US20210363115A2 - Cycloolefin substituted heteroaromatic compounds and their use - Google Patents

Cycloolefin substituted heteroaromatic compounds and their use Download PDF

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US20210363115A2
US20210363115A2 US16/645,329 US201816645329A US2021363115A2 US 20210363115 A2 US20210363115 A2 US 20210363115A2 US 201816645329 A US201816645329 A US 201816645329A US 2021363115 A2 US2021363115 A2 US 2021363115A2
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alkyl
nmr
halo
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US11414390B2 (en
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Wei-guo Su
Guangxiu Dai
Kun Xiao
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Hutchmed Ltd
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Hutchison Medipharma Ltd
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    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07F5/025—Boronic and borinic acid compounds
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
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    • C07—ORGANIC CHEMISTRY
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to cycloolefin substituted heteroaromatic compounds and their use in the treatment of diseases induced by IDH mutations.
  • the survival way of tumor cells is different from that of normal cells, so does the energy intake and utilization.
  • the common metabolic pathway in aerobic organisms is tricarboxylic acid cycle, in which isocitrate dehydrogenase (IDH) catalyzing the conversion of isocitrate to ⁇ -ketoglutaric acid ( ⁇ -KG) is a rate-limiting step.
  • IDH isocitrate dehydrogenase
  • the known IDH family comprises three isozymes, IDH1, IDH2 and IDH3, which are located in different organelles and perform the same biological functions, i.e., catalyzing the formation of ⁇ -KG.
  • IDH1/2 mutations were present in a certain proportion of a variety of tumors, such as glioma (60-80%), chondrosarcoma (55%), acute myeloid leukemia (15-25%), etc.
  • the mutant IDH1 or IDH2 loses the capability of catalyzing the conversion of isocitrate to ⁇ -KG, whereas has the ability of catalyzing the reaction of ⁇ -KG to ⁇ -hydroxyglutaric acid (2-HG).
  • 2-HG can competitively inhibit the activity of many ⁇ -KG dependent enzymes (for example: histone demethylase and methylcytosine hydroxylase of the TET family, and the like) when it accumulates to a certain extent, and thus effects the demethylation of histones and DNA, interferes with normal cell differentiation, and results in the proliferation of immature cells.
  • ⁇ -KG dependent enzymes for example: histone demethylase and methylcytosine hydroxylase of the TET family, and the like
  • AML Acute myeloid leukemia
  • New IDH mutant inhibitors are needed to be developed to meet the need for treatment of patients with hematological tumors, especially acute myeloid leukemia, gliomas and other IDH mutation associated tumors.
  • the present invention addresses these needs.
  • the present invention provides a compound of formula (I):
  • R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 6 , R 7 , R 8 , m, and n are as defined in the detailed description of the invention.
  • compositions comprising at least one compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
  • pharmaceutically acceptable excipient e.g., a pharmaceutically acceptable carrier
  • Also provided is a method of treating a disease induced by IDH mutation comprising administering to the subject in need thereof an effective amount of at least one compound of formula (I) (e.g., any of the compounds described herein) and/or at least one pharmaceutically acceptable salt thereof.
  • at least one compound of formula (I) e.g., any of the compounds described herein
  • at least one pharmaceutically acceptable salt thereof e.g., any of the compounds described herein
  • At least one compound of formula (I) e.g., any of the compounds described herein
  • at least one pharmaceutically acceptable salt thereof for treating a disease induced by IDH mutation.
  • at least one compound of formula (I) e.g., any of the compounds described herein
  • at least one pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease induced by IDH mutation.
  • FIG. 1 shows the general synthetic route I for preparation of the compounds described herein.
  • FIG. 2 shows the general synthetic route II for preparation of the compounds described herein.
  • FIG. 3 shows the general synthetic route III for preparation of the compounds described herein.
  • FIG. 4 shows the general synthetic route IV for preparation of the compounds described herein.
  • FIG. 5 shows the general synthetic route V for preparation of the compounds described herein.
  • FIG. 6 shows the general synthetic route VI for preparation of the compounds described herein.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • —OR 4 is attached through the oxygen.
  • the point of attachment of a group is apparent to those skilled in the art, e.g., a halo substituent, the “-” sign may be omitted.
  • alkyl 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.
  • C 1-6 alkyl refers to an alkyl containing 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), i-propyl (“i-Pr”), n-butyl (“n-Bu”), i-butyl (“i-Bu”), s-butyl (“s-Bu”) and t-butyl (“t-Bu”).
  • alkenyl refers to a straight or branched hydrocarbon radical containing one or more, for example 1, 2, or 3 carbon-carbon double bonds (C ⁇ C) and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms.
  • C 2-6 alkenyl refers to an alkenyl containing 2-6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment for the alkenyl can be on or not on the double bonds.
  • alkynyl refers to a straight or branched hydrocarbon radical containing one or more, for example 1, 2, or 3, carbon-carbon triple bonds (C ⁇ C) and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms.
  • C 2-6 alkynyl refers to an alkynyl containing 2-6 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment for the alkynyl can be on or not on the triple bonds.
  • halogen or “halo” as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.
  • haloalkyl 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 with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other.
  • the term “haloalkyl” as used herein refers to an alkyl radical, as defined herein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are identical to each other.
  • haloalkyl 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 with halogen atoms, wherein the halogen atoms are different from each other.
  • haloalkyl groups include, but are not limited to, —CF 3 , —CHF 2 , —CH 2 CF 3 , and the like.
  • alkoxy refers to the group —O-alkyl, wherein the alkyl is as defined above.
  • alkoxy groups include, but are not limited to, C 1-6 alkoxy, such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, and hexyloxy, including their isomers.
  • cycloalkyl refers to saturated or partially unsaturated cyclic hydrocarbon radical having 3 to 12 ring carbon atoms, such as 3 to 8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms or 3 to 6 ring carbon atoms, which may have one or more rings, such as 1, 2, or 3 rings, preferably 1 or 2 rings.
  • C 3-12 cycloalkyl refers to a cycloalkyl containing 3-12 carbon atoms in the ring.
  • Cycloalkyl also includes a fused or bridged ring, or a spirocyclic ring.
  • the rings of the cycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated), but not fully conjugated, and not an aryl as defined herein.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and bicyclo[3.1.1]hepta-2-ene.
  • heterocycle refers to monocyclic, bicyclic or tricyclic saturated or partially unsaturated cyclic radicals having 3-12 ring atoms, such as 3-8 ring atoms, 5-7 ring atoms, 4-7 ring atoms or 3-6 ring atoms, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms independently chosen from N, O and S in the rings, with the remaining ring atoms being carbon.
  • the heterocycle group also includes those wherein the N or S heteroatom are optionally oxidized to various oxidation states.
  • the point of attachment of heterocyclyl can be on the N heteroatom or carbon.
  • “3-8 membered heterocycly” refers to a heterocyclyl containing 3-8 ring atoms and containing at least one heteroatom independently chosen from N, O and S.
  • the heterocycle group also includes a fused or bridged ring, or a spirocyclic ring, wherein, at least one ring contains at least one heteroatom chosen from O, S, and N and none of the other rings is aryl or heteroaryl as defined herein.
  • the rings of the heterocycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated), but not fully conjugated, and not a heteroaryl as defined herein.
  • heterocycly groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolaneyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.
  • aryl refers to carbocyclic hydrocarbon radical of 6 to 14 carbon atoms consisting of one ring or more fused rings, wherein at least one ring is an aromatic ring.
  • aryl groups include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.
  • heteroaryl refers to:
  • the heteroaryl group also includes those wherein the N heteroatom occurs as N-oxide, such as pyridyl N-oxides.
  • heteroaryl group examples include, but are not limited to, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (such as imidazo[1,2-a]pyridyl), pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridinyl (such as pyrazolo[1,5-a]pyri
  • Haldroxyl refers to the —OH radical.
  • Oxo refers to the ⁇ O radical.
  • a structure herein contains an asterisk “*”, it means that the chiral center of the compound marked by “*” is in either R-configuration or S-configuration, and the content of the compound with single configuration marked by “*” is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between those enumerated values).
  • the configuration of the compounds can be determined using a variety of analytical techniques, for example single crystal X-ray crystallography and/or optical polarimetry according to routine protocols by those of ordinary skill in the art.
  • optionally substituted alkyl encompasses both “unsubstituted alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, chemically incorrect, synthetically non-feasible and/or inherently unstable.
  • substituted or “substituted with . . . ”, as used herein, means that one or more hydrogens on the designated atom or group are replaced with one or more selections from the indicated group of substituents, provided that the designated atom's normal valence is not exceeded.
  • a substituent is oxo (i.e., ⁇ O)
  • 2 hydrogens on a single atom are replaced by the oxo.
  • Combinations of substituents and/or variables are permissible only if such combinations result in a chemically correct and stable compound.
  • a chemically correct and stable compound is meant to imply a compound that is sufficiently robust to survive sufficient isolation from a reaction mixture to be able to identify the chemical structure of the compound, and also sufficiently robust to allow subsequent formulation as an agent having at least one practical utility.
  • substituents are named into the core structure.
  • (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted with one or more substitutents means that one or more hydrogens on the designated atom or group are independently replaced with one or more selections from the indicated group of substituents.
  • substituted with one or more substitutents means that the designated atom or group is substituted with 1, 2, 3, or 4 substitutents independently chosen from the indicated group of substituents.
  • POSITA POSITA
  • some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms.
  • the racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention.
  • the present invention includes all the individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where appropriate, the individual tautomeric forms thereof.
  • the present invention provides compounds of various stereoisomeric purities, i.e., diastereomeric or enantiomeric purity expressed as various “ee” or “de” Values.
  • the compound of formula (I) e.g., as described herein
  • has an enantiomeric purity of at least 60% ee e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between those enumerated values).
  • the compound of formula (I) (e.g., as described herein) has an enantiomeric purity of greater than 99.9% ee, extending up to 100% ee. In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between those enumerated values). In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of greater than 99.9% de.
  • 60% de e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99
  • enantiomeric excess designates how much of one enantiomer is present compared to the other.
  • percent enantiomeric excess is defined as
  • *100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S 1.
  • the percent enantiomeric excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the mixture of enantiomers and [a]max is the optical rotation of the pure enantiomer.
  • diastereomeric excess designates how much of one diastereomer is present compared to the other and is defined by analogy to enantiomeric excess.
  • *100 the percent diastereomeric excess is defined as
  • *100, where D1 and D2 are the respective mole or weight fractions of diastereomers in a mixture such that D1+D2 1.
  • diastereomeric and/or enantiomeric excess can be accomplished using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography and/or optical polarimetry according to routine protocols familiar to those skilled in the art.
  • racemates can be used as such or can be resolved into their individual isomers.
  • the resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers.
  • Methods for separation of isomers are well known (cf. Allinger N. L. and Eliel E. L. 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.
  • individual isomers can be separated chemically from a 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, fractionally crystallizing the salts, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight of the desired stereoisomer.
  • a chiral acid such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diace
  • racemates can be covalently linked to a chiral compound (auxiliary) to produce diastereomers which can be separated by chromatography or by fractional crystallization after which time the chiral auxiliary is chemically removed to afford the pure enantiomers, as is known to the POSITA.
  • auxiliary chiral compound
  • tautomer refers to constitutional isomers of compounds generated by rapid movement of an atom in two positions in a molecule. Tautomers readily interconvert into each other, e.g., enol form and ketone form are tipical tautomers.
  • some compounds disclosed herein can exist in the forms of a, b, c, d, e, f, etc., as shown in the figure below, i.e., compounds in the forms of a, b, c, d, e, f are possible the tautomers of the compound of Formula (I).
  • the signle tautomer and the mixture of these tautomers in any ratio are all included in the compounds described herein.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound of Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound of Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject.
  • the free base can be obtained by basifying a solution of the acid addition salt.
  • an acid addition salt particularly a pharmaceutically acceptable acid addition salt, may be produced 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 base compounds.
  • the POSITA will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts.
  • solvates means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrates, for example, hemihydrates, monohydrate, and dihydrate, as well as variable hydrates.
  • group As used herein, the terms “group”, “radical” and “moiety” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to other fragments of molecules.
  • an “active ingredient” is used to indicate a chemical substance which has biological activity.
  • an “active ingredient” is a chemical substance having pharmaceutical utility.
  • practical pharmaceutical activity can be established by appropriate pre-clinical assays, whether in vitro or in vivo. Pharmaceutical activity sufficient to be accepted by a regulatory agency, such as FDA in the U.S., is a higher standard than the pre-clinical assay. Such a higher standard of pharmaceutical activity, the success of which cannot generally be reasonably expected from the pre-clinical results, can be established by appropriate and successful randomized, double blind, controlled clinical trials in humans.
  • treating refers to administering one or more pharmaceutical substances, especially a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein to a subject that has the disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition toward the disease or disorder.
  • the disease or disorder is cancer.
  • treating in the context of a chemical reaction, mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately lead to the formation of the indicated and/or the desired product.
  • effective amount refers to an amount or dose of an IDH mutation inhibiting agent sufficient to generally bring about a therapeutic benefit in patients in need of treatment for a disease or disorder induced by IDH mutation.
  • Effective amounts or doses of the active ingredient of the present disclosure may be ascertained by methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the attending physician. In the United States, the determination of effective doses is generally difficult to predict from preclinical trials. In fact, the dose is completely unpredictable and the dose will develop a new unpredictable dosing regimen after initial use in a randomized, double-blind, controlled clinical trials.
  • An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's 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 about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID).
  • a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • subject means mammals and non-mammals.
  • Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.
  • non-mammals include, but are not limited to, birds, and the like.
  • the term “subject” does not denote a particular age or sex. In some embodiments, the subject is a human.
  • R 7 is chosen from H, halo, —CN, —OH, or —NH 2 ;
  • R 8 is chosen from halo, —CN, —OH, or —NH 2 ;
  • q is 1 or 2;
  • R 1 is chosen from H, —OH, halo, C1-6 alkyl, C1-6 alkoxyl, —NH 2 , —NH(C1-4 alkyl), —N(C1-4 alkyl) 2 , oxo, or C3-8 cycloalkyl; each of R 2 is independently chosen from H, deuterium, halo, —OH, —NH 2 , —CN, —SH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, oxo, —OR 5 , —OCOR 5 , —NHR 5 , —N(R 5 )(C 1-4 al
  • R 1 is chosen from H, —OH or halo.
  • R 1 is chosen from —OH or halo.
  • R 1 is —OH.
  • R 1 is halo chosen from F, Cl, or Br. In some embodiments of the compound of formula (I), R 1 is F.
  • the two R 2 which attach to the same carbon atom, together with the carbon atom they are attached to form a 3-5 membered cycloalkyl optionally substituted by one or more F.
  • the two R 2 which attach to the same carbon atom, together with the carbon atom they are attached to form a cyclopropyl.
  • each of R 2 is independently chosen from H, deuterium, halo, —OH, —NH 2 , —CN, —SH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, oxo, —OR 5 , —OCOR 5 , —NHR 5 , —N(R 5 )(C 1-4 alkyl), —NHCOR 5 , or 3-8 membered heterocyclyl.
  • each of R 2 is independently chosen from H, deuterium, halo, —OH, —NH 2 , —CN, C 1-6 alkyl, C 1-6 haloalkyl, oxo, —OR 5 , —NHR 5 , or —N(R 5 )(C 1-4 alkyl).
  • each of R 2 is independently chosen from H, deuterium, halo, C 1-6 alkyl, or C 1-6 haloalkyl.
  • each of R 2 is independently chosen from halo, such as F, C 1 , or Br.
  • R 2 is F.
  • m is 0, 1, 2, 3, or 4.
  • m is 0, 1, or 2.
  • m is 1. In some embodiments of the compound of formula (I), m is 2. In some embodiments of the compound of formula (I), m is 3.
  • m is 4.
  • R 3 and R 4 are independently chosen from C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R 5 , —OR 5 , or —NHR 5 , in which each of said C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R 6 ; R 3 ′ and R 4 ′ are independently chosen from H or C 1-6 alkyl.
  • R 3 ′ and R 4 ′ are both H.
  • R 3 and R 4 are independently chosen from C 1-6 alkyl, C 3-12 cycloalkyl, or 3-12 membered heterocyclyl, each of which is optionally substituted with one or more R 6 ; R 3 ′ and R 4 ′ are both H.
  • R 3 and R 4 are independently chosen from C 1-6 alkyl substituted with one ore more halo, 5-12 membered heteroaryl substituted with C 1-6 haloalkyl, or —OR 5 ; R 3 ′ and R 4 ′ are both H.
  • R 3 and R 4 are independently chosen from C 1-6 alkyl optionally substituted with one or more halo; R 3 ′ and R 4 ′ are both H.
  • R 3 is 5-12 membered heteroaryl substituted with C 1-6 haloalkyl
  • R 4 is C 1-6 alkoxyl
  • R 3 ′ and R 4 ′ are both H.
  • R 3 is 5-7 heteroaryl substituted with CF 3 , R 4 is C 1-6 alkoxyl; R 3 ′ and R 4 ′ are both H.
  • R 3 is chosen from H, C 1-6 alkyl optionally substituted by C 1-6 haloalkyl, or 5-12 membered heteroaryl optionally substituted by C 1-6 haloalkyl;
  • R 3 ′ is H;
  • R 5 is C 1-6 alkyl or C 3-8 cycloalkyl.
  • R 5 is C 1-6 alkyl optionally substituted with one or more halo.
  • each of R 6 is independently chosen from deuterium, halo, —CN, —OH, —NH 2 , C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which each of said C 1-6 alkoxyl, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with one or more halo.
  • each of R 6 is independently chosen from deuterium, halo, —OH, C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.
  • each of R 6 is independently chosen from deuterium, halo, —CN, —OH, —NH 2 , C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl.
  • each of R 6 is independently chosen from deuterium, halo, or C 1-6 haloalkyl.
  • n 1
  • R 7 and R 8 are independently chosen from halo or —CN.
  • R 7 and R 8 are independently chosen from F or —CN.
  • the compound of formula (I) is chosen from
  • R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I).
  • formula (I) is formula (I-1), wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I),
  • formula (I) is formula (I-1a), wherein R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I),
  • formula (I) is formula (I-1b), wherein R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I),
  • formula (I) is formula (II), wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, n and A are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • X is F
  • R 1 is F.
  • R 1 is —OH.
  • p 0.
  • p is 1.
  • p is 2.
  • formula (II) is chosen from
  • R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I);
  • X is halo;
  • p is 0, 1, or 2;
  • m is 0, 1, or 2.
  • formula (II) is formula (II-1), wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • formula (II) is formula (II-1a), wherein R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • formula (II) is formula (II-1b), wherein R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • X is F.
  • R 1 is F.
  • R 1 is —OH.
  • p is 1.
  • p is 2.
  • formula (I) is formula (III), wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, n and A are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; v is 0, 1, or 2,
  • X is F
  • R 1 is F.
  • R 1 is —OH.
  • p 0.
  • p is 1.
  • p is 2.
  • v is 0.
  • v is 1.
  • v is 2.
  • formula (III) is chosen from
  • R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I);
  • X is halo;
  • p is 0, 1, or 2;
  • m is 0, 1, or 2;
  • v is 0, 1, or 2.
  • formula (III) is formula (III-1), wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; v is 0, 1, or 2,
  • X is F.
  • R 1 is F.
  • R 1 is —OH.
  • p is 1.
  • p is 2.
  • v 0.
  • v is 1.
  • v is 2.
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
  • a method of treating a disease induced by 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 to inhibit the increase of ⁇ -hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof effective to inhibit the increase of ⁇ -hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.
  • a method of treating a disease induced by IDH mutation in a subject comprising administering to the subject in need thereof an amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) effective to inhibit the increase of ⁇ -hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) effective to inhibit the increase of ⁇ -hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof described herein for treating a disease induced by IDH mutation by inhibiting the increase of ⁇ -hydroxyglutaric acid (2HG) induced by IDH mutation in a subject.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof described herein in the manufacture of a medicament for treating a disease induced by IDH mutation.
  • the IDH mutation is IDH1 gene mutation.
  • the IDH mutation is IDH2 gene mutation.
  • the IDH mutation is IDH1-R132H or IDH2-R140Q gene mutation.
  • the disease induced by IDH mutation is cancer.
  • the cancer is chosen from solid cancer, neurogliocytoma, or hematological malignant tumor, such as leukemia, lymphoma, or myeloma.
  • the cancer is chosen from acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliterative neoplasms (MPN), cholangiocarcinoma, such as intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lung cancer, or non-Hodgkin's lymphoma (NHL).
  • AML acute myeloid leukemia
  • APL acute promyelocytic leukemia
  • GBM glioblastoma
  • MDS myelodysplastic syndrome
  • MPN myeloproliterative neoplasms
  • cholangiocarcinoma such as intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lung cancer
  • a compound of formula (IV) and/or a salt thereof, and/or racemic mixtures or enantiomers thereof which can be used in the manufacture of compounds of formula (I) (e.g., any of the compounds described herein),
  • R 1 , R 2 , m and n are as defined in the compound of formula (I);
  • R a is hosen from halo, —OS(O) 2 CF 3 , —B(OH) 2 , —B(OC 1-6 alkyl) 2 ,
  • R b is H or C 1-6 alkyl.
  • R a is chosen from —B(OH) 2 , —B(OC 1-6 alkyl) 2 ,
  • R b is H or C 1-6 alkyl.
  • R a is chosen from —B(OH) 2 , —B(OCH 3 ) 2 , —B[OCH(CH 3 ) 2 ] 2 ,
  • formula (IV) is formula (IV-1), wherein m is 0, 1, or 2;
  • formula (IV) is formula (IV-2), wherein X is halo; m is 0, 1, or 2;
  • formula (IV) is formula (IV-3), wherein X is halo; p is 0, 1, or 2; m is 0, 1, or 2;
  • R 1 is —OH or oxo.
  • X is F
  • p 0.
  • p is 1.
  • p is 2.
  • the compound of formula (IV) is chosen from
  • the compound of formula (IV) is chosen from
  • substitution reaction of 2,4,6-trichloro-1,3,5-triazine with an amine substituted with R 3 and R 3 ′ provides compound of formula 1-1.
  • substitution reaction of the compound of formula 1-1 with an amine substituted with R 4 and R 4 ′ provides compound of formula 1-2.
  • Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented by formula (IV) under the catalysis of a suitable palladium reagent gives a compound of formula (I-1) as described herein, wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, Ra, m, and n are as defined herein.
  • the Pd-catalyzed C—C coupling 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, and the catalyst used can be selected from Pd(dppf)Cl 2 .CH 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 and the like.
  • 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 can be selected from Pd(dppf)Cl 2 .CH 2 Cl 2 , P
  • Suzuki coupling reaction of compound of formula 1-1 with an intermediate represented by formula (IV) under the catalysis of a suitable palladium reagent affords compound of formula 2-1.
  • Substitution reaction of compound of formula 2-1 with an amine substituted with R 4 and R 4 ′ gives a compound of formula (I-1) as described herein, wherein R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, Ra, m, and n are as defined herein.
  • Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented by formula (IV-1) under the catalysis of a suitable palladium reagent provides compound of formula 3-1.
  • the Pd-catalyzed C—C coupling 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, and the catalyst used can be selected from Pd(dppf)Cl 2 .CH 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc) 2 and the like.
  • Reduction of compound of formula 3-1 provides compound of formula (I-1a) as described herein.
  • Suzuki coupling reaction of compound of formula 1-1 with an intermediate represented by formula (IV-1) under the catalysis of a suitable palladium reagent affords compound of formula 4-1.
  • Reduction of Compound of formula 4-1 provides compound of formula 4-2.
  • Substitution reaction of compound of formula 4-2 with an amine substituted with R 4 and R 4 ′ gives a compound of formula (I-1a) as described herein.
  • Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented by formula (IV-2) under the catalysis of a suitable palladium reagent provides compound of formula 5-1.
  • Halogenation of compound of formula 5-1 using a halogenating reagent such as NFSI and the like, in presence of a base such as LiHMDS, KHMDS, LDA and the like, and in suitable polar solvents such as THF, DCM and the like results in compound of formula 5-2.
  • Reduction of compound of formula 5-2 provides compound of formula (II-1a) as described herein.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.
  • a pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
  • a pharmaceutically acceptable carrier refers to a carrier that is compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein), can be utilized as pharmaceutical excipients for delivery of the active ingredients.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the art.
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • a pharmaceutical composition described herein can be prepared in the form of tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation, or suppository.
  • 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.
  • An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions.
  • Commonly used carriers for tablets include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added to tablets.
  • useful diluents include lactose and dried corn starch.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be present 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 a tablet. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be present 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 a capsule.
  • a sterile injectable composition e.g., aqueous or oleaginous suspension
  • a sterile injectable composition 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 can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • the sterile injectable Intermediate can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the Intermediate of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a topical composition can be formulated in form of oil, cream, lotion, ointment, and the like.
  • suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12).
  • the pharmaceutically acceptable carrier is one in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in those topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.
  • Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • An example of such a cream is one which includes, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
  • An example of such an ointment is one which includes about 30% by weight almond oil and about 70% by weight white soft paraffin.
  • Suitable in vitro assays can be used to evaluate the practical utility of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein, in inhibiting the IDH mutation.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can further be examined for additional practical utility in treating cancer by in vivo assays.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects can be accessed. If the pre-clinical results are successful, the dosage range and administration route for animals, such as humans, can be projected.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be shown to have sufficient pre-clinical practical utility to merit clinical trials hoped to demonstrate a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
  • cancer refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
  • cancer includes, but is not limited to, solid tumors and hematologic malignancies.
  • cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
  • cancer further encompasses primary and metastatic cancers.
  • Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including e.g., malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult
  • Non-limiting 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); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.
  • AML acute myeloid leukemia
  • CML chronic
  • exemplary 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); and lymphoma, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MM multiple myeloma
  • lymphoma such as Hodgkin's lymphoma, non-Hodgkin's lymphoma
  • the 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 subjects with cancer.
  • the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein may be used in combination with additional active ingredients in the treatment of cancer.
  • the additional active ingredients may be coadministered separately with the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein or included with such an ingredient in a pharmaceutical composition according to the disclosure, such as a fixed-dose combination drug product.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of diseases induced by IDH mutation, such as another mutant IDH inhibitor or a compound active against another target associated with the particular disease.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein), decrease one or more side effects, or decrease the required dose of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein.
  • the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein is administered in conjunction with an anti-neoplastic agent.
  • an anti-neoplastic agent refers to any agent that is administered to a subject with cancer for purposes of treating the cancer.
  • Nonlimiting examples anti-neoplastic agents include: radiotherapy; immunotherapy; DNA damaging chemotherapeutic agents; and chemotherapeutic agents that disrupt cell replication.
  • Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (e.g.
  • Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-kappa B inhibitors, including inhibitors of I kappa B kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.
  • the empty balance(s) is(are) the hydrogen atom(s) which is(are) omitted for convenience purpose.
  • I-2 10 390.1 1 H NMR (400 MHz, CD 3 OD): ⁇ 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), 1.39-1.31 (m, 3H).
  • I-12 11 418.1 1 H NMR (400 MHz, CD 3 OD): ⁇ 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), 1.43-1.31 (m, 6H).
  • I-60 49 356.1 1 H NMR (400 MHz, CD 3 OD): ⁇ 4.39-4.18 (m, 2H), 2.99-2.86 (m, 2H), 2.80-2.46 (m, 4H), 2.39-2.23 (m, 1H), 1.89-1.82 (m, 2H), 1.81-1.62 (m, 2H), 0.79-0.67 (m, 2H), 0.55-0.48 (m, 2H).
  • I-40 54 420.1 1 H NMR (400 MHz, CD 3 OD): ⁇ 8.60-8.22 (m, 2H), 8.09-7.74 (m, 1H), 4.38-4.27 (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).
  • I-41 55 365.1 1 H NMR (400 MHz, CD 3 OD): ⁇ 4.36-4.15 (m, 2H), 3.02-2.81 (m, 2H), 2.73-2.41 (m, 3H), 2.40-2.19 (m, 1H), 1.89-1.71 (m, 3H), 1.70-1.59 (m, 1H).
  • I-62 69 418.1 1 H NMR (400 MHz, CD 3 OD): ⁇ 5.00-4.87 (m, 2H), 4.36-4.22 (m, 1H), 2.65-2.51 (m, 1H), 2.43-2.29 (m, 1H), 1.89-1.60 (m, 4H), 1.38-1.29 (m, 6H).
  • Compounds 266 and 267 were prepared according to the procedure of Compound 1, using Compound 246 and NaBD 4 , purified by flash column chromatography (eluting with PE/EA).
  • Compounds 268 and 269 were prepared according to the procedure of Compound 1, using Compound 247 and NaBD 4 , purified by flash column chromatography (eluting with PE/EA).
  • Compound 280 was prepared according to the procedure of Compound 274, using Compound B19 and corresponding reagents. MS (m/z): 358.1 [M+H] + ;
  • U87MGR140Q cells U87MG cells were purchased from ATCC cell bank and then transfected with plasmid containing IDH2-R140Q mutation, and monoclonal cells stably expressing the R140Q mutation were isolated for experiments. The cells were cultured in MEM medium containing 10% FBS.
  • 96-well plate c Greiner, Catalog No. 675076.
  • Enzyme reaction solution 1 mM nicotinamide adenine dinucleotide (NAD), 0.6 ng/ ⁇ L D-2-hydroxyglutarate dehydrogenase (D2HGDH), 0.8 U/mL lipoamidase dehydrogenase (Diaphorase) and 60 ⁇ M Resazurin in 40 mM Tris.HCl pH 8.8 assay buffer.
  • NAD nicotinamide adenine dinucleotide
  • D2HGDH D-2-hydroxyglutarate dehydrogenase
  • Diaphorase 0.8 U/mL lipoamidase dehydrogenase
  • Standard curve stock solution The standard of 2-HG sodium salt was serially diluted in serum-free MEM medium to make a standard curve stock solution.
  • the final gradient concentrations are: 500 ⁇ M, 167 ⁇ M, 56 ⁇ M, 18.5 ⁇ M, 6 ⁇ M, 2 ⁇ M, 0.7 ⁇ M, 0.2 ⁇ M.
  • test compound solution diluted in serum-free MEM (final concentration of test compound: 10 ⁇ M, 3.3 ⁇ M, 1.1 ⁇ M, 0.37 ⁇ M, 0.12 ⁇ M, 0.041 ⁇ M, 0.014 ⁇ M and 0.005 ⁇ M, final DMSO concentration is 0.5%) or 10 ⁇ L of control solution (serum-free MEM medium containing 0.5% DMSO in final concentration) was added and incubated for 72 hours.
  • the plate c was measured on Tecan Infinite F500 Reader instrument at 544 nm excitation and 590 nm emission. A standard curve of the fluorescence value vs. the corresponding 2-HG concentration was made, and the 2-HG concentration corresponding to each concentration point of the compound was calculated, then the inhibition ratio was calculated, and the data was analyzed using XLfit5 (ID Business Solutions Limited) software to obtain the IC 50 value.
  • the inhibition ratio was calculated as follows:
  • Inhibition Ratio (IH %) (1 ⁇ 2-HG concentration of test compound treated cells/2-HG concentration of control cells) ⁇ 100%.
  • the 2-HG inhibitory activity of the compounds of the invention in U87MGR132H cells transfected with the IDH1-R132H mutant plasmid was determined according to the method of Example 3.
  • Male CD1 mouse liver microsomes was supplied by Research Institute for Liver Diseases (Shanghai) Co., Ltd.
  • Male SD rat liver microsomes was supplied by BioreclamationIVT in US.
  • Phenacetin, glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PD), and nicotinamide adenine dinucleotide phosphate (NADP) were supplied by Sigma-Aldrich (Missouri, USA).
  • test compound 10 mM stock solution of test compound: Certain amount of test compound was weighed and dissolved in certain volume of dimethylsulfoxide (DMSO) to get the stock solution of test compound at 10 mM.
  • DMSO dimethylsulfoxide
  • Reaction termination solution Certain amount of phenacetin as internal standard was weighed and dissolved in acetonitrile to get the reaction termination solution at 1000 ng/mL, and stored at room temperature for use.
  • the stock solution of test compound was diluted to the designated concentration with organic solution (usually the mixtures of acetonitrile, methanol and water with different portions depending on the compound solution) to make the final concentration to be 1 ⁇ M and the contents of organic solvents no more than 1% (For DMSO, the controlled margin was 0.1%) in the final incubation system.
  • organic solution usually the mixtures of acetonitrile, methanol and water with different portions depending on the compound solution
  • the controlled margin 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 provide the NADPH regenerating system containing 1 mM NADP, 5 mM G-6-P and 1 U/mL G-6-PD, which was pre-incubated at 37° C.
  • liver microsomes was mixed with 200 mM PBS and diluted with ultrapure water to make the concentrations of liver microsomes and PBS to be 0.5 mg/mL and 50 mM in the final incubation system, respectively.
  • the diluted liver microsomes was mixed with the NADPH regenerating solution, certain volumes of 100 mM EDTA and 300 mM MgCl 2 (concentration of EDTA and MgCl 2 in the final incubation system is 1 mM and 3 mM, respectively) were added, and the incubation system was put into 37° C. water bath.
  • the incubation was commenced by adding the stock solution of test compound and maintained for 30 min.
  • the incubation was terminated by adding the reaction termination solution.
  • the 0 min sample was prepared by adding the reaction termination solution to the incubation system immediately prior to putting the system into the water bath with the addition of the stock solution of test compound.
  • the terminated incubation mixtures were vortexed and centrifuged at 4400 rpm for 10 min, and the supernatant was collected for LC-MS/MS analysis.
  • the concentration of test compound was determined using LC-MS/MS method. Using the peak area ratio of the compound and the internal standard as an index, the percentage of remaining compound after incubation for 30 minutes as compared with the 0 minute sample was calculated, and the metabolic stability of the compound was evaluated.
  • the compounds of the invention showed good metabolic stability.
  • the metabolic stability of some exemplary compounds of the invention is as follows:
  • Sample standard solution About 3-5 mg test compound was accurately weighed and added into a 5 mL sample tube, 5 mL DMSO was added. Shaking and sonicating for 1 hour.
  • pH 2.1 sample solution About 1 mg test compound was accurately weighed and added into a 1 mL sample tube, 1 mL pH 2.1 sodium phosphate buffer was added. Shaking. Adding test compound to the solution, if the solution is visually clear, till there is obvious insoluble in the solution. Sonicating for 1 hour.
  • pH 7.4 sample solution About 1 mg test compound was accurately weighed and added into a 1 mL sample tube, 1 mL pH 7.4 sodium phosphate buffer was added. Shaking. Adding test compound to the solution, if the solution is visually clear, till there is obvious insoluble in the solution. Sonicating for 1 hour.
  • 0.5 mL pH 2.1 sample solution was filtered by syringe filter and was accurately pipetted into a HPLC tube, and 0.5 mL pH 2.1 sodium phosphate buffer was accurately added. Shaking. The peak area was determined by HPLC.
  • 0.5 mL pH 7.4 sample solution was filtered by syringe filter and was accurately pipetted into a HPLC tube, and 0.5 mL pH 7.4 sodium phosphate buffer was accurately added. Shaking. The peak area was determined by HPLC.
  • solubilities of some exemplary compounds of the invention are as follows:

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Abstract

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

Description

    FIELD OF THE INVENTION
  • The present invention relates to cycloolefin substituted heteroaromatic compounds and their use in the treatment of diseases induced by IDH mutations.
    • BACKGROUND OF THE INVENTION
  • The survival way of tumor cells is different from that of normal cells, so does the energy intake and utilization. The common metabolic pathway in aerobic organisms is tricarboxylic acid cycle, in which isocitrate dehydrogenase (IDH) catalyzing the conversion of isocitrate to α-ketoglutaric acid (α-KG) is a rate-limiting step. The known IDH family comprises three isozymes, IDH1, IDH2 and IDH3, which are located in different organelles and perform the same biological functions, i.e., catalyzing the formation of α-KG. Recent studies have shown that heterozygous IDH1/2 mutations were present in a certain proportion of a variety of tumors, such as glioma (60-80%), chondrosarcoma (55%), acute myeloid leukemia (15-25%), etc. The mutant IDH1 or IDH2 loses the capability of catalyzing the conversion of isocitrate to α-KG, whereas has the ability of catalyzing the reaction of α-KG to α-hydroxyglutaric acid (2-HG). As 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, and the like) when it accumulates to a certain extent, and thus effects the demethylation of histones and DNA, interferes with normal cell differentiation, and results in the proliferation of immature cells.
  • Agios Pharmaceuticals published its research results in Science magazine 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 generation of 2HG mediated by mutant IDH1/IDH2 in cells and can induce differentiation of abnormally proliferating cancer cells. Both the treatment of glioma cells harboring mutant IDH1 gene with AGI-5198 and the treatment of leukemia cells carrying mutant IDH2 gene with AG-6780 lead to increase of the expression of mature markers in cells.
  • The Phase I clinical trial of AG-120, a mutant IDH1 inhibitor developed by Agios Pharmaceuticals, showed that in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) having IDH1 mutations, it can be observed that 98% of the patients have decreased levels of α-hydroxyglutaric acid (2HG).
  • Acute myeloid leukemia (AML) is one of the most difficult diseases to be controlled in common hematological malignancies. Its recurrence rate is high. The development of new drug for the disease is slow resulting in the lack of effective drug therapy. Some studies have shown that about 15% of the patients with acute myeloid leukemia have IDH2 gene mutations. Enasidenib (former name AG-221), a mutant IDH2 inhibitor, developed by Agios Pharmaceuticals and Celgene, showed a significant effect on relapsed and refractory acute myelogenous leukemias with IDH2 gene mutations in clinical trial.
  • New IDH mutant inhibitors are needed to be developed to meet the need for treatment of patients with hematological tumors, especially acute myeloid leukemia, gliomas and other IDH mutation associated tumors. The present invention addresses these needs.
    • SUMMARY OF THE INVENTION
  • The present invention provides a compound of formula (I):
  • Figure US20210363115A2-20211125-C00002
  • and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein A, R1, R2, R3, R3′, R4, R4′, R5, R6, R7, R8, m, and n are as defined in the detailed description of the invention.
  • Also provided is a pharmaceutical composition, comprising at least one compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
  • Also provided is a method of treating a disease induced by IDH mutation, comprising administering to the subject in need thereof an effective amount of at least one compound of formula (I) (e.g., any of the compounds described herein) and/or at least one pharmaceutically acceptable salt thereof.
  • Also provided is a use of at least one compound of formula (I) (e.g., any of the compounds described herein) and/or at least one pharmaceutically acceptable salt thereof for treating a disease induced by IDH mutation.
  • Also provided is a use of at least one compound of formula (I) (e.g., any of the compounds described herein) and/or at least one pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease induced by IDH mutation.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows the general synthetic route I for preparation of the compounds described herein.
  • FIG. 2 shows the general synthetic route II for preparation of the compounds described herein.
  • FIG. 3 shows the general synthetic route III for preparation of the compounds described herein.
  • FIG. 4 shows the general synthetic route IV for preparation of the compounds described herein.
  • FIG. 5 shows the general synthetic route V for preparation of the compounds described herein.
  • FIG. 6 shows the general synthetic route VI for preparation of the compounds described herein.
    • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • As used in the present application, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
  • A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —OR4 is attached through the oxygen. However, when the point of attachment of a group is apparent to those skilled in the art, e.g., a halo substituent, the “-” sign may be omitted.
  • Unless clearly indicated otherwise, use of the terms “a”, “an” and the like refer 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, “C1-6 alkyl” refers to an alkyl containing 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), i-propyl (“i-Pr”), n-butyl (“n-Bu”), i-butyl (“i-Bu”), s-butyl (“s-Bu”) and t-butyl (“t-Bu”).
  • 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 double bonds (C═C) and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms. For example, “C2-6 alkenyl” refers to an alkenyl containing 2-6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment for the alkenyl can be on or not on the double bonds.
  • 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 triple bonds (C≡C) and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms. For example, “C2-6 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 point of attachment for the alkynyl can be on or not on the triple bonds.
  • The term “halogen” or “halo” as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.
  • 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 with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other. In certain an embodiment, the term “haloalkyl” as used herein refers to an alkyl radical, as defined herein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are identical to each other. 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 with halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, —CF3, —CHF2, —CH2CF3, and the like.
  • The term “alkoxy” as used herein refers to the group —O-alkyl, wherein the alkyl is as defined above. Examples of alkoxy groups include, but are not limited to, C1-6 alkoxy, such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, and hexyloxy, including their isomers.
  • The term “cycloalkyl” as used herein refers to saturated or partially unsaturated cyclic hydrocarbon radical having 3 to 12 ring carbon atoms, such as 3 to 8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms or 3 to 6 ring carbon atoms, which may have one or more rings, such as 1, 2, or 3 rings, preferably 1 or 2 rings. For example, “C3-12 cycloalkyl” refers to a cycloalkyl containing 3-12 carbon atoms in the ring. “Cycloalkyl” also includes a fused or bridged ring, or a spirocyclic ring. The rings of the cycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated), but not fully conjugated, and not an aryl as defined herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and bicyclo[3.1.1]hepta-2-ene.
  • 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, such as 3-8 ring atoms, 5-7 ring atoms, 4-7 ring atoms or 3-6 ring atoms, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms independently chosen from N, O and S in the rings, with the remaining ring atoms being carbon. The heterocycle group also includes those wherein the N or S heteroatom are optionally oxidized to various oxidation states. The point of attachment of heterocyclyl can be on the N heteroatom or carbon. For example, “3-8 membered heterocycly” refers to a heterocyclyl containing 3-8 ring atoms and containing at least one heteroatom independently chosen from N, O and S.
  • The heterocycle group also includes a fused or bridged ring, or a spirocyclic ring, wherein, at least one ring contains at least one heteroatom chosen from O, S, and N and none of the other rings is aryl or heteroaryl as defined herein. The rings of the heterocycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated), but not fully conjugated, and not a heteroaryl as defined herein. Examples of heterocycly groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolaneyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, and oxaspiro[3.3]heptanyl.
  • The term “aryl” as used herein refers to carbocyclic hydrocarbon radical of 6 to 14 carbon atoms consisting of one ring or more fused rings, wherein at least one ring is 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:
      • 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 chosen from N, O, and S (preferably N) in the ring, with the remaining ring atoms being carbon; and
      • 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 chosen from N, O, and S (preferably N) in the rings, with the remaining ring atoms being carbon, wherein at least one of the rings is aromatic. For example, the bicyclic heteroaryl includes a 5- to 6-membered heterocyclic aromatic ring fused to a 5- to 6-membered cycloalkyl ring.
  • When the total number of S and O atoms in the heteroaryl group exceeds 1, said S and O heteroatoms are not adjacent to one another.
  • The heteroaryl group also includes those wherein the N heteroatom occurs as N-oxide, such as pyridyl N-oxides.
  • Examples of the heteroaryl group include, but are not limited to, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl, benzodioxolyl, benzooxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (such as imidazo[1,2-a]pyridyl), pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridinyl (such as pyrazolo[1,5-a]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.
  • “Hydroxyl” as used herein refers to the —OH radical.
  • “Mercapto” as used herein refers to the —SH radical.
  • “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 by “*” is in either R-configuration or S-configuration, and the content of the compound with single configuration marked by “*” is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between those enumerated values). The configuration of the compounds can be determined using a variety of analytical techniques, for example single crystal X-ray crystallography and/or optical polarimetry according to routine protocols by those of ordinary skill in the art.
  • When a structure herein contains “(RS)”, it means that the chiral center of the compound marked by “(RS)” contains both R-configuration and S-configuration.
  • The term “optional” or “optionally” as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes instances wherein the event or circumstance occur and instances in which it does not occur. For example, “optionally substituted alkyl” encompasses both “unsubstituted alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, chemically incorrect, synthetically non-feasible and/or inherently unstable.
  • The term “substituted” or “substituted with . . . ”, as used herein, means that one or more hydrogens on the designated atom or group are replaced with one or more selections from the indicated group of substituents, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo (i.e., ═O), then 2 hydrogens on a single atom are replaced by the oxo. Combinations of substituents and/or variables are permissible only if such combinations result in a chemically correct and stable compound. A chemically correct and stable compound is meant to imply a compound that is sufficiently robust to survive sufficient isolation from a reaction mixture to be able to identify the chemical structure of the compound, and also sufficiently robust to allow subsequent formulation as an agent having at least one practical utility.
  • Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • The term “substituted with one or more substitutents” as used herein means that one or more hydrogens on the designated atom or group are independently replaced with one or more selections from the indicated group of substituents. In some embodiments, “substituted with one or more substitutents” means that the designated atom or group is substituted with 1, 2, 3, or 4 substitutents independently chosen from the indicated group of substituents.
  • It will be appreciated by the person of ordinary skill in the art (“POSITA”) that some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms. The racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention. It will be further appreciated by the POSITA that the present invention includes all the individual stereoisomers (e.g. enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where appropriate, the individual tautomeric forms thereof.
  • In other words, in some embodiments, the present invention provides compounds of various stereoisomeric purities, i.e., diastereomeric or enantiomeric purity expressed as various “ee” or “de” Values. In some embodiments, the compound of formula (I) (e.g., as described herein) has an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between those enumerated values). In some embodiments, the compound of formula (I) (e.g., as described herein) has an enantiomeric purity of greater than 99.9% ee, extending up to 100% ee. In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between those enumerated values). In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of greater than 99.9% de.
  • The term “enantiomeric excess” or “ee” designates how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R−S|*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S=1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the mixture of enantiomers and [a]max is the optical rotation of the pure enantiomer.
  • The term “diastereomeric excess” or “de” designates how much of one diastereomer is present compared to the other and is defined by analogy to enantiomeric excess. Thus, for a mixture of diastereomers, D1 and D2, the percent diastereomeric excess is defined as |D1−D2|*100, where D1 and D2 are the respective mole or weight fractions of diastereomers in a mixture such that D1+D2=1.
  • The 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 according to routine protocols familiar to those skilled in the art.
  • The racemates can be used as such or can be resolved into their individual isomers. The resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separation of isomers are well known (cf. Allinger N. L. and Eliel E. L. 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, individual isomers can be separated chemically from a 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, fractionally crystallizing the salts, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight of the desired stereoisomer. Alternatively, the racemates can be covalently linked to a chiral compound (auxiliary) to produce diastereomers which can be separated by chromatography or by fractional crystallization after which time the chiral auxiliary is chemically removed to afford the pure enantiomers, as is known to the POSITA.
  • The term “tautomer” as used herein refers to constitutional isomers of compounds generated by rapid movement of an atom in two positions in a molecule. Tautomers readily interconvert into each other, e.g., enol form and ketone form are tipical tautomers. For example, some compounds disclosed herein can exist in the forms of a, b, c, d, e, f, etc., as shown in the figure below, i.e., compounds in the forms of a, b, c, d, e, f are possible the tautomers of the compound of Formula (I). The signle tautomer and the mixture of these tautomers in any ratio are all included in the compounds described herein.
  • Figure US20210363115A2-20211125-C00003
  • A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound of Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. For examples, see, generally, 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.
  • In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be produced 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 base compounds. The POSITA will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts.
  • The term “solvates” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrates, for example, hemihydrates, monohydrate, and dihydrate, as well as variable hydrates.
  • As used herein, the terms “group”, “radical” and “moiety” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to other fragments of molecules.
  • The term “active ingredient” is used to indicate a chemical substance which has biological activity. In some embodiments, an “active ingredient” is a chemical substance having pharmaceutical utility. In the United States, practical pharmaceutical activity can be established by appropriate pre-clinical assays, whether in vitro or in vivo. Pharmaceutical activity sufficient to be accepted by a regulatory agency, such as FDA in the U.S., is a higher standard than the pre-clinical assay. Such a higher standard of pharmaceutical activity, the success of which cannot generally be reasonably expected from the pre-clinical results, can be established by appropriate and successful randomized, double blind, controlled clinical trials in humans.
  • The terms “treating”, “treat,” or “treatment” of a disease or disorder, in the context of achieving therapeutic benefit, refer to administering one or more pharmaceutical substances, especially a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein to a subject that has the disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition toward the disease or disorder. In some embodiments, the disease or disorder is cancer.
  • The terms “treating”, “contacting” and “reacting,” in the context of a chemical reaction, mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately lead to the formation of the indicated and/or the desired product.
  • The term “effective amount” as used herein refers to an amount or dose of an IDH mutation inhibiting agent sufficient to generally bring about a therapeutic benefit in patients in need of treatment for a disease or disorder induced by IDH mutation. Effective amounts or doses of the active ingredient of the present disclosure may be ascertained by methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the attending physician. In the United States, the determination of effective doses is generally difficult to predict from preclinical trials. In fact, the dose is completely unpredictable and the dose will develop a new unpredictable dosing regimen after initial use in a randomized, double-blind, controlled clinical trials.
  • An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's 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 about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day. Once improvement of the patient's disease or disorder has occurred, the dose may be adjusted for maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • The term “subject” as used herein means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex. In some embodiments, the subject is a human.
  • In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%.
  • Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by the POSITA to which the present disclosure pertains.
  • Provided is a compound of formula (I):
  • Figure US20210363115A2-20211125-C00004
  • and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein
    A is chosen from
  • Figure US20210363115A2-20211125-C00005
  • wherein, R7 is chosen from H, halo, —CN, —OH, or —NH2; R8 is chosen from halo, —CN, —OH, or —NH2; q is 1 or 2;
    R1 is chosen from H, —OH, halo, C1-6 alkyl, C1-6 alkoxyl, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, oxo, or C3-8 cycloalkyl;
    each of R2 is independently chosen from H, deuterium, halo, —OH, —NH2, —CN, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, oxo, —OR5, —OCOR5, —NHR5, —N(R5)(C1-4 alkyl), —COR5, —NHCOR5, or 3-8 membered heterocyclyl; in which each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with one or more groups chosen from deuterium, halo, —CN, —OH, —SH, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, or C1-6 alkoxyl; or two R2, which attach to the same carbon atom, together with the carbon atom they are attached to form a 3-5 membered cycloalkyl which is optionally substituted with one or more halo or deuterium;
    R3, R3′, R4 and R4′ are independently chosen from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R5, —OR5, or —NHR5, in which each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; wherein R3, R3′, R4 and R4′ are not H simultaneously; provided that when one of R3 and R4 is optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl, the other one is —OR5 or —NHR5;
    or R3 and R3′ are independently chosen from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R5, —OR5, or —NHR5, in which each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; R4 and R4′ together with the N atom they are attached to form a 3-8 membered heterocyclic ring optionally substituted by one or more R6;
    R5 is chosen from C1-6 alkyl or C3-8 cycloalkyl, each of which is optionally substituted with one or more groups independently chosen from halo, —CN, —OH, —SH, —NH2, or C1-6 alkoxyl;
    each of R6 is independently chosen from deuterium, halo, —CN, —OH, —SH, —NH2, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which each of said C1-6 alkoxyl, C1-6 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with one or more groups independently chosen from halo, —CN, —OH, —SH, —NH2, C1-6 alkoxyl, C1-6 alkynyl, or C1-6 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), R1 is chosen from H, —OH or halo.
