 1H), 2.41-2.21 (m, 1H), 1.90-1.82 (m, 2H), 1.82-1.72 (m, 1H), 1.70- 1.59 (m, 1H), 1.39-1.29 (m, 3H), 0.77-0.68 (m, 2H), 0.55-0.47 (m, 2H). 1-16 240 A CF ₃ N^N FROM Ν ^Ν Ν ^F Η Η 368.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.90 (m, 1H), 4.60-4.52 (m, 1H), 4.494.40 (m, 1H), 4.35-4. 20 (m, 1H), 3.74-3.54 (m, 2H), 2.68-2.45 (m, 1H), 2.43-2.22 (m, 1H), 1.91- 1.81 (m, 2H), 1.81-1.72 (m, 1H), 1.70-1.60 (m, 1H), 1.34 (s, 3H). 1-83 241 a ⁿ L nA ^f a\ AA Ν Ν N CF ₃ HH 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.354.17 (m, 2H), 4.16-4.04 (m, 2H), 3.002.84 (m, 2H), 2.71-2, 48 (m, 3H), 2.422.26 (m, 1H), 1.91-1.82 (m, 2H), 1.821.73 (m, 1H), 1.70-1.60 (m, 1H) . 1-84

Connections 82 and 83:

(*)3 -(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2 -en-6,6D ₂ -1-ol and

-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-1 ,6,6D ₃ -1-ol

(A) 3-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2 -en-1 oh-6,6-D ₂

To a solution of 3-(4,6-6uc(((R)- 1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex2-ene- 1-one (prepared according to the procedure for preparation of compound 1 using Intermediate 1-3, 114 mg, 0.27 mmol) in 1,4-dioxane (6 ml) was added D2O (2 ml) and K ₂ CO ₃ ( 75 mg, 0.54 mmol). The mixture was stirred at 80°C for 4.5 hours. The solvent was then removed under vacuum and the residue was purified by flash column chromatography (elution with a PE/EA gradient = 100:0-0:100), resulting in the title compound in as a yellow oil (64 mg, yield: 56%). MS (m/z): 418.0 [M+H]+ (B) (*)3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino) -1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene6,6-D ₂ -1-ol

Compound 82 was prepared according to the procedure for compound 39. MS (m/z):

- 37 044101

420.1 [M+H]+

1H-NMR (400 MHz, 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 ).

(C) 3-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2 -en-

1,6,6-Dz-1-ol

Compound 83 was prepared according to the procedure for Compound 1, Step (B), using NaBD ₄ . MC (m/z): 421.1 [M+H]+

1H-NMR (400 MHz, 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 82 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+N) ⁺ Ή-NMR Intermediate connection 84 ιζ -by P ¹ P 414.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.98-4.89 (m, 1H), 4.35-4.13 (m, 2H), 3.02-2.81 (m, 2H ), 2.75-2.46 (m, ZN), 2.44-2.24 (m, 1H), 1.821.71 (m, 1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H). 1-54 85 DD R/x A tA N N 408.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.36-4.14 (m, ZN), 2.98-2.85 (m, 4H), 2.67-2.46 (m, 5H ), 2.39-2.22 (m, 1H), 1.82-1.71 (m, 1H), 1.681.57 (m, 1H). 1-10 86 O ъ XZ zh-TV mm ° TZ -PO o-Vo ¹ / □ O ω σ 422.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.60-8.23 (m, 2H), 8.10-7.75 (m, 1H), 4.36-4.28 (m, 1H ), 2.72-2.56 (m, 1H), 2.48-2.33 (m, 1H), 1.831.73 (m, 1H), 1.71-1.63 (m, 1H). 1-41 87 A CF ₃ N% CF ₃ 420.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.02-4.88 (m, 2H), 4.34-4.24 (m, 1H), 2.60-2.48 (m, 1H ), 2.42-2.30 (m, 1H), 1.88-1.72 (m, 1H), 1.701.58 (m, 1H), 1.36-1.31 (m, 6H). 1-32 89 УХ R OU- ΖΧ уч ζχ 7 О 445.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.54-8.35 (m, 2H), 8.03-7.83 (m, 1H), 4.40-4.24 (m, 1H ), 2.74-2.60 (m, 1H), 2.48-2.32 (m, 1H), 1.851.74 (m, 1H), 1.71-1.60 (m, 1H), 1.31(s,9H). 1-63

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 83 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 90 DD F ³ 11 ϊ Η Η 415.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.98-4.89 (m, 1H), 4.35-4.13 (m, 1H), 3.02-2.81 (m, 2H ), 2.75-2.46 (m, 3H), 2.44-2.24 (m, 1H), 1.821.71 (m, 1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H). 1-54 91 DD No. Ή A L ^F VA AA AT Ν Ν NHH 409.1 Ή-NMR (400 MHz, CD3OD): δ 4.36-4.14 (m, 2H), 2.98-2.85 (m, 4H), 2.67-2.46 (m, 5H), 2.39-2.22 (m, 1H), 1.82-1.71 (m, 1H), 1.681.57 (m, 1H). 1-10 92 DD Xx>h FA N ⁴ N 1 ^f aX aa X NNN^ HH 361.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.34-4.18 (m, 1H), 4.18-4.00 (m, 1H), 3.01-2.81 (m, 2H ), 2.72-2.41 (m, 3H), 2.41-2.18 (m, 1H), 1.801.70 (m, 1H), 1.69-1.58 (m, 1H), 1.25-1.11 (br, 6H). 1-37

- 38 044101

Connection 93:

(*)3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex- 2-en1-ol

(A) (R)-2-fluoro-3-(4-((4-methoxybenzyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5- triazin2-yl)cyclohex-2-en-1-one (B2)

The title compound B2 was prepared according to the procedure for preparation of compound 1 using Intermediate I-55.

MS (m/z): 440.1 [M+H]+ (B) (R)-3 -(4-amino-6-(( 1,1,1 -trifluoropropan-2-yl)amino)-1 ,3,5-triazin-2-yl)-2-fluorocyclohex-2-en1-one (B3)

A solution of compound B2 (1.1 g, 2.5 mmol) in TFA (10 ml) was stirred at reflux for 4 hours. The solvent was removed. The residue was washed with saturated aqueous NaHCO ₃ and purified by flash column chromatography (PE/EA gradient elution = 100:0-0:100), resulting in compound B3 as a pale yellow solid. MS (m/z): 320.0 [M+H] ⁺ (C) (*)3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino )-1,3,5-triazin-2-yl)-2-fluorocyclohex-2en-1-ol

Compound 93 was prepared according to the procedure for compound 39. MS (m/z): 322.0 [M+H] ⁺

1H-NMR (400 MHz, 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).

Compounds 95 and 96: 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, optically pure diastereomers

nn nn nn

123 B4 & 96 (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 a nitrogen atmosphere, a solution of compound 123 (1.2 g, 3.30 mmol) in THF (20 ml) was added dropwise to a 1 mol/L solution of LiHMDS/THF (14.85 ml, 14.85 mmol) at -78° C. The mixture was stirred at 0°C for 2 hours. A solution of NFSI (3.12 g, 9.90 mmol) in THF was added slowly dropwise, then the resulting mixture was warmed to room temperature and stirred for 3 hours. After completion of the reaction, the mixture was stopped by adding saturated aqueous NH ₄ Cl solution (30 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried using anhydrous Na ₂ SO ₄ and filtered. The filtrate was condensed under vacuum and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in compound B4 as a white solid (190 mg, yield: 15.2%). MS (m/z): 380.2 [M+H] ⁺ (B) 2,6-difluoro-3 -(4-(isopropylamino)-6-(((R)-1,1,1 -trifluoropropane- 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 preparation of compound 39 and purified by preparative TLC (elution PE/EA=2/1).

Compound 95, Rf« 0.55, MS (m/z): 382.1 [M+H] ⁺ ;

^1H -NMR (400 MHz, 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 (400 MHz, 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).

The compounds listed in the table below were prepared in accordance with the procedure for the preparation of compounds 95 and 96 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

- 39 044101

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 97 Ή QF ₃ An cf ₃ Η Η Rf ~ 0.55 436.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.98-4.88 (m, 2H), 4.82-4.63 (m, 1H), 4.35-4.18 (m, 1H ), 2.64-2.49 (m, 2H), 2.06-1.90 (m, 2H), 1.371.31 (m, 6H). 1-3 98 Ή CF ₃ Ν A CF ₃ Rf ~ 0.50 436.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.03-4.89 (m, 2H), 4.80-4.65 (m, 1H), 4.55-4.38 (m, 1H) , 2.80-2.62 (m, 1H), 2.52-2.34 (m, 1H), 2.172.02 (m, 1H), 1.98-1.84 (m, 1H), 1 .40-1.29 (m, 6H). 1-3 201 & YES A^ ^F Η Η Rf ~ 0.55 424.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.79-4.64 (m, 1H), 4.37-4.15 (m, 3H), 2.99-2.83 (m, 4H ), 2.70-2.47 (m, 6H), 2.06-1.88 (m, 2H). 1-10 202 Ή A Λ A Η Η Rf ~ 0.50 424.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.81-4.64 (m, 1H), 4.52-4.38 (m, 1H), 4.34-4.17 (m, 2H) , 2.99-2.83 (m, 4H), 2.70-2.32 (m, 6H), 2.132.01 (m, 1H), 1.96-1.81 (m, 1H). 1-10

- 40 044101

225 Ή CF ₃ N^N Ν N N H V Rf ~ 0.55 394.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.90 (m, 1H), 4.79-4.62 (m, 1H), 4.35-4.19 (m, 1H ), 3.27-3.11 (m, 2H), 2.65-2.43 (m, 2H), 2.071.87 (m, 2H), 1.40-1.29 (m, 3H), 1.13-1.00 (m, 1H), 0.55-0.40 (m, 2H), 0.31-0.15 (m, 2H). 1-77 226 Ή CF ₃ Ν^Ν 'ΉΓν'^ν^ν'^Ή—ζ η η V Rf~0.50 394.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.00-4.89 (m, 1H), 4.80-4.64 (m, 1H), 4.51-4.37 (m, 1H ), 3.27-3.09 (m, 2H), 2.78-2.57 (m, 1H), 2.522.30 (m, 1H), 2.15-2.01 (m, 1H), 1.97-1.80 (m, 1H), 1.40-1.27 (m, 3H), 1.13-0.98 (m, 1H), 0.55-0.40 (m, 2H ), 0.30-0.14 (m, 2H). 1-77 227 Ή, 9 ^F ₃ ρ/ _f Rf ~ 0.55 430.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.90 (m, 1H), 4.80-4.63 (m, 1H), 4.35-4.11 (m, 2H ), 3.01-2.86 (m, 2H), 2.55 (s, 4H), 2.09-1.92 (m, 2H), 1.42-1.31 (m, 3H). 1-9 228 Ή _F 9 ^F ₃ Ν^Ν pJ _ρ Η Rf ~ 0.50 430.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.05-4.88 (m, 1H), 4.82 - 4.64 (m, 1H), 4.54-4.40 (m, 1H ), 4.36-4.17 (m, 1H), 3.00-2.84 (m, 2H), 2.772.34 (m, 4H), 2.16-2.02 (m, 1H), 1.96-1.83 (m, 1H), 1.41-1.30 (m, 3H). 1-9 23 0& 231 232 233 Ή CF ₃ Ν^Ν Η Η 382.1 Ή-NMR (400 MHz, DMSO-de): δ 7.89-7.69 (m, 1H), 7.54-7.36 (m, 1H), 5.82-5.56 (m, 1H ), 4.93-4.59 (m, 2H), 4.39-4.28 (m, 1H), 3.223.10 (m, 2H), 2.56-2.39 (m, 1H), 2.38-2.20 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.73 (m, 1H), 1.50-1.41 (m, 2H ), 1.29-1.23 (m, 3H), 0.860.79 (m, 3H). 1-18 Ή CF ₃ N% Η Η K CF ₃ Ν ^Ν ρΟ χ JL / Or) ν ν ν (rO Rf ~ 0.55 Ή., rХ Rf ~ 0.50 382.0 444.2 444.2 Ή-NMR (400 MHz, DMSO-de): δ 7.92-7.69 (m, 1H), 7.60-7.34 (m, 1H), 6.11-5.82 (m, 1H ), 4.96-4.59 (m, 2H), 4.24-4.08 (m, 1H), 3.223.09 (m, 2H), 2.45-2.29 (m, 2H), 1.97-1.89 (m, 2H), 1.52-1.40 (m, 2H), 1.29-1.22 (m, 3H), 0.86-0.78 (m, 3H ). Ή-NMR (400 MHz, CD ₃ OD): δ 5.00-4.89 (m, 1H), 4.81-4.63 (m, 1H), 4.52-4.37 (m, 1H ), 4.36-4.19 (m, 1H), 2.65-2.46 (m, 3H), 2.282.14 (m, 2H), 2.13-1.91 (m, 4H), 1.85-1.70 (m, 1H), 1.39-1.29 (m, 3H). Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.89 (m, 1H), 4.80-4.62 (m, 1H), 4.57-4.29 (m, 2H ), 2.74-2.34 (m, 3H), 2.29-1.71 (m, 7H), 1.411.27 (m, 3H). 1-18 1-82 1-82

Note: Compounds 230 and 231 were obtained by flash column chromatography (elution with H ₂ O/MeOH gradient = 100:0-0:100). This compound eluted first was named Compound 230, and the compound eluted first was named Compound 231.

Compounds 242, 266-269: 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2 ,6difluorocyclohex-2-en-1-D-1-ol, optically pure diastereomers

- 41 044101

(A) 3-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex -2-en-1-on

Compound 242 was prepared according to the procedure of Step A of Compounds 95 and 96, using Compound 295 and appropriate reagents.

MS (m/z): 434.0 [M+H]+;

1H-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 ).

(B) 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex -2-en1-one, optically pure diastereomers

Compound 242 was separated by chiral HPLC, resulting in a pair of optically pure diastereomers, Compounds 246 and 247 (chiral HPLC conditions: Column: AD-H (0.46 cm i.d. x 15 cm length); mobile phase: n- heptane/isopropanol=80/20; flow rate: 0.5 ml/min; detection at wavelength: UV 254 nm). 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] ⁺ ).

(C) 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro -cyclohex-2en-1-D-1-ol, optically pure diastereomers

Compounds 266 and 267 were prepared according to the procedure for preparation of compound 1, using Compound 246 and NaBD4, purified by flash column chromatography (PE/EA elution).

Compound 266: Rf - 0.55, MS (m/z): 437.2 [M+H] ⁺ ;

1H-NMR (400 MHz, 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] ⁺ ;

1H-NMR (400

MHz, 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).

Compounds 268 and 269 were prepared according to the procedure for preparation of compound 1, using Compound 247 and NaBD ₄ , purified by flash column chromatography (PE/EA elution).

Compound 268: Rf - 0.55, MS (m/z): 437.2 [M+H] ⁺ ;

1H-NMR (400

MHz, 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] ⁺ ;

1H-NMR (400 MHz, 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 ).

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

- 42 044101 (A) (R)-2,6,6-trifluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3, 5-triazin-2yl)cyclohex-2-en-1-one (B5)

Under a nitrogen atmosphere, a solution of compound 123 (1.2 g, 3.30 mmol) in THF (20 ml) was added dropwise to a solution of 1 mol/L LiHMDS in THF (14.85 ml, 14.85 mmol) at -78° C. The mixture was stirred at 0°C for 2 hours. A solution of NFSI (3.12 g, 9.90 mmol) in THF was then added dropwise to this mixture, then the reaction mixture was slowly warmed to room temperature and stirred for another 3 hours. After completion of the reaction, the mixture was stopped by adding a saturated aqueous solution of NH ₄ Cl (30 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na ₂ SO ₄ and filtered. The filtrate was condensed in vacuo and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in compound B5 as a white solid (25 mg, yield: 1.9%). MS (m/z): 398.1 [M+H]+ (B) 2,6,6-trifluoro-3-(4-(isopropylamino)-6-(((K)-1,1,1- trifluoropropan-2-yl)amino)-1,3,5-triazin-2yl)cyclohex-2-en-1-ol

Compound 94 was prepared according to the procedure for preparation of compound 39, using compound B5 and appropriate reagents.

MS (m/z): 400.2 [M+H]+ 'H-NMR (400 MHz, CD ₃ OD): 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 94 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art: _______________________

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection Won Ή-NMR (400 MHz, CD ₃ OD): δ AA 5.00-4.86 (m, 2H), 4.36-4.17 (m, 196 A ^F 454.1 1H), 2.80-2.65 (m, 1H), 2.58-2.42 1-3 CF ₃ N^N CF ₃ (m, 1H), 2.25-2.05 (m, 2H), 1.37- AAAA 1.31 (m, 6H). Or) ν ν ν (κΛ RF Ή-NMR (400 MHz, CD ₃ OD): δ ><.OH G fRsY 4.37-4.14 (m, 3H), 3.00-2.85 (m, 203 at H: 442.2 4H), 2.74-2.44 (m, 6H), 2.24-2.02 (m, 2H). 1-10 HH _VOH Ή-NMR (400 MHz, CD ₃ OD): δ Af 5.01-4.92 (m, 1H), 4.35-4.01 (m, 208 sp 440.0 3H), 2.77-2.67 (br, 1H), 2.63-2.46 1-76 CF ₃ N^N (m, 1H), 2.33-2.01 (m, 2H), 1.41- AAA <Yn^n-^n^cf ₃ 1.32 (m, 3H). Ή-NMR (400 MHz, CD ₃ OD): δ X 4.99-4.90 (m, 1H), 4.31-4.20 (m, Ox 1H), 3.25-3.16 (m, 2H), 2.79-2.63 209 Λ 412.2 (m, 1H), 2.59-2.44 (m, 1H), 2.23- 1-78 CF ₃ N ^N 2.03 (m, 2H), 1.37-1.31 (m, 3H), η η V 1.13-0.99 (m, 1H), 0.53-0.41 (m, 2H), 0.28-0.17 (m, 2H). Ή-NMR (400 MHz, CD ₃ OD): δ X 5.03-4.89 (m, 1H), 4.55-4.37 (m, Cx 1H), 4.02-3.77 (m, 2H), 2.81-2.61 210 I 400.0 (m, 1H), 2.58-2.37 (m, 1H), 2.17- 1-18 CF ₃ N ^N 2.05 (m, 1H), 2.04-1.84 (m, 1H), 1.81-1.51 (m, 2H), 1.43-1.31 (m, 3H), 1.05-0.90 (m, 3H). Won Ή-NMR (400 MHz, CD ₃ OD): δ [A1C 5.02-4.89 (m, 1H), 4.38-4.14 (m, 239 Ή F 448.0 2H), 3.03-2.86 (m, 2H), 2.78-2.44 1-54 CF ₃ NpN /^7 (m, 4H), 2.30-2.01 (m, 2H), 1.42- Дь NN ΥΥν ν ν Η Η 1.30 (m, 3H). /x\on Ή-NMR (400 MHz, CD ₃ OD): δ A 5.01-4.92 (m, 1H), 4.35-4.01 (m, 245 Ή 440.0 3H), 2.77-2.67 (br, 1H), 2.63-2.46 1-76 CF ₃ Ν^Ν (m, 1H), 2.33-2.01 (m, 2H), 1.41- YYN^N^N^CFa 1.32 (m, 3H).

