NZ762447B2 - Cycloolefin substituted heteroaromatic compounds and their use - Google Patents

Cycloolefin substituted heteroaromatic compounds and their use Download PDF

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NZ762447B2
NZ762447B2 NZ762447A NZ76244718A NZ762447B2 NZ 762447 B2 NZ762447 B2 NZ 762447B2 NZ 762447 A NZ762447 A NZ 762447A NZ 76244718 A NZ76244718 A NZ 76244718A NZ 762447 B2 NZ762447 B2 NZ 762447B2
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compound
formula
nmr
independently chosen
alkyl
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NZ762447A
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NZ762447A (en
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Guangxiu Dai
Wei Guo Su
Kun Xiao
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Hutchison Medipharma Limited
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Priority claimed from CN201710801364.3A external-priority patent/CN109467538A/en
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Publication of NZ762447B2 publication Critical patent/NZ762447B2/en

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    • 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
    • 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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    • C07D239/28—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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
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    • 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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    • 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
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    • 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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    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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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    • C07—ORGANIC CHEMISTRY
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Abstract

Compounds 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. (I)

Description

Cycloolefin substituted heteroaromatic compounds and their use 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 a-ketoglutaric acid (a-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 a-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 a-KG, whereas has the ability of catalyzing the reaction of a-KG to a-hydroxyglutaric acid (2-HG). As the structure of 2-HG is similar to the structure of a-KG, 2-HG can competitively inhibit the activity of many a-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 a-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. It is an object of the present invention to go some way towards addressing these needs; and/or to at least provide the public with a useful choice.
Summary of the Invention In a first aspect the present invention provides a compound of formula (I): and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein A is , R is chosen from H, -OH, halo, C alkyl, C alkoxyl, -NH , -NH(C alkyl), -N(C 1 1-6 1-6 2 1-4 1-4 alkyl) , oxo, or C cycloalkyl; 2 3-8 each of R is independently chosen from H, deuterium, halo, -OH, -NH , -CN, -SH, C 2 2 1-6 alkyl, C alkenyl, C alkynyl, C haloalkyl, C cycloalkyl, oxo, -OR , -OCOR , -NHR , 2-6 2-6 1-6 3-8 5 5 5 -N(R )(C alkyl), -COR , -NHCOR , or 3-8 membered heterocyclyl containing one or more 1-4 5 5 heteroatoms independently chosen from N, O, and S; in which each of said C alkyl, C 1-6 2-6 alkenyl, C alkynyl, C cycloalkyl or 3-8 membered heterocyclyl containing one or more 2-6 3-8 heteroatoms independently chosen from N, O, and S is optionally substituted with one or more groups chosen from deuterium, halo, -CN, -OH, -SH, -NH , -NH(C alkyl), -N(C alkyl) , or 2 1-4 1-4 2 C alkoxyl; or two R , which attach to the same carbon atom, together with the carbon atom 1-6 2 they are attached to form a 3-5 membered cycloalkyl which is optionally substituted with one or more halo or deuterium; R ’ and R ’ are both H; R and R are independently chosen from H, C alkyl, C alkenyl, C alkynyl, C 3 4 1-6 2-6 2-6 3-12 cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently chosen from N, O, and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, -C(O)R , -OR , or -NHR , in which each of said C 5 5 1-6 alkyl, C alkenyl, C alkynyl, C cycloalkyl, 3-12 membered heterocyclyl containing one or 2-6 2-6 3-12 more heteroatoms independently chosen from N, O, and S, phenyl, or 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more R ; provided that R and R are not H simultaneously; provided that 6 3 4 when one of R and R is optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, the other one is -OR or -NHR ; or R and R ’ are independently chosen from H, C alkyl, C alkenyl, C alkynyl, C 3 3 1-6 2-6 2-6 3-12 cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently chosen from N, O, and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, -C(O)R , -OR , or -NHR , in which each of said C 5 5 1-6 alkyl, C alkenyl, C alkynyl, C cycloalkyl, 3-12 membered heterocyclyl containing one or 2-6 2-6 3-12 more heteroatoms independently chosen from N, O, and S, phenyl, or 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more R ; R and R ’ together with the N atom they are attached to form a 6 4 4 3-8 membered heterocycyl containing one or more heteroatoms independently chosen from N, O, and S optionally substituted by one or more R6; R is chosen from C alkyl or C cycloalkyl, each of which is optionally substituted with 1-6 3-8 one or more groups independently chosen from halo, -CN, -OH, -SH, -NH , or C alkoxyl; 2 1-6 each of R is independently chosen from deuterium, halo, -CN, -OH, -SH, -NH , C 6 2 1-6 alkoxyl, C alkyl, C haloalkyl, C cycloalkyl, 3-8 membered heterocyclyl containing one or 1-6 1-6 3-8 more heteroatoms independently chosen from N, O, and S, phenyl, or 5-6 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, in which each of said C alkoxyl, C alkyl, C cycloalkyl, 3-8 membered heterocyclyl containing one or more 1-6 1-6 3-8 heteroatoms independently chosen from N, O, and S, phenyl, or 5-6 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more groups independently chosen from halo, -CN, -OH, -SH, -NH , C 2 1-6 alkoxyl, C alkynyl, or C alkyl; 2-6 1-6 m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; wherein the term "cycloalkyl" as used herein refers to saturated or partially unsaturated cyclic hydrocarbon radical, which may have one or more rings.
In a second aspect the present invention provides a pharmaceutical composition comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient.
In a third aspect the present invention provides a pharmaceutical composition for treating a disease induced by IDH mutation, comprising the compound of the first aspect or a pharmaceutically acceptable salt thereof.
In a fourth aspect the present invention provides a compound selected from: and .
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
Brief Description The present invention provides a compound of formula (I): and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein A, R , R , R , R ’, R , R ’, R , R , R , R , m, and n 1 2 3 3 4 4 5 6 7 8 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 Figure 1 shows the general synthetic route I for preparation of the compounds described herein.
Figure 2 shows the general synthetic route II for preparation of the compounds described herein.
Figure 3 shows the general synthetic route III for preparation of the compounds described herein.
Figure 4 shows the general synthetic route IV for preparation of the compounds described herein.
Figure 5 shows the general synthetic route V for preparation of the compounds described herein.
Figure 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, "C alkenyl" refers to an alkenyl containg 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 cabon atoms, more preferably 2-4 carbon atoms. For example, "C 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, -CF , -CHF , -CH CF , and the like. 3 2 2 3 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, C 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, "C 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]heptaene.
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 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, pyrrolidonecarboxylic 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.
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 H O, 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%.
The term "comprising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this specification, and claims which include the term "comprising", it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner.
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): and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein A is chosen from , wherein, R is chosen from H, halo, -CN, -OH, or -NH ; R is chosen from halo, -CN, -OH, or –NH ; q is 1 or 2 8 2 R is chosen from H, -OH, halo, C alkyl, C alkoxyl, -NH , -NH(C alkyl), -N(C alkyl) , 1 1-6 1-6 2 1-4 1-4 2 oxo, or C cycloalkyl; each of R is independently chosen from H, deuterium, halo, -OH, -NH , -CN, -SH, C alkyl, 2 2 1-6 C alkenyl, C alkynyl, C haloalkyl, C cycloalkyl, oxo, -OR , -OCOR , -NHR , 2-6 2-6 1-6 3-8 5 5 5 -N(R )(C alkyl), -COR , -NHCOR , or 3-8 membered heterocyclyl; in which each of said C 1-4 5 5 1-6 alkyl, C alkenyl, C alkynyl, C cycloalkyl or 3-8 membered heterocyclyl is optionally 2-6 2-6 3-8 substituted with one or more groups chosen from deuterium, halo, -CN, -OH, -SH, -NH , -NH(C alkyl), -N(C alkyl) , or C alkoxyl; or two R , which attach to the same carbon atom, 1-4 1-4 2 1-6 2 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; R , R ’, R and R ’ are independently chosen from H, C alkyl, C alkenyl, C alkynyl, C 3 3 4 4 1-6 2-6 2-6 3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -C(O)R , -OR , or -NHR , in which each of said C alkyl, C alkenyl, C alkynyl, C cycloalkyl, 3-12 1-6 2-6 2-6 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R ; wherein R , R ’, R and R ’ are not H simultaneously; provided that when one of R 6 3 3 4 4 3 and R is optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl, the other one is -OR or -NHR ; or R and R ’ are independently chosen from H, C alkyl, C alkenyl, C alkynyl, C 3 3 1-6 2-6 2-6 3-12 cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -C(O)R , -OR , or -NHR , in which each of said C alkyl, C alkenyl, C alkynyl, C cycloalkyl, 3-12 1-6 2-6 2-6 3-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R ; R and R ’ together with the N atom they are attached to form a 3-8 membered 6 4 4 heterocyclic ring optionally substituted by one or more R ; R is chosen from C alkyl or C cycloalkyl, each of which is optionally substituted with one 1-6 3-8 or more groups independently chosen from halo, -CN, -OH, -SH, -NH2, or C1-6 alkoxyl; each of R is independently chosen from deuterium, halo, -CN, -OH, -SH, -NH , C alkoxyl, 6 2 1-6 C alkyl, C haloalkyl, C cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered 1-6 1-6 3-8 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, -NH , C alkoxyl, C alkynyl, or C 2 1-6 2-6 1-6 alkyl; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2.