  • In some embodiments of the compound of formula (I), R1 is chosen from —OH or halo.
  • In some embodiments of the compound of formula (I), R1 is —OH.
  • In some embodiments of the compound of formula (I), R1 is halo chosen from F, Cl, or Br. In some embodiments of the compound of formula (I), R1 is F.
  • In some embodiments of the compound of formula (I), the two R2, which attach to the same carbon atom, together with the carbon atom they are attached to form a 3-5 membered cycloalkyl optionally substituted by one or more F.
  • In some embodiments of the compound of formula (I), the two R2, which attach to the same carbon atom, together with the carbon atom they are attached to form a cyclopropyl.
  • In some embodiments of the compound of formula (I), each of R2 is independently chosen from H, deuterium, halo, —OH, —NH2, —CN, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, oxo, —OR5, —OCOR5, —NHR5, —N(R5)(C1-4 alkyl), —NHCOR5, or 3-8 membered heterocyclyl.
  • In some embodiments of the compound of formula (I), each of R2 is independently chosen from H, deuterium, halo, —OH, —NH2, —CN, C1-6 alkyl, C1-6 haloalkyl, oxo, —OR5, —NHR5, or —N(R5)(C1-4 alkyl).
  • In some embodiments of the compound of formula (I), each of R2 is independently chosen from H, deuterium, halo, C1-6 alkyl, or C1-6 haloalkyl.
  • In some embodiments of the compound of formula (I), each of R2 is independently chosen from halo, such as F, C1, or Br.
  • In some embodiments of the compound of formula (I), R2 is F.
  • In some embodiments of the compound of formula (I), m is 0, 1, 2, 3, or 4.
  • In some embodiments of the compound of formula (I), m is 0, 1, or 2.
  • In some embodiments of the compound of formula (I), m is 1. In some embodiments of the compound of formula (I), m is 2. In some embodiments of the compound of formula (I), m is 3.
  • In some embodiments of the compound of formula (I), m is 4.
  • In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R5, —OR5, or —NHR5, in which each of said C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; R3′ and R4′ are independently chosen from H or C1-6 alkyl.
  • In some embodiments of the compound of formula (I), R3′ and R4′ are both H.
  • In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C1-6 alkyl, C3-12 cycloalkyl, or 3-12 membered heterocyclyl, each of which is optionally substituted with one or more R6; R3′ and R4′ are both H.
  • In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C1-6 alkyl substituted with one ore more halo, 5-12 membered heteroaryl substituted with C1-6 haloalkyl, or —OR5; R3′ and R4′ are both H.
  • In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C1-6 alkyl optionally substituted with one or more halo; R3′ and R4′ are both H.
  • In some embodiments of the compound of formula (I), R3 is 5-12 membered heteroaryl substituted with C1-6 haloalkyl, R4 is C1-6 alkoxyl; R3′ and R4′ are both H.
  • In some embodiments of the compound of formula (I), R3 is 5-7 heteroaryl substituted with CF3, R4 is C1-6 alkoxyl; R3′ and R4′ are both H.
  • In some embodiments of the compound of formula (I), R3 is chosen from H, C1-6 alkyl optionally substituted by C1-6 haloalkyl, or 5-12 membered heteroaryl optionally substituted by C1-6 haloalkyl; R3′ is H; R4 and R4′ together with the N atom they are attached to form a 3-8 membered heterocyclic ring optionally substituted by one or more groups chosen from halo, —OH, or C1-6 haloalkyl.
  • In some embodiments of the compound of formula (I), R5 is C1-6 alkyl or C3-8 cycloalkyl.
  • In some embodiments of the compound of formula (I), R5 is C1-6 alkyl optionally substituted with one or more halo.
  • In some embodiments of the compound of formula (I), each of R6 is independently chosen from deuterium, halo, —CN, —OH, —NH2, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which each of said C1-6 alkoxyl, C1-6 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with one or more halo.
  • In some embodiments of the compound of formula (I), each of R6 is independently chosen from deuterium, halo, —OH, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.
  • In some embodiments of the compound of formula (I), each of R6 is independently chosen from deuterium, halo, —CN, —OH, —NH2, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, or C3-8 cycloalkyl.
  • In some embodiments of the compound of formula (I), each of R6 is independently chosen from deuterium, halo, or C1-6 haloalkyl.
  • In some embodiments of the compound of formula (I), n is 1.
  • In some embodiments of the compound of formula (I), R7 and R8 are independently chosen from halo or —CN.
  • In some embodiments of the compound of formula (I), R7 and R8 are independently chosen from F or —CN.
  • In some embodiments of the compound of formula (I), the compound of formula (I) is chosen from
  • Figure US20210363115A2-20211125-C00006
  • wherein X is halo; R1, R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I).
  • In some embodiments of the compound of formula (I), formula (I) is formula (I-1), wherein R1, R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I),
  • Figure US20210363115A2-20211125-C00007
  • In some embodiments of the compound of formula (I), formula (I) is formula (I-1a), wherein R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I),
  • Figure US20210363115A2-20211125-C00008
  • In some embodiments of the compound of formula (I), formula (I) is formula (I-1b), wherein R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I),
  • Figure US20210363115A2-20211125-C00009
  • In some embodiments of the compound of formula (I), formula (I) is formula (II), wherein R1, R2, R3, R3′, R4, R4′, n and A are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • Figure US20210363115A2-20211125-C00010
  • In some embodiments of the compound of formula (II), X is F.
  • In some embodiments of the compound of formula (II), R1 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 the compound of formula (I), formula (II) is chosen from
  • Figure US20210363115A2-20211125-C00011
  • wherein R1, R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2.
  • In some embodiments of the compound of formula (I), formula (II) is formula (II-1), wherein R1, R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • Figure US20210363115A2-20211125-C00012
  • In some embodiments of the compound of formula (I), formula (II) is formula (II-1a), wherein R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • Figure US20210363115A2-20211125-C00013
  • In some embodiments of the compound of formula (I), formula (II) is formula (II-1b), wherein R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2,
  • Figure US20210363115A2-20211125-C00014
  • In some embodiments of the compound of formula (II-1)-formula (II-5), X is F.
  • In some embodiments of the compound of formula (II-1)-formula (II-5), R1 is F.
  • In some embodiments of the compound of formula (II-1)-formula (II-5), R1 is —OH.
  • In some embodiments of the compound of formula (II-1)-formula (II-5), p is 0.
  • In some embodiments of the compound of formula (II-1)-formula (II-5), p is 1.
  • In some embodiments of the compound of formula (II-1)-formula (II-5), p is 2.
  • In some embodiments of the compound of formula (I), formula (I) is formula (III), wherein R1, R2, R3, R3′, R4, R4′, n and A are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; v is 0, 1, or 2,
  • Figure US20210363115A2-20211125-C00015
  • 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 1.
  • In some embodiments of the compound of formula (III), v is 2.
  • In some embodiments of the compound of formula (I), formula (III) is chosen from
  • Figure US20210363115A2-20211125-C00016
  • wherein R1, R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I); X is halo; 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 (I), formula (III) is formula (III-1), wherein R1, R2, R3, R3′, R4, R4′, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; m is 0, 1, or 2; v is 0, 1, or 2,
  • Figure US20210363115A2-20211125-C00017
  • In some embodiments of the compound of formula (III-1)-formula (III-5), X is F.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), R1 is F.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), R1 is —OH.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), p is 0.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), p is 1.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), p is 2.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), v is 0.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), v is 1.
  • In some embodiments of the compound of formula (III-1)-formula (III-5), v is 2.
  • Also provided is a compound chosen from Compounds 1-87, 89-184, 186-301, as numbered in the experimental section, and/or a pharmaceutically acceptable salt thereof.
  • In another aspect, provided is a pharmaceutical composition, comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
  • In another aspect, provided is a method of treating a disease induced by 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 to inhibit the increase of α-hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.
  • In another aspect, provided is a method of treating a disease induced by IDH mutation in a subject, comprising administering to the subject in need thereof an amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) effective to inhibit the increase of α-hydroxyglutaric acid (2HG) induced by IDH mutation in said subject.
  • In another aspect, provided is a 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 treating a disease induced by IDH mutation by inhibiting the increase of α-hydroxyglutaric acid (2HG) induced by IDH mutation in a subject.
  • In another aspect, provided is a use of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof described herein in the manufacture of a medicament for treating a disease induced by IDH mutation.
  • In some embodiments, the IDH mutation is IDH1 gene mutation.
  • In some embodiments, the IDH mutation is IDH2 gene mutation.
  • In some embodiments, the IDH mutation is IDH1-R132H or IDH2-R140Q gene mutation.
  • In some embodiments, the disease induced by IDH mutation is cancer.
  • In some embodiments, the cancer is chosen from solid cancer, neurogliocytoma, or hematological malignant tumor, such as leukemia, lymphoma, or myeloma.
  • In some embodiments, the cancer is chosen from acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliterative neoplasms (MPN), cholangiocarcinoma, such as intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lung cancer, or non-Hodgkin's lymphoma (NHL).
  • In another aspect, provided is a compound of formula (IV) and/or a salt thereof, and/or racemic mixtures or enantiomers thereof, which can be used in the manufacture of compounds of formula (I) (e.g., any of the compounds described herein),
  • Figure US20210363115A2-20211125-C00018
  • wherein, R1, R2, m and n are as defined in the compound of formula (I); Ra is hosen from halo, —OS(O)2CF3, —B(OH)2, —B(OC1-6 alkyl)2,
  • Figure US20210363115A2-20211125-C00019
  • Rb is H or C1-6 alkyl.
  • In some embodiments of the compound of formula (IV), Ra is chosen from —B(OH)2, —B(OC1-6 alkyl)2,
  • Figure US20210363115A2-20211125-C00020
  • Rb is H or C1-6 alkyl.
  • In some embodiments of the compound of formula (IV), Ra is chosen from —B(OH)2, —B(OCH3)2, —B[OCH(CH3)2]2,
  • Figure US20210363115A2-20211125-C00021
  • In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-1), wherein m is 0, 1, or 2;
  • Figure US20210363115A2-20211125-C00022
  • In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-2), wherein X is halo; m is 0, 1, or 2;
  • Figure US20210363115A2-20211125-C00023
  • In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-3), wherein X is halo; p is 0, 1, or 2; m is 0, 1, or 2;
  • Figure US20210363115A2-20211125-C00024
  • In some embodiments of the compound of formula (IV), R1 is —OH or oxo.
  • In some embodiments of the compound of formula (IV), X is F.
  • In some embodiments of the compound of formula (IV), p is 0.
  • In some embodiments of the compound of formula (IV), p is 1.
  • In some embodiments of the compound of formula (IV), p is 2.
  • In some embodiments of the compound of formula (IV), the compound of formula (IV) is chosen from
  • Figure US20210363115A2-20211125-C00025
  • In some embodiments of the compound of formula (IV), the compound of formula (IV) is chosen from
  • Figure US20210363115A2-20211125-C00026
    • General Synthetic Methods for Disclosed Embodiments
  • The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be synthesized from commercially available starting material by methods well known in the art, taken together with the disclosure in this patent application. The drawings 1-6 illustrate general methods for preparation of the compounds described herein.
  • As shown in FIG. 1, substitution reaction of 2,4,6-trichloro-1,3,5-triazine with an amine substituted with R3 and R3′ provides compound of formula 1-1. Substitution reaction of the compound of formula 1-1 with an amine substituted with R4 and R4′ provides compound of formula 1-2. Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented by formula (IV) under the catalysis of a suitable palladium reagent gives a compound of formula (I-1) as described herein, wherein R1, R2, R3, R3′, R4, R4′, Ra, m, and n are as defined herein. The Pd-catalyzed C—C coupling reaction can be carried out under suitable conditions, 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 Cs2CO3, Na2CO3, K3PO4 and the like, and the catalyst used can be selected from Pd(dppf)Cl2.CH2Cl2, Pd(PPh3)4, Pd(OAc)2 and the like.
  • As shown in Scheme 2, Suzuki coupling reaction of compound of formula 1-1 with an intermediate represented by formula (IV) under the catalysis of a suitable palladium reagent affords compound of formula 2-1. Substitution reaction of compound of formula 2-1 with an amine substituted with R4 and R4′ gives a compound of formula (I-1) as described herein, wherein R1, R2, R3, R3′, R4, R4′, Ra, m, and n are as defined herein.
  • As shown in Scheme 3, Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented by formula (IV-1) under the catalysis of a suitable palladium reagent provides compound of formula 3-1. The Pd-catalyzed C—C coupling 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 Cs2CO3, Na2CO3, K3PO4 and the like, and the catalyst used can be selected from Pd(dppf)Cl2.CH2Cl2, Pd(PPh3)4, Pd(OAc)2 and the like. Reduction of compound of formula 3-1 provides compound of formula (I-1a) as described herein.
  • As shown in Scheme 4, Suzuki coupling reaction of compound of formula 1-1 with an intermediate represented by formula (IV-1) under the catalysis of a suitable palladium reagent affords compound of formula 4-1. Reduction of Compound of formula 4-1 provides compound of formula 4-2. Substitution reaction of compound of formula 4-2 with an amine substituted with R4 and R4′ gives a compound of formula (I-1a) as described herein.
  • As shown in Scheme 5, Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented by formula (IV-2) under the catalysis of a suitable palladium reagent provides compound of formula 5-1. Halogenation of compound of formula 5-1 using a halogenating reagent such as NFSI and the like, in presence of a base such as LiHMDS, KHMDS, LDA and the like, and in suitable polar solvents such as THF, DCM and the like, results in compound of formula 5-2. Reduction of compound of formula 5-2 provides compound of formula (II-1a) as described herein.
  • As shown in Scheme 6, compound of formula 3-1 reacts with a deuterating reagent such as NaBD4, deuterated borane and the like gives a compound of formula (I-1b) as described herein.
  • The substituents of the compounds thus obtained can be further modified to provide 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 subsequent editions thereof.
  • Before use, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.
    • Pharmaceutical Compositions and Practical Utility
  • The compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein is used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions. A pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).
  • A pharmaceutically acceptable carrier refers to a carrier that is compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which form specific, more soluble complexes with the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein), can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the art.
  • A pharmaceutical composition comprising a compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • A pharmaceutical composition described herein can be prepared in the form of tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, 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.
  • An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used carriers for tablets include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added to tablets. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
  • In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be present 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 a tablet. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be present 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 a capsule.
  • A sterile injectable composition (e.g., 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 can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di-glycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the Intermediate of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • A topical composition can be formulated in form of oil, cream, lotion, ointment, and the like. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in those topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.
  • Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. An example of such a cream is one which includes, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. An example of such an ointment is one which includes about 30% by weight almond oil and about 70% by weight white soft paraffin.
  • Suitable in vitro assays can be used to evaluate the practical utility of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein, in inhibiting the IDH mutation. The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can further be examined for additional practical utility in treating cancer by in vivo assays. For example, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects can be accessed. If the pre-clinical results are successful, the dosage range and administration route for animals, such as humans, can be projected.
  • The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be shown to have sufficient pre-clinical practical utility to merit clinical trials hoped to demonstrate a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
  • As used herein, the term “cancer” refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites. The term “cancer” includes, but is not limited to, solid tumors and hematologic malignancies. The term “cancer” encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term “cancer” further encompasses primary and metastatic cancers.
  • Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including e.g., malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid carcinoma.
  • Non-limiting 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); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), and RAEB in transformation (RAEB-T); and myeloproliferative syndromes.
  • In some embodiment, exemplary 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); and lymphoma, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).
  • The 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 subjects with cancer.
  • In addition, the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein may be used in combination with additional active ingredients in the treatment of cancer. The additional active ingredients may be coadministered separately with the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein or included with such an ingredient in a pharmaceutical composition according to the disclosure, such as a fixed-dose combination drug product. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of diseases induced by IDH mutation, such as another mutant IDH inhibitor or a compound active against another target associated with the particular disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein), decrease one or more side effects, or decrease the required dose of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein.
  • In some embodiments, the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein is administered in conjunction with an anti-neoplastic agent. As used herein, the term “anti-neoplastic agent” refers to any agent that is administered to a subject with cancer for purposes of treating the cancer. Nonlimiting examples anti-neoplastic agents include: radiotherapy; immunotherapy; DNA damaging chemotherapeutic agents; and chemotherapeutic agents that disrupt cell replication.
  • Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, azacitidine (VIDAZA®); mercaptopurine, thioguanine, pentostatin, and hydroxyurea).
  • Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-kappa B inhibitors, including inhibitors of I kappa B kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.
    • EXAMPLES
  • The examples below are intended to be exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data was determined by agilent 6120 or agilent 1100. All NMR data were generated using a Varian 400-MR machine. All reagents, except intermediates, used in this invention are commercially available. All compound names except the reagents were generated by Chemdraw 12.0.
  • If there is any atom with empty valence(s) in any one of the structures disclosed herein, the empty balance(s) is(are) the hydrogen atom(s) which is(are) omitted for convenience purpose.
  • In the present application, in the case of inconsistency of the structure and name of a compound, when the two of which are both given for the compound, it is subject to the structure of the compound, unless the context shows that the structure of the compound is incorrect and the name is correct.
  • In the following examples, the abbreviations below are used:
    • AcOK potassium acetate
    • BAST bis(2-methoxyethyl)aminosulfur trifluoride
    • BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene
    • t-BuONa sodium tert-butoxide
    • (n-Bu3Sn)2 1,1,1,2,2,2-hexabutyldistannane
    • (S)—CBS (S)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole
    • CD3OD methanol-d4
    • DAST diethylaminosulphur trifluoride
    • DCM dichloromethane
    • DIEA N,N-diisopropylethylamine
    • DMF N,N-dimethylformamide
    • DMSO-d6 dimethyl sulfoxide-d6
    • EA/EtOAc ethyl acetate
    • Et3N triethylamine
    • EtOH ethanol
    • Et2Zn diethyl zinc
    • G gram
    • HC(OMe)3 trimethyl orthoformate
    • L litre
    • LiHMDS lithium bis(trimethylsilyl)amide
    • M mol/L
    • MeOH methanol
    • MeCN acetonitrile
    • Mg milligram
    • mL millilitre
    • Mmol millimole
    • Mol mole
    • NaBH(OAc)3 sodium triacetoxyborohydride
    • NaOMe sodium methoxide
    • NaOEt sodium ethoxide
    • NCS N-chlorosuccinimide
    • NFSI N-fluorobenzenesulfonimide
    • PdCl2(PPh3)2 bis(triphenylphosphine)palladium(II) dichloride
    • Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
    • Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
    • Pd(dppf)Cl2.CH2Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex
    • Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
    • 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
    • Tf2O trifluoromethanesulfonic anhydride
    • THF tetrahydrofuran
    • TsOH.H2O 4-methylbenzenesulfonic acid monohydrate
    Example 1 Preparation of Intermediates Intermediate I-1 3-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-ol and Intermediate I-61 (*)3-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00027
    • (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 hours under nitrogen atmosphere. Then, the mixture was 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 (eluting with gradient PE/EA=100:0-0:100) to give compound A1 as 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)
  • Under nitrogen atmosphere, compound A1 (208 mg, 1.6 mmol) was dissolved in DCM and cooled to 0° C. Then, DIEA (415 mg, 3.2 mmol) and Tf2O (540 mg, 1.92 mmol) were added at 0° C. and the mixture was stirred for 2 hours at 0° C. under nitrogen atmosphere. After the reaction was completed, it was quenched by the addition of water and extracted with DCM. The organic layer was collected, condensed and purified by flash column chromatography (eluting with PE/EA) to give compound A2 as 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-triazin-2-amine (A3)
  • A solution of 2,4,6-trichloro-1,3,5-triazine (9.1 g, 49.3 mmol) in dry THF was cooled to 0° C. and (R)-1,1,1-trifluoropropan-2-amine hydrochloride (7.37 g, 49.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After reaction was completed, the mixture was adjusted to pH=7 by the addition of saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give compound A3 as 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-fluoro-cyclohex-2-en-1-one (A4)
  • Under nitrogen atmosphere, a mixture of compound A2 (4.0 g, 15.3 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.3 g, 16.8 mmol), AcOK (3.8 g, 38.3 mmol), Pd(dppf)Cl2 (0.63 g, 0.77 mmol) in 1,4-dioxane (40 mL) was stirred at reflux for 2 hours. Then, the reaction mixture was cooled to room temperature, then was added compound A3 (4.0 g, 15.3 mmol), Cs2CO3 (14.4 g, 38.3 mmol), Pd(PPh3)4 (0.89 g, 0.77 mmol) and water (8 mL) in sequence. The reaction was stirred at 80° C. for another 2 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give compound A4 as 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-fluoro-cyclohex-2-en-1-ol (I-1)
  • To a flask were added compound A4 (1150 mg, 3.41 mmol), CeCl3.7H2O (1269 mg, 3.41 mmol) and EtOH (20 mL). The mixture was cooled to 0° C., NaBH4 (130 mg, 3.41 mmol) was added and the mixture was stirred at 0° C. for 2 hours. After the reaction was completed, the mixture was quenched by the addition of saturated NH4Cl aqueous solution (10 mL) and water (50 mL) and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give I-1 as 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-fluoro-cyclohex-2-en-1-ol (I-61)
  • Under nitrogen atmosphere, to dry THF (5 mL) was added 1 mol/L (S)—CBS/THF solution (2.4 mL, 2.4 mmol) under ice bath cooling ° C., then 2 mol/L BH3.Me2S/THF solution (2.4 mL, 4.8 mmol) was added in one-portion. After stirred for 2 minutes, to the above solution was added compound A4 (800 mg, 2.4 mmol) in THF (3 mL) dropwise. After stirring under ice bath cooling ° C. for 1 hour, to the reaction mixture was added MeOH (0.5 mL), EtOAc (10 mL) and water (20 mL). The organic layer was collected. The aqueous phase was extracted with EtOAc (10 mL). The organic layers were combined, dried over Na2SO4, filtered. The filtrate was condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give Intermediate I-61 as white solid (360 mg). MS (m/z): 341.2 [M+H]+
  • The compounds in the below table were prepared according to the procedure of Intermediate I-1 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by the POSITA:
  • Inter- MS
    mediate Structure (M + H)+
    I-22
    Figure US20210363115A2-20211125-C00028
         		314.0
    I-23
    Figure US20210363115A2-20211125-C00029
         		279.1
    I-24
    Figure US20210363115A2-20211125-C00030
         		265.1
    I-25
    Figure US20210363115A2-20211125-C00031
         		323.0
    I-80
    Figure US20210363115A2-20211125-C00032
         		285.0
    • Intermediate I-2 (R)-6-Chloro-N2-isopropyl-N4-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00033
  • To a sealed tube was added compound A3 (3.5 g, 13.4 mmol), propan-2-amine (872 mg, 14.7 mmol), DIEA (3.5 g, 26.8 mmol) and THF (20 mL) in sequence, and the mixture was stirred at 50° C. overnight. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give Intermediate I-2 as white solid (3.8 g, yield: 100%). MS (m/z): 284.0 [M+H]+
  • The compounds in the below table were prepared according to the procedure of Intermediate 1-2 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • Inter- MS
    mediate Structure (M + H)+
    I-7
    Figure US20210363115A2-20211125-C00034
         		314.0
    I-8
    Figure US20210363115A2-20211125-C00035
         		312.0
    I-9
    Figure US20210363115A2-20211125-C00036
         		332.0
    I-11
    Figure US20210363115A2-20211125-C00037
         		346.0
    I-12
    Figure US20210363115A2-20211125-C00038
         		310.0
    I-13
    Figure US20210363115A2-20211125-C00039
         		298.1
    I-14
    Figure US20210363115A2-20211125-C00040
         		346.0
    I-15
    Figure US20210363115A2-20211125-C00041
         		296.0
    I-16
    Figure US20210363115A2-20211125-C00042
         		282.0
    I-17
    Figure US20210363115A2-20211125-C00043
         		300.0
    I-18
    Figure US20210363115A2-20211125-C00044
         		284.0
    I-19
    Figure US20210363115A2-20211125-C00045
         		270.0
    I-20
    Figure US20210363115A2-20211125-C00046
         		324.1
    I-21
    Figure US20210363115A2-20211125-C00047
         		333.0
    I-30
    Figure US20210363115A2-20211125-C00048
         		332.0
    I-31
    Figure US20210363115A2-20211125-C00049
         		310.0
    I-33
    Figure US20210363115A2-20211125-C00050
         		352.2
    I-35
    Figure US20210363115A2-20211125-C00051
         		298.1
    I-36
    Figure US20210363115A2-20211125-C00052
         		276.0
    I-37
    Figure US20210363115A2-20211125-C00053
         		278.0
    I-38
    Figure US20210363115A2-20211125-C00054
         		290.0
    I-39
    Figure US20210363115A2-20211125-C00055
         		291.1
    I-40
    Figure US20210363115A2-20211125-C00056
         		291.1
    I-42
    Figure US20210363115A2-20211125-C00057
         		285.1
    I-49
    Figure US20210363115A2-20211125-C00058
         		318.0
    I-50
    Figure US20210363115A2-20211125-C00059
         		318.0
    I-51
    Figure US20210363115A2-20211125-C00060
         		321.0
    I-54
    Figure US20210363115A2-20211125-C00061
         		332.0
    I-55
    Figure US20210363115A2-20211125-C00062
         		362.1
    I-71
    Figure US20210363115A2-20211125-C00063
         		284.0
    I-72
    Figure US20210363115A2-20211125-C00064
         		320.4
    I-73
    Figure US20210363115A2-20211125-C00065
         		308.1
    I-74
    Figure US20210363115A2-20211125-C00066
         		296.1
    I-75
    Figure US20210363115A2-20211125-C00067
         		350.9
    I-76
    Figure US20210363115A2-20211125-C00068
         		323.9
    I-77
    Figure US20210363115A2-20211125-C00069
         		296.0
    I-78
    Figure US20210363115A2-20211125-C00070
         		284.0
    I-79
    Figure US20210363115A2-20211125-C00071
         		351.0
    I-81
    Figure US20210363115A2-20211125-C00072
         		321.0
    I-82
    Figure US20210363115A2-20211125-C00073
         		346.0
    I-83
    Figure US20210363115A2-20211125-C00074
         		288.0
    I-84
    Figure US20210363115A2-20211125-C00075
         		318.0
    I-85
    Figure US20210363115A2-20211125-C00076
         		282.2
    I-86
    Figure US20210363115A2-20211125-C00077
         		324.0
    I-87
    Figure US20210363115A2-20211125-C00078
         		333.0
    I-89
    Figure US20210363115A2-20211125-C00079
         		338.0
    I-90
    Figure US20210363115A2-20211125-C00080
         		314.1
    I-91
    Figure US20210363115A2-20211125-C00081
         		314.1
    I-101
    Figure US20210363115A2-20211125-C00082
         		318.0
    I-102
    Figure US20210363115A2-20211125-C00083
         		318.1
    • Intermediate I-3 6-Chloro-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00084
  • At 0° C., to a flask were added 1,4-dioxane (50 mL), 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.99 g, 20 mmol) and DIEA (5.17 g, 40 mmol). The reaction was heated to 60° C. and stirred for 4 hours. After the reaction was completed, the mixture was condensed and purified by flash column chromatography (eluting with gradient water/MeOH=100:0-0:100) to give Intermediate I-3 as yellow solid (2.50 g, yield: 74%). MS (m/z): 338.0 [M+H]+
  • The compounds in the below table were prepared according to the procedure of Intermediate I-3 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • Inter- MS
    mediate Structure (M + H)+
    I-6
    Figure US20210363115A2-20211125-C00085
         		254.1
    I-10
    Figure US20210363115A2-20211125-C00086
         		326.0
    I-32
    Figure US20210363115A2-20211125-C00087
         		338.0
    I-34
    Figure US20210363115A2-20211125-C00088
         		230.1
    I-106
    Figure US20210363115A2-20211125-C00089
         		446.0
  • Intermediate I-4
    • (R)—N-(4-Chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)isobutyramide
  • Figure US20210363115A2-20211125-C00090
  • 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 the reaction was completed, the mixture was cooled to room temperature and concentrated to dryness in vacuo to afford N-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide as yellow solid. Then, to 1,4-dioxane (10 mL) was added N-(4,6-dichloro-1,3,5-triazin-2-yl)isobutyramide obtained above, (R)-1,1,1-trifluoropropan-2-amine hydrochloride (900 mg, 6.06 mmol) and DIEA (2.34 g, 18.18 mmol). The mixture was heated to reflux and stirred for 2 hours. After the reaction was completed, the mixture was quenched by the addition of water, extracted with EtOAc (20 mL). The organic layer was collected, concentrated under reduced pressure and purified by flash column chromatography (eluting with PE/EA) to give Intermediate I-4 (80 mg). MS (m/z): 312.1 [M+H]+
    • Intermediates I-26 and I-27 3-(4-Chloro-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol optically pure diastereoisomers
  • Figure US20210363115A2-20211125-C00091
  • Intermediates I-26 and I-27 were obtained by resolution of Intermediate I-25 using chiral HPLC (chiral HMPL conditions: column: AS-H; mobile phase: n-heptane/isopropanol=80:20; flow rate: 0.5 mL/min; detection wavelength: UV 254 nm). The isomer obtained from the first eluent (RT=1.703 min) was named as I-26, de %=100%, MS (m/z): 400.1 [M+H]+. The isomer obtained from the second eluent (RT=2.067 min) was named as I-27, de %=99.4%, MS (m/z): 400.1 [M+H]+).