Compound 234: 3-(4-((cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5triazin-2-yl)-2 ,6,6-trifluorocyclohex-2-en-1-ol

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(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 according to the procedure of Step A of Compound 94 using Compound B6 (prepared in accordance with the procedure for Preparation of Compound 1 using Intermediate I-77) and appropriate reagents.

(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 preparation of compound 1, using compound B7 and appropriate reagents.

MS (m/z): 412.2 [M+H]+ ^1H- NMR (400 MHz, 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 234 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 211 (A CF ₃ I|An CF ₃ Αν ν'n'w ⁴ 455.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.87 (m, 2H), 2.82-2.66 (m, 1H), 2.622.45 (m, 1H), 2.27-2.02 (m, 2H), 1.401.29 (m, 6H). 1-3 235 ill L> 462.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.024.88 (m, 1H), 4.54-4.39 (m, 1H), 4.334.17 (m, 1H), 2.79-2. 64 (m, 1H), 2.612.44 (m, 2H), 2.29-2.00 (m, 6H), 1.901.67 (m, 1H), 1.39-1.31 (m, 3H) . 1-82 238 x 4 OU-zi 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.054.91 (m, 1H), 4.31-4.20 (m, 1H), 2.862.60 (m, 2H), 2.59-2. 43 (m, 1H), 2.242.04 (m, 2H), 1.38-1.31 (m, 3H), 0.780.66 (m, 2H), 0.57-0.44 (m, 2H) . 1-16 248 CF ₃ N^N HH 400.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.90 (m, 1H), 4.32-4.19 (m, 1H), 3.383.23 (m, 2H), 2.80-2. 61 (m, 1H), 2.602.41 (m, 1H), 2.28-2.02 (m, 2H), 1.641.52 (m, 2H), 1.38-1.30 (m, 3H) , 0.990.87 (m, 3H). 1-18

Compound 259: 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)1,3,5-triazine-2 -yl)-2,6,6-trifluorocyclohex-2-en-1-ol

AT 8

B11 259 (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)

Under nitrogen atmosphere to a mixture of compound B8 (prepared according to the procedure for preparation of Compound 39 using Intermediate I-9: 750 mg, 1.83 mmol) and Et ₃ N (371 mg,

- 44 044101

3.66 mmol) in dry DCM (15 ml) was added a solution of TBSOTf (726 mg, 2.75 mmol) in DCM (5 ml) at

0~5°C. The mixture was stirred for 30 minutes. It was then poured into water and extracted with dichloromethane. The organic layer was collected, dried using anhydrous Na ₂ SO ₄ , condensed under reduced pressure and purified by flash column chromatography (PE/EA elution) to obtain compound B9 as a yellow oil (958 mg, yield: 100%). MS (m/z): 524.1 [M+H]+ (B) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropane -2-yl)amino)-1,3,5-triazin-2yl)-2,6-difluorocyclohex-2-en-1-one (B10)

Under a nitrogen atmosphere, a solution of compound B9 (958 mg, 1.83 mmol) in dry MeCN (20 ml) was added dropwise to a suspension of Selectfluor® (778 mg, 2.20 mmol) in dry acetonitrile (20 ml) dropwise at 0-5°C C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, condensed under reduced pressure and purified by flash column chromatography (PE/EA elution) to obtain compound B10 as a white solid (512 mg, yield: 66%). MS (m/z): 428.0 [M+H] ⁺ .

(C) (R)-3 -(4-((3,3-difluorocyclobutyl)amino)-6-(( 1,1,1 -trifluoropropan-2 -yl)amino)-1,3,5 -triazin- 2yl)-2,6,6-trifluorocyclohex-2-en-1-one (B11)

Under a nitrogen atmosphere, to a solution of compound B10 (512 mg, 1.12 mmol) in dry THF (10 ml), 1 M LiHMDS/THF solution (3.47 ml, 3.47 mmol) was added dropwise at -78°C and stirred within 30 min. A solution of NFSI (388 mg, 1.23 mmol)/THF (10 mL) was then added dropwise to this mixture at -78°C and the reaction mixture was stirred for 2 hours. After completion of the reaction, a saturated aqueous solution of NH4Cl was added to stop the reaction. The mixture was extracted with ethyl acetate. The organic layer was collected, condensed under reduced pressure and purified by flash column chromatography (PE/EA elution) to obtain compound B11 as a yellow solid (230 mg, yield: 46%). MS (m/z): 446.2 [M+H]+ (D) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropane -2-yl)amino)-1,3,5-triazin-2yl)-2,6,6-trifluorocyclohex-2-en-1-ol

Compound 259 was prepared according to the procedure for preparation of compound 39, using compound B11 and appropriate reagents. MS (m/z): 448.0 [M+H]+ ^1H- NMR (400 MHz, 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 259 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 260 Zh A An ν ν 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.99-4.83 (m, 1H), 4.26-4.09 (m, 1H), 2.76-2.53 (m, 2H ), 2.51-2.34 (m, 1H), 2.17-1.95 (m, 2H), 1.311.23 (m, 3H), 0.69-0.59 (m, 2H), 0.48-0.38 (m, 2H). 1-85 261 А° ⁿ DaХА Η Η 394.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.36-4.09 (m, 3H), 3.02-2.87 (m, 2H), 2.79-2.43 (m, 4H ), 2.26-2.04 (m, 2H), 1.28-1.15 (m, 6H). 1-37 270 3^-0 ιζ 7 ¹ ΙΖ -π ο 2 ¹ J ¹ 440.2 Ή-NMR (400 MHz, CD ₃ OD) δ 4.924.82 (m, 1H), 4.28-3.90 (m, 3H), 2.72-2.38 (m, 2H), 2.20 -1.96 (m, 2H), 1.33-1.21 (m, 3H). 1-86 271 ΙΖ X ¹ ΙΖ -π Ο a ¹ 449.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.31-8.20 (m, 1H), 7.63-7.50 (m, 1H), 7.25-7.14 (m, 1H ), 7.13-7.01 (m, 1H), 4.83-4.68 (m, 1H), 4.524.39 (m, 2H), 4.13-3.98 (m, 1H), 2.57-2.18 (m, 2H), 2.08-1.78 (m, 2H), 1.18 -1.00 (m, 3H). 1-87

Compound 274: 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)2,6,6-trifluorocyclohex-2-ene-1 -D-1 -ol

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(A) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2-fluorocyclohex2-en-1-one (B12)

Under nitrogen atmosphere, a mixture of Intermediate I-37 (4.17 g, 15.0 mmol), Intermediate I-88 (4.32 g, 18.0 mmol), Na ₂ PdCl ₄ (221 mg, 0.75 mmol ), DTBPPS (402 mg, 1.5 mmol), K2CO3 (5.18 g, 37.5 mmol), MeCN (40 ml) and H ₂ O (10 ml) were stirred at 60°C for 2 hours. completion of the reaction, the mixture was poured into water and extracted with dichloromethane. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA elution) to obtain B12 as a yellow solid (4.98 g, yield: 93%). MS (m/z): 356.1 [M+H]+ (B) 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazine-2 -yl)-2,6-difluorocyclohex-2-en-1-one (B13)

The title compound B13 was prepared according to steps A and B of the procedure for preparing compound 259, using compound B12 and appropriate reagents. MS (m/z): 374.1 [M+H]+ (C) 3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazine-2 -yl)-2,6,6trifluorocyclohex-2-en-1-one (B14)

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

Compound 274 was prepared according to step B of the preparation procedure for compound 1, using compound B14, NaBD4 and appropriate reagents. MS (m/z): 395.1 [M+H]+ ^1H- NMR (400 MHz, 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 274 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

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Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 275 F. L Kh_on G AG νΑι nA CFa-^^^N^N^N^A ³ n n I ^x 479.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.67-8.30 (m, 2H), 8.06-7.80 (m, 1H), 4.45-4.23 (m, 1H ), 2.93-2.75 (m, 1H), 2.69-2.50 (m, 1H), 2.332.06 (m, 2H), 1.42-1.20 (m, 9H). 1-63 276 nA] nAn cfj^^n^n^n^A n n 480.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.67-8.32 (m, 2H), 8.08-7.80 (m, 1H), 2.91-2.75 (m, 1H ), 2.69-2.52 (m, 1H), 2.32-2.08 (m, 2H), 1.421.26 (m, 9H). 1-63 277 A CF ₃ hr Ν CF ₃ AAAA Whl Ν νΆ HH 454.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.05-4.91 (m, 2H), 4.38-4.16 (m, 1H), 2.83-2.66 (m, 1H ), 2.62-2.45 (m, 1H), 2.29-2.03 (m, 2H), 1.441.26 (m, 6H). 1-89 278 A ^f d CA CF ₃ N^N _l HH 399.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.14-4.92 (m, 1H), 2.88-2.64 (m, 2H), 2.59-2.43 (m, 1H ), 2.32-1.99 (m, 2H), 1.45-1.28 (m, 3H), 0.820.66 (m, 2H), 0.58-0.45 (m, 2H). 1-85 279 A/d ix ^0H ^?f Ta A 399.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.13-4.93 (m, 1H), 2.90-2.64 (m, 2H), 2.61-2.41 (m, 1H ), 2.33-1.99 (m, 2H), 1.49-1.24 (m, 3H), 0.860.67 (m, 2H), 0.62-0.46 (m, 2H). 1-16 281 A Г fRSj CF ₃ N^N CF ₃ AAAA An n nA 436.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.22-6.87 (m, 1H), 5.10-4.91 (m, 2H), 4.49-4.21 (m, 1H ), 2.90-2.54 (m, 2H), 2.34-1.98 (m, 2H), 1.501.20 (m, 6H). 1-3 282 V ^ ³ Ϊ AA ³ ΆΓν N N'fRk HH 437.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.22-6.87 (m, 1H), 5.10-4.91 (m, 2H), 2.90-2.54 (m, 2H ), 2.34-1.98 (m, 2H), 1.50-1.20 (m, 6H). 1-3 283 CF ₃ N^N CF ₃ 454.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.05-4.90 (m, 2H), 4.40-4.19 (m, 1H), 2.84-2.66 (m, 1H ), 2.62-2.45 (m, 1H), 2.30 -2.03 (m, 2H), 1.421.27 (m, 6H). 1-32 293 A CF ₃ N^N VAv H nA 430.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.09-4.91 (m, 1H), 4.34-4.21 (m, 1H), 2.82-2.68 (m, 1H ), 2.61-2.46 (m, 1H), 2.28-2.03 (m, 2H), 1.391.34 (m, 3H), 1.29-1.26 (m, 9H). 1-90 294 S ^0H I ^F CF ₃ N^N Ν N H h A 430.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.09-4.91 (m, 1H), 4.34-4.21 (m, 1H), 2.82-2.68 (m, 1H ), 2.61-2.46 (m, 1H), 2.28-2.03 (m, 2H), 1.391.34 (m, 3H), 1.29-1.26 (m, 9H). 1-91 296 A? ^F 'Λ A ³ An n 452.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.88 (m, 2H), 3.07-2.09 (m, 4H), 1.39-1.31 (m, 6H ). 1-3 298 nA nA CF ₃ ' ^x ^ ^x ^N-^N^N'°r ³ HH 437.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.77-8.34 (m, 2H), 8.01-7.69 (m, 1H), 4.47-4.17 (m, 1H ), 3.81 (s, 3H), 2.89-2.73 (m, 1H), 2.67-2.52 (m, 1H), 2.30-2.06 (m, 2H). 1-92

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Compound 297: 2,6,6-trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5triazine-2 -yl)cyclohex-2-en-1-ol

(A) (R)-3-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6, 6-trifluorocyclohex2-en-1-one (B16)

The title compound B16 was prepared according to steps B and C of the procedure for preparing compound 274, using Intermediate A4 and appropriate reagents. MS (m/z): 375.1 [M+H]+ (B) (R)-2,6,6-trifluoro-3-(4-(methoxyamino)-6-((1,1,1- trifluoropropan-2-yl)amino)-1,3,5-triazin-2yl)cyclohex-2-en-1-one (B17)

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

Compound 297 was prepared according to step B of the preparation procedure for compound 1, using compound B17 and appropriate reagents. MS (m/z): 388.2 [M+H] ⁺

1H-NMR (400 MHz, 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 ).

Compound 280: 3-(4-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6, 6trifluorocyclohex-2-en-1-ol

1-105

HH

B18

^ΗΝΗ2

Β19

1)TBSOTf

2) Selectfluor

O

1)TBSOTf

2) Selectfluor

CF ₃

Α/ν''ν''νη ₂ Η

O

NaBH ₄ , CeC1 ₃ H ₂ O ------------------------*-

he nh ₂

Q ^F 3

7r?n''ν''nh ₂

Η

280 (A) (R)-2-fluoro-3 -(4-((4-methoxyphenyl)amino)-6-(( 1,1,1 -trifluoropropan-2-yl)amino)-1,3,5 -triazin-2yl)cyclohex-2-en-1-one (B18)

The title compound B18 was prepared according to the procedure for preparation of compound 1 using Intermediate I-105 and appropriate reagents. MS (m/z): 440.2 [M+H] ⁺ (B) (R)-3 -(4-amino-6-(( 1,1,1 -trifluoropropan-2-yl)amino)-1 ,3,5-triazin-2-yl)-2-fluorocyclohex-2-en1-one (B19)

A mixture of compound B18 (1.4 g, 3.19 mmol) in TFA (10 ml) was stirred at reflux for 2 hours. The solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO ₃ solution. The organic layer was collected and condensed under reduced pressure to give the title compound B19 as a yellow solid (800 mg, 79% yield), which was used in the next step without purification.

(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

- 48 044101

Compound 280 was prepared according to the procedure for preparation of compound 274, using Compound B19 and appropriate reagents. MS (m/z): 358.1 [M+H]+;

1H-NMR (400 MHz, 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).

Compound 284: 3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol

(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 according to the procedure for preparation of compound 1 using Intermediate I-106 and appropriate reagents.

MS (m/z): 542.1 [M+H] ⁺ (B) 3-(4,6-diamino-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-ene-1 -on (B21)

The title compound B21 was prepared according to step B of the preparation procedure for compound 280, using compound B20 and appropriate reagents.

MS (m/z): 224.0 [M+H] ⁺ (C) 3-(4,6-bis((tert-butyldimethylsilyl)amino)-1,3,5-triazin-2-yl)-2 ,6,6-trifluorocyclohex-2-en-1one (B22)

The title compound B22 was prepared according to steps B and C of the procedure for preparing compound 274, using compound B21 and the appropriate reagents.

MS (m/z): 488.1 [M+H] ⁺ (D) 3-(4,6-diamino-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2 -en-1-on (B23)

A solution of compound B22 (410 mg, 0.84 mmol) in concentrated aqueous solution of HCl (1 ml) and MeOH (5 ml) and stirred at room temperature for 30 min. The mixture was diluted with ethyl acetate and adjusted to pH=8 with saturated aqueous NaHCO ₃ solution. The organic layer was collected, concentrated to dryness in vacuo and purified by flash column chromatography (elution 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] ⁺ (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 step B of the preparation procedure for compound 1, using compound B23 and the appropriate reagents. MS (m/z): 262.0 [M+H] ⁺

1H-NMR (400 MHz, 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).

Compound 99: 3 -(4,6-6uc(((R)- 1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2fluorocyclohex -2-en-1-ol

(A) 3-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2 -fluorocyclohex2-en-1-one (B24)

3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-49 044101 yl)amino)-1,3,5-triazin-2-yl)-2 was sequentially added to a sealed test tube -fluorocyclohex-2-en-1-one (prepared according to the procedure for preparation of compound 1 using Intermediate I-3, 700 mg, 1.69 mmol), NCS (224 mg, 1.69 mmol), TsOH-H ₂ O (321 mg, 1.69 mmol) and MeCN (10 ml). The mixture was heated to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (elution with a PE/EA gradient = 100:0-0:100), resulting in the above title compound B24 as a white solid (320 mg, 42.2% yield). MS (m/z): 450.1, 452.1 [M+H]+ (B) 3-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino )-1,3,5-triazin-2-yl)-6-chloro-2-fluorocyclohex2-en-1-ol

Compound 99 was prepared according to the procedure for preparation of compound 39 using compound B24 and appropriate reagents. MS (m/z): 452.1 [M+H] ⁺

1H-NMR (400 MHz, 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 ).