In some embodiments of the compound of formula (I), R is chosen from H, -OH or halo.
In some embodiments of the compound of formula (I), R is chosen from –OH or halo.
In some embodiments of the compound of formula (I), R is -OH.
In some embodiments of the compound of formula (I), R is halo chosed from F, Cl, or Br. In some embodiments of the compound of formula (I), R 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 R is independently chosen from H, deuterium, halo, -OH, -NH , -CN, -SH, C alkyl, C alkenyl, C alkynyl, C haloalkyl, 2 1-6 2-6 2-6 1-6 C cycloalkyl, oxo, -OR , -OCOR , -NHR , -N(R )(C alkyl), -NHCOR , or 3-8 membered 3-8 5 5 5 5 1-4 5 heterocyclyl.
In some embodiments of the compound of formula (I), each of R is independently chosen from H, deuterium, halo, -OH, -NH , -CN, C alkyl, C haloalkyl, oxo, -OR , -NHR , or -N(R )(C 2 1-6 1-6 5 5 5 1-4 alkyl).
In some embodiments of the compound of formula (I), each of R is independently chosen from H, deuterium, halo, C alkyl, or C haloalkyl. 1-6 1-6 In some embodiments of the compound of formula (I), each of R is independently chosen from halo, such as F, Cl, or Br.
In some embodiments of the compound of formula (I), R 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 C alkyl, C cycloalkyl, 3-12 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, 1-6 3-12 -C(O)R , -OR , or -NHR , in which each of said C alkyl, C cycloalkyl, 3-12 membered 5 5 1-6 3-12 heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with one or more R6; R ’ and R ’ are independently chosen from H or C alkyl. 3 4 1-6 In some embodiments of the compound of formula (I), R ’ and R ’ are both H.
In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C alkyl, C cycloalkyl, or 3-12 membered heterocyclyl, each of which is optionally 1-6 3-12 substituted with one or more R ; R ’ and R ’ are both H. 6 3 4 In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C alkyl substituted with one ore more halo, 5-12 membered heteroaryl substituted with C 1-6 1-6 haloalkyl, or -OR ; R ’ and R ’ are both H. 3 4 In some embodiments of the compound of formula (I), R3 and R4 are independently chosen from C alkyl optionally substituted with one or more halo; R ’ and R ’ are both H. 1-6 3 4 In some embodiments of the compound of formula (I), R is 5-12 membered heteroaryl substituted with C haloalkyl, R is C alkoxyl; R ’ and R ’ are both H. 1-6 4 1-6 3 4 In some embodiments of the compound of formula (I), R is 5-7 membered heteroaryl substituted with CF , R is C alkoxyl; R ’ and R ’ are both H. 3 4 1-6 3 4 In some embodiments of the compound of formula (I), R is chosen from H, C alkyl optionally 3 1-6 substituted by C haloalkyl, or 5-12 membered heteroaryl optionally substituted by C 1-6 1-6 haloalkyl; R ’is H; R and R ’ together with the N atom they are attached to form a 3-8 3 4 4 membered heterocyclic ring optionally substituted by one or more groups chosen from halo, -OH, or C haloalkyl.
In some embodiments of the compound of formula (I), R is C alkyl or C cycloalkyl. 1-6 3-8 In some embodiments of the compound of formula (I), R is C alkyl optionally substituted 1-6 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, -NH , C alkoxyl, C alkyl, C haloalkyl, C cycloalkyl, 3-8 2 1-6 1-6 1-6 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, in which each of said C 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, C alkoxyl, C alkyl, C haloalkyl, C cycloalkyl, 3-8 membered 1-6 1-6 1-6 3-8 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, -NH , C alkoxyl, C alkyl, C haloalkyl, or C cycloalkyl. 2 1-6 1-6 1-6 3-8 In some embodiments of the compound of formula (I), each of R is independently chosen from deuterium, halo, or C haloalkyl.
In some embodiments of the compound of formula (I), n is 1.
In some embodiments of the compound of formula (I), R and R are independently chosen from halo or -CN.
In some embodiments of the compound of formula (I), R and R are independently chosen from F or -CN.
In some embodiments of the compound of formula (I), the compound of formula (I) is chosen wherein X is halo; R , R , R , R ’, R , R ’, m and n are as defined in the compound of formula 1 2 3 3 4 4 In some embodiments of the compound of formula (I), formula (I) is formula (I-1), wherein R , R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I), 2 3 3 4 4 (I-1) .
In some embodiments of the compound of formula (I), formula (I) is formula (I-1a), wherein R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I), 3 3 4 4 .
In some embodiments of the compound of formula (I), formula (I) is formula (I-1b), wherein R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I), 3 3 4 4 In some embodiments of the compound of formula (I), formula (I) is formula (II), wherein R , R , R , R ’, R , R ’, n and A are as defined in the compound of formula (I); X is halo; p is 0, 1, or 2; 3 3 4 4 m is 0, 1, or 2, (II) .
In some embodiments of the compound of formula (II), X is F.
In some embodiments of the compound of formula (II), R is F.
In some embodiments of the compound of formula (II), R 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 wherein R , R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I); X is 1 2 3 3 4 4 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 R , R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, 2 3 3 4 4 or 2; m is 0, 1, or 2, In some embodiments of the compound of formula (I), formula (II) is formula (II-1a), wherein R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, 2 3 3 4 4 or 2; m is 0, 1, or 2, In some embodiments of the compound of formula (I), formula (II) is formula (II-1b), wherein R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1, 2 3 3 4 4 or 2; m is 0, 1, or 2, 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), R is F.
In some embodiments of the compound of formula (II-1) - formula (II-5), R 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 R , R , R , R ’, R , R ’, n and A are as defined in the compound of formula (I); X is halo; p is 0, 1, 2 3 3 4 4 or 2; m is 0, 1, or 2; v is 0, 1, or 2, (III) .
In some embodiments of the compound of formula (III), X is F.
In some embodiments of the compound of formula (III), R is F.
In some embodiments of the compound of formula (III), R 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 (III-2) wherein R , R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I); X is 1 2 3 3 4 4 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 R , R , R , R ’, R , R ’, m and n are as defined in the compound of formula (I); X is halo; p is 0, 1 2 3 3 4 4 1, or 2; m is 0, 1, or 2; v is 0, 1, or 2, 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), R is F.
In some embodiments of the compound of formula (III-1) - formula (III-5), R 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 a-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 a-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 a-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 mamufacutre of compounds of formula (I) (e.g., any of the compounds described herein), wherein, R , R , m and n are as defined in the compound of formula (I); R is chosen from halo, 1 2 a -OS(O) CF , -B(OH) , -B(OC alkyl) , , or ; R is H or C 2 3 2 1-6 2 b 1-6 alkyl.