  • Intermediate I-41
    • 6-Chloro-N2-(propan-2-yl-d7)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00092
    • (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) was added NaHCO3 (1.68 g, 20 mmol) at 0° C. The mixture was stirred at room temperature for 16 hours. After reaction was completed, the mixture was filtered. The filtrate was condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give compound A5 as white solid (2.68 g, yield: 86%). MS (m/z): 309.9 [M+H]+
    • (B) 6-Chloro-N2-(propan-2-yl-d7)-N4-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2,4-diamine
  • To a sealed tube were added compound A5 (465 mg, 1.5 mmol), propan-d7-2-amine hydrochloride (154 mg, 1.5 mmol), DIEA (388 mg, 3.0 mmol) and 1,4-dioxane (20 mL) in sequence. The mixture was heated to 60° C. and stirred for 5 hours. After reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give Intermediate I-41 as white solid (485 mg, yield: 95%). MS (m/z): 340.0 [M+H]+
  • The compounds in the below table were prepared according to the procedure of Intermediate I-41 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • Inter- MS
    mediate Structure (M + H)+
    I-43
    Figure US20210363115A2-20211125-C00093
         		268.0
    I-44
    Figure US20210363115A2-20211125-C00094
         		308.0
    I-45
    Figure US20210363115A2-20211125-C00095
         		304.0
    I-53
    Figure US20210363115A2-20211125-C00096
         		334.0
    I-59
    Figure US20210363115A2-20211125-C00097
         		329.0
    I-63
    Figure US20210363115A2-20211125-C00098
         		363.0
    I-66
    Figure US20210363115A2-20211125-C00099
         		363.0
    I-68
    Figure US20210363115A2-20211125-C00100
         		364.0
    I-92
    Figure US20210363115A2-20211125-C00101
         		321.1
    I-93
    Figure US20210363115A2-20211125-C00102
         		335.1
    I-94
    Figure US20210363115A2-20211125-C00103
         		361.1
    I-96
    Figure US20210363115A2-20211125-C00104
         		329.0
    I-97
    Figure US20210363115A2-20211125-C00105
         		349.1
    I-98
    Figure US20210363115A2-20211125-C00106
         		381.1
    I-99
    Figure US20210363115A2-20211125-C00107
         		385.0
    I-100
    Figure US20210363115A2-20211125-C00108
         		366.9
    I-101
    Figure US20210363115A2-20211125-C00109
         		318.0
    I-103
    Figure US20210363115A2-20211125-C00110
         		428.9
    I-104
    Figure US20210363115A2-20211125-C00111
         		416.9
    I-105
    Figure US20210363115A2-20211125-C00112
         		362.1
    • Intermediate 1-46 2-((4-(Tert-butoxyamino)-6-chloro-1,3,5-triazin-2-yl)amino)isonicotinonitrile
  • Figure US20210363115A2-20211125-C00113
    • (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) was added NaHCO3 (1.26 g, 15 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. After the reaction was completed, the mixture was filtered. The filtrate was condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give compound A6 as 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
  • To a sealed tube were sequentially added compound A6 (0.83 g, 4.0 mmol), 2-aminoisonicotinonitrile (0.48 g, 4.0 mmol), Pd(dppf)Cl2 (0.15 g, 0.2 mmol), t-BuONa (0.77 g, 8.0 mmol) and 1,4-dioxane (10 mL). The mixture was heated to 90° C. and stirred for 3 hours. After reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give Intermediate I-46 as yellow solid (109 mg, yield: 8%). MS (m/z): 320.0 [M+H]+
  • The compounds in the below table were prepared according to the procedure of Intermediate I-46 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • Inter- MS
    mediate Structure (M + H)+
    I-47
    Figure US20210363115A2-20211125-C00114
         		329.0
    I-48
    Figure US20210363115A2-20211125-C00115
         		315.0
    I-52
    Figure US20210363115A2-20211125-C00116
         		305.0
    I-56
    Figure US20210363115A2-20211125-C00117
         		358.0
    I-57
    Figure US20210363115A2-20211125-C00118
         		304.1
    I-58
    Figure US20210363115A2-20211125-C00119
         		295.0
    I-60
    Figure US20210363115A2-20211125-C00120
         		295.1
    I-62
    Figure US20210363115A2-20211125-C00121
         		369.0
    I-64
    Figure US20210363115A2-20211125-C00122
         		385.0
    I-65
    Figure US20210363115A2-20211125-C00123
         		313.0
    I-67
    Figure US20210363115A2-20211125-C00124
         		283.0
    I-69
    Figure US20210363115A2-20211125-C00125
         		304.0
    I-70
    Figure US20210363115A2-20211125-C00126
         		308.0
    I-5
    Figure US20210363115A2-20211125-C00127
         		304.0
    I-28
    Figure US20210363115A2-20211125-C00128
         		309.0
    I-29
    Figure US20210363115A2-20211125-C00129
         		310.0
    I-95
    Figure US20210363115A2-20211125-C00130
         		363.9
    • Intermediate I-88 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one
  • Figure US20210363115A2-20211125-C00131
  • Under nitrogen atmosphere, to a flask were added compound A2 (80 g, 305 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (80 g, 315 mmol), AcOK (74.8 g, 763 mmol), Pd(dppf)Cl2.CH2Cl2 (12.4 g, 15.3 mmol) and 1,4-dioxane (1.4 L) in sequence. 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 (eluting with PE/EA=4/1) to give Intermediate I-88 as yellow solid (76 g, yield 100%). MS (m/z): 159.0 [M+H]+
  • 1H NMR (400 MHz, DMSO-d6): δ 2.47-2.36 (m, 4H), 1.91-1.82 (m, 2H), 1.22 (s, 12H).
    • 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
  • Figure US20210363115A2-20211125-C00132
    • (A) (R)-2-fluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B1)
  • Under nitrogen atmosphere, to a flask were added compound A2 (220 mg, 0.84 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (234 mg, 0.92 mmol), AcOK (206 mg, 2.10 mmol), Pd(dppf)Cl2.CH2Cl2 (32 mg, 0.04 mmol) and 1,4-dioxane (20 mL) in sequence and stirred at reflux for 16 hours. Then, the mixture was cooled to room temperature, and was added Intermediate I-2 (238 mg, 0.84 mmol), Cs2CO3 (682 mg, 2.1 mmol), Pd(PPh3)4 (46.2 mg, 0.04 mmol) and water (4 mL) in sequence, and stirred at 80° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give compound B1 as 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-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol
  • To a flask were added compound B1 (80 mg, 0.22 mmol), CeCl3.7H2O (107 mg, 0.29 mmol) and EtOH (5 mL). The mixture was cooled to 0° C. Then, NaBH4 (11 mg, 0.29 mmol) was added and the mixture was stirred at 0° C. for 2 hours. After the reaction was completed, the mixture was quenched by the addition of saturated NH4Cl aqueous solution (2 mL) and water (20 mL), and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give Compound 1 as a white solid (61 mg, yield: 76.3%). MS (m/z): 364.1 [M+H]+
  • 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 in the below table were prepared according to the procedure of Compound 1 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    2
    Figure US20210363115A2-20211125-C00133
         		418.1 1H NMR (400 MHz, CD3OD): 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), 1.38-1.30 (m, 6H). I-3
    3
    Figure US20210363115A2-20211125-C00134
         		392.1 1H NMR (400 MHz, CD3OD): 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), 3.73-3.60 (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). I-8
    4
    Figure US20210363115A2-20211125-C00135
         		412.1 1H NMR (400 MHz, CD3OD): 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), 1.96-1.56 (m, 4H), 1.44-1.31 (m, 3H). I-30
    5
    Figure US20210363115A2-20211125-C00136
         		406.1 1H NMR (400 MHz, CD3OD): 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), 1.72-1.62 (m, 1H). I-10
    6
    Figure US20210363115A2-20211125-C00137
         		426.1 1H NMR (400 MHz, CD3OD): 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), 2.14-1.96 (m, 2H), 1.90-1.75 (m, 4H), 1.70-1.61 (m, 1H), 1.40-1.31 (m, 3H). I-11
    7
    Figure US20210363115A2-20211125-C00138
         		376.1 1H NMR (400 MHz, CD3OD): 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), 1.92-1.60 (m, 4H), 1.40-1.30 (m, 3H), 1.23-1.15 (m, 6H). I-15
    8
    Figure US20210363115A2-20211125-C00139
         		390.1 1H NMR (400 MHz, CD3OD): 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), 1.91-1.62 (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). I-31
    9
    Figure US20210363115A2-20211125-C00140
         		392.3 1H NMR (400 MHz, CD3OD): 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), 1.62-1.53 (m, 1H), 1.38-1.31 (m, 3H), 1.22-1.15 (m, 6H), 1.06 (s, 3H), 1.00 (s, 3H). I-2
    10
    Figure US20210363115A2-20211125-C00141
         		390.1 1H NMR (400 MHz, CD3OD): 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), 1.39-1.31 (m, 3H). I-12
    11
    Figure US20210363115A2-20211125-C00142
         		418.1 1H NMR (400 MHz, CD3OD): 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), 1.43-1.31 (m, 6H). I-3
    12
    Figure US20210363115A2-20211125-C00143
         		378.1 1H NMR (400 MHz, CD3OD): 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), 1.97-1.59 (m, 5H), 1.41-1.30 (m, 3H), 0.96-0.88 (m, 6H). I-13
    13
    Figure US20210363115A2-20211125-C00144
         		426.1 1H NMR (400 MHz, CD3OD): 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), 1.89-1.61 (m, 4H), 1.39-1.31 (m, 3H). I-14
    14
    Figure US20210363115A2-20211125-C00145
         		418.1 1H NMR (400 MHz, CD3OD): 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), 1.40-1.31 (m, 6H). I-32
    15
    Figure US20210363115A2-20211125-C00146
         		432.3 1H NMR (400 MHz, CD3OD): 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), 1.91-1.74 (m, 4H), 1.71-1.61 (br, 2H), 1.40-1.31 (m, 3H), 1.04-0.93 (m, 3H). I-33
    16
    Figure US20210363115A2-20211125-C00147
         		380.1 1H NMR (400 MHz, CD3OD): 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), 2.46-2.27 (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). I-1
    17
    Figure US20210363115A2-20211125-C00148
         		380.4 1H NMR (400 MHz, CD3OD): 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), 1.41-1.32 (m, 3H), 1.23-1.18 (m, 6H). I-2
    18
    Figure US20210363115A2-20211125-C00149
         		419.1 1H NMR (400 MHz, CD3OD): 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). I-3
    19
    Figure US20210363115A2-20211125-C00150
         		407.1 1H NMR (400 MHz, CD3OD): 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). I-10
    20
    Figure US20210363115A2-20211125-C00151
         		420.2 1H 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). I-10
    21
    Figure US20210363115A2-20211125-C00152
         		432.3 1H NMR (400 MHz, CD3OD): 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), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H). I-3
    22
    Figure US20210363115A2-20211125-C00153
         		421.1 1H NMR (400 MHz, CD3OD): 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), 1.75-1.59 (m, 3H). I-10
    23
    Figure US20210363115A2-20211125-C00154
         		365.2 1H NMR (400 MHz, CD3OD): 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), 1.37-1.29 (m, 3H), 1.20-1.17 (m, 6H). I-2
    24
    Figure US20210363115A2-20211125-C00155
         		427.1 1H NMR (400 MHz, CD3OD): 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), 2.01-1.82 (m, 3H), 1.72-1.60 (m, 3H), 1.39-1.13 (m, 3H). I-9
    25
    Figure US20210363115A2-20211125-C00156
         		310.1 1H NMR (400 MHz, CD3OD): 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), 1.82-1.72 (m, 1H), 1.70-1.60 (m, 1H), 1.19 (s, 12H). I-34
    26
    Figure US20210363115A2-20211125-C00157
         		378.1 1H NMR (400 MHz, CD3OD): 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), 1.70-1.59 (m, 1H), 1.35 (d, J = 5.3 Hz, 3H), 1.16 (d, J = 6.5 Hz, 6H). I-35
    27
    Figure US20210363115A2-20211125-C00158
         		356.1 1H NMR (400 MHz, CD3OD): 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), 1.83-1.60 (m, 2H), 0.82-0.67 (m, 2H), 0.60-0.45 (m, 2H). I-36
    28
    Figure US20210363115A2-20211125-C00159
         		358.1 1H NMR (400 MHz, CD3OD): 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), 1.90-1.83 (m, 2H), 1.83-1.60 (m, 2H), 1.20 (s, 6H). I-37
    29
    Figure US20210363115A2-20211125-C00160
         		372.1 1H NMR (400 MHz, CD3OD): 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), 1.37-1.29 (m, 3H). I-39
    30
    Figure US20210363115A2-20211125-C00161
         		372.1 1H NMR (400 MHz, CD3OD): 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), 1.37-1.29 (m, 3H). I-40
    31
    Figure US20210363115A2-20211125-C00162
         		412.1 1H NMR (400 MHz, CD3OD): 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), 1.95-1.59 (m, 4H), 1.41-1.31 (m, 3H). I-9
    32
    Figure US20210363115A2-20211125-C00163
         		412.1 1H NMR (400 MHz, CD3OD): 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), 1.94-1.60 (m, 4H), 1.42-1.32 (m, 3H). I-54
    33
    Figure US20210363115A2-20211125-C00164
         		364.1 1H NMR (400 MHz, CD3OD): 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), 2.03-1.58 (m, 4H), 1.42-1.29 (m, 3H), 1.23-1.10 (m, 6H). I-71
    34
    Figure US20210363115A2-20211125-C00165
         		431.0 1H NMR (400 MHz, CD3OD) 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), 2.47-2.35 (m, 341H), 1.92-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.73-1.65 (m, 1H), 1.32 (s, 9H). I-75
    200
    Figure US20210363115A2-20211125-C00166
         		384.1 1H NMR (400 MHz, CD3OD): 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), 1.91-1.63 (m, 4H), 1.29-1.20 (m, 6H). I-5
    205
    Figure US20210363115A2-20211125-C00167
         		390.1 1H NMR (400 MHz, CD3OD): 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). I-29
    219
    Figure US20210363115A2-20211125-C00168
         		444.2 1H NMR (400 MHz, CD3OD): 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), 1.39-1.32 (m, 6H), 1.03-0.94 (m, 1H), 0.78-0.68 (m, 1H), 0.51-0.40 (m, 3H). I-3
    229
    Figure US20210363115A2-20211125-C00169
         		401.0 1H NMR (400 MHz, CD3OD): 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), 2.72-2.56 (m, 1H), 2.48-2.33 (m, 1H), 1.93-1.63 (m, 4H), 1.29-1.21 (m, 6H). I-81
    • Compound 35 6-(2,3-Difluorocyclohex-1-en-1-yl)-N2-isopropyl-N4—((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00170
  • At 0° C., Compound 1 (20 mg, 0.06 mmol) was dissolved in DCM (3 mL), and DAST (17 mg, 0.12 mmol) was added. The mixture was stirred at 0° C. for 2.5 hours. After the reaction was completed, the mixture was quenched by the addition of saturated NH4C1 aqueous solution (5 mL) and water (5 mL), and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give the title compound as a white solid (14 mg, yield: 70%). MS (m/z): 366.2 [M+H]+
  • 1H 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 in the below table were prepared according to the procedure of Compound 35 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    36
    Figure US20210363115A2-20211125-C00171
         		348.0 1H NMR (400 MHz, CD3OD): δ 7.16-6.94 (m, 1H), 5.25-5.06 (m, 1H), 5.05-4.89 (m, 1H), 4.27-4.06 (m, 1H), 2.63-2.26 (m, 2H), 1.95-1.63 (m, 4H), 1.39-1.30 (d, J = 5.2 Hz, 3H), 1.24-1.16 (m, 6H). Comp. 124
    37
    Figure US20210363115A2-20211125-C00172
         		348.3 1H NMR (400 MHz, CD3OD): δ 7.26-7.00 (m, 1H), 5.08-4.85 (m, 2H), 4.26-4.07 (m, 1H), 2.87-2.70 (m, 1H), 2.68-2.53 (m, 1H), 2.44-2.26 (m, 2H), 1.95-1.80 (m, 2H), 1.36-1.30 (m, 3H), 1.20-1.16 (m, 6H). Comp. 144
    38
    Figure US20210363115A2-20211125-C00173
         		348.3 1H NMR (400 MHz, CD3OD): δ 7.13-6.85 (m, 1H), 5.03-4.85 (m, 2H), 4.24-4.07 (m, 1H), 2.63-2.35 (m, 4H), 2.01-1.82 (m, 2H), 1.36-1.31 (m, 3H), 1.20-1.16 (m, 6H). Com. 145
    • Compound 39 (*)3-(4,6-Bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohept-2-en-1-ol
  • Figure US20210363115A2-20211125-C00174
  • Under nitrogen atmosphere, 1 mol/L (S)—CBS/THF solution (1.4 mL, 1.4 mmol) was added to dry THF (5 mL) under ice bath cooling ° C., then to the solution was added 2 mol/L BH3-Me2S/THF solution (1.4 mL, 2.8 mmol) in one-portion. After stirred for 2 minutes, 3-(4,6-bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazin-2-yl)-2-fluoro cyclohept-2-en-1-one (prepared according to the procedure of Compound 1 using Intermediate I-10, 600 mg, 1.4 mmol) in THF (3 mL) was added dropwise and the mixture was stirred in ice-bath for 1 hour. Then, MeOH (0.5 mL), EtOAc (10 mL) and water (20 mL) were added to the reaction mixture. The organic layer was collected. The aqueous was extracted with EtOAc (10 mL). The organic layers were combined, dried over Na2SO4 and filtered. The filtrate was condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give the title compound as white solid (60 mg, yield: 10%). MS (m/z): 420.1 [M+H]+
  • 1H 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, 3H), 2.37-2.23 (m, 1H), 2.01-1.82 (m, 3H), 1.74-1.60 (m, 3H).