Compound 122: (R)-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2yl)cyclohex-2-ene -1 -he

122

Intermediate 1-2 (500 mg, 1.76 mmol), 3-(4,4,5,5-tertramethyl1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one, was added to the flask (391 mg, 1.76 mmol), Cs ₂ CO ₃ (1144 mg, 3.52 mmol), Pd(PPh ₃ ) ₄ (101 mg, 0.09 mmol), 1,4-dioxane (20 ml) and water (4 ml). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution) to provide the title compound as a white solid (350 mg, 57.9% yield). MS (m/z): 344.1 [M+H] ⁺

1H-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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 122 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 123 ΤΖ ω ¹ 9t ___ -P O 362.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.014.90 (m, 1H), 4.22-4.10 (m, 1H), 2.892.77 (m, 2H), 2.64-2, 55 (m, 2H), 2.122.02 (m, 2H), 1.39-1.32 (m, 3H), 1.231.17 (m, 6H). 1-2 295 a QF ₃ N^N CF ₃ 416.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.88 (m, 2H), 2.91-2.78 (m, 2H), 2.622.53 (m, 2H), 2.11-2, 00 (m, 2H), 1,401.30 (m, 6H). 1-3

Compound 124: 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2yl)cyclohex-2-ene -1 -ol

122 124

Compound 122 (250 mg, 0.73 mmol), CCCl ₃ -7H ₂ O (353 mg, 0.95 mmol) and EtOH (10 ml) were added to the flask. The mixture was cooled to 0°C, NaBH ₄ (36 mg, 0.95 mmol) was added and the reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the mixture was stopped by adding a saturated aqueous solution of NH ₄ Cl (3 ml) and water (20 ml) and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA elution) to provide 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), 2.51-2.30 (m, 2H), 2.01-1.82 (m, 2H), 1.71-1.49 (m, 2H), 1.38-1.30 (m, 3H), 1.23-1.12 (m, 6H).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 124 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 125 /° ^Н t—((RS) CF ₃ N^ _N i Η Η 332.0 Ή-NMR (400 MHz, CD ₃ OD): δ 6.886.70 (m, 1H), 5.07-4.87 (m, 2H), 4.234.08 (m, 1H), 2.90-2, 77 (m, 1H), 2.632.49 (m, 1H), 2.43-2.30 (m, 1H), 1.851.69 (m, 1H), 1.39-1.31 (m, 3H) , 1.221.17 (m, 6H). 1-2 126 <ν ^0Η QF ₃ An cf ₃ 400.0 Ή-NMR (400 MHz, CD ₃ OD): δ 7.237.01 (m, 1H), 5.08-4.87 (m, 2H), 4.374.27 (m, 1H), 2.49-2. 35 (m, 2H), 1,981.82 (m, 2H), 1.68-1.53 (m, 2H), 1,391.32 (m, 6H). 1-3 127 & ja Αν Ο. ΑΑ _Ν A _Ν Α _Ν A/ Η Η 388.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.93 (m, 1H), 4.36-4.19 (m, 3H), 2.972.87 (m, 4H), 2.69-2. 50 (m, 4H), 2.452.34 (m, 2H), 1.97-1.80 (m, 2H), 1.671.51 (m, 2H). 1-10 128 AV ^0H cf ₃ nA Η Η 358.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.266.90 (m, 1H), 5.10-4.92 (m, 1H), 4.604.26 (m, 2H), 2.56-2. 23 (m, 4H), 2.111.81 (m, 4H), 1.79-1.49 (m, 4H), 1.421.28 (m, 3H). 1-15 129 <ν ^0Η ί iRsj cf ₃ nA . ΑΓν'^ν'^ν'^ Η Η 344.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.276.85 (m, 1H), 5.17-4.95 (m, 1H), 4.454.20 (m, 1H), 2.84-2. 63 (m, 1H), 2.532.27 (m, 2H), 2.00-1.82 (m, 2H), 1.741.51 (m, 2H), 1.43-1.29 (m, 3¾ 0.840 .67 (m, 2H), 0.58-0.46 (m, 2H). 1-16 130 α° ^Η CF ₃ nA Η Η 372.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.89 (m, 1H), 5.09-4.92 (m, 1H), 4.414.18 (m, 2H), 2.54-2, 31 (m, 2H), 2,091.82 (m, 4H), 1.80-1.69 (m, 2H), 1,671.44 (m, 6H), 1.40-1.31 (m, 3H) . 1-12 131 Γ iRsT CF ₃ Ν^Ν η η 1 he 376.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.246.95 (m, 1H), 5.12-4.90 (m, 1H), 4.434.25 (m, 1H), 3.53-3, 37 (m, 2H), 2.472.33 (m, 2H), 2.01-1.81 (m, 2H), 1.691.52 (m, 2H), 1.38-1.33 (m, 3H) , 1.19 (s, 6H). 1-7

- 51 044101

132 CF ₃ ΉΝ Η Η 362.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.236.91 (m, 1H), 5.12-4.91 (m, 1H), 4.434.25 (m, 1H), 3.65-3, 46 (m, 4H), 3.36 (s, 3H), 2.53-2.32 (m, 2H), 2.01-1.83 (m, 2H), 1.69-1.52 ( m, 2H), 1.40-1.31 (m, 3H). 1-17 133 Γ (κϋΓ CF ₃ Ν^Ν Αν Α Α-^ Η Η 346.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.026.87 (m, 1H), 5.11-4.90 (m, 1H), 4.404.23 (m, 1H), 3.40-3, 30 (m, 2H), 2.552.28 (m, 2H), 1.98-1.81 (m, 2H), 1.681.53 (m, 4H), 1.39-1.31 (m, 3H) , 0.970.89 (m, 3H). 1-18 134 Χ ^ΟΗ ψ CF ₃ ν^ν ΉνΑΑα η η 1 360.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.236.90 (m, 1H), 5.14-4.89 (m, 1H), 4.454.21 (m, 1H), 3.25-3, 07 (m, 2H), 2,502.33 (m, 2H), 1.97-1.80 (m, 3H), 1,741.51 (m, 2H), 1.38-1.31 (m, 3H) , 0.950.89 (m, 6H). 1-13 135 ί IRSjI CF ₃ Ν^Ν Αν Α Α^ Η Η 332.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.286.88 (m, 1H), 5.14-4.93 (m, 1H), 4.404.22 (m, 1H), 3.48-3, 35 (m, 2H), 2,572.27 (m, 2H), 1.98-1.83 (m, 2H), 1,701.52 (m, 2H), 1.40-1.31 (m, 3H) , 1.201.13 (m, 3H). 1-19 136 A CF ₃ Ν^Ν ΉΉ Η Η 386.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.92 (m, 1H), 5.11-4.88 (m, 1H), 4.414.26 (m, 1H), 3.95-3, 72 (m, 1H), 2.532.31 (m, 2H), 2.08-1.86 (m, 4H), 1.791.70 (m, 2H), 1.68-1.53 (m, 3H) , 1.411.20 (m, 8H). 1-20 137 rX ^OH CF ₃ Ν^Ν Ο ΑΛΑ Η Η 1 374.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.317.215 (m, 1H), 5.09-4.95 (m, 1H), 4.394.30 (m, 1H), 3.16-2.81 ( m, 1H), 2.512.37 (m, 2H), 2.01-1.84 (m, 2H), 1.711.51 (m, 2H), 1.40-1.34 (m, 3H), 1.221 ,11 (m, 6H). 1-4

Compound 138: (R)-6-(3,3-difluorocyclohex-1-en-1-yl) ^-N2- isopropyl- ^N4- (1,1,1-trifluoropropan-2yl)-1,3,5 -triazine-2,4-diamine

¹²² 138

Compound 122 (100 mg, 0.29 mmol), DAST (1 mL), BAST (1 mL), and DCM (10 mL) were added to a sealed tube. The mixture was stirred at 80°C for 48 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution) to obtain 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).

Compound 139, listed in the table below, was prepared in accordance with the procedure for preparing compound 138 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:_______________

Compound Structure MS (M+H) ⁺ Ή-NMR Intermediate connection 139 A CF ₃ N ^N - II J 0 -Άν'Ά'ΆΆ/ HH 394.0 Ή-NMR (400 MHz, CD ₃ OD): δ 7.126.83 (m, 1H), 5.07-4.92 (m, 1H), 4.644.41 (m, 1H), 4.03-3, 88 (m, 2H), 3.873.76 (m, 1H), 3.72-3.60 (m, 1H), 2.642.46 (m, 2H), 2.34-2.18 (m, 1H) , 2.132.00 (m, 2H), 1.95-1.82 (m, 3H), 1.421.30 (m, 3H). 1-8

Compound 140: 6-(3-methoxycyclohex-1-en-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5triazin- 2,4-diamine

- 52 044101

A mixture of compound 126 (100 mg, 0.25 mmol) and Ag ₂ O (115 mg, 0.5 mmol) in CH ₃ I (4 ml) was stirred at reflux for 16 hours. After completion of the reaction, the mixture was cooled to room temperature , condensed and purified by flash column chromatography (PE/EA elution) to obtain the title compound as a white solid (60 mg, yield: 58.3%). MS (m/z): 414.0 [M+H]+;

1H-NMR (400 MHz, 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).

Compound 141: 6-(3 -(dimethylamino)cyclohex-1-en-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2yl)-1,3,5 -triazine-2,4-diamine

To a solution of compound 126 (50 mg, 0.125 mmol) in dry DCM (3 mL) was added SOCl ₂ (16 mg, 0.137 mmol) at ice bath temperature and the mixture was stirred in the ice bath for 30 minutes. The solution was then placed in a sealed tube, dimethylamine hydrochloride (20 mg, 0.25 mmol) was added and the mixture was stirred at reflux overnight. After completion of the reaction, the mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA elution) to obtain 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), 2.44-2.38 (m, 6H), 2.38-2.25 (m, 1H), 2.05-1.92 (m, 2H ), 1.66-1.53 (m, 2H), 1.39-1.31 (m, 6H).

Compound 142, listed in the table below, was prepared in accordance with the procedure for preparing compound 141 using Intermediates and reagents under suitable conditions that are understood by one skilled in the art:

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 142 n Г fRSjT CF ₃ N^N CF ₃ Η Η 413.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.267.06 (m, 1H), 5.08-4.91 (m, 2H), 3.893.73 (m, 1H), 2.74-2.66 (m, 3H), 2.632.44 (m, 2H), 2.19-2.07(m, 1H), 2.021.92 (m, 1H), l.76-l.57(m, 2H), 1.381.33 (m, 6H). Connection 126

Compound 143: 3 -(4,6-6uc(((R)- 1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-1 -(trifluoromethyl) cyclohex-2-en-1-ol

To a solution of 3-(4,6-6uc(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclo-hex-2-ene -1 she (prepared according to the procedure for preparation of compound 122 using the appropriate Intermediates and reagents, 100 mg, 0.25 mmol) and trimethyl(trifluoromethyl)silane (142 mg, 1.25 mmol) in dry THF (10 ml) TBAF (1 M, 1.25 mL) was added at ice bath temperature. The mixture was stirred at reflux for 2 hours, the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA elution) to obtain the title compound as a white solid (10 mg, yield: 8.6%). MS (m/z): 468.0 [M+H]+;

- 53 044101

Ή-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).

Compound 144: 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2yl)cyclohex-3-ene -1 -ol

n n

144 (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, Intermediate I-2 (320 mg, 1.13 mmol), 4,4,5,5tretramethyl-2-(1,4-dioxaspiro[4,5]dec-7-ene-7- yl)-1,3,2-dioxaborolane (300 mg, 1.13 mmol), Cs ₂ CO ₃ (734 mg, 2.26 mmol), Pd(PPh ₃ ) 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 completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution) to obtain the title compound B25 as a white solid.

(B) (R)-3-(4-(isopropylamino)-6-(( 1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex3-ene -1-on (B26)

To a solution of compound B25 in dry DCM (3 ml) was added TFA (3 ml) and the resulting mixture was stirred overnight at room temperature. After completion of the reaction, it was quenched by adding saturated aqueous NaHCO ₃ solution and extracted with ethyl acetate. The organic layer was collected, condensed and purified by flash column chromatography (PE/EA elution) to obtain the title compound B26 as a yellow solid (200 mg, yield: 51.5%). MS (m/z): 344.3 [M+H]+ (C) 3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino) -1,3,5-triazin-2-yl)cyclohex3-en-1-ol

Compound 144 was prepared according to the procedure for preparation of compound 124 using compound B26 and appropriate reagents. MS (m/z): 346.3 [M+H] ⁺

1H-NMR (400 MHz, 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).

Compound 145, listed in the table below, was prepared in accordance with the procedure for preparing compound 144 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 145 he CF ₃ Η Η 346.3 Ή-NMR (400 MHz, CD ₃ OD): δ 7.1-6.90 (m, 1H), 5.04-4.88 (m, 1H), 4.25-4.07 (m, 1H ), 3.97-3.85 (m, 1H), 2.74-2.60 (m, 1H), 2.57-2.48 (m, 1H), 2.46-2.33 (m , 1H), 2.21-2.09 (m, 1H), 1.97-1.87 (m, 1H), 1.70-1.58 (m, 1H), 1.36-1.29 (m, 3H), 1.21-1.14 (m, 6H). 1-2

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

1-1 152

Intermediate I-1 (50 mg, 0.15

- 54 044101 mmol), (R)-1-phenylethan-1-amine (36 mg, 0.30 mmol), DIEA (77 mg, 0.60 mmol) and 1,4-dioxane (3 ml).

The mixture was stirred at 100°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution) to obtain the title compound as a white solid (15 mg , exit:

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), 1.89-1.73 (m, 3H), 1.67-1.58 (m, 1H), 1.50-1.44 (m, 3H ), 1.34-1.28 (m, 2H), 1.16-1.07 (m, 1H).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 152 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (M+H) ⁺ 'n-yamr Intermediate connection 153 <v ^0H G (kzL ^9F3 aX xA Α/ν ν ν 394.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.2Ιό,96 (m, 1H), 5.09-4.88 (m, 1H), 4.39-4.13 (m, 2H), 2.99-2.87 (m, 2H), 2.71-2.50 (m, 2H), 2.47-2.32 (m, 2H), 1.99-1.81 (m, 2H ), 1.671.52 (m, 2H), 1.39-1.31 (m, 3H). 1-25 154 Αγ ^ΟΗ CF ₃ Ν^Ν Ν Ν Ά F ₃ Η Η 386.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.267.03 (m, 1H), 5.07-4.90 (m, 1H), 4.38-4.26 (m, 1H), 4. 21-4.02 (m, 2H), 2.49-2.33 (m, 2H), 1.97-1.82 (m, 2H), 1.67-1.52 (m, 2H), 1.391.31 (m, 3H). 1-25 155 1 CF ₃ Ν^Ν 1 Η Η 360.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.2Ιό,89 (m, 1H), 5.07-4.87 (m, 1H), 4.36-4.24 (m, 1H), 2.48-2.33 (m, 2H), 1.97-1.83 (m, 2H), 1.68-1.52 (m, 2H), 1.43 (s, 9H), 1. 38-1.32 (m, 3H). 1-25 156 ΙΖ “ > ^ζ νΉ\ θ 358.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.256.90 (m, 1H), 5.13-4.93 (m, 1H), 4.38-4.23 (m, 1H), 2. 54-2.31 (m, 2H), 1.97-1.81 (m, 2H), 1.69-1.51 (m, 2H), 1.42-1.31 (m, 6H), 0.800.72 (m, 2H), 0.66-0.58 (m, 2H). 1-25 157 r ^F CF ₃ NX 426.4 Ή-NMR (400 MHz, CD ₃ OD): δ 7.407.15 (m, 5H), 5.23-4.62 (m, 2H), 4.34-4.18 (m, 1H), 2. 62-2.24 (m, 2H), 1.88-1.60 (m, 4H), 1.53-1.44 (m, 3H), 1.35-1.29 (m, 2H), 1.181.07 (m, 1H). 1-1 158 T ^F cf ₃ nA _ξ x JE x Ά Ν Ν Ν ΚΡπ HHV 390.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.994.88 (m, 1H), 4.33-4.22 (m, 1H), 3.61-3.40 (m, 1H), 2. 65-2.47 (m, 1H), 2.43-2.25 (m, 1H), 1.91-1.72 (m, 3H), 1.70-1.59 (m, 1H), 1.361.31 (m, 3H), 1.27-1.21 (m, 3H), 1.03 - 0.86 (m, 1H), 0.56-0.30 (m, 3H), 0. 26-0.15 (m, 1H). 1-1

- 55 044101

159 yag ^he Τ' g. CF ₃ N^N Ή / A L A An NN N N 416.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.974.88 (m, 1H), 4.35-4.13 (m, 2H), 2.60-2.47 (m, 1H), 2. 44-2.26 (m, 3H), 2.10-2.02 (m, 2H), 1.97-1.76 (m, 9H), 1.70-1.60 (m, 1H), 1.381.29 (m, 3H). 1-1 160 G fRsJ cf ₃ nA g-7?/ ^f ALA At -^*Ν Ν Ν' Η Η 452.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.974.89 (s, 1H), 4.43-4.22 (m, 2H), 2.682.43 (m, 7H), 2.37-2, 25 (m, 1H), 2.121-2.06 (m, 2H), 1.91-1.73 (m, 3H), 1.73-1.58 (m, 1H), 1.37-1, 29 (m, 3H). 1-1 161 φζ ^?F3 H Η Η 418.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.974.88 (m, 1H), 4.78-4.71 (m, 2H), 4.64-4.55 (m, 2H), 4. 37-4.14 (m, 2H), 2.70-2.48 (m, 3H), 2.38-2.12 (m, 3H), 1.90-1.61 (m, 4H), 1.381.29 (m, 3H). 1-1 162 ^ ^0Η T ^F Γ'ΧΛ Λ Η Η 362.3 Ή-NMR (400 MHz, CD ₃ OD): δ 5.104.89 (m, 1H), 4.33-4.20 (m, 1H), 2.79-2.67 (m, 1H), 2. 64-2.48 (m, 1H), 2.40-2.22 (m, 1H), 1.89-1.72 (m, 3H), 1.70-1.59 (br, 1H), 1.401.31 (m, 3H), 0.77-0.67 (m, 2H), 0.55-0.48 (m, 2H). 1-1 163 ^ ^ΟΗ Τ CF ₃ Ν^Ν = AAAA / Νΐ^γ η η 1 392.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.89 (m, 1H), 4.33-4.22 (m, 1H), 4.00-3.86 (m, 1H), 2.62 -2.47 (m, 1H), 2.41-2.23 (m, 1H), 1.89-1.72 (m, 4H), 1.71-1.60 (m, 1H), 1.381 .30 (m, 3H), 1.15-1.07 (m, 3H), 0.96-0.88 (m, 6H). 1-1 164 r^r ^0H T ^F CF ₃ Ν^ Ν ζ ΛΑ 1 X ζ Ν 378.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.974.90 (m, 1H), 4.34-4.22 (m, 1H), 4.03-3.91 (m, 1H), 2.63 -2.48 (m, 1H), 2.40-2.24 (m, 1H), 1.90-1.73 (m, 3H), 1.69-1.61 (m, 1H), 1.581 .47 (m, 2H), 1.39-1.30 (m, 3H), 1.19-1.11 (m, 3H), 0.97-0.88 (m, 3H). 1-1 165 Μ° ^Η Θς CF ₃ νΑ _ν А Λ AA / An nn/sK Η Η 378.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.974.90 (m, 1H), 4.34-4.22 (m, 1H), 4.03-3.91 (m, 1H), 2.63 -2.48 (m, 1H), 2.40-2.24 (m, 1H), 1.90-1.73 (m, 3H), 1.69-1.61 (m, 1H), 1.581 .47 (m, 2H), 1.39-1.30 (m, 3H), 1.19-1.11 (m, 3H), 0.97-0.88 (m, 3H). 1-1