In some embodiments of the compound of formula (IV), R is chosen from -B(OH) , -B(OC a 2 1-6 alkyl) , , or ; R is H or C alkyl. 2 b 1-6 In some embodiments of the compound of formula (IV), R is chosen from -B(OH) , -B(OCH ) , a 2 3 2 -B[OCH(CH ) ] , , or . 3 2 2 In some embodiments of the compound of formula (IV), formula (IV) is formula (IV-1), wherein m is 0, 1, or 2; 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; 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; In some embodiments of the compound of formula (IV), R 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 , , or .
In some embodiments of the compound of formula (IV), the compound of formula (IV) is chosen 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 Figure 1, substitution reaction of 2,4,6-trichloro-1,3,5-triazine with an amine substituted with R and R ’ provides compound of formula 1-1. Substitution reaction of the compound of formula 1-1 with an amine substituted with R and R ’ 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 , R , R , R ’, R , R ’, Ra, m, and n are 1 2 3 3 4 4 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 CO , Na CO , K PO and the like, and the catalyst used can be selected from 2 3 2 3 3 4 Pd(dppf)Cl ·CH Cl , Pd(PPh ) , Pd(OAc) and the like. 2 2 2 3 4 2 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 R and R ’ gives a compound of formula (I-1) as described herein, wherein R , R , R , R ’, R , R ’, Ra, m, and n are as defined herein. 1 2 3 3 4 4 As shown in Scheme 3, Suzuki coupling reaction of compound of formula 1-2 with an intermediate represented byformula (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 CO , Na CO , K PO and the like, and the catalyst used can be selected from 2 3 2 3 3 4 Pd(dppf)Cl ·CH Cl , Pd(PPh ) , Pd(OAc) and the like. Reduction of compound of formula 3-1 2 2 2 3 4 2 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 R and R ’ 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 NaBD , 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.
Pharmceutical 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 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, , 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. Patents 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 balence(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-Bu Sn) 1,1,1,2,2,2-hexabutyldistannane (S)-CBS (S)-3,3-diphenylmethylpyrrolidino[1,2-c]-1,3,2-oxazaborole CD OD methanol-d DAST diethylaminosulphur trifluoride DCM dichloromethane DIEA N,N-diisopropylethylamine DMF N,N- dimethylformamide DMSO-d6 dimethyl sulfoxide-d6 EA/ EtOAc ethyl acetate Et N triethylamine EtOH ethanol Et Zn diethyl zinc g gram HC(OMe) 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) sodium triacetoxyborohydride NaOMe sodium methoxide NaOEt sodium ethoxide NCS N- chlorosuccinimide NFSI N- fluorobenzenesulfonimide PdCl (PPh ) bis(triphenylphosphine)palladium(II) dichloride 2 3 2 Pd (dba) tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl ·CH Cl [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 2 2 2 dichloromethane complex Pd(PPh ) tetrakis(triphenylphosphine)palladium(0) PE petroleum ether Selectfluor® 1-chloromethylfluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), TBAF tetrabutylammonium fluoride TBSOTf tert-butyldimethylsilyltrifluoromethanesulfonate TFA trifluoroacetic acid Tf O trifluoromethanesulfonic anhydride THF tetrahydrofuran TsOH·H O 4-methylbenzenesulfonic acid monohydrate Example 1 Preparation of intermediates Intermediate I-1 3-(4-Chloro(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluorocyclohex-2 -enol and Intermediate I-61 (*)3-(4-Chloro(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenol (A) 2-Fluorohydroxycyclohexenone (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-Fluorooxocyclohexenyl 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 Tf O (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-trifluoropropanyl)-1,3,5-triazinamine (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-trifluoropropanamine 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)(4-chloro((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenone (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, .3 mmol), Cs CO (14.4 g, 38.3 mmol), Pd(PPh ) (0.89 g, 0.77 mmol) and water (8 mL) in 2 3 3 4 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(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenol (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, NaBH (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(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenol (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 BH ·Me S/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 Na SO , 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: MS MS Intermediate Structure Intermediate Structure (M+H) (M+H) 314.0 I-25 323.0 I-23 279.1 I-80 285.0 I-24 265.1 Intermediate I-2 (R)Chloro-N -isopropyl-N -(1,1,1-trifluoropropanyl)-1,3,5-triazine-2,4-diamine To a sealed tube was added compound A3 (3.5 g, 13.4 mmol), propanamine (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 I-2 using the corresponding intermediates and reagents under appropriate conditions that will be recognized by POSITA: Inter- MS Inter- MS Structure Structure mediate (M+H) mediate (M+H) 314.0 I-50 318.0 I-8 312.0 I-51 321.0 I-9 332.0 I-54 332.0 I-11 346.0 I-55 362.1 I-12 310.0 I-71 284.0 I-13 298.1 I-72 320.4 I-14 346.0 I-73 308.1 I-15 296.0 I-74 296.1 I-16 282.0 I-75 350.9 I-17 300.0 I-76 323.9 I-18 284.0 I-77 296.0 I-19 270.0 I-78 284.0 I-20 324.1 I-79 351.0 I-21 333.0 I-81 321.0 I-30 332.0 I-82 346.0 I-31 310.0 I-83 288.0 I-33 352.2 I-84 318.0 I-35 298.1 I-85 282.2 I-36 276.0 I-86 324.0 I-37 278.0 I-87 333.0 I-38 290.0 I-89 338.0 I-39 291.1 I-90 314.1 I-40 291.1 I-91 314.1 I-42 285.1 I-101 318.0 I-49 318.0 I-102 318.1 Intermediate I-3 6-Chloro-N ,N -bis((R)-1,1,1-trifluoropropanyl)-1,3,5-triazine-2,4-diamine 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 mmo), (R)-1,1,1-trifluoropropanamine 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 Inter- MS Structure Structure mediate (M+H) mediate (M+H) 254.1 I-34 230.1 I-10 326.0 I-106 446.0 I-32 338.0 Intermediate I-4 (R)-N-(4-Chloro((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)isobutyramide A mixture of 4,6-dichloro-1,3,5-triazinamine (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-triazinyl)isobutyramide as yellow solid. Then, to 1,4-dioxane (10 mL) was added N-(4,6-dichloro-1,3,5-triazinyl)isobutyramide obtained above, (R)-1,1,1-trifluoropropanamine 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(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)cyclohexenol optically pure diastereoisomers 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-N -(propanyl-d7)-N -(2-(trifluoromethyl)pyridinyl)-1,3,5-triazine-2,4- diamine (A) 4,6-Dichloro-N-(2-(trifluoromethyl)pyridinyl)-1,3,5-triazinamine (A5) To a solution of 2,4,6-trichloro-1,3,5-triazine (1.84 g, 10 mmol) and 2-(trifluoromethyl)pyridinamine (1.62 g, 10 mmol) in dry THF (20 mL) was added NaHCO (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-N -(propanyl-d7)-N -(2-(trifluoromethyl)pyridinyl)-1,3,5-triazine-2,4- diamine To a sealed tube were added compound A5 (465 mg, 1.5 mmol), propan-d 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 Inter- MS Structure Structure mediate (M+H) mediate (M+H) 268.0 I-94 361.1 308.0 I-96 329.0 I-45 304.0 I-97 349.1 I-53 334.0 I-98 381.1 I-59 329.0 I-99 385.0 I-63 363.0 I-100 366.9 I-66 363.0 I-101 318.0 I-68 364.0 I-103 428.9 I-92 321.1 I-104 416.9 I-93 335.1 I-105 362.1 Intermediate I-46 2-((4-(Tert-butoxyamino)chloro-1,3,5-triazinyl)amino)isonicotinonitrile (A) O-(Tert-butyl)-N-(4,6-dichloro-1,3,5-triazinyl)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 NaHCO (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)chloro-1,3,5-triazinyl)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)Cl (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 Inter- MS Structure Structure mediate (M+H) mediate (M+H) 329.0 I-65 313.0 I-48 315.0 I-67 283.0 I-52 305.0 I-69 304.0 I-56 358.0 I-70 308.0 I-57 304.1 I-5 304.0 I-58 295.0 I-28 309.0 I-60 295.1 I-29 310.0 I-62 369.0 I-95 363.9 I-64 385.0 Intermediate I-88 2-Fluoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohexenone 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)Cl ·CH Cl (12.4 g, 15.3 mmol) and 1,4-dioxane (1.4 L) in sequence. The 2 2 2 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] H NMR (400 MHz, DMSO-d ): d 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(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazin yl)cyclohexenol (A) (R)fluoro(4-(isopropylamino)((1,1,1-trifluoropropanyl)amino)-1,3,5-triazin- 2-yl)cyclohexenone (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)Cl ·CH Cl (32 mg, 0.04 mmol) and 1,4-dioxane (20 mL) in sequence and 2 2 2 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), Cs CO (682 mg, 2.1 mmol), Pd(PPh ) (46.2 mg, 0.04 2 3 3 4 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(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenol To a flask were added compound B1 (80 mg, 0.22 mmol), CeCl ·7H O (107 mg, 0.29 mmol) and EtOH (5 mL). The mixture was cooled to 0 C. Then, NaBH (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 NH Cl 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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 5.01- 4.88 (m, 2H), 4.36-4.24 (m, 1H), 2.66-2.50 (m, 1H), 2.41-2.31 (m, 1H), 418.1 I-3 1.97-1.60 (m, 4H), 1.38-1.30 (m, 6H).