  • The compounds in the below table were prepared according to the procedure of Compound 39 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    40
    Figure US20210363115A2-20211125-C00175
         		426.1 1H NMR (400 MHz, CD3OD): δ 4.98-4.87 (m, 1H), 4.51-4.41 (m, 1H), 4.31-4.16 (m, 1H), 2.97-2.84 (m, 2H), 2.73-2.49 (m, 3H), 2.37-2.23 (m, 1H), 2.00-1.81 (m, 3H), 1.72-1.58 (m, 3H), 1.39-1.30 (m, 3H). I-9
    41
    Figure US20210363115A2-20211125-C00176
         		400.1 1H NMR (400 MHz, CD3OD): δ 5.00-4.89 (m, 1H), 4.69-4.44 (m, 5H), 4.34-4.22 (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). I-72
    42
    Figure US20210363115A2-20211125-C00177
         		388.2 1H NMR (400 MHz, CD3OD): δ 5.00-4.89 (m, 1H), 4.33-4.21 (m, 1H), 3.13-2.99 (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). I-73
    43
    Figure US20210363115A2-20211125-C00178
         		376.1 1H NMR (400 MHz, CD3OD): δ 4.51-4.18 (m, 5H), 3.01-2.82 (m, 2H), 2.71-2.45 (m, 3H), 2.38-2.20 (m, 1H), 1.87-1.59 (m, 4H), 1.27-1.19 (m, 3H). I-74
    44
    Figure US20210363115A2-20211125-C00179
         		438.1 1H NMR (400 MHz, CD3OD): δ 8.47-8.11 (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). I-56
    45
    Figure US20210363115A2-20211125-C00180
         		384.1 1H NMR (400 MHz, CD3OD): δ 8.37-8.29 (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). I-57
    46
    Figure US20210363115A2-20211125-C00181
         		375.1 1H NMR (400 MHz, CD3OD): δ 8.63-8.10 (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), 2.68-2.50 (m, 1H), 2.43-2.28 (m, 1H), 1.89-1.61 (m, 4H), 1.23-1.16 (m, 6H). I-58
    47
    Figure US20210363115A2-20211125-C00182
         		409.2 1H NMR (400 MHz, CD3OD): δ 8.48-8.19 (m, 1H), 8.14-8.04 (m, 1H), 7.65-7.46 (m, 1H), 4.38-4.26 (m, 1H), 2.73-2.58 (m, 1H), 2.49-2.34 (m, 1H), 1.91-1.64 (m, 4H), 1.32 (s, 9H). I-59
    48
    Figure US20210363115A2-20211125-C00183
         		375.2 1H NMR (400 MHz, CD3OD): δ 7.50-7.42 (m, 1H), 7.26-7.20 (m, 1H), 6.81-6.68 (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). I-60
    49
    Figure US20210363115A2-20211125-C00184
         		356.1 1H NMR (400 MHz, CD3OD): δ 4.39-4.18 (m, 2H), 2.99-2.86 (m, 2H), 2.80-2.46 (m, 4H), 2.39-2.23 (m, 1H), 1.89-1.82 (m, 2H), 1.81-1.62 (m, 2H), 0.79-0.67 (m, 2H), 0.55-0.48 (m, 2H). I-36
    50
    Figure US20210363115A2-20211125-C00185
         		370.1 1H NMR (400 MHz, CD3OD): δ 4.45-4.14 (m, 2H), 3.05-2.82 (m, 2H), 2.79-2.23 (m, 5H), 1.91-1.61 (m, 4H), 1.18-0.45 (m, 6H). I-38
    51
    Figure US20210363115A2-20211125-C00186
         		358.1 1H NMR (400 MHz, CD3OD): δ 4.35-4.20 (m, 2H), 4.20-4.06 (m, 1H), 2.98-2.86 (m, 2H), 2.70-2.45 (m, 3H), 2.38-2.23 (m, 1H), 1.89-1.82 (m, 2H), 1.81-1.60 (m, 2H), 1.19 (s, 6H). I-37
    52
    Figure US20210363115A2-20211125-C00187
         		371.1 1H NMR (400 MHz, CD3OD): δ 4.99-4.87 (m, 1H), 4.33-4.23 (m, 1H), 2.64-2.45 (m, 1H), 2.40-2.21 (m, 1H), 1.89-1.71 (m, 3H), 1.70-1.58 (m, 1H), 1.36-1.30 (m, 3H). I-39
    53
    Figure US20210363115A2-20211125-C00188
         		371.1 1H NMR (400 MHz, CD3OD): δ 4.98-4.88 (m, 1H), 4.35-4.19 (m, 1H), 2.63-2.44 (m, 1H), 2.44-2.21 (m, 1H), 1.93-1.70 (m, 3H), 1.70-1.53 (m, 1H), 1.39-1.29 (m, 3H). I-40
    54
    Figure US20210363115A2-20211125-C00189
         		420.1 1H NMR (400 MHz, CD3OD): δ 8.60-8.22 (m, 2H), 8.09-7.74 (m, 1H), 4.38-4.27 (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). I-41
    55
    Figure US20210363115A2-20211125-C00190
         		365.1 1H NMR (400 MHz, CD3OD): δ 4.36-4.15 (m, 2H), 3.02-2.81 (m, 2H), 2.73-2.41 (m, 3H), 2.40-2.19 (m, 1H), 1.89-1.71 (m, 3H), 1.70-1.59 (m, 1H). I-42
    56
    Figure US20210363115A2-20211125-C00191
         		360.1 1H NMR (400 MHz, CD3OD): δ 4.32-4.19 (m, 2H), 4.19-4.04 (m, 1H), 2.98-2.83 (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). I-37
    57
    Figure US20210363115A2-20211125-C00192
         		348.1 1H NMR (400 MHz, CD3OD): δ 8.16-7.44 (m, 2H), 4.38-4.24 (m, 1H), 4.24-4.10 (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). I-43
    58
    Figure US20210363115A2-20211125-C00193
         		388.0 1H NMR (400 MHz, CD3OD): δ 8.61-8.24 (m, 2H), 8.04-7.81 (m, 1H), 4.39-4.27 (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). I-44
    59
    Figure US20210363115A2-20211125-C00194
         		348.1 1H NMR (400 MHz, CD3OD): δ 8.39-8.25 (m, 2H), 7.86-7.79 (m, 1H), 7.13-7.02 (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). I-45
    60
    Figure US20210363115A2-20211125-C00195
         		400.1 1H NMR (400 MHz, CD3OD): δ 9.07-8.95 (m, 1H), 8.49-8.43 (m, 1H), 7.68-7.57 (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). I-46
    61
    Figure US20210363115A2-20211125-C00196
         		409.1 1H NMR (400 MHz, CD3OD): δ 8.91-8.64 (m, 1H), 8.27-8.16 (m, 1H), 7.11-6.99 (m, 1H), 4.38-4.28 (m, 1H), 2.74-2.56 (m, 1H), 2.48-2.33 (m, 1H), 1.92-1.84 (m, 2H), 1.84-1.76 (m, 1H), 1.73-1.64 (m, 1H), 1.33 (s, 9H). I-47
    62
    Figure US20210363115A2-20211125-C00197
         		395.1 1H NMR (400 MHz, CD3OD): δ 8.75-8.53 (m, 1H), 8.25-8.15 (m, 1H), 7.83-7.73 (m, 2H), 7.66-7.59 (m, 1H), 7.45-7.36 (m, 1H), 4.39-4.28 (m, 1H), 4.26-4.15 (m, 1H), 2.73-2.56 (m, 1H), 2.48-2.33 (m, 1H), 1.92-1.85 (m, 2H), 1.85-1.75 (m, 1H), 1.72-1.63 (m, 1H), 1.27-1.20 (m, 6H). I-48
    63
    Figure US20210363115A2-20211125-C00198
         		398.1 1H NMR (400 MHz, CD3OD): δ 8.18-8.11 (m, 1H), 8.09-8.01 (m, 1H), 7.52-7.46 (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), 1.90-1.84 (m, 2H), 1.84-1.74 (m, 1H), 1.71-1.63 (m, 1H), 1.25-1.18 (m, 6H). I-49
    64
    Figure US20210363115A2-20211125-C00199
         		398.1 1H NMR (400 MHz, CD3OD): δ 8.25-8.10 (m, 1H), 7.94-7.86 (m, 1H), 7.66-7.39 (m, 2H), 4.35-4.25 (br, 1H), 4.23-4.11 (m, 1H), 4.02 (s, 3H), 2.70-2.51 (m, 1H), 2.45-4.28 (m, 1H), 1.91-1.83 (m, 2H), 1.83-1.74 (m, 1H), 1.71-1.62 (m, 1H), 1.26-1.17 (m, 6H). I-50
    65
    Figure US20210363115A2-20211125-C00200
         		401.1 1H NMR (400 MHz, CD3OD): δ 8.89-8.84 (m, 1H), 8.83-8.66 (m, 1H), 7.98-7.91 (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). I-51
    66
    Figure US20210363115A2-20211125-C00201
         		385.1 1H NMR (400 MHz, CD3OD/CDCl3 = 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). I-52
    67
    Figure US20210363115A2-20211125-C00202
         		414.1 1H NMR (400 MHz, CD3OD): δ 8.38-8.22 (m, 2H), 7.89-7.76 (m, 1H), 7.12-7.01 (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). I-53
    68
    Figure US20210363115A2-20211125-C00203
         		449.1 1H NMR (400 MHz, CD3OD): δ 8.86-7.07 (m, 6H), 5.19-4.97 (m, 1H), 4.41-4.27 (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). I-62
    69
    Figure US20210363115A2-20211125-C00204
         		418.1 1H NMR (400 MHz, CD3OD): δ 5.00-4.87 (m, 2H), 4.36-4.22 (m, 1H), 2.65-2.51 (m, 1H), 2.43-2.29 (m, 1H), 1.89-1.60 (m, 4H), 1.38-1.29 (m, 6H). I-32
    70
    Figure US20210363115A2-20211125-C00205
         		443.1 1H NMR (400 MHz, CD3OD): δ 8.64-7.73 (m, 3H), 4.43-4.27 (m, 1H), 3.53-3.43 (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). I-66
    71
    Figure US20210363115A2-20211125-C00206
         		443.1 1H NMR (400 MHz, CD3OD): δ 8.55-8.36 (m, 2H), 8.01-7.90 (m, 1H), 4.41-4.30 (m, 1H), 2.77-2.62 (m, 1H), 2.52-2.32 (m, 1H), 1.96-1.64 (m, 4H), 1.31 (s, 9H). I-63
    72
    Figure US20210363115A2-20211125-C00207
         		465.0 1H NMR (400 MHz, CD3OD): δ 8.58-7.52 (m, 5H), 7.14-6.94 (m, 2H), 4.42-4.27 (m, 1H), 2.80-2.65 (m, 1H), 2.56-2.37 (m, 1H), 1.94-1.66 (m, 4H). I-64
    73
    Figure US20210363115A2-20211125-C00208
         		393.1 1H NMR (400 MHz, CD3OD): δ 8.09-7.85 (m, 2H), 7.51-7.39 (m, 1H), 4.41-4.26 (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). I-65
    74
    Figure US20210363115A2-20211125-C00209
         		363.1 1H NMR (400 MHz, CD3OD): δ 8.02-7.88 (m, 1H), 7.85-7.72 (m, 1H), 7.52-7.39 (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). I-67
    75
    Figure US20210363115A2-20211125-C00210
         		444.1 1H NMR (400 MHz, CD3OD): δ 9.18-8.77 (m, 2H), 4.45-4.24 (m, 1H), 2.81-2.64 (m, 1H), 2.53-2.34 (m, 1H), 2.00-1.66 (m, 4H), 1.37-1.26 (m, 9H). I-68
    76
    Figure US20210363115A2-20211125-C00211
         		384.1 1H NMR (400 MHz, CD3OD): δ 9.63-9.01 (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). I-69
    77
    Figure US20210363115A2-20211125-C00212
         		388.1 1H NMR (400 MHz, CD3OD): δ 6.59-6.32 (m, 1H), 4.36-4.27 (m, 1H), 4.23-4.10 (m, 1H), 4.03-3.90 (m, 2H), 2.82-2.72 (m, 2H), 2.65-2.51 (m, 1H), 2.46-2.29 (m, 1H), 2.09-1.97 (m, 2H), 1.90-1.63 (m, 6H), 1.25-1.16 (m, 6H). I-70
    78
    Figure US20210363115A2-20211125-C00213
         		378.2 1H NMR (400 MHz, CD3OD): δ 5.04-4.89 (m, 1H), 4.34-4.24 (m, 1H), 3.25-3.07 (m, 2H), 2.65-2.48 (m, 1H), 2.40-2.20 (m, 1H), 1.96-1.59 (m, 5H), 1.38-1.30 (m, 3H), 0.95-0.87 (m, 6H). I-13
    79
    Figure US20210363115A2-20211125-C00214
         		404.1 1H NMR (400 MHz, CD3OD): δ 5.03-4.90 (m, 1H), 4.35-4.26 (m, 1H), 4.21-4.00 (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). I-76
    80
    Figure US20210363115A2-20211125-C00215
         		376.1 1H NMR (400 MHz, CD3OD): δ 5.50-4.87 (m, 1H), 4.34-4.23 (m, 1H), 3.26-3.14 (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). I-77
    81
    Figure US20210363115A2-20211125-C00216
         		364.1 1H NMR (400 MHz, CD3OD): δ 5.01-4.87 (m, 1H), 4.34-4.22 (m, 1H), 3.37-3.30 (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). I-78
    199
    Figure US20210363115A2-20211125-C00217
         		431.0 1H NMR (400 MHz, CD3OD): δ 8.91-8.85 (m, 1H), 8.80-8.66 (m, 1H), 7.99-7.91 (m, 1H), 7.82-7.72 (m, 1H), 4.38-4.28 (m, 1H), 3.53-3.40 (m, 2H), 2.72-2.58 (m, 1H), 2.48-4.34 (m, 1H), 1.93-1.85 (m, 2H), 1.84-1.76 (m, 1H), 1.73-1.65 (m, 1H), 1.25-1.19 (m, 6H). I-79
    204
    Figure US20210363115A2-20211125-C00218
         		389.1 1H NMR (400 MHz, CD3OD): δ 8.30-8.09 (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). I-28
    224
    Figure US20210363115A2-20211125-C00219
         		362.0 1H NMR (400 MHz, CD3OD): δ 5.12-4.89 (m, 1H), 4.36-4.21 (m, 1H), 2.81-2.66 (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). I-16
    240
    Figure US20210363115A2-20211125-C00220
         		368.0 1H NMR (400 MHz, CD3OD): δ 4.98-4.90 (m, 1H), 4.60-4.52 (m, 1H), 4.49-4.40 (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). I-83
    241
    Figure US20210363115A2-20211125-C00221
         		398.0 1H NMR (400 MHz, CD3OD): δ 4.35-4.17 (m, 2H), 4.16-4.04 (m, 2H), 3.00-2.84 (m, 2H), 2.71-2.48 (m, 3H), 2.42-2.26 (m, 1H), 1.91-1.82 (m, 2H), 1.82-1.73 (m, 1H), 1.70-1.60 (m, 1H). I-84
    • Compounds 82 and 83 (*)3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-6,6-D2-1-ol and 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1,6,6-D3-1-ol
  • Figure US20210363115A2-20211125-C00222
    • (A) 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one-6,6-D2
  • To a solution of 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (prepared according to the procedure of Compound 1 using Intermediate I-3, 114 mg, 0.27 mmol) in 1,4-dioxane (6 mL) was added D2O (2 mL) and K2CO3 (75 mg, 0.54 mmol). The mixture was stirred at 80° C. for 4.5 hours. Then, the solvent was removed in vacuo and the residue was purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to afford the title compound as 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-fluoro-cyclohex-2-en-6,6-D2-1-ol
  • Compound 82 was prepared according to the procedure of Compound 39. MS (m/z): 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-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1,6,6-D3-1-ol
  • Compound 83 was prepared according to the procedure of Compound 1 step (B), using NaBD4. MS (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 in the below table were prepared according to the procedure of Compound 82 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    84
    Figure US20210363115A2-20211125-C00223
         		414.1 1H NMR (400 MHz, CD3OD): δ 4.98-4.89 (m, 1H), 4.35-4.13 (m, 2H), 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), 1.38-1.28 (m, 3H). I-54
    85
    Figure US20210363115A2-20211125-C00224
         		408.1 1H NMR (400 MHz, CD3OD): δ 4.36-4.14 (m, 3H), 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). I-10
    86
    Figure US20210363115A2-20211125-C00225
         		422.1 1H NMR (400 MHz, CD3OD): 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), 1.83-1.73 (m, 1H), 1.71-1.63 (m, 1H). I-14
    87
    Figure US20210363115A2-20211125-C00226
         		420.0 1H NMR (400 MHz, CD3OD): 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), 1.70-1.58 (m, 1H), 1.36-1.31 (m, 6H). I-32
    89
    Figure US20210363115A2-20211125-C00227
         		445.1 1H NMR (400 MHz, CD3OD): 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), 1.85-1.74 (m, 1H), 1.71-1.60 (m, 1H), 1.31 (s, 9H). I-63
  • The compounds in the below table were prepared according to the procedure of Compound 83 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    90
    Figure US20210363115A2-20211125-C00228
         		415.1 1H NMR (400 MHz, CD3OD): 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), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H). I-54
    91
    Figure US20210363115A2-20211125-C00229
         		409.1 1H 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), 1.68-1.57 (m, 1H). I-10
    92
    Figure US20210363115A2-20211125-C00230
         		361.1 1H NMR (400 MHz, CD3OD): 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), 1.80-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.25-1.11 (br, 6H). I-37
    • Compound 93 (*)3-(4-Amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00231
    • (A) (R)-2-fluoro-3-(4-((4-methoxybenzyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B2)
  • The title Compound B2 was prepared according to the procedure 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-fluoro-cyclohex-2-en-1-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 NaHCO3 aqueous solution and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give Compound B3 as 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-fluoro-cyclohex-2-en-1-ol
  • Compound 93 was prepared according to the procedure of 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 Diastereoisomers
  • Figure US20210363115A2-20211125-C00232
    • (A) 2,6-difluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B4)
  • Under nitrogen atmosphere, to 1 mol/L of LiHMDS/THF solution (14.85 mL, 14.85 mmoL) was added dripwise a solution of Compound 123 (1.2 g, 3.30 mmol) in THF (20 mL) 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 added drop-wise slowly, then the mixture was warmed to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was quenched by the addition of saturated NH4Cl aqueous solution (30 mL). The organic layer was collected and the aqueous was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was condensed in vacuo and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give Compound B4 as 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-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol
  • Compounds 95 and 96 were prepared according to the procedure of Compound 39, and purified by preparative TLC (eluting with 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 (F, 3H), 1.23-1.13 (s, 6H).
  • Compound 96, Rf≈0.50, MS (m/z): 382.2 [M+H]+; 1H NMR (400 MHz, CD3OD): δ 4.97-4.90 (4, 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 in the below table were prepared according to the procedure of Compounds 95 and 96 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
     97
    Figure US20210363115A2-20211125-C00233
         		436.2 1H NMR (400 MHz, CD3OD): 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), 1.37-1.31 (m, 6H). I-3
     98
    Figure US20210363115A2-20211125-C00234
         		436.1 1H NMR (400 MHz, CD3OD): 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), 2.17-2.02 (m, 1H), 1.98-1.84 (m, 1H), 1.40-1.29 (m, 6H). I-3
    201
    Figure US20210363115A2-20211125-C00235
         		424.2 1H NMR (400 MHz, CD3OD): 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). I-10
    202
    Figure US20210363115A2-20211125-C00236
         		424.2 1H NMR (400 MHz, CD3OD): 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), 2.13-2.01 (m, 1H), 1.96-1.81 (m, 1H). I-10
    225
    Figure US20210363115A2-20211125-C00237
         		394.2 1H NMR (400 MHz, CD3OD): 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), 2.07-1.87 (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). I-77
    226
    Figure US20210363115A2-20211125-C00238
         		394.2 1H NMR (400 MHz, CD3OD): 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), 2.52-2.30 (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). I-77
    227
    Figure US20210363115A2-20211125-C00239
         		430.0 1H NMR (400 MHz, CD3OD): 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). I-9
    228
    Figure US20210363115A2-20211125-C00240
         		430.0 1H NMR (400 MHz, CD3OD): 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), 2.77- 2.34 (m, 4H), 2.16-2.02 (m, 1H), 1.96-1.83 (m, 1H), 1.41-1.30 (m, 3H). I-9
    230 & 231
    Figure US20210363115A2-20211125-C00241
         		382.1 1H NMR (400 MHz, DMSO-d6): 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), 3.22-3.10 (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), 0.86-0.79 (m, 3H). I-18
    Figure US20210363115A2-20211125-C00242
         		382.0 1H NMR (400 MHz, DMSO-d6): 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), 3.22-3.09 (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). I-18
    232
    Figure US20210363115A2-20211125-C00243
         		444.2 1H NMR (400 MHz, CD3OD): 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), 2.28-2.14 (m, 2H), 2.13-1.91 (m, 4H), 1.85-1.70 (m, 1H), 1.39-1.29 (m, 3H). I-82
    233
    Figure US20210363115A2-20211125-C00244
         		444.2 1H NMR (400 MHz, CD3OD): 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), 1.41-1.27 (m, 3H). I-82
    Note:
    Compounds 230 and 231 were obtained via flash column chromatography (eluting with gradient H2O/MeOH = 100:0-0:100). The compound obtained from the first elution was named as Compound 230 and the compound obtained from the second elution was named as Compound 231.
    • Compounds 242, 266-269 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-D-1-ol, Optically Pure Diastereoisomers
  • Figure US20210363115A2-20211125-C00245
    • (A) 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluoro-cyclohex-2-en-1-one
  • Compound 242 was prepared according to the procedure of Step A of Compounds 95 and 96, using Compound 295 and corresponding 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-difluoro-cyclohex-2-en-1-one, optically pure diastereoisomers
  • Compound 242 was separated by chiral HPLC to give a pair of optically pure diastereoisomers, Compounds 246 and 247 (Chiral HMPL conditions: Column: AD-H (0.46 cm I.D.×15 cm L); mobile phase: n-heptane/isopropanol=80/20; flow rate: 0.5 mL/min; detection wavelength: UV 254 nm). The first elution (Compound 246: RT=2.025 min, de %=100%, MS (m/z): 434.0 [M+H]+). The 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-2-en-1-D-1-ol, Optically Pure Diastereoisomers
  • Compounds 266 and 267 were prepared according to the procedure of Compound 1, using Compound 246 and NaBD4, purified by flash column chromatography (eluting with PE/EA).
  • 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 of Compound 1, using Compound 247 and NaBD4, purified by flash column chromatography (eluting with PE/EA).
  • 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
  • Figure US20210363115A2-20211125-C00246
    • (A) (R)-2,6,6-trifluoro-3-(4-(isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B5)
  • Under nitrogen atmosphere, to a solution of 1 mol/L LiHMDS in THF (14.85 mL, 14.85 mmoL) was added a solution of Compound 123 (1.2 g, 3.30 mmol) in THF (20 mL) dropwise at −78° C. The mixture was stirred at 0° C. for 2 hours. Then, to the mixture was added a solution of NFSI (3.12 g, 9.90 mmol) in THF drop-wise, then the reaction was warmed to room temperature slowly and stirred for another 3 hours. After the reaction was completed, the mixture was quenched by the addition of saturated NH4Cl aqueous solution (30 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and filtered. The filtrate was condensed in vacuo and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give compound B5 as a white solid (25 mg, yield: 1.9%). MS (m/z): 398.1 [M+H]+
    • (B) 2,6,6-Trifluoro-3-(4-(isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol
  • Compound 94 was prepared according to the procedure of Compound 39, using compound B5 and corresponding reagents. MS (m/z): 400.2 [M+H]N
  • 1H NMR (400 MHz, CD3OD): δ 4.97-4.88 (m, 1H), 4.33-4.19 (m, 1H), 4.19-4.07 (m, H), 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 (n, 6H).