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166 <V ^H r ^F CF ₃ ΝΆ r-\ l 1 AJ@ ^s >) Ά~Ν NN yC HH (/ F 426.3 Ή-NMR (400MHz, CD ₃ 0D): δ 5.024.95 (m, 1H), 4.78-4.57 (m, 1H), 4.41-4.22 (m, 1H), 2.57 -2.52 (m, 1H), 2.43-2.31 (m, 1H), 2.27-2.05 (m, 3H), 1.95-1.62 (m, 7H), 1.431 .31 (m, 3H). 1-1 167 Ar ^0H T ^F CF ₃ N ^N . X Λ AA / ^NN N'Sy HH | 392.4 Ή-NMR (400 MHz, CD ₃ 0D): δ 5.004.93 (m, 1H), 4.36-4.23 (m, 1H), 4.04-3.90 (m, 1H), 2. 64-2.50 (m, 1H), 2.40-2.27 (m, 1H), 1.90-1.63 (m, 5H), 1.40-1.32 (m, 3H), 1.181.09 (m, 3H), 0.98-0.88 (m, 6H). 1-1 168 X'O zz « zz -l o G ¹ o z 389.3 Ή-NMR (400 MHz, CD ₃ 0D): δ 4.994.93 (m, 1H), 4.42-4.25 (m, 2H), 2.88-2.71 (m, 2H), 2. 66-2.52 (m, 1H), 2.44-2.28 (m, 1H), 1.92-1.83 (m, 2H), 1.82-1.73 (m, 1H), 1.711.63 (m, 1H), 1.42-1.31 (m, 6H). 1-1 169 te te i ^F Άν ν νΆ Η Η 382.2 Ή-NMR (400 MHz, CD ₃ 0D): δ 5.014.92 (m, 1H), 4.51-4.26 (m, 4H), 2.64-2.49 (m, 1H), 2. 39-2.25 (m, 1H), 1.90-1.61 (m, 4H), 1.40-1.31 (m, 3H), 1.27-1.19 (m, 3H). 1-1 170 << ^ΟΗ C( _F •^Ν Ν NisA 382.3 Ή-NMR (400 MHz, CD ₃ 0D): δ 5.014.92 (m, 1H), 4.51-4.26 (m, 4H), 2.64-2.49 (m, 1H), 2. 39-2.25 (m, 1H), 1.90-1.61 (m, 4H), 1.40-1.31 (m, 3H), 1.27-1.19 (m, 3H). 1-1 171 Ζγ ^0Η [ fRsrt CF ₃ ΝΆ ρ Η Η \_> 426.3 Ή-NMR (400 MHz, CD ₃ 0D): δ 4.994.91 (m, 1H), 4.34-4.24 (m, 1H), 3.67-3.44 (m, 2H), 3. 19-3.03 (m, 1H), 2.60-2.30 (m, 4H), 1.95-1.74 (m, 4H), 1.70-1.62 (m, 1H), 1.581.49 (m, 1H), 1.39-1.33 (m, 3H). 1-1 172 <γ° ^Η ? ^F CF ₃ Ν^Ν Η Η % 394.3 Ή-NMR (400 MHz, CD ₃ 0D): δ 5.024.93 (m, 1H), 4.33-4.26 (m, 1H), 2.63-2.55 (m, 1H), 2. 34-2.28 (m, 1H), 1.90-1.76 (m, 3H), 1.71-1.62 (m, 1H), 1.38-1.35 (m, 3H), 1.28(s,9H). 1-1 173 Ή, CF ₃ Ν^Ν ^Ν . AAA 1) -^/Ν Ν NW^ 405.2 Ή-NMR (400 MHz, CD ₃ 0D): δ 5.014.90 (m, 1H), 4.58-4.43 (m, 1H), 4.35-4.25 (m, 1H), 3. 00-2.84 (m, 1H), 2.71-2.42 (m, 4H), 2.40-2.21 (m, 5H), 1.89-1.58 (m, 5H), 1.401.28 (m, 3H). 1-61

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174 CF ₃ Ν^Ν ι AL A X f An Ν ΝίΥ Η Η jL 400.2 Ή-NMR (400 MHz, CD ₃ OD): δ 6.075.70 (m, 1H), 5.01-4.88 (m, 1H), 4.52-4.35 (m, 1H), 4. 33-4.23 (m, 1H), 2.65-2.51 (m, 1H), 2.44-2.25 (m, 1H), 1.89-1.61 (m, 4H), 1.381.30 (m, 3H), 1.28-1.21 (m, 3H). 1-61 175 ar CF ₃ Ν^Ν ι 11 AX / ^{Η Η} FF 414.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.89 (m, 1H), 4.69-4.51 (m, 1H), 4.35-4.22 (m, 1H), 2. 68-2.50 (m, 1H), 2.41-2.25 (m, 1H), 1.90-1.73 (m, 3H), 1.68-1.50 (m, 4H), 1.381.31 (m, 3H), 1.28-1.22 (m, 3H). 1-61 176 ί/νθπ cf ₃ HA ΓΛχΡ ι II J AAG An nm^ ⁷ F HH 408.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.276.94 (m, 1H), 5.10-4.87 (m, 1H), 4.57-4.38 (m, 1H), 4. 36-4.25 (m, 1H), 2.62-2.48 (m, 1H), 2.47-2.32 (m, 2H), 2.28-2.15 (m, 2H), 2.131.97 (m, 2H), 1.96-1.72 (m, 3H), 1.66-1.50 (m, 2H), 1.39-1.31 (m, 3H). 1-26 177 ^aOH ? ^F 3 h ? CA ^F An NN^ ^/ F HH 408.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.276.94 (m, 1H), 5.10-4.87 (m, 1H), 4.57-4.38 (m, 1H), 4. 36-4.25 (m, 1H), 2.62-2.48 (m, 1H), 2.47-2.32 (m, 2H), 2.28-2.15 (m, 2H), 2.131.97 (m, 2H), 1.96-1.72 (m, 3H), 1.66-1.50 (m, 2H), 1.39-1.31 (m, 3H). 1-27 178 σ ^0Η aDa Η Η 360.0 Ή-NMR (400 MHz, CD ₃ OD): δ 7.176.98 (m, 1H), 5.18-4.90 (m, 2H), 4.90-4.86 (m, 2H), 4.66 -4.59 (m, 2H), 4.35-4.26 (m, 1H), 2.46-2.35 (m, 2H), 1.97-1.81 (m, 2H), 1.671 .52 (m, 2H), 1.35-1.30 (m, 3H). 1-27 179 cr A ³ AAC° Ά7ν N NAY 374 Ή-NMR (400 MHz, CD ₃ OD): δ 7.236.95 (m, 1H), 5.08-4.90 (m, 1H), 4.61-4.44 (m, 1H), 4. 35-4.25 (m, 1H), 4.00-3.89 (m, 2H), 3.85-3.76 (m, 1H), 3.70-3.59 (m, 1H), 2.482.35 (m, 2H), 2.29-2.18 (m, 1H), 1.96-1.83 (m, 3H), 1.68-1.52 (m, 2H), 1, 37-1.31 (m, 3H). 1-27 180 cr AA A X> ΆΓν Ν NAY HH 374 Ή-NMR (400 MHz, CD ₃ OD): δ 7.236.95 (m, 1H), 5.08-4.90 (m, 1H), 4.61-4.44 (m, 1H), 4. 35-4.25 (m, 1H), 4.00-3.89 (m, 2H), 3.85-3.76 (m, 1H), 3.70-3.59 (m, 1H), 2.482.35 (m, 2H), 2.29-2.18 (m, 1H), 1.96-1.83 (m, 3H), 1.68-1.52 (m, 2H), 1, 37-1.31 (m, 3H). 1-27 181 ?. CF ₃ N^N AAp A Λ AAJ An ν n — HH 422.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.236.93 (m, 1H), 5.13-4.88 (m, 1H), 4.39-4.27 (m, 1H), 4. 14-3.91 (m, 1H), 2.53-2.35 (m, 2H), 2.14-1.81 (m, 8H), 1.73-1.51 (m, 4H), 1.401.30 (m, 3H). 1-27 182 σ ^0Η X ^HO <s) CF ₃ N^N ΥΛ AAAA / An nn^t HH 388.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.246.90 (m, 1H), 5.10-4.88 (m, 1H), 4.39-4.27 (m, 1H), 4.23 -4.08 (m, 2H), 2.46-2.35 (m, 2H), 2.07-1.97 (m, 1H), 1.95-1.80 (m, 4H), 1.701 .52 (m, 5H), 1.37-1.31 (m, 3H). 1-27 183 ? ^0H CF ₃ N^N . AAAX o An ν n AY HH 376.3 Ή-NMR (400 MHz, CD ₃ OD): δ 7.206.93 (m, 1H), 5.07-4.89 (m, 1H), 4.37-4.19 (m, 2H), 3. 48-3.41 (m, 1H), 3.38-3.32 (m, 4H), 2.45-2.34 (m, 2H), 1.96-1.81 (m, 2H), 1.671.53 (m, 2H), 1.37-1.31 (m, 3H), 1.20-1.15 (m, 3H). 1-27 184 ? ^0H CF ₃ N^N ι a AAA% he An nn^^ HH 362.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.196.91 (m, 1H), 5.06-4.90 (m, 1H), 4.35-4.07 (m, 2H), 3.63 -3.48 (m, 2H), 2.47-2.33 (m, 2H), 1.96-1.81 (m, 2H), 1.67-1.52 (m, 2H), 1.361 .31 (m, 3H), 1.22-1.16 (m, 3H). 1-27

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Compound 186. 6-(cyclohex-1-en-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine2, 4-diamine

Under a nitrogen atmosphere, Intermediate I-3 (150 mg, 0.44 mmol), cyclohex-1-en-1-ylboronic acid (85 mg, 0.66 mmol), Cs ₂ CO ₃ (290 mg, 0.88 mmol), Pd(PPh ₃ ) ₄ (26 mg, 0.022 mmol), 1,4-dioxane (10 ml) and water (2 ml). The mixture was stirred at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution) to obtain 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-d ₆ ): 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 186 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 187 9 AA Ν Ν Ν >~7 V n n V 300.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.206.87 (m, 1H), 3.27-3.16 (m, 4H), 2.45-2.34 (m, 2H), 2. 26-2.18 (m, 2H), 1.74-1.60 (m, 4H), 1.12-1.00 (m, 2H), 0.53-0.39 (m, 4H), 0.29-0.16 (m, 4H). 1-6 188 9 CF ₃ Ν^ Ν Η Η |όη 360.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.416.99 (m, 1H), 5.11-4.88 (m, 1H), 3.60-3.34 (m, 2H), 2. 55-2.35 (m, 2H), 2.29-2.15 (m, 2H), 1.81-1.57 (m, 4H), 1.40-1.30 (m, 3H), 1.19(s,6H). 1-7 189 9 CF ₃ n AI Η Η 316.1 Ή-NMR (400 MHz, CD ₃ OD): δ 6, Οδό,78 (m, 1H), 5.06-4.87 (m, 1H), 4.25-4.07 (m, 1H), 2 .72-2.62 (m, 2H), 2.56-2.49 (m, 2H), 2.03-1.93 (m, 2H), 1.38-1.30 (m, 3H) , 1.22-1.15 (m, 6H). 1-2

Compound 190. (R)-6-(cyclohex-1 -en-1 -yl)-N ² -isopropyl-N ⁴ -( 1,1,1 -trifluoropropan-2-yl)-1,3,5triazin-2 ,4-diamine

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 in a microwave oven at 150°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (PE/EA elution), resulting in 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).

The compounds listed in the table below were prepared in accordance with the procedure for preparing compound 190 using Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

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Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 191 ..... ZI G 328.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.19-6.85 (m, 1H), 3.60-3.40 (m, 2H), 2.46-2.29 (m, 2H ), 2.25-2.16 (m, 2H), 1.73-1.60 (m, 4H), 1.23 (d, J = 6.6 Hz, 6H), 0.97-0, 85 (m, 2H), 0.53-0.30 (m, 6H), 0.23-0.15 (m, 2H). 1-23 192 9 CF ₃ N^N Ν kУ Ν 'Ή-? N H V 342.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.30-7.02 (m, 1H), 5.08-4.90 (m, 1H), 3.28-3.16 (m, 2H ), 2.50-2.34 (m, 2H), 2.28-2.18 (m, 2H), 1.791.59 (m, 4H), 1.40-1.31 (m, 3H), 1.15-1.01 (m, 1H), 0.56-0.44 (m, 2H), 0.30-0.19 (m, 2H). 1-24 193 2 V Η Η 260.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.25-6.82 (m, 1H), 3.28-3.13 (m, 2H), 2.89 (s, 3H), 2. 47-2.33 (m, 2H), 2.27-2.17 (m, 2H), 1.75-1.60 (m, 4H), 1.14-0.99 (m, 1H), 0.530.42 (m, 2H), 0.31-0.17 (m, 2H). 1-24 194 9 Ν ^Λ Ν ϊ ζχ ΑλΧ VT N Ν V Η Η 288.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.24-6.85 (m, 1H), 4.27-4.06 (m, 1H), 3.28-3.17 (m, 2H ), 2.45-2.35 (m, 2H), 2.26-2.19 (m, 2H), 1.751.61 (m, 4H), 1.19 (d, J = 6.5 Hz, 6H), 1.12-1.01 (m, 1H), 0.53-0.43 (m, 2H), 0.29-0.18 (m, 2H). 1-24 195 9 318.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.26-6.89 (m, 1H), 3.45-3.35 (m, 2H), 3.27-3.16 (m, 2H ), 2.45-2.35 (m, 2H), 2.26-2.19 (m, 2H), 1.751.61 (m, 4H), 1.20 (s, 6H), 1.1 ΟΙ .02 (m, 1H), 0.52-0.43 (m, 2H), 0.26-0.19 (m, 2H). 1-24

Connections 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

206 207 (A) Mixture of 2-chloro-5-fluoro-N ⁴ ,N ⁶ -bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidin-4,6-diamine and 6-chloro5- fluoro-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidin-2,4-diamine

Under a nitrogen atmosphere, a mixture of 2,4,6-trichloro-5-fluoropyrimidine (1.12 g, 5.6 mmol), (R)-1,1,1trifluoropropan-2-amine hydrochloride (2.51 g, 16.8 mmol), DIEA (4.22 g, 56 mmol) and Nmethylpyrrolidone (5 ml) were stirred in a microwave oven at 200°C for 1 hour. After cooling to room temperature, the mixture was immediately injected into an RP-d8 column and purified by flash column -chromatography (elution with a gradient of water/MeOH=100:0-0:100), resulting in the product being obtained as a white solid (80 mg, yield 4.2%). MS (m/z): 354.9 [M+H]+ (B) Mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl) amino)pyrimidin-2-yl) cyclohex-2en-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 a nitrogen atmosphere, a mixture of the product obtained in step (A) (80 mg, 0.23 mmol), 3-(4,4,5,5tretramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-ene -1-one (50 mg, 0.23 mmol), Cs ₂ CO ₃ (150 mg, 0.46 mmol), 1,4-dioxane (5 ml) and water (1.5 ml) were stirred in a microwave oven at 130°C for 40 min. After cooling to room temperature, the mixture was condensed and purified by flash column chromatography (PE/EA gradient elution = 100:0-0:100), resulting in the product as a white solid (60 mg, yield: 63. 2%). MS (m/z): 415.0 [M+H]+ (C) 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino )pyrimidin-2-yl)-cyclohex-2-en-1-ol and

Compounds 206 and 207 were prepared according to the procedure for compound 124 using the resulting mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin- 2yl)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 obtained in step (B) and the corresponding reagents, and purified by flash column chromatography (elution with a gradient of PE/EA=100:0-0:100).

Compound 206, MS (m/z): 417.0 [M+H] ⁺ .

1H-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] ⁺ .

1H-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).