H NMR (400 MHz, CD OD): d .06-4.90 (m, 1H), 4.61-4.46 (m, 1H), 3 4.37-4.21 (m, 1H), 4.04-3.87 (m, 2H), 392.1 I-8 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).
H NMR (400 MHz, CD OD): d .01-4.87 (m, 1H), 4.37-4.15 (m, 2H), 3.05-2.84 (m, 2H), 2.77-2.49 (m, 3H), 412.1 I-30 2.42-2.24 (m, 1H), 1.96-1.56 (m, 4H), 1.44-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d 4.37-4.22 (m, 3H), 3.02-2.86 (m, 4H), 406.1 I-10 2.73-2.50 (m, 5H), 2.41-2.25 (m, 1H), 1.91-1.72 (m, 3H), 1.72-1.62 (m, 1H).
H NMR (400 MHz, CD OD): d .00-4.90 (m, 1H), 4.51-4.41 (m, 1H), 6 4.34-4.25 (m, 1H), 2.62-2.47 (m, 2H), 426.1 I-11 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).
H NMR (400 MHz, CD OD): d .02-4.89 (m, 1H), 4.33-4.24 (m, 1H), 376.1 4.19-4.06 (m, 1H), 2.63-2.47 (m, 1H), I-15 2.40-2.25 (m, 1H), 1.92-1.60 (m, 4H), 1.40-1.30 (m, 3H), 1.23-1.15 (m, 6H).
H NMR (400 MHz, CD OD): d 4.99-4.87 (m, 1H), 4.36-4.22 (m, 1H), 8 3.60-3.40 (m, 1H), 2.66-2.47 (m, 1H), 390.1 I-31 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).
H NMR (400MHz, CD OD): d 4.99-4.88 (m, 1H), 4.42-4.34 (m, 1H), 9 4.18-4.07 (m, 1H), 2.40-2.17 (m, 2H), 392.3 I-2 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).
H NMR (400 MHz, CD OD): d .03-4.89 (m, 1H), 4.37-4.16 (m, 2H), 2.64-2.47 (m, 1H), 2.40-2.24 (m, 1H), 390.1 I-12 2.04-1.44 (m, 12H), 1.39-1.31 (m, H NMR (400 MHz, CD OD): d .04-4.90 (m, 2H), 4.35-4.24 (m, 1H), 2.66-2.52 (m, 1H), 2.43-2.27 (m, 1H), 418.1 I-3 1.95-1.60 (m, 4H), 1.43-1.31 (m, 6H).
H NMR (400 MHz, CD OD): d .00-4.89 (m, 1H), 4.35-4.23 (m, 1H), 12 3.26-3.05 (m, 2H), 2.66-2.48 (m, 1H), 378.1 I-13 2.42-2.25 (m, 1H), 1.97-1.59 (m, 5H), 1.41- 1.30 (m, 3H), 0.96-0.88 (m, H NMR (400 MHz, CD OD): d .02-4.89 (m, 1H), 4.35-4.23 (m, 1H), 3.63-3.40 (m, 2H), 2.65-2.51 (m, 3H), 426.1 I-14 2.47-2.21 (m, 4H), 1.89-1.61 (m, 4H), 1.39-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d .03-4.90 (m, 2H), 4.36-4.23 (m, 1H), 14 418.1 I-32 2.67-2.49 (m, 1H), 2.42-2.26 (m, 1H), 1.94-1.61 (m, 4H), 1.40-1.31 (m, 6H).
H NMR (400 MHz, CD3OD): d .04-4.93 (m, 1H), 4.82-4.70 (m, 1H), 4.34-4.23 (m, 1H), 2.65-2.51 (m, 1H), 432.3 I-33 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).
H NMR (400 MHz, CD OD): d .12-4.92 (m, 1H), 4.80-4.53 (m, 1H), 4.37-4.26 (m, 1H), 2.87-2.77 (m, 1H), 16 380.1 2.68-2.51 (m, 1H), 2.46-2.27 (m, 1H), I-1 1.97- 1.60 (m, 4H), 1.43-1.31 (m, 3H), 1.2-1.06 (m, 1H), 1.02-0.87 (m, H NMR (400 MHz, CD OD): d .00-4.92 (m, 1H), 4.22-4.07 (m, 2H), 17 380.4 2.50-2.27 (m, 2H), 1.95-1.81 (m, 3H), I-2 1.76-1.66 (m, 1H), 1.41-1.32 (m, 3H), 1.23-1.18 (m, 6H).
H NMR (400 MHz, CD OD): d .02-4.87 (m, 2H), 2.68-2.51 (m, 1H), 18 419.1 I-3 2.44-2.28 (m, 1H), 1.92-1.63 (m, 4H), 1.42-1.30 (m, 6H).
H NMR (400 MHz, CD OD): d 4.38-4.15 (m, 2H), 3.05-2.85 (m, 4H), 19 407.1 I-10 2.72-2.48 (m, 5H), 2.40-2.26 (m, 1H), 1.90-1.61 (m, 4H).
H NMR (400 MHz, CD OD): d 4.52-4.38 (m, 1H), 4.33-4.17 (m, 2H), 420.2 2.99-2.84 (m, 4H), 2.71-2.48 (m, 5H), I-10 2.37-2.23 (m, 1H), 2.01-1.82 (m, 3H), 1.74-1.60 (m, 3H).
H NMR (400MHz, CD OD): d .02-4.89 (m, 2H), 4.53-4.41 (m, 1H), 21 432.3 2.77-2.62 (m, 1H), 2.40-2.27 (m, 1H), I-3 2.02-1.83 (m, 3H), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H).
H NMR (400 MHz, CD OD): d 4.36-4.16 (m, 2H), 3.00-2.84 (m, 4H), 22 421.1 I-10 2.73-2.50 (m, 5H), 2.39-2.21 (m, 1H), 2.01-1.82 (m, 3H), 1.75-1.59 (m, 3H).
H NMR (400 MHz, CD3OD): d 4.99-4.86 (m, 1H), 4.20-4.07 (m, 1H), 2.61-2.47 (m, 1H), 2.37-2.25 (m, 1H), 23 365.2 I-2 1.88-1.62 (m, 4H), 1.37-1.29 (m, 3H), 1.20-1.17 (m, 6H).
H NMR (400 MHz, CD OD): d 4.99-4.86 (m, 1H), 4.34-4.15 (m, 1H), 2.97-2.83 (m, 2H), 2.73-2.51 (m, 3H), 24 427.1 I-9 2.37-2.25 (m, 1H), 2.01-1.82 (m, 3H), 1.72-1.60 (m, 3H), 1.39-1.13 (m, 3H).
H NMR (400 MHz, CD OD): d 4.36-4.24 (m, 1H), 4.24-4.00 (m, 2H), 310.1 2.62-2.43 (m, 1H), 2.39-2.22 (m, 1H), I-34 1.91-1.82 (m, 2H), 1.82-1.72 (m, 1H), 1.70-1.60 (m, 1H), 1.19 (s, 12H).