  • The compounds in the below table were prepared according to the procedure of Compound 94 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    196
    Figure US20210363115A2-20211125-C00247
         		454.1 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). I-3
    203
    Figure US20210363115A2-20211125-C00248
         		442.2 1H NMR (400 MHz, CD3OD): δ 4.37-4.14 (m, 3H), 3.00-2.85 (m, 4H), 2.74-2.44 (m, 6H), 2.24-2.02 (m, 2H). I-10
    208
    Figure US20210363115A2-20211125-C00249
         		440.0 1H NMR (400 MHz, CD3OD): δ 5.01-4.92 (m, 1H), 4.35-4.01 (m, 3H), 2.77-2.67 (br, 1H), 2.63-2.46 (m, 1H), 2.33-2.01 (m, 2H), 1.41-1.32 (m, 3H). I-76
    209
    Figure US20210363115A2-20211125-C00250
         		412.2 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). I-78
    210
    Figure US20210363115A2-20211125-C00251
         		400.0 1H NMR (400 MHz, CD3OD): δ 5.03-4.89 (m, 1H), 4.55-4.37 (m, 1H), 4.02-3.77 (m, 2H), 2.81-2.61 (m, 1H), 2.58-2.37 (m, 1H), 2.17-2.05 (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). I-18
    239
    Figure US20210363115A2-20211125-C00252
         		448.0 1H NMR (400 MHz, CD3OD): δ 5.02-4.89 (m, 1H), 4.38-4.14 (m, 2H), 3.03-2.86 (m, 2H), 2.78-2.44 (m, 4H), 2.30-2.01 (m, 2H), 1.42-1.30 (m, 3H). I-54
    245
    Figure US20210363115A2-20211125-C00253
         		440.0 1H NMR (400 MHz, CD3OD): δ 5.01-4.92 (m, 1H), 4.35-4.01 (m, 3H), 2.77-2.67 (br, 1H), 2.63-2.46 (m, 1H), 2.33-2.01 (m, 2H), 1.41-1.32 (m, 3H). I-76
    • Compound 234 3-(4-((Cyclopropylmethyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00254
    • (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 according to the procedure of Compound 1 using Intermediate I-77) and corresponding 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 of Compound 1, using compound B7 and corresponding 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 in the below table were prepared according to the procedure of Compound 234 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    211
    Figure US20210363115A2-20211125-C00255
         		455.1 1H NMR (400 MHz, CD3OD): δ 5.03-4.87 (m, 2H), 2.82-2.66 (m, 1H), 2.62-2.45 (m, 1H), 2.27-2.02 (m, 2H), 1.40-1.29 (m, 6H). I-3
    235
    Figure US20210363115A2-20211125-C00256
         		462.2 1H NMR (400 MHz, CD3OD): δ 5.02-4.88 (m, 1H), 4.54-4.39 (m, 1H), 4.33-4.17 (m, 1H), 2.79-2.64 (m, 1H), 2.61-2.44 (m, 2H), 2.29-2.00 (m, 6H), 1.90-1.67 (m, 1H), 1.39-1.31 (m, 3H). I-82
    238
    Figure US20210363115A2-20211125-C00257
         		398.0 1H NMR (400 MHz, CD3OD): δ 5.05-4.91 (m, 1H), 4.31-4.20 (m, 1H), 2.86-2.60 (m, 2H), 2.59-2.43 (m, 1H), 2.24-2.04 (m, 2H), 1.38-1.31 (m, 3H), 0.78-0.66 (m, 2H), 0.57-0.44 (m, 2H). I-16
    248
    Figure US20210363115A2-20211125-C00258
         		400.0 1H NMR (400 MHz, CD3OD): δ 4.98-4.90 (m, 1H), 4.32-4.19 (m, 1H), 3.38-3.23 (m, 2H), 2.80-2.61 (m, 1H), 2.60-2.41 (m, 1H), 2.28-2.02 (m, 2H), 1.64-1.52 (m, 2H), 1.38-1.30 (m, 3H), 0.99-0.87 (m, 3H). I-18
    • Compound 259 3-(4-((3,3-Difluorocyclobutyl)amino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00259
    • (A) (R)-6-(3-((tert-butyldimethylsilyl)oxy)-2-fluorocyclohexa-1,3-dien-1-yl)-N2-(3,3-difluorocyclobutyl)-N4-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (B9)
  • Under N2, to a mixture of compound B8 (prepared according to Compound 39 using Intermediate I-9: 750 mg, 1.83 mmol) and Et3N (371 mg, 3.66 mmol) in dry DCM (15 mL) 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. Then, it was poured into water and extracted with DCM. The organic layer was collected, dried over anhydrous Na2SO4 condensed under reduced pressure and purified by flash column chromatography (eluting with PE/EA) to give 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-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one (B10)
  • Under N2, a solution of compound B9 (958 mg, 1.83 mmol) in dry MeCN (20 mL) was added to the suspension of Selectfluor® (778 mg, 2.20 mmol) in dry acetonitrile (20 mL) dropwise at 0-5° C. and stirred for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was collected, condensed under reduce pressure and purified by flash column chromatography (eluting with PE/EA) to give compound B10 as 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-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B11)
  • Under N2, to a solution of compound B10 (512 mg, 1.12 mmol) in dry THF (10 mL) was added 1M LiHMDS/THF solution (3.47 mL, 3.47 mmol) dropwise at −78° C. and stirred for 30 minutes. Then to the mixture was added NFSI (388 mg, 1.23 mmol)/THF solution (10 mL) dropwise at −78° C. and the reaction was stirred for 2 hours. After the reaction was completed, saturated NH4Cl aqueous solution was added to quench the reaction. The mixture was extracted with EtOAc. The organic layer was collected, condensed under reduce pressure and purified by flash column chromatography (eluting with PE/EA) to give compound B11 as 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-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol
  • Compound 259 was prepared according to the procedure of Compound 39, using compound B11 and corresponding 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 in the below table were prepared according to the procedure of Compound 259 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    260
    Figure US20210363115A2-20211125-C00260
         		398.0 1H NMR (400 MHz, CD3OD): 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), 1.31-1.23 (m, 3H), 0.69-0.59 (m, 2H), 0.48-0.38 (m, 2H). I-85
    261
    Figure US20210363115A2-20211125-C00261
         		394.2 1H NMR (400 MHz, CD3OD): 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). I-37
    270
    Figure US20210363115A2-20211125-C00262
         		440.2 1H NMR (400 MHz, CD3OD) δ 4.92-4.82 (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). I-86
    271
    Figure US20210363115A2-20211125-C00263
         		449.2 1H NMR (400 MHz, CD3OD): 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), 4.52-4.39 (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). I-87
    • Compound 274 3-(4-((3,3-difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-D-1-ol
  • Figure US20210363115A2-20211125-C00264
    Figure US20210363115A2-20211125-C00265
    • (A) 3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2-fluoro-cyclohex-2-en-1-one (B12)
  • Under N2, a mixture of Intermediate I-37 (4.17 g, 15.0 mmol), Intermediate I-88 (4.32 g, 18.0 mmol), Na2PdCl4 (221 mg, 0.75 mmol), DTBPPS (402 mg, 1.5 mmol), K2CO3 (5.18 g, 37.5 mmol), MeCN (40 mL) and H2O (10 mL) was stirred at 60° C. for 2 hours. After the reaction was completed, the mixture was poured into water and extracted with DCM. The organic layer was collected, condensed and purified by flash column chromatography (eluting with PE/EA) to give Compound B12 as 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-triazin-2-yl)-2,6-difluorocyclohex-2-en-1-one (B13)
  • The title compound B13 was prepared according to the procedures of Steps A and B of Compound 259, using Compound B12 and corresponding reagents. MS (m/z): 374.1 [M+H]+
    • (C) 3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-one (B14)
  • The title compound B14 was prepared according to the procedures of Steps A and B of Compound 259, using compound B13 and corresponding reagents. MS (m/z): 392.0 [M+H]+
    • (D) 3-(4-((3,3-Difluorocyclobutyl)amino)-6-(isopropylamino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-D-1-ol
  • Compound 274 was prepared according to the procedure of Step B of Compound 1, using Compound B14, NaBD4 and corresponding 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 in the below table were prepared according to the procedure of Compound 274 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    275
    Figure US20210363115A2-20211125-C00266
         		479.2 1H NMR (400 MHz, CD3OD): 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), 2.33- 2.06 (m, 2H), 1.42-1.20 (m, 9H). I-63
    276
    Figure US20210363115A2-20211125-C00267
         		480.2 1H NMR (400 MHz, CD3OD): 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), 1.42- 1.26 (m, 9H). I-63
    277
    Figure US20210363115A2-20211125-C00268
         		454.2 1H NMR (400 MHz, CD3OD): 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), 1.44- 1.26 (m, 6H). I-89
    278
    Figure US20210363115A2-20211125-C00269
         		399.2 1H NMR (400 MHz, CD3OD): 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), 0.82- 0.66 (m, 2H), 0.58-0.45 (m, 2H). I-85
    279
    Figure US20210363115A2-20211125-C00270
         		399.0 1H NMR (400 MHz, CD3OD): 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), 0.86- 0.67 (m, 2H), 0.62-0.46 (m, 2H). I-16
    281
    Figure US20210363115A2-20211125-C00271
         		436.2 1H NMR (400 MHz, CD3OD): 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), 1.50- 1.20 (m, 6H). I-3
    282
    Figure US20210363115A2-20211125-C00272
         		437.2 1H NMR (400 MHz, CD3OD): 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). I-3
    283
    Figure US20210363115A2-20211125-C00273
         		454.0 1H NMR (400 MHz, CD3OD): 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), 1.42-1.27 (m, 6H). I-32
    293
    Figure US20210363115A2-20211125-C00274
         		430.2 1H NMR (400 MHz, CD3OD): 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), 1.39- 1.34 (m, 3H), 1.29-1.26 (m, 9H). I-90
    294
    Figure US20210363115A2-20211125-C00275
         		430.2 1H NMR (400 MHz, CD3OD): 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), 1.39- 1.34 (m, 3H), 1.29-1.26 (m, 9H). I-91
    296
    Figure US20210363115A2-20211125-C00276
         		452.1 1H NMR (400 MHz, CD3OD): δ 5.01-4.88 (m, 2H), 3.07-2.09 (m, 4H), 1.39-1.31 (m, 6H). I-3
    298
    Figure US20210363115A2-20211125-C00277
         		437.1 1H NMR (400 MHz, CD3OD): 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). I-92
    • Compound 297 2,6,6-Trifluoro-3-(4-(methoxyamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00278
    • (A) (R)-3-(4-chloro-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluoro-cyclohex-2-en-1-one (B16)
  • The title compound B16 was prepared according to the procedure of Steps B and C of Compound 274, using Intermediate A4 and corresponding 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-2-yl)cyclohex-2-en-1-one (B17)
  • The title compound B17 was prepared according to the procedure of Compound 190, using Compound B16 and corresponding 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-2-yl)cyclohex-2-en-1-ol
  • Compound 297 was prepared according to the procedure of Step B of Compound 1, using compound B17 and corresponding 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)-2,6,6-trifluoro-cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00279
    • (A) (R)-2-fluoro-3-(4-((4-methoxyphenyl)amino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (B18)
  • The title compound B18 was prepared according to the procedure of Compound 1, using Intermediate I-105 and corresponding 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-fluoro-cyclohex-2-en-1-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 under vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 aqueous solution. The organic layer was collected, condensed under reduced pressure to give title compound B19 as yellow solid (800 mg, yield 79%), which was used for 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
  • Compound 280 was prepared according to the procedure of Compound 274, using Compound B19 and corresponding 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
  • Figure US20210363115A2-20211125-C00280
    • (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 of Compound 1, using Intermediate I-106 and corresponding reagents. MS (m/z): 542.1 [M+H]+
    • (B) 3-(4,6-Diamino-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (B21)
  • The title compound B21 was prepared according to the procedure of Step B of Compound 280, using compound B20 and corresponding 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-1-one (B22)
  • The title compound B22 was prepared according to the procedure of Steps B and C of Compound 274, using compound B21 and corresponding 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-one (B23)
  • A solution of Compound B22 (410 mg, 0.84 mmol) in concentrated HCl aqueous solution (1 mL) and MeOH (5 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc and adjusted to pH=8 with saturated NaHCO3 aqueous solution. The organic layer was collected, concentrated to dryness under vacuo and purified by flash column chromatography (eluting with MeOH and water) to give the title compound B23 as 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 the procedure of Step B of Compound 1, using Compound B23 and corresponding 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-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00281
    • (A) 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-one (B24)
  • To a sealed tube was added 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-fluorocyclohex-2-en-1-one (prepared according to the procedure of Compound 1 using Intermediate I-3, 700 mg, 1.69 mmol), NCS (224 mg, 1.69 mmol), TsOH.H2O (321 mg, 1.69 mmol) and MeCN (10 mL) in sequence. The mixture was heated to 80° C. and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give the title compound B24 as white solid (320 mg, yield 42.2%). MS (m/z): 450.1, 452.1 [M+H]+
    • (B) 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-6-chloro-2-fluoro-cyclohex-2-en-1-ol
  • Compound 99 was prepared according to the procedure of Compound 39 using Compound B24 and corresponding 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-2-yl)cyclohex-2-en-1-one
  • Figure US20210363115A2-20211125-C00282
  • To a flask were added Intermediate I-2 (500 mg, 1.76 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (391 mg, 1.76 mmol), Cs2CO3 (1144 mg, 3.52 mmol), Pd(PPh3)4 (101 mg, 0.09 mmol), 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 80° C. for 2 hours under nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as a white solid (350 mg, yield 57.9%). MS (m/z): 344.1 [M+H]+
  • 1H NMR (400 MHz, CD3OD): S 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 in the below table were prepared according to the procedure of Compound 122 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    123
    Figure US20210363115A2-20211125-C00283
         		362.1 1H NMR (400 MHz, CD3OD): δ 5.01-4.90 (m, 1H), 4.22-4.10 (m, 1H), 2.89-2.77 (m, 2H), 2.64-2.55 (m, 2H), 2.12-2.02 (m, 2H), 1.39-1.32 (m, 3H), 1.23-1.17 (m, 6H). I-2
    295
    Figure US20210363115A2-20211125-C00284
         		416.2 1H NMR (400 MHz, CD3OD): δ 5.00-4.88 (m, 2H), 2.91-2.78 (m, 2H), 2.62-2.53 (m, 2H), 2.11-2.00 (m, 2H), 1.40-1.30 (m, 6H). I-3
    • Compound 124 3-(4-(Isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00285
  • To a flask were added Compound 122 (250 mg, 0.73 mmol), CeCl3.7H2O (353 mg, 0.95 mmol) and EtOH (10 mL). The mixture was cooled to 0° C., NaBH4 (36 mg, 0.95 mmol) was added and the reaction was stirred at 0° C. for 2 hours. After the reaction was completed, the mixture was quenched by the addition of saturated NH4Cl aqueous solution (3 mL) and water (20 mL) and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as a white solid (210 mg, yield: 83.3%). MS (m/z): 346.0 [M+H]+
  • 1H 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 in the below table were prepared according to the procedure of Compound 124 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    125
    Figure US20210363115A2-20211125-C00286
         		332.0 1H NMR (400 MHz, CD3OD): δ 6.88-6.70 (m, 1H), 5.07-4.87 (m, 2H), 4.23-4.08 (m, 1H), 2.90-2.77 (m, 1H), 2.63-2.49 (m, 1H), 2.43-2.30 (m, 1H), 1.85-1.69 (m, 1H), 1.39-1.31 (m, 3H), 1.22-1.17 (m, 6H). I-2
    126
    Figure US20210363115A2-20211125-C00287
         		400.0 1H NMR (400 MHz, CD3OD): δ 7.23-7.01 (m, 1H), 5.08-4.87 (m, 2H), 4.37-4.27 (m, 1H), 2.49-2.35 (m, 2H), 1.98-1.82 (m, 2H), 1.68-1.53 (m, 2H), 1.39-1.32 (m, 6H). I-3
    127
    Figure US20210363115A2-20211125-C00288
         		388.1 1H NMR (400 MHz, CD3OD): δ 7.22-6.93 (m, 1H), 4.36-4.19 (m, 3H), 2.97-2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.45-2.34 (m, 2H), 1.97-1.80 (m, 2H), 1.67-1.51 (m, 2H). I-10
    128
    Figure US20210363115A2-20211125-C00289
         		358.1 1H NMR (400 MHz, CD3OD): δ 7.26-6.90 (m, 1H), 5.10-4.92 (m, 1H), 4.60-4.26 (m, 2H), 2.56- 2.23 (m, 4H), 2.11-1.81 (m, 4H), 1.79-1.49 (m, 4H), 1.42-1.28 (m, 3H). I-15
    129
    Figure US20210363115A2-20211125-C00290
         		344.1 1H NMR (400 MHz, CD3OD): δ 7.27-6.85 (m, 1H), 5.17-4.95 (m, 1H), 4.45-4.20 (m, 1H), 2.84-2.63 (m, 1H), 2.53-2.27 (m, 2H), 2.00-1.82 (m, 2H), 1.74-1.51 (m, 2H), 1.43-1.29 (m, 3H), 0.84-0.67 (m, 2H), 0.58-0.46 (m, 2H). I-16
    130
    Figure US20210363115A2-20211125-C00291
         		372.1 1H NMR (400 MHz, CD3OD): δ 7.22-6.89 (m, 1H), 5.09-4.92 (m, 1H), 4.41-4.18 (m, 2H), 2.54-2.31 (m, 2H), 2.09-1.82 (m, 4H), 1.80-1.69 (m, 2H), 1.67-1.44 (m, 6H), 1.40-1.31 (m, 3H). I-12
    131
    Figure US20210363115A2-20211125-C00292
         		376.1 1H NMR (400 MHz, CD3OD): δ 7.24-6.95 (m, 1H), 5.12-4.90 (m, 1H), 4.43-4.25 (m, 1H), 3.53-3.37 (m, 2H), 2.47-2.33 (m, 2H), 2.01-1.81 (m, 2H), 1.69-1.52 (m, 2H), 1.38-1.33 (m, 3H), 1.19 (s, 6H). I-7
    132
    Figure US20210363115A2-20211125-C00293
         		362.1 1H NMR (400 MHz, CD3OD): δ 7.23-6.91 (m, 1H), 5.12-4.91 (m, 1H), 4.43-4.25 (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). I-17
    133
    Figure US20210363115A2-20211125-C00294
         		346.1 1H NMR (400 MHz, CD3OD): δ 7.02-6.87 (m, 1H), 5.11-4.90 (m, 1H), 4.40-4.23 (m, 1H), 3.40-3.30 (m, 2H), 2.55-2.28 (m, 2H), 1.98-1.81 (m, 2H), 1.68-1.53 (m, 4H), 1.39-1.31 (m, 3H), 0.97- 0.89 (m, 3H). I-18
    134
    Figure US20210363115A2-20211125-C00295
         		360.1 1H NMR (400 MHz, CD3OD): δ 7.23-6.90 (m, 1H), 5.14-4.89 (m, 1H), 4.45-4.21 (m, 1H), 3.25-3.07 (m, 2H), 2.50-2.33 (m, 2H), 1.97-1.80 (m, 3H), 1.74- 1.51 (m, 2H), 1.38-1.31 (m, 3H), 0.95-0.89 (m, 6H). I-13
    135
    Figure US20210363115A2-20211125-C00296
         		332.1 1H NMR (400 MHz, CD3OD): δ 7.28-6.88 (m, 1H), 5.14-4.93 (m, 1H), 4.40-4.22 (m, 1H), 3.48-3.35 (m, 2H), 2.57-2.27 (m, 2H), 1.98-1.83 (m, 2H), 1.70-1.52 (m, 2H), 1.40-1.31 (m, 3H), 1.20-1.13 (m, 3H). I-19
    136
    Figure US20210363115A2-20211125-C00297
         		386.1 1H NMR (400 MHz, CD3OD): δ 7.22-6.92 (m, 1H), 5.11-4.88 (m, 1H), 4.41-4.26 (m, 1H), 3.95-3.72 (m, 1H), 2.53-2.31 (m, 2H), 2.08-1.86 (m, 4H), 1.79-1.70 (m, 2H), 1.68-1.53 (m, 3H), 1.41-1.20 (m, 8H). I-20
    137
    Figure US20210363115A2-20211125-C00298
         		374.1 1H NMR (400 MHz, CD3OD): δ 7.31-7.215 (m, 1H), 5.09-4.95 (m, 1H), 4.39-4.30 (m, 1H), 3.16-2.81 (m, 1H), 2.51-2.37 (m, 2H), 2.01- 1.84 (m, 2H), 1.71-1.51 (m, 2H), 1.40-1.34 (m, 3H), 1.22-1.11 (m, 6H). I-4
    • Compound 138 (R)-6-(3,3-difluorocyclohex-1-en-1-yl)-N2-isopropyl-N4-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00299
  • To a sealed tube were added Compound 122 (100 mg, 0.29 mmol), DAST (1 mL), BAST (1 mL) and DCM (10 mL). The mixture was stirred at 80° C. for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as a white solid (40 mg, yield: 38.1%). MS (m/z): 366.1 [M+H]+
  • 1H 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 in the below table was prepared according to the procedure of Compounds 138 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    139
    Figure US20210363115A2-20211125-C00300
         		394.0 1H NMR (400 MHz, CD3OD): δ 7.12-6.83 (m, 1H), 5.07-4.92 (m, 1H), 4.64-4.41 (m, 1H), 4.03-3.88 (m, 2H), 3.87-3.76 (m, 1H), 3.72-3.60 (m, 1H), 2.64-2.46 (m, 2H), 2.34-2.18 (m, 1H), 2.13-2.00 (m, 2H), 1.95-1.82 (m, 3H), 1.42-1.30 (m, 3H). I-8
    • Compound 140 6-(3-Methoxycyclohex-1-en-1-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00301
  • A mixture of Compound 126 (100 mg, 0.25 mmol) and Ag2O (115 mg, 0.5 mmol) in CH3I (4 mL) was stirred at reflux for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give 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)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00302
  • To a solution of Compound 126 (50 mg, 0.125 mmol) in dry DCM (3 mL) was added SOCl2 (16 mg, 0.137 mmol) under ice bath cooling ° C., and the mixture was stirred in ice bath for 30 minutes. Then, the solution was charged into a sealed tube, dimethylamine hydrochloride (20 mg, 0.25 mmol) was added, and the mixture was stirred at reflux overnight. After the reaction was completed, the mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was collected, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as a white solid (10 mg, yield: 18.9%). MS (m/z): 427.0 [M+H]+
  • 1H NMR (400 MHz, CD3OD): δ 7.27-7.11 (m, 1H), 5.06-4.89 (m, 2H), 3.58-3.44 (m, 1H), 2.64-2.53 (m, 1H), 2.44-2.38 (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 in the below table was prepared according to the procedure of Compound 141 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    142
    Figure US20210363115A2-20211125-C00303
         		413.1 1H NMR (400MHz, CD3OD): δ 7.26-7.06 (m, 1H), 5.08-4.91 (m, 2H), 3.89-3.73 (m, 1H), 2.74-2.66 (m, 3H), 2.63-2.44 (m, 2H), 2.19-2.07(m, 1H), 2.02-1.92 (m, 1H), 1.76-1.57(m, 2H), 1.38-1.33 (m, 6H). Comp. 126
    • Compound 143 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-1-(trifluoromethyl)-cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00304
  • To a solution of 3-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-2-en-1-one (prepared according to the procedure of Compound 122 using corresponding intermediates and reagents, 100 mg, 0.25 mmol) and trimethyl(trifluoromethyl)silane (142 mg, 1.25 mmol) in dry THF (10 mL) was added TBAF (1M, 1.25 mL) uner ice bath cooling ° C. The mixture was stirred at reflux for 2 hours, quenched by the addition of saturated NH4Cl aqueous solution and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as a white solid (10 mg, yield: 8.6%). MS (m/z): 468.0 [M+H]+;
  • 1H NMR (400 MHz, CD3OD): δ 7.10 (s, 1H), 5.05-4.88 (m, 2H), 2.81-2.63 (m, 1H), 2.35-2.21 (m, 1H), 1.92-1.77 (m, 4H), 1.39-1.31 (m, 6H).
    • Compound 144 3-(4-(Isopropylamino)-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-ol
  • Figure US20210363115A2-20211125-C00305
    • (A) (R)—N2-isopropyl-6-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-N4-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (B25)
  • Under nitrogen atmosphere, to a flask were added Intermediate I-2 (320 mg, 1.13 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1,3,2-dioxaborolane (300 mg, 1.13 mmol), Cs2CO3 (734 mg, 2.26 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 80° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound B25 as white solid.
    • (B) (R)-3-(4-(Isopropylamino)-6-((1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)cyclohex-3-en-1-one (B26)
  • To the solution of Compound B25 in dry DCM (3 mL) was added TFA (3 mL) and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction was quenched by the addition of saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was collected, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound B26 as 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)cyclohex-3-en-1-ol
  • Compound 144 was prepared according to the procedure of Compound 124 using Compound B26 and corresponding 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 in the below table was prepared according to the procedure of Compound 144 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    145
    Figure US20210363115A2-20211125-C00306
         		346.3 1H NMR (400 MHz, CD3OD): 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). I-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
  • Figure US20210363115A2-20211125-C00307
  • To a sealed tube was added Intermediate I-1 (50 mg, 0.15 mmol), (R)-1-phenylethan-1-amine (36 mg, 0.30 mmol), DIEA (77 mg, 0.60 mmol) and 1,4-dioxane (3 mL) in sequence. The mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as white solid (15 mg, yield: 23.4%). MS (m/z): 426.3 [M+H].
  • 1H NMR (400 MHz, CD3OD): δ 7.35-7.15 (m, 5H), 5.22-4.60 (m, 2H), 4.33-4.21 (m, 1H), 2.62-2.23 (m, 2H), 1.89-1.73 (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 in the below table were prepared according to the procedure of Compound 152 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    153
    Figure US20210363115A2-20211125-C00308
         		394.1 1H NMR (400 MHz, CD3OD): δ 7.21-6.96 (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), 1.67-1.52 (m, 2H), 1.39-1.31 (m, 3H). I-25
    154
    Figure US20210363115A2-20211125-C00309
         		386.1 1H NMR (400 MHz, CD3OD): δ 7.26-7.03 (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), 1.39-1.31 (m, 3H). I-25
    155
    Figure US20210363115A2-20211125-C00310
         		360.1 1H NMR (400 MHz, CD3OD): δ 7.21-6.89 (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). I-25
    156
    Figure US20210363115A2-20211125-C00311
         		358.1 1H NMR (400 MHz, CD3OD): δ 7.25-6.90 (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), 0.80-0.72 (m, 2H), 0.66-0.58 (m, 2H). I-25
    157
    Figure US20210363115A2-20211125-C00312
         		426.4 1H NMR (400 MHz, CD3OD): δ 7.40-7.15 (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), 1.18-1.07 (m, 1H). I-1
    158
    Figure US20210363115A2-20211125-C00313
         		390.1 1H NMR (400 MHz, CD3OD): δ 4.99-4.88 (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), 1.36-1.31 (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). I-1
    159
    Figure US20210363115A2-20211125-C00314
         		416.3 1H NMR (400 MHz, CD3OD): δ 4.97-4.88 (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), 1.38-1.29 (m, 3H). I-1
    160
    Figure US20210363115A2-20211125-C00315
         		452.3 1H NMR (400 MHz, CD3OD): δ 4.97-4.89 (s, 1H), 4.43-4.22 (m, 2H), 2.68-2.43 (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). I-1
    161
    Figure US20210363115A2-20211125-C00316
         		418.3 1H NMR (400 MHz, CD3OD): δ 4.97-4.88 (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), 1.38-1.29 (m, 3H). I-1
    162
    Figure US20210363115A2-20211125-C00317
         		362.3 1H NMR (400 MHz, CD3OD): δ 5.10-4.89 (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), 1.40-1.31 (m, 3H), 0.77-0.67 (m, 2H), 0.55-0.48 (m, 2H). I-1
    163
    Figure US20210363115A2-20211125-C00318
         		392.3 1H NMR (400 MHz, CD3OD): δ 4.98-4.89 (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), 1.38-1.30 (m, 3H), 1.15-1.07 (m, 3H), 0.96-0.88 (m, 6H). I-1
    164
    Figure US20210363115A2-20211125-C00319
         		378.3 1H NMR (400 MHz, CD3OD): δ 4.97-4.90 (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), 1.58-1.47 (m, 2H), 1.39-1.30 (m, 3H), 1.19-1.11 (m, 3H), 0.97-0.88 (m, 3H). I-1
    165
    Figure US20210363115A2-20211125-C00320
         		378.3 1H NMR (400MHz, CD3OD): δ 4.97-4.90 (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), 1.58-1.47(m, 2H), 1.39-1.30 (m, 3H), 1.19-1.11 (m, 3H), 0.97-0.88 (m, 3H). I-1
    166
    Figure US20210363115A2-20211125-C00321
         		426.3 1H NMR (400MHz, CD3OD): 5.02-4.95 (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), 1.43-1.31 (m, 3H). I-1
    167
    Figure US20210363115A2-20211125-C00322
         		392.4 1H NMR (400 MHz, CD3OD): δ 5.00-4.93 (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), 1.18-1.09 (m, 3H), 0.98-0.88 (m, 6H). I-1
    168
    Figure US20210363115A2-20211125-C00323
         		389.3 1H NMR (400 MHz, CD3OD): δ 4.99-4.93 (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), 1.71-1.63 (m, 1H), 1.42-1.31 (m, 6H). I-1
    169
    Figure US20210363115A2-20211125-C00324
         		382.2 1H NMR (400 MHz, CD3OD): δ 5.01-4.92 (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). I-1
    170
    Figure US20210363115A2-20211125-C00325
         		382.3 1H NMR (400 MHz, CD3OD): δ 5.01-4.92 (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). I-1
    171
    Figure US20210363115A2-20211125-C00326
         		426.3 1H NMR (400 MHz, CD3OD): δ 4.99-4.91 (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), 1.58-1.49 (m, 1H), 1.39-1.33 (m, 3H). I-1
    172
    Figure US20210363115A2-20211125-C00327
         		394.3 1H NMR (400 MHz, CD3OD): δ 5.02-4.93 (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). I-1
    173
    Figure US20210363115A2-20211125-C00328
         		405.2 1H NMR (400 MHz, CD3OD): δ 5.01- 4.90 (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), 1.40-1.28 (m, 3H). I-61
    174
    Figure US20210363115A2-20211125-C00329
         		400.2 1H NMR (400 MHz, CD3OD): δ 6.07-5.70 (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), 1.38-1.30 (m, 3H), 1.28-1.21 (m, 3H). I-61
    175
    Figure US20210363115A2-20211125-C00330
         		414.2 1H NMR (400 MHz, CD3OD): δ 5.03-4.89 (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), 1.38-1.31 (m, 3H), 1.28-1.22 (m, 3H). I-61
    176
    Figure US20210363115A2-20211125-C00331
         		408.1 1H NMR (400 MHz, CD3OD): δ 7.27-6.94 (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), 2.13-1.97 (m, 2H), 1.96-1.72 (m, 3H), 1.66- 1.50 (m, 2H), 1.39-1.31 (m, 3H). I-26
    177
    Figure US20210363115A2-20211125-C00332
         		408.1 1H NMR (400 MHz, CD3OD): δ 7.27-6.94 (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), 2.13-1.97 (m, 2H), 1.96-1.72 (m, 3H), 1.66- 1.50 (m, 2H), 1.39-1.31 (m, 3H). I-27
    178
    Figure US20210363115A2-20211125-C00333
         		360.0 1H NMR (400 MHz, CD3OD): δ 7.17-6.98 (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), 1.67-1.52 (m, 2H), 1.35-1.30 (m, 3H). I-27
    179
    Figure US20210363115A2-20211125-C00334
         		374 1H NMR (400 MHz, CD3OD): δ 7.23-6.95 (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), 2.48-2.35 (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). I-27
    180
    Figure US20210363115A2-20211125-C00335
         		374 1H NMR (400 MHz, CD3OD): δ 7.23-6.95 (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), 2.48-2.35 (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). I-27
    181
    Figure US20210363115A2-20211125-C00336
         		422.1 1H NMR (400 MHz, CD3OD): δ 7.23-6.93 (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), 1.40-1.30 (m, 3H). I-27
    182
    Figure US20210363115A2-20211125-C00337
         		388.2 1H NMR (400 MHz, CD3OD): δ 7.24-6.90 (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), 1.70-1.52 (m, 5H), 1.37-1.31 (m, 3H). I-27
    183
    Figure US20210363115A2-20211125-C00338
         		376.3 1H NMR (400 MHz, CD3OD): δ 7.20-6.93 (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), 1.67-1.53 (m, 2H), 1.37-1.31 (m, 3H), 1.20-1.15 (m, 3H). I-27
    184
    Figure US20210363115A2-20211125-C00339
         		362.2 1H NMR (400 MHz, CD3OD): δ 7.19-6.91 (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), 1.36-1.31 (m, 3H), 1.22-1.16 (m, 3H). I-27
    • Compound 186 6-(Cyclohex-1-en-1-yl)-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00340
  • Under nitrogen atmosphere, to a flask was added Intermediate I-3 (150 mg, 0.44 mmol), cyclohex-1-en-1-ylboronic acid (85 mg, 0.66 mmol), Cs2CO3 (290 mg, 0.88 mmol), Pd(PPh3)4 (26 mg, 0.022 mmol), 1,4-dioxane (10 mL) and water (2 mL) in sequence. The mixture was stirred at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as white solid (154 mg, yield: 90.4%). MS (m/z): 384.1 [M+H]+
  • 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.60 (m, 2H), 7.18 (s, 1H), 5.07-4.76 (m, 2H), 2.40-2.28 (m, 2H), 2.25-2.16 (m, 2H), 1.68-1.52 (m, 4H), 1.34-1.25 (m, 6H).