The compounds listed in the table below were prepared in accordance with the preparation procedure described above using the appropriate Intermediates and reagents under suitable conditions that would be understood by one skilled in the art:

Compound Structure MS (Μ+Η) ⁺ Ή-NMR Intermediate connection 212 X Ν ^<ί?4 >ι Ν'^Ν Λ Λ o / CF ₃ '^ ^t ^ Ν Ν Ν' Η Η 451.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.54-8.35 (m, 2H), 7.98-7.78 (m, 1H), 4.37-4.24 (m, 1H ), 4.10-3.94 (m, 2H), 2.89-2.72 (m, 1H), 2.662.52 (m, 1H), 2.33-2.05 (m, 2H), 1.33-1.24 (m, 3H). 1-93 213 F. A >Ο ^οη χι Δ 477.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.50-8.31 (m, 2H), 8.00-7.88 (m, 1H), 4.41-4.24 (m, 1H ), 3.78 (d, J = 7.2 Hz, 2H), 2.90-2.73 (m, 1H), 2.66-2.49 (m, 1H), 2.32-2, 05 (m, 2H), 1.26-1.09 (m, 1H), 0.62-0.51 (m, 2H), 0.35-0.25 (m, 2H). 1-94 214 X X nA CFa^N^N^N^N^X Η Η Ο 480.0 Ή-NMR (400 MHz, CD ₃ OD): δ 8.92-8.76 (m, 1H), 8.73-8.64 (m, 1H), 4.40-4.26 (m, 1H ), 2.93-2.77 (m, 1H), 2.71-2.55 (m, 1H), 2.342.07 (m, 2H), 1.31 (s, 9H). 1-95 215 X Ν^Ν A Α -Ο. / F Ν Ν Ν X Η η Ο 429.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.05-7.88 (m, 2H), 7.47-7.43 (m, 1H), 4.34-4.30 (m, 1H ), 2.85-2.77 (m, 1H), 2.65-2.55 (m, 1H), 2.312.06 (m, 2H), 1.32 (s, 9H). 1-65 216 k νΧ) nA Χ>Χ A A -o./ cr Ν Ν Ν χ Η η X 445.0 Ή-NMR (400 MHz, CD ₃ OD): δ 8.31 (s, 1H), 8.13-8.02 (m, 1H), 7.64-7.47 (m, 1H), 4. 38-4.23 (m, 1H), 2.89-2.71 (m, 1H), 2.66-2.50 (m, 1H), 2.32-2.03 (m, 2H), 1.32(s,9H). 1-96 217 χ L II II J ₀ CF ₃ ^^^N Ν Ν' ΆΧ 465.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.61-8.28 (m, 2H), 8.07-7.76 (m, 1H), 4.42-4.16 (m, 1H ), 4.03-3.82 (m, 2H), 2.88-2.72 (m, 1H), 2.672.50 (m, 1H), 2.31-2.06 (m, 2H), 1.80-1.63 (m, 2H), 1.10-0.90 (m, 3H). 1-97 218 Ο ь vAA f—z -Π O % ¹ -π ⁴¹ 497.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.61-8.26 (m, 2H), 7.91-7.74 (m, 1H), 4.45-4.21 (m, 1H ), 3.98-3.77 (m, 4H), 2.90-2.75 (m, 1H), 2.652.41 (m, 3H), 2.30-2.05 (m, 2H). 1-98 220 A Ό ι ^Ν Υ 501.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.77-7.63 (m, 2H), 7.68 (s, 1H), 4.39-4.18 (m, 1H), 3. 27-3.16 (m, 1H), 2.89-2.45 (m, 2H), 2.33-2.02 (m, 2H), 1.17-0.98 (m, 2H), 0.600.47 (m, 2H), 0.44-0.27 (m, 6H). 1-99

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221 A Ν^Ν YES Λ A F 483.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.50-8.37 (m, 2H), 7.88-7.80 (m, 1H), 4.60-4.40 (m, 4H ), 4.34-4.27 (m, 1H), 2.85-2.75 (m, 1H), 2.652.55 (m, 1H), 2.31-2.05 (m, 2H). I-100 243 A CF ₃ N^N h F 434.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.03-4.86 (m, 1H), 4.49-4.34 (m, 4H), 4.30-4.20 (m, 1H ), 2.75-2.65 (m, 1H), 2.55-2.45 (m, 1H), 2.272.02 (m, 2H), 1.45-1.33 (m, 3H). 1-101 244 A' CF ₃ νΆ I HH 400.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.01-4.90 (br, 1H), 4.37-4.20 (m, 1H), 4.19-4.03 (m, 1H ), 2.85-2.39 (m, 2H), 2.32-2.02 (m, 2H), 1.431.29 (m, 3H), 1.23-1.09 (m, 6H). 1-2 299 LL ¹ ' J O U- Z^ aCk A-^z=< CO ZI O 434.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.04-4.86 (m, 1H), 4.50-4.34 (m, 4H), 4.31-4.20 (m, 1H ), 2.78-2.65 (m, 1H), 2.59-2.44 (m, 1H), 2.291.98 (m, 2H), 1.41-1.31 (m, 3H). 1-102 300 A। ⁿ CF3 ^x %AnA _n A _n ^,OH ^H M CF ₃ 545.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.60-8.47 (m, 1H), 8.43-8.38 (m, 1H), 7.86-7.70 (m, 1H ), 4.38-4.23 (m, 1H), 4.01 -3.66 (m, 4H), 2.892.73 (m, 1H), 2.69-2.51 (m, 1H), 2.41-2.06 (m, 4H). 1-103 301 A। ^N F ^F 533.1 Ή-NMR (400 MHz, CD ₃ OD): δ 8.51-8.43 (m, 1H), 8.42-8.38 (m, 1H), 7.91-7.84 (m, 1H ), 4.40-4.29 (m, 1H), 4.24-4.12 (m, 4H), 2.932.77 (m, 1H), 2.69-2.55 (m, 1H), 2.36-2.06 (m, 2H). 1-104

Compounds 197 and 198: 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6 ,6trifluorocyclohex-2-en-1-ol, optically pure diastereomers

196 197 & 198

The title compound 196 was separated by chiral HPLC to yield a pair of optically pure diastereomers, compounds 197 and 198 (HPLC chiral conditions: separation apparatus: Shimadzu LC-10AD vp; column: Daicel AD-H (250 mm x 30 mm, 5 μm) ; mobile phase: nheptane/isopropanol = 90/10; flow rate: 40 ml/min; column temperature: 40°C). The first compound to elute (RT=4.203 min) was concentrated and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in the compound named compound 197, de%=99.27%, MS (m/z): 454.1 [M+1]+. The second compound eluted (RT=5.906 min) was concentrated and purified by flash column chromatography (PE/EA gradient elution=100:0-0:100), resulting in the compound designated compound 198, de%=97.82%, MS (m/z): 454.2 [M+1]+.

Compound 197: 1H-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: 1H-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).

The compounds listed in the table below were prepared according to the procedure for preparation of compounds 197 and 198 using the compound and under suitable HPLC conditions (flow rate: 0.5 ml/min; detection at wavelength: UV 254 nm):

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Compound Structure MS (M+H) ⁺ Ή-NMR Retention time, min Purity Chiral HPLC conditions Connection for separation 100 SK ♦ CF ₃ N^N 1 CF ₃ N^N i ⁷ AA 1 ⁷ AA 1 HHHH 100 & 101 364.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.89 (m, 1H), 4.33-4.24 (m, 1H), 4.21-4.06 (m, 1H), 2. 63-2.47 (m, 1H), 2.41-2.47 (br, 1H), 1.93-1.71 (m, 3H), 1.70-1.61 (m, 1H), 1.401.30 (m, 3H), 1.21-1.15 (m, 6H). 1,230 her%= 100% Column: OJ-H (0.46 cm ID x 15 cm length); Mobile phase: pheptane/isopropanol (0.1% Et ₂ NH) = 90/10 1 101 364.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.014.90 (m, 1H), 4.34-4.24 (m, 1H), 4.20-4.06 (m, 1H), 2. 65-2.48 (m, 1H), 2.43-2.23 (m, 1H), 1.92-1.72 (m, 3H), 1.68-1.59 (m, 1H), 1.40-1.31 (m, 3H), 1.21-1.14 (m, 6H). 1.316 her%= 100% 102 CX , CA QF ₃ N^N CF ₃ CF ₃ N^N CF ₃ Αγν n ^HH HH 102 & 103 418.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.88 (m, 2H), 4.34-4.25 (m, 1H), 2.68-2.51 (m, 1H), 2. 41-2.26 (m, 1H), 1.90-1.74 (m, 3H), 1.70-1.58 (m, 1H), 1.37-1.31 (m, 6H) 1,899 de%= 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropanol (0.1% Et ₂ NH) = 80/20 2 103 418.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.024.87 (m, 2H), 4.34-4.24 (m, 1H), 2.64-2.50 (m, 1H), 2. 45-2.32 (m, 1H), 1.91-1.71 (m, 3H), 1.69-1.71 (m, 1H), 1.38-1.30 (m, 6H). 2,263 de%= 100% 104 ar. _ ar _ff JA i ⁿ Α ^f Aa a^a aA ^f HHHH 104 & 105 406.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.374.22 (m, 3H), 3.02-2.86 (m, 4H), 2.73-2.50 (m, 5H), 2. 41-2.25 (m, 1H), 1.91-1.72 (m, 3H), 1.72-1.62 (m, 1H). 3,608 her%= 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropanol (0.1% Et ₂ NH) = 70/30 5 105 406.3 Ή-NMR (400 MHz, CD ₃ OD): δ 4.374.22 (m, 3H), 3.02-2.86 (m, 4H), 2.73-2.50 (m, 5H), 2. 41-2.25 (m, 1H), 1.91-1.72 (m, 3H), 1.72-1.62 (m, 1H). 3.871 her%= 100% 106 KCA* ^OH / ^- A..YUN CF ₃ N^N CF ₃ CF ₃ N^N CF ₃ HHHH 106 & 107 432.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.024.89 (m, 2H), 4.53-4.41 (m, 1H), 2.77-2.62 (m, 1H), 2. 40-2.27 (m, 1H), 2.02-1.83 (m, 3H), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H) 10,540 de% = 97.79% Column: AS-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropanol = 90/10 19 107 432.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.024.89 (m, 2H), 4.53-4.41 (m, 1H), 2.77-2.62 (m, 1H), 2. 40-2.27 (m, 1H), 2.02-1.83 (m, 3H), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H) 18,120 de% = 97.84% 108 χ/OH φζ ₊ Ca° ^f Va A _f fAa A /~A ^f HHHH 108 & 109 407.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.384.15 (m, 2H), 3.05-2.85 (m, 4H), 2.72-2.48 (m, 5H), 2. 40-2.26 (m, 1H), 1.90-1.61 (m, 4H) 4,596 de% = 99.8% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropanol = 70/30 109 407.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.384.15 (m, 2H), 3.05-2.85 (m, 4H), 2.72-2.48 (m, 5H), 2. 40-2.26 (m, 1H), 1.90-1.61 (m, 4H). 4,897 de% = 99.32%

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110 Dx/ ^OH CF ₃ N^N CF ₃ CF ₃ nA CF ₃ AL Ax Ax A Ax A ^(R) Ν Ν Ν <яЛ 'iR) Ν Ν Ν (яЛ 110& 111 419.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.024.87 (m, 2H), 2.68-2.51 (m, 1H), 2.44-2.28 (m, 1H), 1. 92-1.63 (m, 4H), 1.42-1.30 (m, 6H) 10,090 de% = 100% Column: AD-H (0.46 cm bh. dia. x 15 cm length); Mobile phase: nheptane/isopropanol = 90/10 18 111 419.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.024.87 (m, 2H), 2.68-2.51 (m, 1H), 2.44-2.28 (m, 1H), 1. 92-1.63 (m, 4H), 1.42-1.30 (m, 6H) 16,800 de% = 100% 112 DDDD X^oh X di A _t CX CF ₃ N^N CF ₃ CF ₃ N^N CF ₃ A Ax A ^x A Ax A 'iR) Ν Ν N (яЛ Ή) nn N (R> HHHH 112 & 113 421.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.87 (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) 5,500 de% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropano l = 80/20 83 FROM 421.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.87 (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) 7,420 de% = 97.54% 114 DDDD & , . Ή, CF ₃ N^N Hz _f CF ₃ N^N /< _p Η Η π π 114& 115 415.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.89 (m, 1H), 4.35-4.13 (m, 1H), 3.02-2.81 (m, 2H), 2. 75-2.46 (m, 3H), 2.44-2.24 (m, 1H), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1,381.28 (m, 3H) 5,960 de% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropanol = 80/20 90 115 415.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.984.89 (m, 1H), 4.35-4.13 (m, 1H), 3.02-2.81 (m, 2H), 2. 75-2.46 (m, 3H), 2.44-2.24 (m, 1H), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1,381.28 (m, 3H) 7,800 de% = 98.30% 116 DDDD ΑΆ ^0Η Х ^he w ₊ fAx ϊ a? aA ^f Aa άλ aA HHHH 116 & 117 409.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.364.14 (m, 2H), 2.98-2.85 (m, 4H), 2.67-2.46 (m, 5H), 2. 39-2.22 (m, 1H), 1.82-1.71 (m, 1H), 1.68-1.57 (m, 1H) 10,170 de% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: pheptane/isopropanol = 80/20 91 117 409.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.364.14 (m, 2H), 2.98-2.85 (m, 4H), 2.67-2.46 (m, 5H), 2. 39-2.22 (m, 1H), 1.82-1.71 (m, 1H), 1.68-1.57 (m, 1H) 13,590 de% = 99.16% 118 Ή , er CF ₃ N^N i CF ₃ N^N i HHHH 118 & 119 364.1 Ή-NMR (400 MHz, CD3OD): δ 5.004.89 (m, 1H), 4.36-4.25 (m, 1H), 4.19-4.08 (m, 1H), 2.68- 2.50 (m, 1H), 2.40-2.24 (m, 1H), 1.96-1.57 (m, 4H), 1.41-1.29 (m, 3H), 1.231, 12 (m, 6H) 1.334 de% = 97.56% Column: AS-H (0.46 cm inner diameter x 15 cm length); Mobile phase: pheptane/isopropanol = 90/10 33 119 364.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.014.89 (m, 1H), 4.32-4.25 (m, 1H), 4.20-4.07 (m, 1H), 2. 64-2.48 (m, 1H), 2.42-2.26 (m, 1H), 1.93-1.59 (m, 4H), 1.38-1.31 (m, 3H), 1,221.15 (m, 6H) 1.403 de% = 100% 120 412.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.054.89 (m, 1H), 4.41-4.13 (m, 2H), 3.08-2.80 (m, 2H), 2. 78-2.24 (m, 4H), 2.01-1.60 (m, 4H), 1.47-1.24 (m, 3H) 2,589 de% = 100% Column: OJ-H (0.46 cm inner diameter x 15 cm length); 31 121 /x^ON ,ΌΗ Г ^f Ί Γ Ή CF ₃ Ν^Ν rX _F QF ₃ N^N /X- _f HHHH 120 & 121 412.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.074.88 (m, 1H), 4.39-4.13 (m, 2H), 3.06-2.83 (m, 2H), 2. 77-2.23 (m, 4H), 1.95-1.60 (m, 4H), 1.45-1.28 (m, 3H) 3,189 de% = 100% Mobile phase: pheptane/isopropanol (0.1% Et ₂ NH) = 90/10 146 /k.DN φ Θ CF ₃ N^NI CF ₃ nA I HHHH 146 & 147 346.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.2Ιό,90 (m, 1H), 5.03-4.92 (m, 1H), 4.36-4.26 (m, 1H), 4.22-4.07 (m, 1H), 2.48-2.34 (m, 2H), 1.96-1.83 (m, 2H), 1.66-1.54 (m, 2H ), 1.371.31 (m, 3H), 1.26-1.13 (m, 6H) 1.526 de% = 100% Column: AS-H (0.46 cm inner diameter x 15 cm length); Mobile phase: pheptane/isopropanol = 80/20 124 147 346.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.186.93 (m, 1H), 5.06-4.91 (m, 1H), 4.37-4.25 (m, 1H), 4. 24-4.06 (m, 1H), 2.51-2.28 (m, 2H), 1.98-1.79 (m, 2H), 1.69 -1.49 (m, 2H), 1.381.30 (m, 3H), 1.22-1.15 (m, 6H) 1.995 de% = 99.77 4% 148 Wed Cp cf ₃ nA cf ₃ cf ₃ nA cf ₃ ΧΓν^ν^νΆ NN NN 148 & 149 400.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.227.03 (m, 1H), 5.06-4.87 (m, 2H), 4.36-4.26 (m, 1H), 2. 50-2.34 (m, 2H), 1.99-1.81 (m, 2H), 1.68-1.50 (m, 2H), 1.38-1.31 (m, 6H) 1.169 de% = 100% Column: AS-H (0.46 cm inner diameter x 15 cm length); Mobile phase: pheptane/isopropanol (0.1% Et ₂ NH) = 80/20 126 149 400.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.227.03 (m, 1H), 5.06-4.87 (m, 2H), 4.36-4.26 (m, 1H), 2. 50-2.34 (m, 2H), 1.99-1.81 (m, 2H), 1.68-1.50 (m, 2H), 1.38-1.31 (m, 6H) 2,443 de% = 100%

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150 t t νΆ g-J G-У N^N rJ l a Xt ^ff aX a a At ^f Ν Ν Ν Ν Ν N HHHH 150 & 151 388.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.93 (m, 1H), 4.36-4.19 (m, 3H), 2.972.87 (m, 4H), 2.69-2. 50 (m, 4H), 2,452.34 (m, 2H), 1.97-1.80 (m, 2H), 1,671.51 (m, 2H) 2,492 ee% = 100% Column: AS-H (0.46 cm bh. dia. x 15 cm length); Mobile phase: nheptane/isopropanol = 70/30 127 151 388.1 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.93 (m, 1H), 4.36-4.19 (m, 3H), 2.972.87 (m, 4H), 2.69-2. 50 (m, 4H), 2,452.34 (m, 2H), 1.97-1.80 (m, 2H), 1,671.51 (m, 2H) 3.658 ee% = 100% 222 a _t α A Λ Λχ 4AJL AA І ^N H U І ^N И У 222 & 223 431.0 Ή-NMR (400 MHz, CD ₃ OD): δ 8.938.78 (m, 2H), 7.98-7.93 (m, 1H), 7.847.77 (m, 1H), 4.37-4, 30 (m, 1H), 2.702.61 (m, 1H), 2.48-2.36 (m, 1H), 1.921.86 (m, 2H), 1.85-1.76 (m, 1H) , 1.731.65 (m, 1H), 1.33 (s, 9H) 5,097 ee% = 99.89% Column: ICH (0.46 cm ID x 15 cm length); Mobile phase: pheptane/isopropanol = 60/40 34 223 431.0 Ή-NMR (400 MHz, CD ₃ OD): δ 8.938.75 (m, 2H), 7.98-7.93 (m, 1H), 7.837.77 (m, 1H), 4.37-4, 30 (m, 1H), 2.712.61 (m, 1H), 2.48-2.36 (m, 1H), 1.921.86 (m, 2H), 1.85-1.77 (m, 1H) , 1.731.66 (m, 1H), 1.33 (s, 9H) 6,651 ee% = 97.67% 236 442.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.414.08 (m, 3H), 3.01-2.82 (m, 4H), 2.742.43 (m, 6H), 2.25-2. 02 (m, 2H) 4.121 ee% = 100% Column: AD-H (0.46 cm i.d. 203 237 ,/,-. /. Λχ ΓΙχΛ АхПхС HHHH 236 & 237 442.2 Ή-NMR (400 MHz, CD ₃ OD): δ 4.414.08 (m, 3H), 3.01-2.82 (m, 4H), 2.742.43 (m, 6H), 2.25-2. 02 (m, 2H) 4.453 ee% = 100% x 15 cm length); Mobile phase: p-heptane/isopropanol (0D% Et ₂ NH) = 80/20 249 у > ^oh У p ^h W . CF ₃ N^ _N CF ₃ CF ₃ N^N CF ₃ X. JI <AA^ A^ A^ A^ 'm Ν Ν Ν (nL <R? Ν Ν Ν HHHH 249 & 250 455.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.87 (m, 2H), 2.82-2.66 (m, 1H), 2.622.45 (m, 1H), 2.27-2. 02 (m, 2H), 1,401.29 (m, 6H) 2,293 de% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol (0.1% Et ₂ NH) = 80/20 211 250 455.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.87 (m, 2H), 2.82-2.66 (m, 1H), 2.622.45 (m, 1H), 2.27-2. 02 (m, 2H), 1,401.29 (m, 6H) 2,898 de% = 100% 251 A. A Qf ₃ 11 A ? ^F3 11 ϊ A ΑΓν^ν^ν HHHH 251 & 252 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.144.92 (m, 1H), 4.33-4.19 (m, 1H), 2.812.60 (m, 2H), 2.60-2. 41 (m, 1H), 2.252.05 (m, 2H), 1.38-1.32 (m, 3H), 0.770.69 (m, 2H), 0.55-0.48 (m, 2H) 2,179 de% = 100% Column: OJH (0.46 cm inner diameter x 15 cm length); Mobile phase: p-heptane/isopropanol = 90/10 238 252 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.044.94 (m, 1H), 4.32-4.19 (m, 1H), 2.832.61 (m, 2H), 2.58-2. 42 (m, 1H), 2.232.05 (m, 2H), 1.39-1.32 (m, 3H), 0.770.69 (m, 2H), 0.57-0.47 (m, 2H) 2.465 de% = 99.76% 253 _Ήf . a CF ₃ N^NA _f ^cf 3 νΆ γΑ-F HHHH 253 & 254 448.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.044.89 (m, 1H), 4.38-4.16 (m, 2H), 3.052.85 (m, 2H), 2.81-2. 43 (m, 4H), 2.31 -1.96 (m, 2H), 1.42-1.30 (m, 3H) 3.225 de% = 100% Column: OJH (0.46 cm inner diameter x 15 cm length); Mobile phase: p-heptane/ethanol = 80/20 239 254 448.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.054.92 (m, 1H), 4.34-4.14 (m, 2H), 3.022.85 (m, 2H), 2.80-2. 45 (m, 4H), 2.29 -2.01 (m, 2H), 1.43-1.29 (m, 3H) 3,790 de% = 100% 255 XX CF ₃ N^N CF ₃ N^N ^TN^N^N^CFs ^N^N^N^CFa HHHH 255 & 256 440.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.974.83 (m, 1H), 4.29-3.90 (m, 3H), 2.772.58 (m, 1H), 2.51-2. 37 (m, 1H), 2.261.93 (m, 2H), 1.37-1.20 (m, 3H) 3.119 de% = 100% Column: OJH (0.46 cm inner diameter x 15 cm length); Mobile phase: p-heptane/isopropanol = 80/20 245 256 440.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.82 (m, 1H), 4.27 -3.84 (m, 3H), 2.75-2.58 (m, 1H), 2. 52-2.35 (m 1H), 2.21-1.95 (m, 2H), 1.39-1.23 (m, 3H) 3,644 de% = 100% 257 XX CF ₃ N^N CF ₃ N^N HHHH 257 & 258 400.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.904.81 (m, 1H), 4.24-4.11 (m, 1H), 3.333.14 (m, 2H), 2.70-2. 55 (m, 1H), 2.482.34 (m, 1H), 2.17-2.96 (m, 2H), 1.561.44 (m, 2H), 1.29-1.23 (m, 3H) , 0.880.80 (m, 3H) 3.436 de% = 99.24% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 80/20 248 258 400.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.904.83 (m, 1H), 4.25-4.10 (m, 1H), 3.343.13 (m, 2H), 2.70-2, 54 (m, 1H), 2.542.33 (m, 1H), 2.19-1.96 (m, 2H), 1.561.44 (m, 2H), 1.29-1.22 (m, 3H) , 0.890.81 (m, 3H) 4.005 de% = 99.74%