H NMR (400 MHz, CD OD): d .19-4.88 (m, 2H), 4.38-4.22 (m, 1H), 2.96 (s, 3H), 2.68-2.49 (m, 1H), 26 378.1 2.43-2.28 (m, 1H), 1.91-1.83 (m, 2H), I-35 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).
H NMR (400 MHz, CD OD): d 4.42-4.13 (m, 2H), 3.02-2.86 (m, 2H), 27 356.1 2.83-2.46 (m, 4H), 2.44-2.21 (m, 1H), I-36 1.92-1.83 (m, 2H), 1.83-1.60 (m, 2H), 0.82-0.67 (m, 2H), 0.60-0.45 (m, 2H).
H NMR (400 MHz, CD OD): d 4.36-4.20 (m, 2H), 4.20-4.04 (m, 1H), 28 358.1 3.01-2.84 (m, 2H), 2.71-2.45 (m, 3H), I-37 2.40-2.23 (m, 1H), 1.90-1.83 (m, 2H), 1.83-1.60 (m, 2H), 1.20 (s, 6H).
H NMR (400 MHz, CD OD): d 4.98-4.88 (m, 1H), 2.65-2.43 (m, 1H), 29 372.1 I-39 2.41-2.23 (m, 1H), 1.92-1.70 (m, 3H), 1.70-1.59 (m, 1H), 1.37-1.29 (m, 3H).
H NMR (400 MHz, CD OD): d 4.97-4.89 (m, 1H), 2.70-2.42 (m, 1H), 372.1 I-40 2.41-2.21 (m, 1H), 1.90-1.72 (m, 3H), 1.69-1.59 (m, 1H), 1.37-1.29 (m, 3H).
H NMR (400 MHz, CD OD): d .02-4.89 (m, 1H), 4.38-4.14 (m, 2H), 31 412.1 3.03-2.86 (m, 2H), 2.80-2.49 (m, 3H), I-9 2.44-2.26 (m, 1H), 1.95-1.59 (m, 4H), 1.41-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d .03-4.90 (m, 1H), 4.38-4.16 (m, 2H), 32 412.1 3.02-2.86 (m, 2H), 2.82-2.50 (m, 3H), I-54 2.43-2.25 (m, 1H), 1.94-1.60 (m, 4H), 1.42-1.32 (m, 3H).
H NMR (400 MHz, CD OD): d .02-4.90 (m, 1H), 4.38-4.22 (m, 1H), 33 364.1 4.18-4.04(m, 1H), 2.66-2.49 (m, 1H), I-71 2.39-2.20 (m, 1H), 2.03-1.58 (m, 4H), 1.42-1.29 (m, 3H), 1.23-1.10 (m, 6H).
H NMR (400 MHz, CD OD) d 8.93-8.75 (m, 2H), 7.98-7.93 (m, 1H), 7.83-8.77 (m, 1H), 4.37-4.29 (m, 1H), 34 431.0 2.72-2.60 (m, 1H), 2.47-2.35 (m, I-75 341H), 1.92-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.73-1.65 (m, 1H), 1.32 (s, H NMR (400 MHz, CD OD): d 9.55 (s, 1H), 7.91-7.78 (m, 1H), 7.64-7.48 (m, 1H), 7.33-7.13 (m, 1H), 6.62-6.47 200 384.1 I-5 (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).
H NMR (400 MHz, CD OD): d 8.59-8.34 (m, 2H), 4.39-4.28 (m, 1H), 205 390.1 2.74-2.61 (m, 1H), 2.55 (s, 3H), 2.51- I-29 2.37 (m, 1H), 1.98-1.66 (m, 4H), 1.31 (s, 9H).
H NMR (400 MHz, CD OD): d .05-4.86 (m, 2H), 3.49-3.39 (m, 1H), 2.73-2.58 (m, 1H), 2.53-2.38 (m, 1H), 219 444.2 I-3 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).
H NMR (400 MHz, CD OD): d 9.34-9.19 (m, 1H), 8.60-8.36 (m, 1H), 7.73-7.54 (m, 2H), 4.39-4.30 (m, 1H), 229 401.0 I-81 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).
Compound 35 6-(2,3-Difluorocyclohexenyl)-N -isopropyl-N -((R)-1,1,1-trifluoropropanyl)-1,3,5-tr iazine-2,4-diamine 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 NH Cl 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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 7.16-6.94 (m, 1H), 5.25-5.06 (m, 1H), 36 5.05-4.89 (m, 1H), 4.27-4.06 (m, 1H), Comp. 348.0 2.63-2.26 (m, 2H), 1.95-1.63 (m, 4H), 124 1.39-1.30 (d, J = 5.2 Hz, 3H), 1.24-1.16 (m, 6H).
H NMR (400 MHz, CD OD): d 7.26-7.00 (m, 1H), 5.08-4.85 (m, 2H), 37 4.26-4.07 (m, 1H), 2.87-2.70 (m, 1H), Comp. 348.3 2.68-2.53 (m, 1H), 2.44-2.26 (m, 2H), 144 1.95-1.80 (m, 2H), 1.36-1.30 (m, 3H), 1.20-1.16 (m, 6H).
H NMR (400 MHz, CD OD): d 7.13-6.85 (m, 1H), 5.03-4.85 (m, 2H), 38 Com. 4.24-4.07 (m, 1H), 2.63-2.35 (m, 4H), 348.3 2.01-1.82 (m, 2H), 1.36-1.31 (m, 3H), 1.20-1.16 (m, 6H).
Compound 39 (*)3-(4,6-Bis((3,3-difluorocyclobutyl)amino)-1,3,5-triazinyl)fluorocycloheptenol 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 BH ·Me S/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-triazinyl)fluoro cycloheptenone (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 Na SO 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] H NMR (400MHz, CD OD): d 4.52-4.38 (m, 1H), 4.33-4.17 (m, 2H), 2.99-2.84 (m, 4H), 2.71-2.48 (m, 5H), 2.37-2.23 (m, 1H), 2.01-1.82 (m, 3H), 1.74-1.60 (m, 3H).
The compounds 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 H NMR (M+H) mediate H NMR (400MHz, CD OD): d 4.98-4.87 (m, 1H), 4.51-4.41 (m, 1H), 40 4.31-4.16 (m, 1H), 2.97-2.84 (m, 2H), 426.1 I-9 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).
H NMR (400 MHz, CD OD): d .00-4.89 (m, 1H), 4.69-4.44 (m, 5H), 4.34-4.22 (m, 1H), 2.65- 2.50 (m, 1H), 41 400.1 I-72 2.40-2.25 (m, 1H), 1.89-1.57 (m, 4H), 1.38-1.29 (m, 3H).
H NMR (400 MHz, CD OD): d .00-4.89 (m, 1H), 4.33-4.21 (m, 1H), 3.13-2.99 (m, 1H), 2.62- 2.47 (m, 1H), 42 388.2 I-73 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).
H NMR (400 MHz, CD3OD): d 4.51-4.18 (m, 5H), 3.01-2.82 (m, 2H), 2.71-2.45 (m, 3H), 2.38- 2.20 (m, 1H), 43 376.1 I-74 1.87-1.59 (m, 4H), 1.27-1.19 (m, 3H).
H NMR (400 MHz, CD OD): d 8.47-8.11 (m, 2H), 7.66 (s, 1H), 7.49-7.37 (m, 1H), 7.18-7.05 (m, 1H), 44 438.1 I-56 .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).
H NMR (400 MHz, CD OD): d 8.37-8.29 (br, 1H), 8.29-8.16 (m, 1H), 7.65 (s, 1H), 7.47-7.38 (m, 1H), 45 384.1 I-57 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).
H NMR (400 MHz, CD OD): d 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, 46 375.1 I-58 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).
H NMR (400MHz, CD OD): d 8.48-8.19 (m, 1H), 8.14-8.04 (m, 1H), 47 409.2 7.65-7.46 (m, 1H), 4.38-4.26 (m, 1H), I-59 2.73-2.58 (m, 1H), 2.49-2.34 (m, 1H), 1.91-1.64 (m, 4H), 1.32 (s, 9H).