  • The compounds in the below table were prepared according to the procedure of Compound 186 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    187
    Figure US20210363115A2-20211125-C00341
         		300.2 1H NMR (400 MHz, CD3OD): 7.20-6.87 (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). I-6
    188
    Figure US20210363115A2-20211125-C00342
         		360.1 1H NMR (400 MHz, CD3OD): δ 7.41-6.99 (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). I-7
    189
    Figure US20210363115A2-20211125-C00343
         		316.1 1H NMR (400 MHz, CD3OD): δ 6.96-6.78 (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). I-2
    • Compound 190 (R)-6-(cyclohex-1-en-1-yl)-N2-isopropyl-N4-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
  • Figure US20210363115A2-20211125-C00344
  • 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 under microwave at 150° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, condensed and purified by flash column chromatography (eluting with PE/EA) to give the title compound as yellow solid (18 mg, yield 14%). MS (m/z): 330.1 [M+H]+
  • 1H 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 in the below table were prepared according to the procedure of Compound 190 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    191
    Figure US20210363115A2-20211125-C00345
         		328.2 1H NMR (400 MHz, CD3OD): 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). I-23
    192
    Figure US20210363115A2-20211125-C00346
         		342.1 1H NMR (400 MHz, CD3OD): 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), 1.79-1.59 (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). I-24
    193
    Figure US20210363115A2-20211125-C00347
         		260.1 1H NMR (400 MHz, CD3OD): 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), 0.53-0.42 (m, 2H), 0.31-0.17 (m, 2H). I-24
    194
    Figure US20210363115A2-20211125-C00348
         		288.2 1H NMR (400 MHz, CD3OD): 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), 1.75-1.61 (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). I-24
    195
    Figure US20210363115A2-20211125-C00349
         		318.2 1H NMR (400 MHz, CD3OD): 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), 1.75-1.61 (m, 4H), 1.20 (s, 6H), 1.10-1.02 (m, 1H), 0.52-0.43 (m, 2H), 0.26-0.19 (m, 2H). I-24
    • Compounds 206 and 207 3-(5-Fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-ol and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-ol
  • Figure US20210363115A2-20211125-C00350
    • (A) A mixture of 2-chloro-5-fluoro-N4,N6-bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-4,6-diamine and 6-chloro-5-fluoro-N2,N4-bis((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4-diamine
  • Under nitrogen atmosphere, a mixture of 2,4,6-trichloro-5-fluoropyrimidine (1.12 g, 5.6 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (2.51 g, 16.8 mmol), DIEA (4.22 g, 56 mmol) and N-methylpyrrolidone (5 mL) was stirred under microwave at 200° C. for 1 hour. After cooled to room temperature, the mixture was directly injected into RP-C18 column and purified by flash column chromatography (eluting with gradient water/MeOH=100:0-0:100) to give the product as white solid (80 mg, yield 4.2%). MS (m/z): 354.9 [M+H]+
    • (B) A mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-one
  • Under nitrogen atmosphere, a mixture of the product obtained in step (A) (80 mg, 0.23 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (50 mg, 0.23 mmol), Cs2CO3 (150 mg, 0.46 mmol), 1,4-dioxane (5 mL) and water (1.5 mL) was stirred under microwave at 130° C. for 40 minutes. After cooled to room temperature, the mixture was condensed and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give the product as 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 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclohex-2-en-1-ol
  • Compounds 206 and 207 were prepared according to the procedure of Compound 124 using the mixture of 3-(5-fluoro-4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-2-yl)cyclohex-2-en-1-one and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoro propan-2-yl)amino)pyrimidin-4-yl) cyclohex-2-en-1-one obtained in step (B) and corresponding reagents, and purified by flash column chromatography (eluting with gradient 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 ((, 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, 0H), 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 417.0 Hz, 3H).
  • The compounds in the below table were prepared according to the procedure described above, using corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA:
  • MS Inter-
    Comp. Structure (M + H)+ 1H NMR mediate
    212
    Figure US20210363115A2-20211125-C00351
         		451.2 1H NMR (400 MHz, CD3OD): 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), 2.66-2.52 (m, 1H), 2.33-2.05 (m, 2H), 1.33-1.24 (m, 3H). I-93
    213
    Figure US20210363115A2-20211125-C00352
         		477.2 1H NMR (400 MHz, CD3OD): 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). I-94
    214
    Figure US20210363115A2-20211125-C00353
         		480.0 1H NMR (400 MHz, CD3OD): 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), 2.34-2.07 (m, 2H), 1.31 (s, 9H). I-95
    215
    Figure US20210363115A2-20211125-C00354
         		429.2 1H NMR (400 MHz, CD3OD): 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), 2.31-2.06 (m, 2H), 1.32 (s, 9H). I-65
    216
    Figure US20210363115A2-20211125-C00355
         		445.0 1H NMR (400 MHz, CD3OD): 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). I-96
    217
    Figure US20210363115A2-20211125-C00356
         		465.2 1H NMR (400 MHz, CD3OD): 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), 2.67- 2.50 (m, 1H), 2.31-2.06 (m, 2H), 1.80-1.63 (m, 2H), 1.10-0.90 (m, 3H). I-97
    218
    Figure US20210363115A2-20211125-C00357
         		497.2 1H NMR (400 MHz, CD3OD): 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), 2.65- 2.41 (m, 3H), 2.30-2.05 (m, 2H). I-98
    220
    Figure US20210363115A2-20211125-C00358
         		501.1 1H NMR (400 MHz, CD3OD): 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), 0.60- 0.47 (m, 2H), 0.44-0.27 (m, 6H). I-99
    221
    Figure US20210363115A2-20211125-C00359
         		483.2 1H NMR (400 MHz, CD3OD): 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), 2.65- 2.55 (m, 1H), 2.31-2.05 (m, 2H). I-100
    243
    Figure US20210363115A2-20211125-C00360
         		434.0 1H NMR (400 MHz, CD3OD): 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), 2.27- 2.02 (m, 2H), 1.45-1.33 (m, 3H). I-101
    244
    Figure US20210363115A2-20211125-C00361
         		400.0 1H NMR (400 MHz, CD3OD): 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), 1.43- 1.29 (m, 3H), 1.23-1.09 (m, 6H). I-2
    299
    Figure US20210363115A2-20211125-C00362
         		434.0 1H NMR (400 MHz, CD3OD): 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), 2.29- 1.98 (m, 2H), 1.41-1.31 (m, 3H). I-102
    300
    Figure US20210363115A2-20211125-C00363
         		545.1 1H NMR (400 MHz, CD3OD): 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), 2.89- 2.73 (m, 1H), 2.69-2.51 (m, 1H), 2.41-2.06 (m, 4H). I-103
    301
    Figure US20210363115A2-20211125-C00364
         		533.1 1H NMR (400 MHz, CD3OD): 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), 2.93-2.77 (m, 1H), 2.69-2.55 (m, 1H), 2.36-2.06 (m, 2H). I-104
    • Compounds 197 and 198 3-(4,6-Bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,6,6-trifluorocyclohex-2-en-1-ol, optically pure diastereoisomers
  • Figure US20210363115A2-20211125-C00365
  • The Compound 196 was resolved by chiral HPLC to provide a pair of optically pure diastereoisomers, Compounds 197 and 198 (Chiral HPLC conditions: Preparation instrument: Shimadzu LC-10AD vp; Column: Daicel AD-H (250 mm*30 mm, 5 um); mobile phase: n-heptane/isopropanol=90/10; flow rate: 40 mL/min; column temperature: 40° C.). The first eluent (RT=4.203 min) was concentrated and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give a compound named as Compound 197, de %=99.27%, MS (m/z): 454.1 [M+1]*. The second eluent (RT=5.906 min) was concentrated and purified by flash column chromatography (eluting with gradient PE/EA=100:0-0:100) to give a compound named as 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 in the below table were prepared according to the procedure of Compounds 197 and 198 using the corresponding compounds and under appropriate HPLC conditions (flow rate: 0.5 mL/min; detection wavelength: UV 254 nm):
  • MS RT Chiral HPLC Comp. for
    Comp. Structure (M + H)+ 1H NMR (min) Purity Condition separation
    100
    Figure US20210363115A2-20211125-C00366
         		364.1 1H NMR (400 MHz, CD3OD): δ 5.00-4.89 (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), 1.40-1.30 (m, 3H), 1.21-1.15 (m, 6H). 1.230 ee% = 100% Column: OJ-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et2NH) = 90/10 1
    101 364.1 1NMR (400 MHz, CD3OD): δ 5.01-4.90 (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 ee% = 100%
    102
    Figure US20210363115A2-20211125-C00367
         		418.0 1NMR (400 MHz, CD3OD): δ 5.03-4.88 (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. × 15 cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et2NH) = 80/20 2
    103 418.1 1HNMR (400 MHz, CD3OD): δ 5.02-4.87 (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
    Figure US20210363115A2-20211125-C00368
         		406.3 1H NMR (400 MHz, CD3OD): 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), 1.72-1.62 (m, 1H). 3.608 ee% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et2NH) = 70/30 5
    105 406.3 1NMR (400 MHz, CD3OD):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), 1.72-1.62 (m, 1H). 3.871 ee% = 100%
    106
    Figure US20210363115A2-20211125-C00369
         		432.1 1H NMR (400 MHz, CD3OD): 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), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H) 10.540 de%= 97.79% Column: AS-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 90/10 19
    107 432.2 1H NMR (400 MHz, CD3OD): 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), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H) 18.120 de% = 97.84%
    108
    Figure US20210363115A2-20211125-C00370
         		407.1 1H NMR (400 MHz, CD3OD): 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) 4.596 de% = 99.8% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 70/30
    109 407.1 1H NMR (400 MHz, CD3OD): 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). 4.897 de% = 99.32%
    110
    Figure US20210363115A2-20211125-C00371
         		419.1 1H NMR (400 MHz, CD3OD): 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) 10.090 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 90/10 18
    111 419.1 1H NMR (400 MHz, CD3OD): 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) 16.800 de% = 100%
    112
    Figure US20210363115A2-20211125-C00372
         		421.1 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) 5.500 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane /isopropanol = 80/20 83
    113 421.1 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) 7.420 de% = 97.54%
    114
    Figure US20210363115A2-20211125-C00373
         		415.1 1H NMR (400 MHz, CD3OD): 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), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H) 5.960 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 90
    115 415.1 1H NMR (400 MHz, CD3OD): 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), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H) 7.800 de% = 98.30%
    116
    Figure US20210363115A2-20211125-C00374
         		409.1 1H NMR (400 MHz, CD3OD): 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), 1.68-1.57 (m, 1H) 10.170 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 91
    117 409.1 1H 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), 1.68-1.57 (m, 1H) 13.590 de% = 99.16%
    118
    Figure US20210363115A2-20211125-C00375
         		364.1 1H NMR (400 MHz, CD3OD): 5.00-4.89 (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), 1.23-1.12 (m, 6H) 1.334 de% = 97.56% Column: AS-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 90/10 33
    119 364.1 1H NMR (400 MHz, CD3OD): 5.01-4.89 (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), 1.22-1.15 (m, 6H) 1.403 de% = 100%
    120
    Figure US20210363115A2-20211125-C00376
         		412.0 1NMR (400 MHz, CD3OD): 5.05-4.89 (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 I.D. × 25 cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et2NH) = 90/10 31
    121 412.0 1H NMR (400 MHz, CD3OD): δ 5.07-4.88 (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%
    146
    Figure US20210363115A2-20211125-C00377
         		346.1 1H NMR (400 MHz, CD3OD):δ 7.21-6.90 (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), 1.37-1.31 (m, 3H), 1.26-1.13 (m, 6H) 1 .526 de% = 100% Column: AS-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 124
    147 346.1 1NMR (400 MHz, CD3OD): δ 7.18-6.93 (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), 1.38-1.30 (m, 3H), 1.22-1.15 (m, 6H) 1.995 de% = 99.774%
    148
    Figure US20210363115A2-20211125-C00378
         		400.1 1H NMR (400 MHz, CD3OD): δ 7.22-7.03 (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 I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et2NH) = 80/20 126
    149 400.1 1H NMR (400 MHz, CD3OD): δ 7.22-7.03 (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%
    150
    Figure US20210363115A2-20211125-C00379
         		388.1 1H NMR (400 MHz, CD3OD): 7.22-6.93 (m, 1H), 4.36-4.19 (m, 3H), 2.97-2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.45-2.34 (m, 2H), 1.97-1.80 (m, 2H), 1.67-1.51 (m, 2H) 2.492 ee% = 100% Column: AS-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 70/30 127
    151 388.1 1NMR (400 MHz, CD3OD): δ 7.22-6.93 (m, 1H), 4.36-4.19 (m, 3H), 2.97-2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.45-2.34 (m, 2H), 1.97-1.80 (m, 2H), 1.67-1.51 (m, 2H) 3.658 ee% = 100%
    222
    Figure US20210363115A2-20211125-C00380
         		431.0 1NMR (400 MHz, CD3OD): δ 8.93-8.78 (m, 2H), 7.98-7.93 (m, 1H), 7.84-7.77 (m, 1H), 4.37-4.30 (m, 1H), 2.70-2.61 (m, 1H), 2.48-2.36 (m, 1H), 1.92-1.86 (m, 2H), 1.85-1.76 (m, 1H), 1.73-1.65 (m, 1H), 1.33 (s, 9H) 5.097 ee% = 99.89% Column: IC-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 60/40 34
    223 431.0 1H NMR (400 MHz, CD3OD) δ 8.93-8.75 (m, 2H), 7.98-7.93 (m, 1H), 7.83-7.77 (m, 1H), 4.37-4.30 (m, 1H), 2.71-2.61 (m, 1H), 2.48-2.36 (m, 1H), 1.92-1.86 (m, 2H), 1.85-1.77 (m, 1H), 1.73-1.66 (m, 1H), 1.33 (s, 9H) 6.651 ee% = 97.67%
    236
    Figure US20210363115A2-20211125-C00381
         		442.2 1H NMR (400 MHz, CD3OD): δ 4.41-4.08 (m, 3H), 3.01-2.82 (m, 4H), 2.74-2.43 (m, 6H), 2.25-2.02 (m, 2H) 4.121 ee% = 100% Column: AD-H (0.46 cm I.D. ×15 cm L); Mobile phase: n-heptane/ isopropanol (0.1% et2NH) = 80/20 203
    237 442.2 1H NMR (400 MHz, CD3OD): δ 4.41-4.08 (m, 3H), 3.01-2.82 (m, 4H), 2.74-2.43 (m, 6H), 2.25-2.02 (m, 2H) 4.453 ee% = 100%
    249
    Figure US20210363115A2-20211125-C00382
         		455.2 1H NMR (400 MHz, CD3OD): δ 5.03-4.87 (m, 2H), 2.82-2.66 (m, 1H), 2.62-2.45 (m, 1H), 2.27-2.02 (m, 2H), 1.40-1.29 (m, 6H) 2.293 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol (0.1% Et2NH) = 80/20 211
    250 455.2 1H NMR (400 MHz, CD3OD): δ 5.03-4.87 (m, 2H), 2.82-2.66 (m, 1H), 2.62-2.45 (m, 1H), 2.27-2.02 (m, 2H), 1.40-1.29 (m, 6H) 2.898 de% = 100%
    251
    Figure US20210363115A2-20211125-C00383
         		398.0 1H NMR (400 MHz, CD3OD): δ 5.14-4.92 (m, 1H), 4.33-4.19 (m, 1H), 2.81-2.60 (m, 2H), 2.60-2.41 (m, 1H), 2.25-2.05 (m, 2H), 1.38-1.32 (m, 3H), 0.77-0.69 (m, 2H), 0.55-0.48 (m, 2H) 2.179 de% = 100% Column: OJ-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 90/10 238
    252 398.0 1H NMR (400 MHz, CD3OD): δ 5.04-4.94 (m, 1H), 4.32-4.19 (m, 1H), 2.83-2.61 (m, 2H), 2.58-2.42 (m, 1H), 2.23-2.05 (m, 2H), 1.39-1.32 (m, 3H), 0.77-0.69 (m, 2H), 0.57-0.47 (m, 2H) 2.465 de% = 99.76%
    253
    Figure US20210363115A2-20211125-C00384
         		448.0 1H NMR (400 MHz, CD3OD): 5.04-4.89 (m, 1H), 4.38-4.16 (m, 2H), 3.05-2.85 (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: OJ-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ ethanol = 80/20 239
    254 448.0 1H NMR (400 MHz, CD3OD): δ 5.05-4.92 (m, 1H), 4.34-4.14 (m, 2H), 3.02-2.85 (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
    Figure US20210363115A2-20211125-C00385
         		440.0 1H NMR (400 MHz, CD3OD): δ 4.97-4.83 (m, 1H), 4.29-3.90 (m, 3H), 2.77-2.58 (m, 1H), 2.51-2.37 (m, 1H), 2.26-1.93 (m, 2H), 1.37-1.20 (m, 3H) 3.119 de% = 100% Column: OJ-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isoproanol = 80/20 245
    256 440.0 1H NMR (400 MHz, CD3OD): 5.03-4.82 (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
    Figure US20210363115A2-20211125-C00386
         		400.0 1NMR (400 MHz, CD3OD): δ 4.90-4.81 (m, 1H), 4.24-4.11 (m, 1H), 3.33-3.14 (m, 2H), 2.70-2.55 (m, 1H), 2.48-2.34 (m, 1H), 2.17-2.96 (m, 2H), 1.56-1.44 (m, 2H), 1.29-1.23 (m, 3H), 0.88-0.80 (m, 3H) 3.436 de% = 99.24% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 248
    258 400.0 1H NMR (400 MHz, CD3OD): δ 4.90-4.83 (m, 1H), 4.25-4.10 (m, 1H), 3.34-3.13 (m, 2H), 2.70-2.54 (m, 1H), 2.54-2.33 (m, 1H), 2.19-1.96 (m, 2H), 1.56- 1.44 (m, 2H), 1.29-1.22 (m, 3H), 0.89-0.81 (m, 3H) 4.005 de% = 99.74%
    262
    Figure US20210363115A2-20211125-C00387
         		447.9 1H NMR (400 MHz, CD3OD): δ 5.04-4.95 (m, 1H), 4.42-4.14 (m, 2H), 3.04-2.87 (m, 2H), 2.84-2.45 (m, 4H), 2.31-2.06 (m, 2H), 1.45-1.33 (m, 3H) 3.388 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 259
    263 448.0 1H NMR (400 MHz, CD3OD): δ 4.92-4.83 (m, 1H), 4.31-4.04 (m, 2H), 2.94-2.73 (m, 2H), 2.72-2.34 (m, 4H), 2.18-1.91 (m, 2H), 1.32-1.21 (m, 3H) 3.968 de% = 99.48%
    264
    Figure US20210363115A2-20211125-C00388
         		398.0 1H NMR (400 MHz, CD3OD): δ 5.00-4.83 (m, 1H), 4.26-4.09 (m, 1H), 2.73-2.53 (m, 2H), 2.53-2.34 (m, 1H), 2.17-1.94 (m, 2H), 1.31-1.22 (m, 3H), 0.70-0.58 (m, 2H), 0.47-0.39 (m, 2H) 3.524 de% = 99.56% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 260
    265 398.0 1H NMR (400 MHz, CD3OD): 5.03-4.83 (m, 1H), 4.26-4.10 (m, 1H), 2.78-2.54 (m, 2H), 2.52-2.32 (m, 1H), 2.19-1.94 (m, 2H), 1.32-1.22 (m, 3H), 0.71-0.53 (m, 2H), 0.51-0.35 (m, 2H) 3.737 de% = 99.58%
    272
    Figure US20210363115A2-20211125-C00389
         		394.1 1H NMR (400 MHz, CD3OD): 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) 4.176 ee% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 70/30 261
    273 394.0 1H NMR (400 MHz, CD3OD): 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) 4.696 ee% = 100%
    285
    Figure US20210363115A2-20211125-C00390
         		479.2 1H NMR (400 MHz, CD3OD):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), 2.33-2.06 (m, 2H), 1.42-1.20 (m, 9H) 3.399 ee% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 70/30 275
    286 479.2 1H NMR (400 MHz, CD3OD): 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), 2.33-2.06 (m, 2H), 1.42-1.20 (m, 9H) 4.089 ee% = 100%
    287
    Figure US20210363115A2-20211125-C00391
         		480.2 1NMR (400 MHz, CD3OD): 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), 1.42-1.26 (m, 9H) 3.400 ee% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 70/30 276
    288 480.2 1H NMR (400 MHz, CD3OD): 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), 1.42-1.26 (m, 9H) 4 086 ee% = 100%
    289
    Figure US20210363115A2-20211125-C00392
         		358.2 1NMR (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) 3.506 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol = 80/20 280
    290 358.1 1NMR (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) 3.754 de% = 100%
    291
    Figure US20210363115A2-20211125-C00393
         		436.2 1H NMR (400 MHz, CD3OD): 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), 1.50-1.20 (m, 6H) 2.376 de% = 100% Column: AD-H (0.46 cm I.D. × 15 cm L); Mobile phase: n-heptane/ isopropanol +32 80/20 281
    292 436.2 1H NMR (400 MHz, CD3OD): 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), 1.50-1.20 (m, 6H) 3.321 de% = 100%
    • Example 3 Fluorescent Determination of IDH2-R140Q Cell Activity Materials:
  • U87MGR140Q cells: U87MG cells were purchased from ATCC cell bank and then transfected with plasmid containing IDH2-R140Q mutation, and monoclonal cells stably expressing the R140Q mutation were isolated for experiments. The cells were cultured in MEM medium containing 10% FBS.