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262 A _F . A CF ₃ N^NA CF ₃ N^NA _F НН НН 262 & 263 447.9 Ή-NMR (400 MHz, CD ₃ OD): δ 5.044.95 (m, 1H), 4.42-4.14 (m, 2H), 3.042.87 (m, 2H), 2.84-2, 45 (m, 4H), 2.312.06 (m, 2H), 1.45-1.33 (m, 3H) 3,388 de% = 100% Column: AD-H (0.46 cm bh. dia. x 15 cm length); Mobile phase: n-heptane/isopropanol = 80/20 259 263 448.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.924.83 (m, 1H), 4.31-4.04 (m, 2H), 2.942.73 (m, 2H), 2.72-2, 34 (m, 4H), 2.181.91 (m, 2H), 1.32-1.21 (m, 3H) 3,968 de% = 99.48% 264 A . A CF ₃ N^N d CF ₃ N^N d NN NN 264 & 265 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.83 (m, 1H), 4.26-4.09 (m, 1H), 2.732.53 (m, 2H), 2.53-2. 34 (m, 1H), 2.171.94 (m, 2H), 1.31-1.22 (m, 3H), 0.700.58 (m, 2H), 0.47-0.39 (m, 2H) 3,524 de% = 99.56% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 80/20 260 265 398.0 Ή-NMR (400 MHz, CD ₃ OD): δ 5.034.83 (m, 1H), 4.26-4.10 (m, 1H), 2.782.54 (m, 2H), 2.52-2, 32 (m, 1H), 2.191.94 (m, 2H), 1.32-1.22 (m, 3H), 0.7ΙΟ.53 (m, 2H), 0.51-0.35 (m, 2H) 3.737 de% = 99.58% 272 A . A ι A A NN NN 272 & 273 394.1 Ή-NMR (400 MHz, CD ₃ OD): δ 4.364.09 (m, 3H), 3.02-2.87 (m, 2H), 2.792.43 (m, 4H), 2.26-2. 04 (m, 2H), 1,281.15 (m, 6H) 4,176 ee% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 70/30 261 273 394.0 Ή-NMR (400 MHz, CD ₃ OD): δ 4.364.09 (m, 3H), 3.02-2.87 (m, 2H), 2.792.43 (m, 4H), 2.26-2. 04 (m, 2H), 1,281.15 (m, 6H) 4,696 ee% = 100% 285 ΧχΟΗ Х.ОН I ^F + I ^F nA n^n nA n^n aI a A ,o___- xAJL AA ___' π π | π π | 285 & 286 479.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.678.30 (m, 2H), 8.06-7.80 (m, 1H), 4.454.23 (m, 1H), 2.93-2. 75 (m, 1H), 2,692.50 (m, 1H), 2.33-2.06 (m, 2H), 1,421.20 (m, 9H) 3,399 ee% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 70/30 275 286 479.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.678.30 (m, 2H), 8.06-7.80 (m, 1H), 4.454.23 (m, 1H), 2.93-2. 75 (m, 1H), 2,692.50 (m, 1H), 2.33-2.06 (m, 2H), 1,421.20 (m, 9H) 4,089 ee% = 100% 287 A. A n<A n^A n^% 287 & 288 480.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.678.32 (m, 2H), 8.08-7.80 (m, 1H), 2.912.75 (m, 1H), 2.69-2. 52 (m, 1H), 2.322.08 (m, 2H), 1.42-1.26 (m, 9H) 3,400 ee% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 70/30 276 288 480.2 Ή-NMR (400 MHz, CD ₃ OD): δ 8.678.32 (m, 2H), 8.08-7.80 (m, 1H), 2.912.75 (m, 1H), 2.69-2. 52 (m, 1H), 2.322.08 (m, 2H), 1.42-1.26 (m, 9H) 4,086 ee% = 100% 289 A. A CF ₃ N^N CF ₃ N^N ArTn^N^NI^ AAm^N^YNg Η Η 289 & 290 358.2 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.92 (m, 1H), 4.38-4.18 (m, 1H), 2.802.61 (m, 1H), 2.61-2, 44 (m, 1H), 2.312.10 (m, 2H), 1.50-1.23 (m, 3H) 3,506 de% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 80/20 280 290 358.1 Ή-NMR (400 MHz, CD ₃ OD): δ 5.004.92 (m, 1H), 4.38-4.18 (m, 1H), 2.802.61 (m, 1H), 2.61-2, 44 (m, 1H), 2.312.10 (m, 2H), 1.50-1.23 (m, 3H) 3,754 de% = 100% 291 ^F \/ ^FF \/ ^F >A*on X yun 1 A 1 A CF ₃ N^N CF ₃ CF ₃ N^N CF ₃ HHHH 291 & 292 436.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.87 (m, 1H), 5.10-4.91 (m, 2H), 4.494.21 (m, 1H), 2.90-2, 54 (m, 2H), 2,341.98 (m, 2H), 1.50-1.20 (m, 6H) 2,376 de% = 100% Column: AD-H (0.46 cm i.d. x 15 cm length); Mobile phase: p-heptane/isopropanol = 80/20 281 292 436.2 Ή-NMR (400 MHz, CD ₃ OD): δ 7.226.87 (m, 1H), 5.10-4.91 (m, 2H), 4.494.21 (m, 1H), 2.90-2, 54 (m, 2H), 2,341.98 (m, 2H), 1.50-1.20 (m, 6H) 3.321 de% = 100%

Example 3. Fluorescent determination of IDH2-R140Q activity

Materials

U87MGR140Q cells: U87MG cells were purchased from the ATCC cell bank and then transfected with a plasmid containing the IDH2-R140Q mutation, and monoclonal cells stably expressing the R140Q mutation were isolated for experiments. These cells were grown in MEM medium containing 10% FBS.

96-well plate a: Beckman Dickinson, cat. No. 353072;

96-well plate b: Thermo, cat. No. 249952;

96-well plate with: Greiner, cat. No. 675076.

Preparation of the solution

Enzyme reaction solution: 1 mM nicotinamide adenine dinucleotide (NAD), 0.6 ng/μl D-2hydroxyglutarate dehydrogenase (D2-HGDH), 0.8 U/ml lipoamidase dehydrogenase (diaphorase) and 60 μM resazurin in 40 mM Tris-HCl , assay buffer pH 8.8.

Stock solution for constructing a standard curve:

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A standard solution of sodium 2-HG salt was serially diluted in serum-free MEM to obtain a stock solution for constructing a standard curve. The final gradient concentrations were: 500 µM, 167 µM, 56 µM, 18.5 µM, 6 µM, 2 µM, 0.7 µM, 0.2 µM.

Methods

100 μl of U87MGR140Q cells were seeded at a density of 6x10 ⁴ /ml in each well of a 96-well plate a. The plate was incubated at 37°C under 5% CO2 overnight, then 10 µl per well of test compound solution diluted in serum-free MEM was added (final test compound concentrations: 10 µM, 3.3 µM, 1.1 µM, 0.37 µM, 0.12 µM, 0.041 µM, 0.014 µM and 0.005 µM, final concentration of DMSO was 0.5%) or 10 µl control solution (serum-free MEM medium containing 0.5% DMSO as final concentration) and incubated for 72 hours.

From each well of 96-well plate a, 50 μl of the supernatant medium was transferred to the corresponding wells of 96-well plate b; at the same time, 50 μL of stock solution was added to each well of 96-well plate b to construct a standard curve. Then 10 μl of 360 mM hydrochloric acid was added to each well. After mixing, the plate was kept on ice for 10 min, and then 10 μl of 420 mM Tris base was added. After mixing, the plate was placed on ice for an additional 5 minutes. The plate was then centrifuged at 2500 rpm for 10 minutes.

After centrifugation, 20 μl of supernatant was transferred from each well of 96-well plate b to 96-well plate c. An additional 80 μL of enzyme reaction solution was added to each well and incubated at 25°C for 90 min.

Detection

The plate was placed in a Tecan Infinite F500 Reader and measured at an excitation length of 544 nm and an emission length of 590 nm. A standard curve was plotted against the fluorescence value versus the corresponding 2-HG concentration, and the 2-HG concentration corresponding to each compound concentration was calculated. The inhibition level was then calculated and the data analyzed using XLfit5 software (ID Business Solutions Limited) to obtain an IC ₅₀ value.

The level of inhibition was calculated as follows:

Inhibition rate (IH%) = (1 - 2-HG concentration in cells treated with test compound / 2-HG concentration in control cells) x 100%.

Below are the activity values of some compounds according to the present invention, determined in this example.

Compound 1C ₅₀ , µM Compound 1C ₅₀ , µM Compound 1C ₅₀ , µM Compound 1C ₅₀ , µM 1 0.097 73 0.064 148 1.558 221 0.487 2 0.137 74 0.034 149 0.177 222 0.065 3 0.866 75 0.218 150 0.541 224 0.137 4 0.080 78 0.069 151 0.039 225 0.036 5 0.093 79 0.106 152 0.300 226 0.361 6 0.115 80 0.079 153 0.099 227 0.048 7 0.087 81 0.099 154 0.202 228 0.417 8 0.216 82 0.075 155 0.319 229 0.383 9 0.571 83 0.203 156 0.657 230 0.658 10 0.113 84 0.048 157 0.141 231 0.037 AND 0.284 85 0.035 158 0.278 232 0.040 12 0.199 86 0.021 159 0.205 233 0.368 13 0.373 87 0.205 160 0.180 234 0.078

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14 0.230 89 0.057 162 0.177 235 0.130 15 0.259 90 0.065 163 0.162 236 0.045 16 0.326 91 0.058 164 0.176 237 1,492 17 1.616 92 0.143 165 0.198 238 0.139 18 0.110 94 0.131 166 0.180 239 0.046 19 0.083 95 0.043 167 0.327 240 0.984 20 0.232 96 0.675 169 0.738 241 0.100 21 0.099 97 0.052 170 1,382 242 0.802 22 0.336 98 0.344 171 0.268 243 1.175 23 0.192 99 0.553 172 0.344 244 0.053 24 0.197 100 2,905 174 0.096 245 0.102 25 0.665 101 0.080 175 0.291 248 0.093 27 0.148 102 0.051 176 0.612 249 0.072 28 0.123 103 1.002 177 0.046 250 2,473 29 0.177 104 2,079 178 0.934 252 0.050 thirty 0.228 105 0.040 179 0.598 254 0.025 31 0.110 106 0.106 180 0.531 255 0.078 32 0.080 107 0.554 181 0.177 257 0.056 34 0.145 108 2.226 182 1.231 259 0.057 35 0.591 109 0.057 183 0.507 260 0.094 36 0.181 110 0.070 184 3,779 261 0.094 37 1,911 111 2,257 186 0.677 262 0.056 38 1.619 112 0.098 187 0.742 263 1,394 39 0.164 FROM 2,059 188 5.015 264 0.084 40 0.106 114 1.716 189 1.415 266 0.033 41 0.297 115 0.059 190 0.413 267 1.327 42 0.152 116 2,620 191 0.999 268 0.349 43 0.328 117 0.095 192 0.314 269 0.137 44 3.149 118 0.106 196 0.094 270 0.109 47 0.059 119 3,393 197 0.041 272 0.051 49 0.210 120 2,397 198 0.845 273 1.228 50 0.072 121 0.068 199 1,504 274 0.084 51 0.125 122 1,340 200 0.632 275 0.062 52 0.229 124 0.137 201 0.045 276 0.081

- 68 044101

53 0.131 125 1.671 202 0.383 277 0.156 54 0.015 126 0.086 203 0.098 278 0.148 55 0.103 127 0.064 204 0.209 279 0.170 56 0.093 128 0.092 205 0.803 280 >10 57 2,180 129 0.171 207 0.564 281 0.690 58 0.169 130 0.067 208 0.102 282 0.343 59 0.221 131 2,798 209 0.078 283 0.174 60 0.590 133 0.174 210 0.093 285 0.034 61 0.170 134 0.100 211 0.097 286 0.165 62 1,343 135 0.336 212 0.063 287 0.095 64 1.628 136 0.296 213 0.038 288 0.035 65 0.152 137 1,540 214 0.108 291 0.201 67 2,374 138 0.504 215 0.079 292 3.456 68 0.435 139 2,505 216 0.082 293 0.637 69 0.173 140 2,390 217 0.069 294 0.425 70 0.112 144 2,748 218 0.381 296 0.423 71 0.050 146 0.999 219 0.707 297 2,660 72 0.042 147 0.067 220 0.059 298 0.620

Example 4. Fluorescent determination of activity of IDH1-R132H cells

The 2-HG inhibitory activity of the compounds of the present invention in U87MGR132H cells transfected with the mutant IDH1-R132H plasmid was determined according to the method of Example 3.

Compound 1C ₅₀ , µM Compound IC50, µM Compound IC50, µM Compound IC50, µM 2 0.365 94 1,144 198 1,893 245 1,499 4 0.750 95 0.317 199 >10 248 4.338 5 0.869 96 2,703 200 >10 249 0.134 6 0.670 97 0.047 201 0.109 250 2,480 7 1,503 98 0.254 202 1.101 252 2.621 8 1.221 99 0.938 203 0.733 254 0.262

- 69 044101

AND 1.016 101 1.141 204 >10 255 0.715 13 2,076 102 0.232 205 >10 257 1,380 14 1.326 103 2,501 207 1,510 259 0.213 15 0.619 105 0.351 208 1,499 260 >10 18 0.219 106 0.272 209 1,763 261 2.231 19 0.421 107 1.751 210 4.338 262 0.182 21 0.234 109 0.279 211 0.175 263 3,513 24 0.769 110 0.160 212 >10 264 >10 31 0.280 118 2,141 213 >10 266 0.043 32 0.610 119 >10 214 >10 267 3,566 34 >10 121 0.186 215 >10 268 0.939 39 1,913 124 0.658 216 8,519 269 0.296 40 0.450 126 0.289 217 >10 270 2.853 41 1.627 127 0.203 218 >10 272 2,086 47 5.636 130 0.733 219 3.232 273 >10 51 6,042 134 2,472 220 2,878 274 3,284 52 2.245 136 1,342 221 >10 275 8,017 54 1.683 147 0.372 222 >10 276 8,367 60 >10 149 0.693 224 4,650 277 1,030 61 >10 151 0.256 225 0.917 278 >10 62 2,703 152 2,008 226 5.123 279 9.426 64 >10 153 0.447 227 0.081 280 >10 65 >10 155 2.245 228 0.705 281 0.455 67 >10 157 4,350 229 >10 282 0.444 71 3,054 158 1,520 230 >10 283 1.319 73 >10 159 2,717 231 1.528 285 3,587 74 7,441 163 0.809 232 0.070 286 >10 75 >10 166 1,347 233 0.628 287 >10 78 1,407 167 3.171 234 1,763 288 2.695 79 1,296 169 9,464 235 0.246 291 0.179 80 2.695 170 6,933 236 0.252 292 3.639 81 3,571 171 1.575 238 7.355 293 >10 82 0.181 174 0.343 239 0.344 294 9,184 83 0.282 175 0.495 240 >10 296 1.135 84 0.268 177 0.094 241 2,060 297 >10 85 0.207 181 0.476 242 3.523 298 >10 87 0.781 196 0.210 243 >10 89 2.957 197 0.120 244 1,082

Example 5 Metabolic Stability Test in Liver Microsomes

Materials

Male CD1 mouse liver microsomes were purchased from Research Institute for Liver Diseases (Shanghai) Co., Ltd.. Male SD rat liver microsomes were purchased from Bioreclamation IVT in the USA.