H NMR (400MHz, CD OD): d 7.50-7.42 (m, 1H), 7.26-7.20 (m, 1H), 6.81-6.68 (m, 1H), 4.36-4.13 (m, 2H), 48 375.2 I-60 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).
H NMR (400 MHz, CD OD): d 4.39-4.18 (m, 2H), 2.99-2.86 (m, 2H), 2.80-2.46 (m, 4H), 2.39-2.23 (m, 1H), 49 356.1 I-36 1.89-1.82 (m, 2H), 1.81-1.62 (m, 2H), 0.79-0.67 (m, 2H), 0.55-0.48 (m, 2H).
H NMR (400 MHz, CD OD): d 4.45-4.14 (m, 2H), 3.05-2.82 (m, 2H), 50 370.1 I-38 2.79-2.23 (m, 5H), 1.91-1.61 (m, 4H), 1.18-0.45 (m, 6H).
H NMR (400 MHz, CD OD): d 4.35-4.20 (m, 2H), 4.20-4.06 (m, 1H), 2.98-2.86 (m, 2H), 2.70-2.45 (m, 3H), 51 358.1 I-37 2.38-2.23 (m, 1H), 1.89-1.82 (m, 2H), 1.81-1.60 (m, 2H), 1.19 (s, 6H).
H NMR (400 MHz, CD OD): d 4.99-4.87 (m, 1H), 4.33-4.23 (m, 1H), 2.64-2.45 (m, 1H), 2.40-2.21 (m, 1H), 52 371.1 I-39 1.89-1.71 (m, 3H), 1.70-1.58 (m, 1H), 1.36-1.30 (m, 3H).
H NMR (400 MHz, CD OD): d 4.98-4.88 (m, 1H), 4.35-4.19 (m, 1H), 2.63-2.44 (m, 1H), 2.44-2.21 (m, 1H), 53 371.1 I-40 1.93-1.70 (m, 3H), 1.70-1.53 (m, 1H), 1.39- 1.29 (m, 3H).
H NMR (400 MHz, CD OD): d 8.60-8.22 (m, 2H), 8.09-7.74 (m, 1H), 54 420.1 4.38-4.27 (m, 1H), 2.75- 2.58 (m, 1H), I-41 2.48-2.33 (m, 1H), 1.91-1.75 (m, 3H), 1.73-1.64 (m, 1H).
H NMR (400 MHz, CD OD): d 4.36-4.15 (m, 2H), 3.02-2.81 (m, 2H), 2.73-2.41 (m, 3H), 2.40- 2.19 (m, 1H), 55 365.1 I-42 1.89-1.71 (m, 3H), 1.70-1.59 (m, 1H).
H NMR (400 MHz, CD OD): d 4.32-4.19 (m, 2H), 4.19-4.04 (m, 1H), 2.98-2.83 (m, 2H), 2.72- 2.43 (m, 3H), 56 360.1 I-37 2.39-2.21 (m, 1H), 1.80-1.70 (m, 1H), 1.68-1.58 (m, 1H), 1.25-1.11 (br, 6H).
H NMR (400 MHz, CD OD): d 8.16-7.44 (m, 2H), 4.38-4.24 (m, 1H), 4.24-4.10 (m, 1H), 3.84 (s, 3H), 57 348.1 I-43 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).
H NMR (400 MHz, CD OD): d 8.61-8.24 (m, 2H), 8.04-7.81 (m, 1H), 58 388.0 4.39-4.27 (m, 1H), 2.75- 2.58 (m, 1H), I-44 2.51-2.31 (m, 1H), 1.92-1.75 (m, 3H), 1.73-1.64 (m, 1H).
H NMR (400 MHz, CD OD): d 8.39-8.25 (m, 2H), 7.86-7.79 (m, 1H), 7.13-7.02 (m, 1H), 6.42- 6.36 (m, 1H), 59 348.1 4.37-4.28 (m, 1H), 4.26-4.15 (m, 1H), I-45 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).
H NMR (400 MHz, CD OD): d 9.07-8.95 (m, 1H), 8.49-8.43 (m, 1H), 7.68-7.57 (m, 2H), 7.57- 7.52 (m, 1H), 60 400.1 7.30-7.25 (m, 1H), 4.39-4.28 (m, 1H), I-46 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).
H NMR (400 MHz, CD OD): d 8.91-8.64 (m, 1H), 8.27-8.16 (m, 1H), 7.11-6.99 (m, 1H), 4.38-4.28 (m, 1H), 61 409.1 I-47 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).
H NMR (400 MHz, CD OD): d 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), 62 395.1 I-48 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).
H NMR (400 MHz, CD OD): d 8.18-8.11 (m, 1H), 8.09-8.01 (m, 1H), 7.52-7.46 (m, 1H), 7.46- 7.32 (m, 1H), 63 398.1 4.35-4.26 (m, 1H), 4.22-4.16 (m, 1H), I-49 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).
H NMR (400 MHz, CD OD): d 8.25-8.10 (m, 1H), 7.94-7.86 (m, 1H), 7.66-7.39 (m, 2H), 4.35- 4.25 (br, 1H), 64 398.1 4.23-4.11 (m, 1H), 4.02 (s, 3H), I-50 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).
H NMR (400 MHz, CD OD): d 8.89-8.84 (m, 1H), 8.83-8.66 (m, 1H), 7.98-7.91 (m, 1H), 7.82– 7.70 (m, 1H), 65 401.1 4.36-4.28 (m, 1H), 4.25-4.18 (m, 1H), I-51 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).
H NMR (400 MHz, CD OD/ CDCl3 = 2/1): d 8.63-8.54 (m, 1H), 7.62-7.57 (m, 2H), 7.13- 7.04 (m, 1H), 4.38-4.12 66 385.1 I-52 (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).
H NMR (400 MHz, CD OD): d 8.38-8.22 (m, 2H), 7.89-7.76 (m, 1H), 7.12-7.01 (m, 1H), 6.45- 6.34 (m, 1H), 67 414.1 4.38-4.27 (m, 1H), 3.51-3.42 (m, 2H), I-53 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).
H NMR (400 MHz, CD3OD): d 8.86-7.07 (m, 6H), 5.19-4.97 (m, 1H), 68 449.1 4.41-4.27 (m, 1H), 2.78- 2.60 (m, 1H), I-62 2.53-2.37 (m, 1H), 1.94-1.78 (m, 3H), 1.76-1.65 (m, 1H), 1.45-1.36 (m, 3H).
H NMR (400 MHz, CD OD): d .00-4.87 (m, 2H), 4.36-4.22 (m, 1H), 2.65-2.51 (m, 1H), 2.43- 2.29 (m, 1H), 69 418.1 I-32 1.89-1.60 (m, 4H), 1.38-1.29 (m, 6H).
H NMR (400 MHz, CD OD): d 8.64-7.73 (m, 3H), 4.43-4.27 (m, 1H), 70 443.1 3.53-3.43 (m, 2H), 2.79- 2.61 (m, 1H), I-66 2.52-2.36 (m, 1H), 1.92-1.67 (m, 4H), 1.24-1.16 (m, 6H).
H NMR (400 MHz, CD OD): d 8.55-8.36 (m, 2H), 8.01-7.90 (m, 1H), 71 443.1 4.41-4.30 (m, 1H), 2.77- 2.62 (m, 1H), I-63 2.52-2.32 (m, 1H), 1.96-1.64 (m, 4H), 1.31 (s, 9H).
H NMR (400 MHz, CD OD): d 8.58-7.52 (m, 5H), 7.14-6.94 (m, 2H), 72 465.0 I-64 4.42-4.27 (m, 1H), 2.80- 2.65 (m, 1H), 2.56-2.37 (m, 1H), 1.94-1.66 (m, 4H).
H NMR (400 MHz, CD OD): d 8.09-7.85 (m, 2H), 7.51-7.39 (m, 1H), 73 393.1 4.41- 4.26 (m, 1H), 2.74- 2.57 (m, 1H), I-65 2.49-2.32 (m, 1H), 1.96-1.64 (m, 4H), 1.32-1.29 (m, 9H).