  • 96-well plate a: Beckman Dickinson, Catalog No. 353072;
  • 96-well plate b: Thermo, Catalog No. 249952;
  • 96-well plate c: Greiner, Catalog No. 675076.
    • Solution Preparation:
  • Enzyme reaction solution: 1 mM nicotinamide adenine dinucleotide (NAD), 0.6 ng/μL D-2-hydroxyglutarate dehydrogenase (D2HGDH), 0.8 U/mL lipoamidase dehydrogenase (Diaphorase) and 60 μM Resazurin in 40 mM Tris.HCl pH 8.8 assay buffer.
  • Standard curve stock solution: The standard of 2-HG sodium salt was serially diluted in serum-free MEM medium to make a standard curve stock solution. The final gradient concentrations are: 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 6×104/mL per well in a 96-well plate a. The plate was incubated at 37° C. with 5% CO2 overnight, then 10 μL per well of test compound solution diluted in serum-free MEM (final concentration of test compound: 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 DMSO concentration is 0.5%) or 10 μL of control solution (serum-free MEM medium containing 0.5% DMSO in final concentration) was added and incubated for 72 hours.
  • From each well of 96-well plate a, 50 μL of the culture supernatant was transferred to the corresponding well of 96-well plate b; at the same time, 50 μL of standard curve stocking solution was added to other wells of 96-well plate b. Then 10 μl of 360 mM hydrochloric acid was added to all the wells. After shaking and mixing, the plate was placed on ice for 10 minutes, and then 10 μl of 420 mM Tris-base was added. After shaking and mixing, the plate was placed on ice for additional 5 minutes. Then the plate was centrifuged at 2500 rpm for 10 minutes.
  • After centrifuging, from each well of 96-well plate b, 20 μL of the supernatant was transferred to 96-well plate c. An additional 80 μL of the enzyme reaction solution was added to each well and incubated at 25° C. for 90 minutes.
    • Detection:
  • The plate c was measured on Tecan Infinite F500 Reader instrument at 544 nm excitation and 590 nm emission. A standard curve of the fluorescence value vs. the corresponding 2-HG concentration was made, and the 2-HG concentration corresponding to each concentration point of the compound was calculated, then the inhibition ratio was calculated, and the data was analyzed using XLfit5 (ID Business Solutions Limited) software to obtain the IC50 value.
  • The inhibition ratio was calculated as follows:

  • Inhibition Ratio (IH %)=(1−2-HG concentration of test compound treated cells/2-HG concentration of control cells)×100%.
  • The followings are the activity values of some of the compounds of the invention determined in this example.
  • Compound IC50 (μM)
    1 0.097
    2 0.137
    3 0.866
    4 0.080
    5 0.093
    6 0.115
    7 0.087
    8 0.216
    9 0.571
    10 0.113
    11 0.284
    12 0.199
    13 0.373
    14 0.230
    15 0.259
    16 0.326
    17 1.616
    18 0.110
    19 0.083
    20 0.232
    21 0.099
    22 0.336
    23 0.192
    24 0.197
    25 0.665
    27 0.148
    28 0.123
    29 0.177
    30 0.228
    31 0.110
    32 0.080
    34 0.145
    35 0.591
    36 0.181
    37 1.911
    38 1.619
    39 0.164
    40 0.106
    41 0.297
    42 0.152
    43 0.328
    44 3.149
    47 0.059
    49 0.210
    50 0.072
    51 0.125
    52 0.229
    53 0.131
    54 0.015
    55 0.103
    56 0.093
    57 2.180
    58 0.169
    59 0.221
    60 0.590
    61 0.170
    62 1.343
    64 1.628
    65 0.152
    67 2.374
    68 0.435
    69 0.173
    70 0.112
    71 0.050
    72 0.042
    73 0.064
    74 0.034
    75 0.218
    78 0.069
    79 0.106
    80 0.079
    81 0.099
    82 0.075
    83 0.203
    84 0.048
    85 0.035
    86 0.021
    87 0.205
    89 0.057
    90 0.065
    91 0.058
    92 0.143
    94 0.131
    95 0.043
    96 0.675
    97 0.052
    98 0.344
    99 0.553
    100 2.905
    101 0.080
    102 0.051
    103 1.002
    104 2.079
    105 0.040
    106 0.106
    107 0.554
    108 2.226
    109 0.057
    110 0.070
    111 2.257
    112 0.098
    113 2.059
    114 1.716
    115 0.059
    116 2.620
    117 0.095
    118 0.106
    119 3.393
    120 2.397
    121 0.068
    122 1.340
    124 0.137
    125 1.671
    126 0.086
    127 0.064
    128 0.092
    129 0.171
    130 0.067
    131 2.798
    133 0.174
    134 0.100
    135 0.336
    136 0.296
    137 1.540
    138 0.504
    139 2.505
    140 2.390
    144 2.748
    146 0.999
    147 0.067
    148 1.558
    149 0.177
    150 0.541
    151 0.039
    152 0.300
    153 0.099
    154 0.202
    155 0.319
    156 0.657
    157 0.141
    158 0.278
    159 0.205
    160 0.180
    162 0.177
    163 0.162
    164 0.176
    165 0.198
    166 0.180
    167 0.327
    169 0.738
    170 1.382
    171 0.268
    172 0.344
    174 0.096
    175 0.291
    176 0.612
    177 0.046
    178 0.934
    179 0.598
    180 0.531
    181 0.177
    182 1.231
    183 0.507
    184 3.779
    186 0.677
    187 0.742
    188 5.015
    189 1.415
    190 0.413
    191 0.999
    192 0.314
    196 0.094
    197 0.041
    198 0.845
    199 1.504
    200 0.632
    201 0.045
    202 0.383
    203 0.098
    204 0.209
    205 0.803
    207 0.564
    208 0.102
    209 0.078
    210 0.093
    211 0.097
    212 0.063
    213 0.038
    214 0.108
    215 0.079
    216 0.082
    217 0.069
    218 0.381
    219 0.707
    220 0.059
    221 0.487
    222 0.065
    224 0.137
    225 0.036
    226 0.361
    227 0.048
    228 0.417
    229 0.383
    230 0.658
    231 0.037
    232 0.040
    233 0.368
    234 0.078
    235 0.130
    236 0.045
    237 1.492
    238 0.139
    239 0.046
    240 0.984
    241 0.100
    242 0.802
    243 1.175
    244 0.053
    245 0.102
    248 0.093
    249 0.072
    250 2.473
    252 0.050
    254 0.025
    255 0.078
    257 0.056
    259 0.057
    260 0.094
    261 0.094
    262 0.056
    263 1.394
    264 0.084
    266 0.033
    267 1.327
    268 0.349
    269 0.137
    270 0.109
    272 0.051
    273 1.228
    274 0.084
    275 0.062
    276 0.081
    277 0.156
    278 0.148
    279 0.170
    280 >10
    281 0.690
    282 0.343
    283 0.174
    285 0.034
    286 0.165
    287 0.095
    288 0.035
    291 0.201
    292 3.456
    293 0.637
    294 0.425
    296 0.423
    297 2.660
    298 0.620
    • Example 4 Fluorescent Determination of IDH1-R132H Cell Activity
  • The 2-HG inhibitory activity of the compounds of the invention in U87MGR132H cells transfected with the IDH1-R132H mutant plasmid was determined according to the method of Example 3.
  • The followings are the activity values of some of the compounds of the invention determined in this example.
  • Compound IC50 (μM)
    2 0.365
    4 0.750
    5 0.869
    6 0.670
    7 1.503
    8 1.221
    11 1.016
    13 2.076
    14 1.326
    15 0.619
    18 0.219
    19 0.421
    21 0.234
    24 0.769
    31 0.280
    32 0.610
    34 >10
    39 1.913
    40 0.450
    41 1.627
    47 5.636
    51 6.042
    52 2.245
    54 1.683
    60 >10
    61 >10
    62 2.703
    64 >10
    65 >10
    67 >10
    71 3.054
    73 >10
    74 7.441
    75 >10
    78 1.407
    79 1.296
    80 2.695
    81 3.571
    82 0.181
    83 0.282
    84 0.268
    85 0.207
    87 0.781
    89 2.957
    94 1.144
    95 0.317
    96 2.703
    97 0.047
    98 0.254
    99 0.938
    101 1.141
    102 0.232
    103 2.501
    105 0.351
    106 0.272
    107 1.751
    109 0.279
    110 0.160
    118 2.141
    119 >10
    121 0.186
    124 0.658
    126 0.289
    127 0.203
    130 0.733
    134 2.472
    136 1.342
    147 0.372
    149 0.693
    151 0.256
    152 2.008
    153 0.447
    155 2.245
    157 4.350
    158 1.520
    159 2.717
    163 0.809
    166 1.347
    167 3.171
    169 9.464
    170 6.933
    171 1.575
    174 0.343
    175 0.495
    177 0.094
    181 0.476
    196 0.210
    197 0.120
    198 1.893
    199 >10
    200 >10
    201 0.109
    202 1.101
    203 0.733
    204 >10
    205 >10
    207 1.510
    208 1.499
    209 1.763
    210 4.338
    211 0.175
    212 >10
    213 >10
    214 >10
    215 >10
    216 8.519
    217 >10
    218 >10
    219 3.232
    220 2.878
    221 >10
    222 >10
    224 4.650
    225 0.917
    226 5.123
    227 0.081
    228 0.705
    229 >10
    230 >10
    231 1.528
    232 0.070
    233 0.628
    234 1.763
    235 0.246
    236 0.252
    238 7.355
    239 0.344
    240 >10
    241 2.060
    242 3.523
    243 >10
    244 1.082
    245 1.499
    248 4.338
    249 0.134
    250 2.480
    252 2.621
    254 0.262
    255 0.715
    257 1.380
    259 0.213
    260 >10
    261 2.231
    262 0.182
    263 3.513
    264 >10
    266 0.043
    267 3.566
    268 0.939
    269 0.296
    270 2.853
    272 2.086
    273 >10
    274 3.284
    275 8.017
    276 8.367
    277 1.030
    278 >10
    279 9.426
    280 >10
    281 0.455
    282 0.444
    283 1.319
    285 3.587
    286 >10
    287 >10
    288 2.695
    291 0.179
    292 3.639
    293 >10
    294 9.184
    296 1.135
    297 >10
    298 >10
    • Example 5 Metabolic Stability Test in Liver Microsomes Materials:
  • Male CD1 mouse liver microsomes was supplied by Research Institute for Liver Diseases (Shanghai) Co., Ltd. Male SD rat liver microsomes was supplied by BioreclamationIVT in US.
  • Phenacetin, glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase (G-6-PD), and nicotinamide adenine dinucleotide phosphate (NADP) were supplied by Sigma-Aldrich (Missouri, USA).
    • Solution Preparation:
  • 10 mM stock solution of test compound: Certain amount of test compound was weighed and dissolved in certain volume of dimethylsulfoxide (DMSO) to get the stock solution of test compound at 10 mM.
  • Reaction termination solution: Certain amount of phenacetin as internal standard was weighed and dissolved in acetonitrile to get the reaction termination solution at 1000 ng/mL, and stored at room temperature for use.
    • Experimental Method:
  • The stock solution of test compound was diluted to the designated concentration with organic solution (usually the mixtures of acetonitrile, methanol and water with different portions depending on the compound solution) to make the final concentration to be 1 μM and the contents of organic solvents no more than 1% (For DMSO, the controlled margin 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 provide the NADPH regenerating system containing 1 mM NADP, 5 mM G-6-P and 1 U/mL G-6-PD, which was pre-incubated at 37° C. water-bath for 10 min and then cooled on ice until being added into the reaction system. 20 mg/ml liver microsomes was mixed with 200 mM PBS and diluted with ultrapure water to make the concentrations of liver microsomes and PBS to be 0.5 mg/mL and 50 mM in the final incubation system, respectively. After the diluted liver microsomes was mixed with the NADPH regenerating solution, certain volumes of 100 mM EDTA and 300 mM MgCl2 (concentration of EDTA and MgCl2 in the final incubation system is 1 mM and 3 mM, respectively) were added, and the incubation system was put into 37° C. water bath. The incubation was commenced by adding the stock solution of test compound and maintained for 30 min. The incubation was terminated by adding the reaction termination solution. The 0 min sample was prepared by adding the reaction termination solution to the incubation system immediately prior to putting the system into the water bath with the addition of the stock solution of test compound. The terminated incubation mixtures were vortexed and centrifuged at 4400 rpm for 10 min, and the supernatant was collected for LC-MS/MS analysis.
    • Analytical Method:
  • The concentration of test compound was determined using LC-MS/MS method. Using the peak area ratio of the compound and the internal standard as an index, the percentage of remaining compound after incubation for 30 minutes as compared with the 0 minute sample was calculated, and the metabolic stability of the compound was evaluated.
  • According to the above tests, the compounds of the invention showed good metabolic stability. The metabolic stability of some exemplary compounds of the invention is as follows:
  • Rat liver microsome Mouse liver microsome
    Compound stability stability
    1 73.8% 83.5%
    2 99.0% 83.8%
    4 62.9% 82.1%
    5 76.8% 58.6%
    6 70.0% 76.3%
    7 50.3% 49.8%
    11 87.6% 80.3%
    18 91.5% 82.7%
    19 83.8% 66.2%
    82 92.9% 93.1%
    83 96.6% 83.7%
    84 67.8% 78.9%
    85 78.1% 64.0%
    87 97.9% 88.5%
    90 82.4% 80.9%
    91 86.6% 70.5%
    94 82.6% 65.4%
    95 74.8% 80.1%
    97 98.5% 89.5%
    98 99.2% 83.7%
    101 88.0% 84.6%
    102 92.7% 86.2%
    103 89.7% 78.5%
    105 84.0% 67.3%
    109 85.4% 58.8%
    124 74.1% 44.1%
    126 79.8% 58.2%
    127 49.8% 28.7%
    128 34.0% 15.9%
    147 65.0% 48.1%
    149 66.8% 59.7%
    153 41.7% 46.9%
    177 45.9% 31.0%
    196 100.0% 95.2%
    197 99.5% 98.4%
    201 91.6% 79.3%
    202 94.2% 96.4%
    203 92.1% 91.3%
    211 98.8% 99.7%
    227 88.8% 81.4%
    232 86.6% 76.3%
    235 89.0% 75.5%
    236 91.3% 83.9%
    239 93.0% 91.8%
    249 98.0% 100.0%
    254 100.0% 90.9%
    259 95.1% 86.9%
    262 98.3% 92.2%
    266 98.2% 91.5%
    291 100.0% 98.9%
    • Example 6 Determination of Solubility 1. Preparation of Sample Solution
  • Sample standard solution: About 3-5 mg test compound was accurately weighed and added into a 5 mL sample tube, 5 mL DMSO was added. Shaking and sonicating for 1 hour.
  • pH 2.1 sample solution: About 1 mg test compound was accurately weighed and added into a 1 mL sample tube, 1 mL pH 2.1 sodium phosphate buffer was added. Shaking. Adding test compound to the solution, if the solution is visually clear, till there is obvious insoluble in the solution. Sonicating for 1 hour.
  • pH 7.4 sample solution: About 1 mg test compound was accurately weighed and added into a 1 mL sample tube, 1 mL pH 7.4 sodium phosphate buffer was added. Shaking. Adding test compound to the solution, if the solution is visually clear, till there is obvious insoluble in the solution. Sonicating for 1 hour.
    • 2. Determination
  • 1 mL sample standard solution was accurately pipetted into a HPLC tube. The peak area was determined by HPLC.
  • 0.5 mL pH 2.1 sample solution was filtered by syringe filter and was accurately pipetted into a HPLC tube, and 0.5 mL pH 2.1 sodium phosphate buffer was accurately added. Shaking. The peak area was determined by HPLC.
  • 0.5 mL pH 7.4 sample solution was filtered by syringe filter and was accurately pipetted into a HPLC tube, and 0.5 mL pH 7.4 sodium phosphate buffer was accurately added. Shaking. The peak area was determined by HPLC.
  • HPLC condition:
  • Instrument: Agilent 1200
  • Column: Agilent SB-C18 5 u 4.6*150 mm
  • Mobile phase:
      • Phase A: Water (containing 0.1% formic acid)
      • Phase B: MeOH (containing 0.1% formic acid)
      • Gradient table
  • Time (min) % A % B
    0 95 5
    10 5 95
    13 5 95
    14 95 5
    16 95 5
    • 3. Calculation
  • The solubility of the test compound in pH 2.1 and pH 7.4 sodium phosphate buffers were calculated by the following formulae:

  • Sample solubility at pH 2.1 (mg/mL)=2×A×Y÷X

  • Sample solubility at pH 7.4 (mg/mL)=2×A×Z÷X
  • wherein:
      • A: The concentration of the test compound in sample standard solution, mg/mL;
      • X: The peak area of sample standard solution;
      • Y: The peak area of pH 2.1 sample solution;
      • Z: The peak area of pH 7.4 sample solution.
  • The solubilities of some exemplary compounds of the invention are as follows:
  • Solubility (mg/mL)
    Compound pH 2.1 pH 7.4
    3 >1.000 0.716
    9 >1.000 0.085
    20 0.570 0.062
    68 0.141 <0.005
    71 0.064 0.055
    82 0.146 0.037
    97 0.077 0.021
    102 0.729 <0.005
    125 0.448 0.019
    219 0.190 0.060
    223 0.060 0.016
    243 0.055 <0.005
    249 0.036 0.011
    262 0.237 0.013
    271 0.974 0.124
    284 0.789 0.818

Claims (21)

1. A compound of formula (I):
Figure US20210363115A2-20211125-C00394
and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein
A is chosen from
Figure US20210363115A2-20211125-C00395
 wherein, R7 is chosen from H, halo, —CN, —OH, or —NH2; R8 is chosen from halo, —CN, —OH, or —NH2; q is 1 or 2;
R1 is chosen from H, —OH, halo, C1-6 alkyl, C1-6 alkoxyl, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, oxo, or C3-8 cycloalkyl;
each of R2 is independently chosen from H, deuterium, halo, —OH, —NH2, —CN, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, oxo, —OR5, —OCOR5, —NHR5, —N(R5)(C1-4 alkyl), —COR5, —NHCOR5, or 3-8 membered heterocyclyl; in which each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with one or more groups chosen from deuterium, halo, —CN, —OH, —SH, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, or C1-6 alkoxyl; or two R2, which attach to the same carbon atom, together with the carbon atom they are attached to form a 3-5 membered cycloalkyl which is optionally substituted with one or more halo or deuterium;
R3, R3′, R4 and R4′ are independently chosen from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R5, —OR5, or —NHR5, in which each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; wherein R3, R3′, R4 and R4′ are not H simultaneously; provided that when one of R3 and R4 is optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl, the other one is —OR5 or —NHR5;
or R3 and R3′ are independently chosen from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R5, —OR5, or —NHR5, in which each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; R4 and R4′ together with the N atom they are attached to form a 3-8 membered heterocyclic ring optionally substituted by one or more R6;
R5 is chosen from C1-6 alkyl or C3-8 cycloalkyl, each of which is optionally substituted with one or more groups independently chosen from halo, —CN, —OH, —SH, —NH2, or C1-6 alkoxyl;
each of R6 is independently chosen from deuterium, halo, —CN, —OH, —SH, —NH2, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which each of said C1-6 alkoxyl, C1-6 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with one or more groups independently chosen from halo, —CN, —OH, —SH, —NH2, C1-6 alkoxyl, C1-6 alkynyl, or C1-6 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 a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, R1 is chosen from H, —OH or halo.
3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, R1 is —OH.
4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, each of R2 is independently chosen from H, deuterium, halo, —OH, —NH2, —CN, —SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, oxo, —OR5, —OCOR5, —NHR5, —N(R5)(C1-4 alkyl), —NHCOR5, or 3-8 membered heterocyclyl.
5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, each of R2 is independently chosen from H, deuterium, halo, C1-6 alkyl, or C1-6 haloalkyl.
6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, R3 and R4 are independently chosen from C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, —C(O)R5, —OR5, or —NHR5, in which each of said C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; R3′ and R4′ are independently chosen from H or C1-6 alkyl.
7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, R3 and R4 are independently chosen from C1-6 alkyl substituted with one or more halo, 5-12 membered heteroaryl substituted with C1-6 haloalkyl, or —OR5; R3′ and R4′ are both H.
8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, R5 is C1-6 alkyl optionally substituted with one or more halo.
9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, each of R6 is independently chosen from deuterium, halo, —CN, —OH, —NH2, C1-6 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which each of said C1-6 alkoxyl, C1-6 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with one or more halo.
10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, n is 1.
11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, R3 is chosen from H, C1-6 alkyl optionally substituted by C1-6 haloalkyl, or 5-12 membered heteroaryl optionally substituted by C1-6 haloalkyl; R3′ is H; R4 and R4′ together with the N atom they are attached to form a 3-8 membered heterocyclic ring optionally substituted by one or more groups chosen from halo, —OH, or C1-6 haloalkyl.
12. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, the compound of formula (I) is chosen from
Figure US20210363115A2-20211125-C00396
wherein X is halo.
13. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, the compound of formula (I) has the structure of formula (II); wherein X is halo; p is 0, 1, or 2; m is 0, 1, or 2;
Figure US20210363115A2-20211125-C00397
14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, the compound of formula (I) is chosen from
Figure US20210363115A2-20211125-C00398
wherein, X is halo; p is 0, 1, or 2; m is 0, 1, or 2.
15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diasteromers, and tautomers thereof, wherein, the compound of formula (I) has the structure of formula (II-1); wherein X is halo; p is 0, 1, or 2; m is 0, 1, or 2;
Figure US20210363115A2-20211125-C00399
16. The compound of formula (I) according to claim 1, chosen from:
Figure US20210363115A2-20211125-C00400
Figure US20210363115A2-20211125-C00401
Figure US20210363115A2-20211125-C00402
Figure US20210363115A2-20211125-C00403
Figure US20210363115A2-20211125-C00404
Figure US20210363115A2-20211125-C00405
Figure US20210363115A2-20211125-C00406
Figure US20210363115A2-20211125-C00407
Figure US20210363115A2-20211125-C00408
Figure US20210363115A2-20211125-C00409
Figure US20210363115A2-20211125-C00410
Figure US20210363115A2-20211125-C00411
Figure US20210363115A2-20211125-C00412
Figure US20210363115A2-20211125-C00413
Figure US20210363115A2-20211125-C00414
Figure US20210363115A2-20211125-C00415
Figure US20210363115A2-20211125-C00416
Figure US20210363115A2-20211125-C00417
Figure US20210363115A2-20211125-C00418
Figure US20210363115A2-20211125-C00419
Figure US20210363115A2-20211125-C00420
Figure US20210363115A2-20211125-C00421
Figure US20210363115A2-20211125-C00422
Figure US20210363115A2-20211125-C00423
Figure US20210363115A2-20211125-C00424
Figure US20210363115A2-20211125-C00425
Figure US20210363115A2-20211125-C00426
Figure US20210363115A2-20211125-C00427
Figure US20210363115A2-20211125-C00428
Figure US20210363115A2-20211125-C00429
Figure US20210363115A2-20211125-C00430
Figure US20210363115A2-20211125-C00431
Figure US20210363115A2-20211125-C00432
Figure US20210363115A2-20211125-C00433
Figure US20210363115A2-20211125-C00434
Figure US20210363115A2-20211125-C00435
Figure US20210363115A2-20211125-C00436
Figure US20210363115A2-20211125-C00437
Figure US20210363115A2-20211125-C00438
Figure US20210363115A2-20211125-C00439
Figure US20210363115A2-20211125-C00440
Figure US20210363115A2-20211125-C00441
Figure US20210363115A2-20211125-C00442
Figure US20210363115A2-20211125-C00443
Figure US20210363115A2-20211125-C00444
Figure US20210363115A2-20211125-C00445
Figure US20210363115A2-20211125-C00446
Figure US20210363115A2-20211125-C00447
Figure US20210363115A2-20211125-C00448
Figure US20210363115A2-20211125-C00449
Figure US20210363115A2-20211125-C00450
Figure US20210363115A2-20211125-C00451
Figure US20210363115A2-20211125-C00452
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient.
18. A use of a compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease induced by IDH mutation in a subject.
19. The use of claim 18, wherein, the disease induced by IDH mutation is cancer, which is chosen from solid tumors, neurogliocytoma, or hematological malignant tumor, such as leukemia, lymphoma, or myeloma.
20. The use of claim 19, wherein, the cancer is chosen from acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), glioblastoma (GBM), myelodysplastic syndrome (MDS), myeloproliterative neoplasms (MPN), cholangiocarcinoma, such as intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, giant cell tumor, intestinal cancer, melanoma, lung cancer, or non-Hodgkin's lymphoma (NHL).
21. A compound of formula (IV),
Figure US20210363115A2-20211125-C00453
and a racemic mixture or enantiomers thereof, wherein, R1, R2, m and n are defined as in any one of the claims 1-15; Ra is chosen from halo, —OS(O)2CF3, —B(OH)2, —B(OC1-6 alkyl)2,
Figure US20210363115A2-20211125-C00454
Rb is H or C1-6 alkyl.
US16/645,329 2017-09-07 2018-09-07 Cycloolefin substituted heteroaromatic compounds and their use Active US11414390B2 (en)

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