Phenacetin, glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PD), and nicotinamide adenine dinucleotide phosphate (NADP) were purchased from Sigma-Aldrich (MO, USA).

Preparation of mM test compound stock solution: A quantity of test compound was weighed and dissolved in a volume of dimethyl sulfoxide (DMSO) to obtain a 10 mM test compound stock solution.

Stop Solution: A quantity of phenacetin as an internal standard was weighed and dissolved in acetonitrile to obtain a stop solution at a concentration of 1000 ng/mL, and stored at room temperature until use.

- 70 044101

Experimental method

The stock solution of the test compound was diluted to the desired concentration with an organic solution (usually a mixture of acetonitrile, methanol and water of various compositions was prepared depending on the solution of the specified compound) to obtain a final concentration of 1 μM and an organic solvent content of no more than 1% (for DMSO the control limit was 0. 1%) in the final incubation system. 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 regeneration system containing 1 mM NADP, 5 mM G-6-P, and 1 U/mL G -6-PD, which was pre-conditioned at 37°C in a water bath for 10 min and then cooled on ice before being added to the reaction system. 20 mg/mL liver microsomes were mixed with 200 mM PBS and diluted with ultrapure water to obtain liver microsomes and PBS concentrations of 0.5 mg/mL and 50 mM in the final incubation system, respectively.

After the diluted liver microsomes were mixed with the NADPH regeneration solution, certain volumes of 100 mM EDTA and 300 mM MgC _l2 were added (the concentrations of EDTA and MgCl ₂ in the final incubation system were 1 and 3 mM, respectively), and the specified incubation system was placed in a water bath at 37°C. Incubation was started by adding a stock solution of the test compound and continued for 30 min. This incubation was stopped by adding a solution to stop the reaction. The 0 minute sample was prepared by adding a stop solution to the incubation system immediately before placing the system in a water bath containing a stock solution of the test compound. The stopped incubation mixtures were thoroughly mixed and centrifuged at 4400 rpm for 10 min, and the supernatant was collected for LC-MS/MS analysis.

Analytical method

The concentration of the test compound was determined using the LC-MS/MS method. Using the peak area ratio of the compound and the internal standard as indices, the percentage of compound remaining after 30 min incubation compared to the 0 min sample was calculated and the metabolic stability of the compound was assessed.

According to the results of the above test, the compounds of the present invention showed good metabolic stability. The metabolic stability of some compounds of the present invention used as examples is given below:

Compound Stability in rat liver microsomes Stability in mouse liver microsomes Compound Stability in rat liver microsomes Stability in mouse liver microsomes 1 73.8% 83.5% 124 74.1% 44.1% 2 99.0% 83.8% 126 79.8% 58.2% 4 62.9% 82.1% 127 49.8% 28.7% 5 76.8% 58.6% 128 34.0% 15.9% 6 70.0% 76.3% 147 65.0% 48.1% 7 50.3% 49.8% 149 66.8% 59.7% AND 87.6% 80.3% 153 41.7% 46.9% 18 91.5% 82.7% 177 45.9% 31.0%

- 71 044101

19 83.8% 66.2% 196 100.0% 95.2% 82 92.9% 93.1% 197 99.5% 98.4% 83 96.6% 83.7% 201 91.6% 79.3% 84 67.8% 78.9% 202 94.2% 96.4% 85 78.1% 64.0% 203 92.1% 91.3% 87 97.9% 88.5% 211 98.8% 99.7% 90 82.4% 80.9% 227 88.8% 81.4% 91 86.6% 70.5% 232 86.6% 76.3% 94 82.6% 65.4% 235 89.0% 75.5% 95 74.8% 80.1% 236 91.3% 83.9% 97 98.5% 89.5% 239 93.0% 91.8% 98 99.2% 83.7% 249 98.0% 100.0% 101 88.0% 84.6% 254 100.0% 90.9% 102 92.7% 86.2% 259 95.1% 86.9% 103 89.7% 78.5% 262 98.3% 92.2% 105 84.0% 67.3% 266 98.2% 91.5% 109 85.4% 58.8% 291 100.0% 98.9%

Example 6. Determination of solubility 1.

Preparation of sample solution

Standard sample solution: about 3-5 mg of the test compound was carefully weighed and added to a 5 ml test tube, 5 ml of DMSO was added. Shake and sonicate for 1 hour.

Sample solution pH 2.1:

Approximately 1 mg of the test compound was carefully weighed and added to a 1 ml test tube, and 1 ml of sodium phosphate buffer, pH 2.1, was added. Shake, add the test compound to the specified solution, if this solution was visually clear, until it became obvious that it did not dissolve in the specified solution. Sound treated for 1 hour.

Sample solution pH 7.4:

Approximately 1 mg of the test compound was carefully weighed and added to a 1 ml test tube, and 1 ml of sodium phosphate buffer, pH 7.4, was added. Shake, add the test compound to the specified solution, if this solution was visually clear, until it became obvious that it did not dissolve in the specified solution. Sound treated for 1 hour.

2. Determination ml of standard sample solution was carefully pipetted onto the HPLC column. The peak area was determined by HPLC.

0.5 mL of pH 2.1 sample solution was filtered using a filter syringe and pipetted onto an HPLC column, and 0.5 mL of sodium phosphate buffer pH 2.1 was carefully added. Shaked. The peak area was determined by HPLC.

0.5 mL of pH 7.4 sample solution was filtered using a filter syringe and pipetted onto an HPLC column, and 0.5 mL of sodium phosphate buffer pH 7.4 was carefully added. Shaked. The peak area was determined by HPLC.

HPLC conditions:

: Agilent 1200

Column: Agilent SB-C18 5 µm, 4.6x150 mm

Mobile phase:

Phase A: Water (containing 0.1% formic acid)

Phase B: MeOH (containing 0.1% formic acid)

Gradient table ___________________________________

Time, min %

Claims

3. Calculation

The solubility of the test compound in sodium phosphate buffers pH 2.1 and pH 7.4 was calculated using the following formulas:

Sample solubility at pH 2.1 (mg/ml) = 2xAxY<X

Solubility of the sample at pH 7.4 (mg/ml) = 2xAxZ^X in this case:

A: Concentration of the test compound in the standard sample solution, mg/ml;

X: Peak area of the sample in standard solution;

Y: Area of the pH 2.1 peak in the sample solution;

Z: Area of the pH 7.4 peak in the sample solution.

The solubilities of some compounds according to the present invention, selected as examples, are given below:

Compound Solubility, mg/ml Compound Solubility, mg/ml pH 2.1 pH 7.4 pH 2.1 pH 7.4

3 >1,000 0.716 125 0.448 0.019

9 >1,000 0.085 219 0.190 0.060

20 0.570 0.062 223 0.060 0.016

68 0.141 <0.005 243 0.055 <0.005

71 0.064 0.055 249 0.036 0.011

82 0.146 0.037 262 0.237 0.013

97 0.077 0.021 271 0.974 0.124

102 0.729 <0.005 284 0.789 0.818

CLAIM

1. Compound of formula (I) ^^/NR ₃ R ₃ '

Τ Τ nr ₄ r ₄ ' ^pR ₂ ) _m (I) and/or its pharmaceutically acceptable salt, and/or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, wherein

A selected from

wherein R ₇ is selected from H, halo, -CN, -OH or -NH ₂ ;

R1 is selected from H, -OH, halo, O _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , oxo or C _3-8 cycloalkyl;

each of R ₂ is independently selected from H, deuterium, halo, -OH, -NH ₂ , -CN, -SH, C _1-6 alkyl, C _2-6 alkenyl, O _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, oxo, -OR5, -OCOR5, -NHR5, -N(R ₅ )(C _1-4 alkyl), -COR5, -NHCOR5 or 3-8 membered heterocyclyl containing one or more heteroatoms, independently selected from N, O and S; wherein each of said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S , optionally contains as substituents one or more groups selected from deuterium, halo, -CN, -OH, -SH, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ or C _1-6 alkoxy; or two R ₂ which are attached to the same carbon atom, together with the specified carbon atom to which they are attached, form a 3-5 membered cycloalkyl, which optionally contains one or more halo or deuterium as substituents;

_R3 ' and R4' are both H; a R ₃ and R 4 are independently selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, -C(O)R5, -OR5 or -NHR5, in which each of said C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optionally containing one or more R6 as substituents; provided that _R3 and R4 are not both H; provided that when one of R ₃ and R 4 is optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, the other is is -OR ₅ or -NHR5; or

R ₃ and R ₃ ' are independently selected from H, C ₁ . ₆ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl, 5-12 membered heteroaryl, -C(O)R ₅ , -OR ₅ or -NHR ₅ , in which each of the indicated C ₁ . ₆ αlkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optional contains one or more R6 as substituents; a R4 and R4 together with the N atom to which they are attached form a 3-8 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O and S, optionally substituted by one or more R6;

R ₅ is selected from C ₁ . ₆ αlkyl or C ₃ . ₈ cycloalkyl, each of which optionally contains as substituents one or more groups independently selected from halo, -CN, -OH, -SH, -NH2 or C ₁ - ₆ alkoxyl;

each of R6 is independently selected from deuterium, halo, -CN, -OH, -SH, -NH2, C ₁ . ₆ αlkoxyl, C ₁ . ₆ αlkyl, C ₁ . ₆ haloalkyl, C ₃ . ₈ cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, in in which each of the specified C ₁ . ₆ αlkoxyl, C ₁ . ₆ alkyl, C ₃ . ₈ cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optionally contains in as substituents one or more groups independently selected from halo, -CN, -OH, -SH, -NH2, C ₁ . ₆ alkoxyl, C ₁ . ₆ αlkynyl or C ₁ . ₆ alkyl;

m is 0, 1, 2, 3, 4, 5 or 6;

n is 0, 1 or 2.

2. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that R1 is selected from H, -OH or halo.

3. The compound of formula (I) according to claim 2 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that R ₁ represents -OH.

4. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its racemic mixture, enantiomers, diastereomers and tautomers, characterized in that each of R2 is independently selected from H, deuterium, halo, -OH, - NH2, -CN, -SH, _C1 . ₆ αlkyl, C ₂ . ₆ αlkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₈ cycloalkyl, oxo, -OR ₅ , -OCOR5, -NHR ₅ , -N(R ₅ )(C ₁ . ₄ alkyl), -NHCOR5 or 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S.

5. The compound of formula (I) according to claim 4 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that each of R ₂ is independently selected from H, deuterium, halo, C ₁ . ₆ alkyl or C ₁ . ₆ haloalkyl.

6. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, characterized in that R ₃ and R ₄ are independently selected from C ₁ . ₆ alkyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, - C(O)R5, -OR5 or -NHR5, in which each of the specified C ₁ . ₆ αlkyl, C ₃ . ₁₂ cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optional contains one or more R6 as substituents.

7. The compound of formula (I) according to claim 6 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, characterized in that R ₃ and R ₄ are independently selected from C ₁ . ₆ alkyl substituted with one or more halos, 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, substituted with C ₁ . ₆ haloalkyl or -OR ₅ .

8. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that R3 and R4 are independently selected from C ₁ . ₆ alkyl substituted with one or more halos.

9. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that R5 represents C ₁ . ₆ alkyl, optionally substituted with one or more halos.

10. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that each of R6 is independently selected from deuterium, halo, -CN, - OH, -NH2, C ₁ . ₆ alkoxyl, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl,

- 74 044101

C ₃ . ₈ cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, in in which each of the specified C ₁ . ₆ alkoxyl, C ₁ . ₆ alkyl, C ₃ . ₈ cycloalkyl, 3-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O and S, phenyl or 5-6 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optional contains one or more halos as substituents.

11. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that n is 1.

12. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that R3 is selected from H, C ₁ . ₆ alkyl, optionally substituted with C ₁ . ₆ haloalkyl, or 5-12 membered heteroaryl containing one or more heteroatoms independently selected from N, O and S, optionally substituted with C ₁ . ₆ haloalkyl; R3' is H; R ₄ and R ₄ ', together with the N atom to which they are attached, form a 3-8 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O and S, optionally substituted by one or more groups selected from halo , -OH or C ₁ . ₆ haloalkyl.

13. A compound of formula (I) according to any one of claims 1 to 12 or its pharmaceutically acceptable salts, and/or solvates thereof, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that said compound of formula (I) is selected from

wherein X represents a halogen.

14. A compound of formula (I) according to any one of claims 1 to 12 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, characterized in that said compound of formula (I) has the structure of the formula ( II);

wherein X represents a halogen;

p is 0, 1 or 2;

m is 0, 1 or 2;

15. The compound of formula (I) according to claim 14 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixture, enantiomers, diastereomers and tautomers, characterized in that said compound of formula (I) is selected from

- 75 044101

wherein X represents a halogen;

p is 0, 1 or 2;

m is 0, 1 or 2.

16. The compound of formula (I) according to claim 15 or its pharmaceutically acceptable salts, and/or its solvates, racemic mixtures, enantiomers, diastereomers and tautomers, characterized in that said compound of formula (I) has the structure of formula (II-1) ;

wherein X represents a halogen;

p is 0, 1 or 2;

m is 0, 1 or 2;

17. Connection selected from

Compound Structure Compound Structure

1 GT 1 ^F CF ₃ Ν ^Ν ι Η Η 152 G/ ^OH [ iRSjT CF ₃ N% = A. A <R) Ν Ν Ν η

2 Gr ^0H Τ ^F QF ₃ gАА ^CF 3 A?n Em 153 Αυ ^οη Г (RSH ΑΓν ν ν

3 pr ^0H A CF ₃ N^ N r-\ ⁷ AAA/ ⁰ An n νΆ Η Η 154 Γ (RS)| Q ^F 3 Ν^Ν ΑΓνΆ^νΆ^ Η π

4 A, CF ₃ N^N /~A _F 155 Αυ ^οη Γ fRsjl CF ₃ Ν^Ν ι ΑΓν'^ν^ν'^ Η Η

5 Ag ^oh φζ cA ^f a\ a A Ja ^f Ν Ν N HH 156 ^•ιΟ ΙΖ “Η >= ^ζ νΛΛ ΙΖ Ο G ¹

- 76 044101

6 xy ^oh L _Fp AL A xO 157 IZ ω iz -P o A- ¹ w

7 Χγ ^0Η L Gu X? n n 158 A CF ₃ N^N = AAXA An ν ΝΑπ H Η V

8 gХ ^0Н I ^F CF ₃ N^N А к χ I N N'SYt η η V 159 A I ^F Г. CF ₃ N^N 7 AAA Ar An nn ^ HH

9 f CF ₃ nA I XX AX Άν ν ν'^ HH 160 Oy ^oh a _FF CF ₃ N^n A?/ ^F AAA AJ ⁷ An nn' HH

10 A ^0H T ^F CF ₃ N^N rX А А A A Az O/nn HH 161 CF ₃ N^N rA~/° AAAX A/nnn HH

I rX ^0H l ^F CF ₃ N^ N CF ₃ AAAA An n nA HH 162 rX° ^H r ^F Г AAX HH

12 A CF ₃ N^N AAA / An ν νΆ η η 1 163 ^ ^OH T ^F CF ₃ N^ N = AAAA / An n n'wt η h |

13 rX ^0H T ^F CF ₃ N^ NAAA An ν νΑί r HH ΑχΡ F 164 rX ^OH T ^F CF ₃ N^ N -. AAXA / O/nn na?A^ HH

- 77 044101

14 A° ⁿ T ^F CF ₃ N ^N CF ₃ 165 Α ^0Η T ^F CF ₃ Ν^Ν Η Η

15 <y ^oh G (RsT g 166 a; CF ₃ νΆ y-L Λ Λ A Αν ν νΆΑ Η Η (/ F

16 za ^oh G A CF ₃ nA _a ΑΛΑ An Ν nA 'F Η Η 167 Α ^ΟΗ ? ^F CF ₃ νΆ ι Α Α Α Λ / Αν ν νΑΚ Η Η ι

17 Ήυ ^οη Γ (RsY st CF ₃ nA 1 ΛΑ AX Αν ν Η Η 168 Α< ^0Η a CF ₃ ΝΆ A _K1 A _m A _k1 A_.cn Αν ν ν (rs/^ Η Η