H NMR (400 MHz, CD OD): d 8.02-7.88 (m, 1H), 7.85-7.72 (m, 1H), 7.52-7.39 (m, 1H), 4.39- 4.29 (m, 1H), 74 363.1 I-67 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).
H NMR (400 MHz, CD OD): d 9.18-8.77 (m, 2H), 4.45-4.24 (m, 1H), 75 444.1 I-68 2.81-2.64 (m, 1H), 2.53- 2.34 (m, 1H), 2.00-1.66 (m, 4H), 1.37-1.26 (m, 9H).
H NMR (400 MHz, CD OD): d 9.63-9.01 (m, 1H), 7.74 (s, 1H), 7.54-7.48 (m, 1H), 7.47-7.40 (m, 1H), 76 384.1 7.38-7.22 (m, 1H), 4.39- 4.29 (m, 1H), I-69 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).
H NMR (400 MHz, CD OD): d 6.59-6.32 (m, 1H), 4.36-4.27 (m, 1H), 4.23-4.10 (m, 1H), 4.03-3.90 (m, 2H), 77 388.1 I-70 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).
H NMR (400 MHz, CD OD): d .04-4.89 (m, 1H), 4.34-4.24 (m, 1H), 3.25-3.07 (m, 2H), 2.65-2.48 (m, 1H), 78 378.2 I-13 2.40-2.20 (m, 1H), 1.96-1.59 (m, 5H), 1.38- 1.30 (m, 3H), 0.95-0.87 (m, 6H).
H NMR (400 MHz, CD OD): d .03-4.90 (m, 1H), 4.35-4.26 (m, 1H), 4.21-4.00 (m, 2H), 2.65- 2.49 (m, 1H), 79 404.1 I-76 2.43-2.24 (m, 1H), 1.93-1.59 (m, 4H), 1.42-1.30 (m, 3H).
H NMR (400 MHz, CD OD): d .50-4.87 (m, 1H), 4.34-4.23 (m, 1H), 3.26-3.14 (m, 2H), 2.62- 2.47 (m, 1H), 80 376.1 2.39-2.22 (m, 1H), 1.89-1.82 (m, 2H), I-77 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).
H NMR (400 MHz, CD OD): d .01-4.87 (m, 1H), 4.34-4.22 (m, 1H), 3.37-3.30 (m, 1H), 3.28- 3.23 (m, 1H), 81 364.1 2.62-2.48 (m, 1H), 2.38-2.22 (m, 1H), I-78 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).
H NMR (400 MHz, CD OD) : d 8.91-8.85 (m, 1H), 8.80-8.66 (m, 1H), 7.99-7.91 (m, 1H), 7.82-7.72 (m, 1H), 199 431.0 4.38-4.28 (m, 1H), 3.53-3.40 (m, 2H), I-79 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).
H NMR (400 MHz, CD OD): d 8.30-8.09 (m, 1H), 7.93 -7.58 (m, 2H), 204 389.1 4.40-4.28 (m, 1H), 2.75-2.60 (m, 1H), I-28 2.52-2.36 (m, 4H), 1.95-1.65 (m, 4H), 1.32 (s, 9H).
H NMR (400 MHz, CD OD): d .12-4.89 (m, 1H), 4.36-4.21 (m, 1H), 2.81-2.66 (m, 1H), 2.65- 2.46 (m, 1H), 224 362.0 2.41-2.21 (m, 1H), 1.90-1.82 (m, 2H), I-16 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).
H NMR (400 MHz, CD OD): d 4.98-4.90 (m, 1H), 4.60-4.52 (m, 1H), 4.49-4.40 (m, 1H), 4.35- 4.20 (m, 1H), 240 368.0 3.74-3.54 (m, 2H), 2.68-2.45 (m, 1H), I-83 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).
H NMR (400 MHz, CD OD): d 4.35-4.17 (m, 2H), 4.16-4.04 (m, 2H), 241 398.0 3.00-2.84 (m, 2H), 2.71-2.48 (m, 3H), I-84 2.42-2.26 (m, 1H), 1.91-1.82 (m, 2H), 1.82- 1.73 (m, 1H), 1.70-1.60 (m, 1H).
Compounds 82 and 83 (*)3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluorocyclohex en-6,6-D2ol and 3-(4,6-bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluorocyclohexen- 1,6,6-D3ol (A) 3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluorocyclohex- 2-enone-6,6-D To a solution of 3-(4,6-bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl) fluorocyclohexenone (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 D O (2 mL) and K CO 2 2 3 (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-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexen-6,6-D ol Compound 82 was prepared according to the procedure of Compound 39. MS (m/z): 420.1 [M+H] H NMR (400MHz, CD OD): d 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-trifluoropropanyl)amino)-1,3,5-triazinyl)fluorocyclohex- 2-en-1,6,6-D ol Compound 83 was prepared according to the procedure of Compound 1 step (B), using NaBD .
MS (m/z): 421.1 [M+H] H NMR (400MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 4.98-4.89 (m, 1H), 4.35-4.13 (m, 84 2H), 3.02-2.81 (m, 2H), 2.75-2.46 414.1 I-54 (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).
H NMR (400 MHz, CD OD): d 4.36-4.14 (m, 3H), 2.98-2.85 (m, 4H), 2.67-2.46 (m, 5H), 2.39-2.22 85 408.1 I-10 (m, 1H), 1.82-1.71 (m, 1H), 1.68-1.57 (m, 1H).
H NMR (400 MHz, CD OD): d 8.60-8.23 (m, 2H), 8.10-7.75 (m, 1H), 4.36-4.28 (m, 1H), 2.72-2.56 86 422.1 I-41 (m, 1H), 2.48-2.33 (m, 1H), 1.83-1.73 (m, 1H), 1.71-1.63 (m, H NMR (400 MHz, CD OD): d .02-4.88 (m, 2H), 4.34-4.24 (m, 1H), 2.60-2.48 (m, 1H), 2.42-2.30 87 420.0 I-32 (m, 1H), 1.88-1.72 (m, 1H), 1.70-1.58 (m, 1H), 1.36-1.31 (m, H NMR (400 MHz, CD OD): d 8.54-8.35 (m, 2H), 8.03-7.83 (m, 1H), 4.40-4.24 (m, 1H), 2.74-2.60 89 445.1 I-63 (m, 1H), 2.48-2.32 (m, 1H), 1.85-1.74 (m, 1H), 1.71- 1.60 (m, 1H), 1.31 (s, 9H).
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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 4.98-4.89 (m, 1H), 4.35-4.13 (m, 90 1H), 3.02-2.81 (m, 2H), 2.75-2.46 415.1 I-54 (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).
H NMR (400 MHz, CD OD): d 4.36-4.14 (m, 2H), 2.98-2.85 (m, 4H), 2.67-2.46 (m, 5H), 2.39-2.22 91 409.1 I-10 (m, 1H), 1.82-1.71 (m, 1H), 1.68-1.57 (m, 1H).
H NMR (400 MHz, CD OD): d 4.34-4.18 (m, 1H), 4.18-4.00 (m, 1H), 3.01-2.81 (m, 2H), 2.72-2.41 92 361.1 I-37 (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).
Compound 93 (*)3-(4-Amino(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenol (A) (R)fluoro(4-((4-methoxybenzyl)amino)((1,1,1-trifluoropropanyl)amino)- 1,3,5-triazinyl)cyclohexenone (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)(4-amino((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenone (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 NaHCO 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(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenol Compound 93 was prepared according to the procedure of Compound 39. MS (m/z): 322.0 [M+H] H NMR (400MHz, CD3OD): d 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(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazin- 2-yl)cyclohexenol, optically pure diastereoisomers (A) 2,6-difluoro(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenone (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) inTHF (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 NH Cl aqueous solution (30 mL). The organic layer was collected and the aqueous was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na SO 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(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohex- 2-enol 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] ; H NMR (400MHz, CD OD): d 4.97-4.90 (m, 1H), 4.72-4.55 (m, 1H), 4.38-4.03 (m, 2H), 2.63-2.46 (m, 2H), 2.06-1.90 (m, 2H), 1.38-1.31 (m, 3H), 1.23-1.13 (s, 6H).