18 T ^F QF ₃ Ν CF ₃ ΑΑνΛΆ 169 Α ^ΟΗ a _F CF ₃ NS f ^F AL A Λ An ν nA'

19 IZ -P O o -Π 170 a _F CF ₃ N^N / ^F A Λ AA An n nA HH

20 Θζ ^0Η Λ Αν ^F Λ Λ X/ ^F Η Η 171 A ^OH A cf ₃ n A _f 4AW HH \A

21 θ-ΟΚ a GL X ³ Αν ν nA 172 A CF ₃ N^N ΑΝ^Ν^Ν'θΆ Η Η

- 78 044101

22 0$ V, N^NA ^F A\AAA ^f Ν Ν NHH 173 A CF ₃ N^N rN AAA A> -^NN NtA HH

23 CF ₃ N^N ί HH 174 A CF ₃ N^N ί AAAX f -X'N'^N^NiXy'

24 Θ$ CF ₃ An rJ 4nA> _n ^ ^f HH 175 A CF ₃ ΝΆ ί AAAX / <rTn Ν Ν^ξ< ^HH FF

25 ί ^fRS l 1 ^N l 1 ΑΑΑΛ HH 176 cr ^?F 3 H'S rXx ^F ί Ji A A^'n^'n'^n'^ ⁷ F HH

26 _g A Ou- Z— L O7g 177 a ^0H CF ₃ N^N r^\ _F aaaach HH

27 LA N^N _l f>C x l Λ HH 178 A ³ AAZ/° ^N-^N^N-^ HH

28 ^ОИ L ^iRS; l Aa5a HH 179 cr Tal C° -^NN N''(RT HH

29 G R% QF ₃ |A CD ₃ HD ^C ° ³ 180 cr CF ₃ N^N r^\ AAAA /° An ν ΝΎξΑ HH

- 79 044101

30 Γ cf ₃ nA cd ₃ WX H HD ³ 181 Λ. CF ₃ Ν^Ν TM-F ALL X Λ Αννν^/ Η Η

31 Θζ CF ₃ nA Λ AA XT ^F ΑΓν Ν N' HH 182 σ ^0Η X Η<\™ CF ₃ Ν^Ν TL l l l X/ 'ΧΝ Ν NW ⁴ ' Η Η

32 ec HH 183 σ ^0Η CF ₃ nA * ΛΑ Λ Λ ο Ν Η Η

33 <^ ^0H cf ₃ nA ϊ HH 184 /χ,ΟΗ CF ₃ nA Α μ X, Α _Κ1 Μ°η ^(R) Ν Ν Ν Η Η

34 0 IZ Ηλά UM IZ -no b ¹ % 186 X, ΑΓν^ν^νΆ-

35 θζ ^?F1 H l ΑΓν'Ά'Ά'Α Η Η 187 ?. γΑν^νΧα? V η η V

36 CF ₃ Ν^Ν ϊ AL A X ΑΓν ν ν^ Η Η 188 9 CF ₃ Ν^Ν ΛΑ 1 _Λ ζ An n nV,, , Η Η |όη

37 6r ^F XVA Η Η 189 9 CF ₃ Ν^Ν ϊ ΑΓν^ν^νΧΗ Η

- 80 044101

38 F Ash ^5F 'll i Ά ν 190 9 CF ₃ N^N ϊ AAAA XrTN NN ^ HH

39 Qc,° A A X H H 191 A A A A A γΑν N N'CTY? V η η V

40 iz 7 ¹ ZZ “P ' d ¹ τι 192 9 CF ₃ νΆ AAA WN Ν ΝΆ7 HHV

41 or CF ₃ N^N < ^F ΆΓν'^ν ^< ^ν' ^χ ^' ^ι= HH 193 2 γ/ΆΛ' V η h

42 A X ³ D A „A , ΧΑ N nIrs) VHH 194 .9 VHH

43 OG A A g ^F LA AAA Ν N nAA HH 195 .9

44 A CQ А А X ³ ν^^ν^ν^νΆ HH 196 rA ^0H 1 ^F CF ₃ N ^N CF ₃ AAAA ArTn n nIA HH

45 ar XXX aa XHH 197 and 198 Λ CF ₃ N^N CF ₃ A9nXaXi9rA HH

- 81 044101

46 D Η Η d J A ³ -^Ν Ν Η Η

47 ar ΝΑ nA _C |O<A _n A _n A Η Η D 199 ar \d 1 A l ^N Jon

48 α: ^νΆ νΆ I Η Η 200 I pcs Shall n n

49 ar A Π X ^l A/v Η Η 201 and 202 & Xu n^n /A n n

50 S^F F D d Hu κΑν gА ^f Xa _n a> n n

51 χ: A and d ALAA Η Η 203 Sr Hu n^n gO, n n

52 D CF ₃ Ν^Ν CD ₃ A?nAAn^CD ₃ 204 d Ν^Αΐ ^Ν<ί<Ν AAAAm-aa Ν Ν Ν >< Η Η A

53 ar ZH D ³ 4nA ^a n4cd ₃ N HD ³ 205 χ№ ^Η 1 ^fRS l Ν^Ν η η

- 82 044101

206 G fRsJ QF ₃ nA cf ₃ Α/Ν'^^νΆ' h [L h

55 _ρ Ατ νΆ cd ₃ H HD ³ 207 fS QF ₃ nA< ^F CF ₃ ^ΧιΑγ^νΆ HM

56 “Π AHA IZ -no /- ¹ 208 Sr CF ₃ N^NAAA ΆνΆΑΆρ ₃

57 N^. N^NI HH 209 CF ₃ NX AAANN η η V

210 Sr CF ₃ NX AAA / -<Κ?Ν NNHH

59 ar a ^N -nX N^NI HH 211 Sj ? ^F GI g HH

60 ъ IZ Nld >Ам IZ -no b ¹ A 212 A νΛι νΆ AAAAO / ΟΡΓ^-Ά Ν Ν' ³ Η Η

61 ar An n^n _C iAA _n aA _n ^xO x Η H a 213 ο ъ ΙΖ >= ^Η νΛΛΖ ΙΖ -π ο ¹

- 83 044101

62 α AAA νΧ IL JL U A l 1 Ν Ν Ν'^' Η Η 214 Ν nA Αν ³ Η Η A

63 X Ή Ο U- ΖΙ Μ/ ^ζ= < ИА/ ΖΙ И ζ 1 215 0 ΙΖ >= ^Z AV ΧΖ -Π ο

64 τ -( Ο U- ΖΧ Μ/ ^ζ= < У/ ΖΙ .И ζ 216 X 9^ Ο u- ΖΧ %Ηη ΖΙ α ο

65 8 ΙΖ >= ^ζ ΛΑ ΤΖ -Π Ο __ τ 217 Ν nA nA A JL Λ A Ο CFf^^NNN''— ³ Η Η

66 - Ν 4 , ^Ν ~Ν Ν^Ν 1 '—4 AAA JL νΆΆΆ-ά Η Η 218 Ή nA ν^ν α£ λ λ _Ρ CFa''''^-'Ά Ν ΝΑ< ^Η LA

67 γ ΛΑ Np η η 1 he 219 Ά l Άν ν νΆ

68 χ OU-ζχ ON ΖΙ 8 220 Ο 8 τζ υΗΑ χ^ -π Ο

69 Ν CF ₃ A QF ₃ Α ^λ /ά Η Η 221 Λ ζχ Y ο

- 84 044101

222 and 223 8 ΙΖ Nm ΛΑ ΙΖ -π Ο ¹

71 Ή νΛ| νΆ cf ₃ AA _n AA'°X Η Η Ή 8 ΙΖ Al ΙΖ I Ο ¹

72 ο 8 ΙΖ nNa ΙΖ -Π Ο 6 -π 224 «Γ α'ΧΛ % Ή ^Ν Y

73 o. t ON ZI 0 LL 225 Η CF ₃ NX ΛΑ Α Άν ν ν ο-^ η η V

74 T*Chiral 1 ^F nA nx । to JI Ill F^^NN N'^ HH 226 Η CF ₃ Ν^Χ AAA ΧΝ Ν Ν χ η η V

75 to nA νΆ «.AADA ³ Η Η Ή 227 'G. CF ₃ Ν^ Ν : L II Γρ Η Η

76 ar nA I AJX _n a _n AA Η Η 228 ?- CF ₃ Ν ^χ Ν rJ A A A X/ ^F AkN NN HH

- 85 044101

77 A \ /=1 N^N 1 ^Ν 'ν^νΛ^ν^ HH 229 pr ^OH X ^F LL Ν ^Λ Ν , \ JAAAA HH

78 «G CF ₃ nA A to A A/s m yzh η h | 230 and hr CF ₃ N^N AAA Άν ν ν'^HH

79 ar CF ₃ N^N a XX NN CF ₃ HH 231 gr CF ₃ N^N AAA / afN NN^a' HH

80 ar CF ₃ N^N a XX An NN Xv η η V 232 Ou- ZX Zhn Sh ^zx On

81 ar CF ₃ N% AAA / Ά Ν N - HH 233 X CF ₃ N^N r\ AAAX / N

82 DD P ^gFi A i ³ •^NNN ^- ^ HH

83 DD X™ ^? >α Г An N N'T' HH 235 rA° ^H T ^F v CF ₃ N ^NA; A L AX? ^WN N NW ⁷

84 DD A, CF ₃ N% g-L WA HH 236 and 237 & ^OH A УХ AMA ^F HH

- 86 044101

85 A An A ^f Ά II j £t ^f HH A ^H A aa ^f Aa> HH

238 A ^0H 1 ^F ΑνΆγΆ HH

87 DD A CF ₃ A QF ₃ Άν^ν^νΆ 239 A CF ₃ N^n HH

89 s. t °LS/A ZI 4 o 240 ar CF ₃ N^N AfAAn^ ^f HH

90 A iWA HH 241 ar Al n^n ^F \AAA /x 'Ν Ν N CF ₃ HH

91 DD A to Λ D. ^f A\a _n a _n A ^p HH 242 A QF ₃ N^N CF ₃ Ά/ν^ν^νΆ HH

92 DDA° ^h A\ ^N ^ ^N 1 ^fJ A^/A HH 243 A CF ₃ N^N AAA Λν nn^\ h Ay ^F F

- 87 044101

93 a; CF ₃ nA L L A An Ν NH ₂ Η 244 A A A A 1 An ^a nAA Η Η

94 Sc CF ₃ nA I HH A CF ₃ N% । 246 and with θΉ Г Αν ν νΆ

95 and 96 H H η H

97 and fG? ^F3 1 A 1 HH c QF ₃ N^N CF ₃ Αν ^Λ νΑΑ HH 247 ά: CF ₃ Ν^Ν CF ₃ AAAA An n nA HH

98 c QF ₃ lA CF ₃ AnAAA c CF ₃ N^N CF ₃ Αν^ν^νΙκΕ-

HH 249 and H H

Cl A. /OH 6c 250 'X ' ^OH A

99 Λ QF ₃ N^N CF ₃ AnAAA HH Λ ^ ^F3 AA a ³ An ν νΆ HH

- 88 044101

100 and 101 «G1 1 n n 251 and 252 Λ CF ₃ A d An A ⁿ ^n^ HH gХ ^he a _F CF ₃ N^N 1 An A X Αν ν ν'^ Η Η A Άν^ν^ν· ^^ Η Η

102 and 103 X 84 OH. ΖΙ Μ ΖΤ o..(g 253 and 254 A _F CF ₃ N^N r~J HH

^.Λ° ^Η α Δ λ ³ Αν ν νΧ X _F CF ₃ N^N /Ύ ALAH HH

104 and 105 X ⁿ Θζ V nA A Α ^α Ά 255 and 256 >3 yOY zz -PO / ¹ /\ Λ° ^Η Γ Ή AA F Λ F nA W Η Η Ao XZ w AkLL/ ¹ o J ¹

106 and 107 θτ Ία λ' Άν Ν Ν'ίΧ 257 and 258 CF ₃ N^N AnAA^ HH

SA ^? Ίλ λ' Αν ν nA Η Η to CF ₃ N^N Λ AA /^ / An nn - HH

108 and 109 ^> ^0Η X X Λ l ^F W ^F Η Η 259 _F CF ₃ N^N r^J L L L A/ ^F An NN' HH

- 89 044101 n n 260 A CF ₃ νΆ _l AAA^ n n

POi 111 CFj N А CFj 261 A Aa + A n n

G ^f HP? 262 and 263 ^O UoA ΙΖ -PO l ¹ -P

112i FROM DD & ^?Рз П Г XrIn Ν Νκ6 A _F CF ₃ N^N r~J y ³ ii l Γγ-f Η Η

DDA <η)'Ν'^Ν'^νΆ 264 and 265 0 Chapter Λ L ΑΓν ^α ν ^α ν^ Η Η

114 and 115 A HH + CF ₃ Ν^Ν _Λ γαγΆ Η Η

DD A CF ₃ N% Η Η 266 267 268 269 A ^?F3 1 A G XW'N N NW ⁴

Ibi 117 A ζζ -Π □ O A ¹ G _? ^F3 A CF ₃ <R?N Ν νΆ

- 90 044101

DD •l L- N N X a ³ An n nW ⁴

118 and 119 a; A ³ ΛΑ L n n F ? DX CF ₃ νΆ CF ₃ 4АА _й Ах\ ,όη Hf CF ₃ Ν^Ν ι χχχΧ HH 270 A cf ₃ An X/n^nAf,

120 and 121 X _F CF ₃ nA ι—/ A Λ A AA~ ^f An nn HH 271 X CF ₃ nA _n ΑΑν^ν^νΎ^Χ ^HH XX χ\ _Λ ΟΗ Г Ή у ¹ '' ¹ CF ₃ N^ N rJ A L A Ay ΆΓν ν n HH 272 and 273 X wA HH

122 σ CF ₃ N^N ι A Λ AX AA nn^ HH A , HH

123 A CF ₃ nA ι A L AX AAn ν n HH 274 ^F \Z ^F OH & 1 nH rX λχυχχ HH

124 Aa ^oh G (RsjT CF ₃ N^N । An^n^n^ HH 275 OU- zx / ^N A -VA χ ZI X o

- 91 044101

125 he /—URS) CF ₃ N^N ι HH 276 o I 9 U- ZT αΜ\ ^ζ =< ZI Q LL o

126 Av ^0H 1 fRsj CF ₃ N^N CF ₃ A. <A A. Gr; ν ν n р?Л 277 Sc CF ₃ N^N CF ₃ GrI'n'^n'^n'A HH

127 IZ >= ^ζ νΛΛ IZ О к “Π 278 A ^F 0 A™ L'A A L G^nnn ^x HH

128 & ^he CF ₃ nA _n Gr/n^n^n'^'^ HH 279 St _F ^0H ^? G1 % G ^N AND

129 Αγ ^0Η [ (RSj 9 ^F ₃ N^N d ATn^n^n^^ HH 280 TI O Ll z w ^ZI OI..^

130 AA^i [ fRSjl cf ₃ An g-l GrTn^n^n^^ HH 281 A ^0H CF ₃ N^N CF ₃ AT Ν N

131 Ar ^0H [ (W CF ₃ n^n AnAAnAC HH |oh 282 θ^ ^0Η CF ₃ N^N CF ₃ GrTn'^n^n'^G HH

132 <V ^0H ψ CF ₃ nA _N Gr? N ^N Ν HH 283 G CF ₃ ΝΆ CF ₃ J, A. <A x Gs; Ν Ν N fsG

- 92 044101

133 xy ^oh ί (wsl CF ₃ A D A /x / ΧΑ Ν Η Η 284 Ν<^Ν A A η ₂ ν ν νη ₂

134 <α ^0Η Γ fRSj CF ₃ Ν% A D D /x / ΧΑ ν η η 1 285 i o g ΙΖ NxHL/· iz -P O

135 <α ^0Η ί fRSjl CF ₃ nA А Д A ^χ Χο ν ν^· Η Η 286 оъ ΙΖ VzXpX iz -by ¹

₁₃₆ ^? _{_}

137 ^χ,ΟΗ ί (RsT CF ₃ Ν^Α Ο aaxv η η 1 288 оъ ΧΖ ΙΖ' -Π _{α t} O X

138 Λ CF ₃ Ν^Ν ί AAA Λ ΧΑ Ν Η Η 289 and A CF ₃ nAn A A A ХА N nh ₂

139 / CF ₃ Ν Α f-\ A A A D /° ΧΑ ν nAA 290 A CF ₃ N^N A A A ХА ν nh ₂

140 ^a'a d ³ ΧΑ ν nAA Η Η 291 and 292 A' ^?F 11 d ³ ХА ν νΑτ

- 93 044101

141 CF ₃ N'M CF ₃ ΑΓν'^ν^νΧ' Η Η 9“ CF ₃ Ν^Ν CF ₃ An^n^ntX

142 143 144 145 146 and 147 148 and 149 Η Γ cf ₃ nA _C f _{3 Α/ν νΧ Η Η [ΧΧοη CF 3} _nA CF ₃ ΑΓν'Ά^νΆ Η Η Αυ ^οη τ CF ₃ Ν^Ν ϊ Α/νΧνΧν ^Χ Η Η OH Adi CF ₃ νΆ _ν . ΑΓν^ΧαΧ Η Η Θ'™ CF ₃ Ν^Ν ϊ AT Ν hX Ν 'Χ Η Η >V ^H 6 CF ₃ νΑ _Ν . ΑΓν-Χ^ΧΧ Η Η I CF ₃ Ν^Ν CF ₃ A. A '(R) Ν Ν Ν A Η Η Τ>· ^ΟΗ τ CF ₃ nA CF ₃ ΑΓν ν'ν'Χ Η Η 293 294 295 296 297 298 299 300 Χ CF ₃ nA ΧΧΧά Η Η Ή Λ ^0Η 1 ^F CF ₃ Ν ^Ν ΑΓΝ^Ν^Ν-θΆ Η Η Ή Xl ^F CF ₃ Ν^Ν CF ₃ Άν'^'ν^'ν 'Χ & CF ₃ N^N CF ₃ A CF ₃ N^N A/n^n^n' ⁰ ^ HH nA nA As. JL AA, o. Ν NHH A CF ₃ N^N ΧρΧ _Ν Α _Ν ^F & nA n^n Al AA oh CF ₃ Ν Ν ΝΛ/ ^υπ ^H TcF ₃

150 and 151 VX ^f XX λ a XX ^F Ν Ν Ν Η Η 301 O U- ^-X u/vaA=< ZI 4 and ^F vX λ a XX ^f Ν Ν Ν Η Η or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition containing a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease caused by an isocitrate dehydrogenase (IDH) mutation in a subject, characterized in that said disease caused by an IDH mutation

- 94 044101 is a cancer that is selected from solid tumors, neurogliocytoma or hematological malignancy such as leukemia, lymphoma or myeloma.

20. Use according to claim 19, characterized in that said cancer is selected from leukemia, lymphoma or myeloma.

21. Use according to claim 19, characterized in that said 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, gastrointestinal cancer, melanoma, lung cancer or non-Hodgkin's lymphoma (NHL).

22. Use according to claim 21, wherein said cancer is intrahepatic cholangiocarcinoma (IHCC).

23. Compound of formula (IV)

and a racemic mixture thereof or enantiomers thereof, wherein R1 represents -OH or oxo, _R2 and m are defined in any one of claims 1 to 16;

n is 1 or 2;

Ra selected from halo, -OS(O) ₂ CF ₃ , -B(OH) ₂ , -B(OC ₁ . ₆ alkyl) ₂ ,

Rb represents H or C ₁ . ₆ alkyl.

24. The compound of formula (IV) according to claim 23, characterized in that said compound of formula (IV) has the structure of formula (IV-1), wherein m is 0, 1 or 2,

Ch?p G ^(R2 4 (IV-1)

25. The compound of formula (IV) according to claim 23, characterized in that it has the structure of formula (IV-2), wherein X is a halo;

m is equal to 0, 1 or 2, r ^p G ^(R2) -I ^{x R} a (IV-2)

26. The compound of formula (IV) according to claim 23, characterized in that it has the structure of formula (IV-3), wherein X is a halo;

p is 0, 1 or 2;

m is 0, 1 or 2,

27. The compound of formula (IV) according to claim 23, characterized in that the specified compound of formula (IV) that the specified compound of formula (IV) the specified compound of formula (IV) that

-