Compound 96, Rf ˜ 0.50, MS (m/z): 382.2 [M+H] ; H NMR (400MHz, CD OD): d 4.97-4.90 (m, 1H), 4.71-4.55 (m, 1H), 4.51-4.40 (m, 1H), 4.20-4.05 (m, 1H), 2.76-2.58 (m, 1H), 2.48-2.31 (m, 1H), 2.15-2.01 (m, 1H), 1.98-1.81 (m, 1H), 1.40-1.30 (m, 3H), 1.22-1.12 (m, 6H).
The compounds 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 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), 436.2 I-3 1.37-1.31 (m, 6H).
Rf ˜ 0.55 H NMR (400MHz, CD OD): d .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), 98 436.1 I-3 2.17-2.02 (m, 1H), 1.98-1.84 (m, 1H), 1.40-1.29 (m, 6H).
Rf ˜ 0.50 H NMR (400 MHz, CD OD): d 4.79-4.64 (m, 1H), 4.37-4.15 (m, 3H), 2.99-2.83 (m, 4H), 2.70-2.47 201 424.2 I-10 (m, 6H), 2.06-1.88 (m, 2H).
Rf ˜ 0.55 H NMR (400MHz, CD OD): d 4.81-4.64 (m, 1H), 4.52-4.38 (m, 1H), 4.34-4.17 (m, 2H), 2.99-2.83 202 424.2 I-10 (m, 4H), 2.70-2.32 (m, 6H), 2.13-2.01 (m, 1H), 1.96-1.81 (m, Rf ˜ 0.50 H NMR (400 MHz, CD OD): d .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), 225 394.2 I-77 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).
Rf ˜ 0.55 H NMR (400 MHz, CD OD): d .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), 226 394.2 2.52-2.30 (m, 1H), 2.15-2.01 (m, I-77 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, Rf ˜ 0.50 H NMR (400 MHz, CD OD): d .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, 227 430.0 I-9 2H), 1.42-1.31 (m, 3H).
Rf ˜ 0.55 H NMR (400 MHz, CD OD): d .05-4.88 (m, 1H), 4.82 - 4.64 (m, 1H), 4.54-4.40 (m, 1H), 4.36-4.17 228 430.0 (m, 1H), 3.00-2.84 (m, 2H), 2.77- I-9 2.34 (m, 4H), 2.16-2.02 (m, 1H), 1.96-1.83 (m, 1H), 1.41-1.30 (m, Rf ˜ 0.50 H NMR (400 MHz, DMSO-d ): d 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), 382.1 3.22-3.10 (m, 2H), 2.56-2.39 (m, I-18 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).
H NMR (400 MHz, DMSO-d ): d 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), 382.0 I-18 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).
H NMR (400 MHz, CD OD): d .00-4.89 (m, 1H), 4.81-4.63 (m, 1H), 4.52-4.37 (m, 1H), 4.36-4.19 232 444.2 (m, 1H), 2.65-2.46 (m, 3H), I-82 2.28-2.14 (m, 2H), 2.13-1.91 (m, 4H), 1.85-1.70 (m, 1H), 1.39-1.29 Rf ˜ 0.55 (m, 3H).
H NMR (400 MHz, CD OD): d .01-4.89 (m, 1H), 4.80-4.62 (m, 1H), 4.57-4.29 (m, 2H), 2.74-2.34 233 444.2 (m, 3H), 2.29-1.71 (m, 7H), I-82 1.41-1.27 (m, 3H).
Rf ˜ 0.50 Note: Compounds 230 and 231 were obtained via flash column chromatography (eluting with gradient H O/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 Compounds 242, 266-269 3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6-difluorocyclohex enDol, optically pure diastereoisomers Chiral separation (A) 3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6-difluoro- cyclohexenone 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] ; H NMR (400 MHz, CD OD): d 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-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6-difluoro- cyclohexenone, 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-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6-difluoro- cyclohexenDol, optically pure diastereoisomers Compounds 266 and 267 were prepared according to the procedure of Compound 1, using Compound 246 and NaBD , purified by flash column chromatography (eluting with PE/EA).
Compound 266: Rf ˜ 0.55, MS (m/z): 437.2 [M+H] ; H NMR (400MHz, CD OD): d 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] ; H NMR (400MHz, CD OD): d 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 NaBD , purified by flash column chromatography (eluting with PE/EA).
Compound 268: Rf ˜ 0.55, MS (m/z): 437.2 [M+H] ; H NMR (400MHz, CD OD): d 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] ; H NMR (400MHz, CD3OD): d 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(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenol (A) (R)-2,6,6-trifluoro(4-(isopropylamino)((1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenone (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 NH Cl aqueous solution (30 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na SO 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(4-(isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenol Compound 94 was prepared according to the procedure of Compound 39, using compound B5 and corresponding reagents. MS (m/z): 400.2 [M+H] H NMR (400MHz, CD OD): d 4.97-4.88 (m, 1H), 4.33-4.19 (m, 1H), 4.19-4.07 (m, 1H), 2.78-2.61 (m, 1H), 2.59-2.40 (m, 1H), 2.21-2.00 (m, 2H), 1.37-1.30 (m, 3H), 1.21-1.12 (m, 6H).
The compounds 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d .00-4.86 (m, 2H), 4.36-4.17 (m, 1H), 2.80-2.65 (m, 1H), 2.58-2.42 454.1 I-3 (m, 1H), 2.25-2.05 (m, 2H), 1.37-1.31 (m, 6H).
H NMR (400 MHz, CD OD): d 4.37-4.14 (m, 3H), 3.00-2.85 (m, 4H), 2.74-2.44 (m, 6H), 2.24-2.02 203 442.2 I-10 (m, 2H).
H NMR (400 MHz, CD OD): d .01-4.92 (m, 1H), 4.35-4.01 (m, 3H), 2.77-2.67 (br, 1H), 2.63-2.46 208 440.0 I-76 (m, 1H), 2.33-2.01 (m, 2H), 1.41-1.32 (m, 3H).
H NMR (400 MHz, CD OD): d 4.99-4.90 (m, 1H), 4.31-4.20 (m, 1H), 3.25-3.16 (m, 2H), 2.79-2.63 209 412.2 (m, 1H), 2.59-2.44 (m, 1H), I-78 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).
H NMR (400 MHz, CD OD): d .03-4.89 (m, 1H), 4.55-4.37 (m, 1H), 4.02-3.77 (m, 2H), 2.81-2.61 210 400.0 (m, 1H), 2.58-2.37 (m, 1H), I-18 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).
H NMR (400 MHz, CD OD): d .02-4.89 (m, 1H), 4.38-4.14 (m, 2H), 3.03- 2.86 (m, 2H), 2.78-2.44 239 448.0 I-54 (m, 4H), 2.30-2.01 (m, 2H), 1.42-1.30 (m, 3H).
H NMR (400 MHz, CD OD): d .01-4.92 (m, 1H), 4.35-4.01 (m, 3H), 2.77-2.67 (br, 1H), 2.63-2.46 245 440.0 I-76 (m, 1H), 2.33-2.01 (m, 2H), 1.41-1.32 (m, 3H).
Compound 234 3-(4-((Cyclopropylmethyl)amino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazin yl)-2,6,6-trifluorocyclohexenol (A) (R)(4-((cyclopropylmethyl)amino)((1,1,1-trifluoropropanyl)amino)-1,3,5- triazin- 2-yl)-2,6,6-trifluorocyclohexenone (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)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)-2,6,6-trifluorocyclohexenol Compound 234 was prepared according to the procedure of Compound 1, using compound B7 and corresponding reagents. MS (m/z): 412.2 [M+H] H NMR (400MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400MHz, CD OD): d .03-4.87 (m, 2H), 2.82-2.66 (m, 1H), 211 455.1 2.62-2.45 (m, 1H), 2.27-2.02 (m, 2H), I-3 1.40-1.29 (m, 6H).
H NMR (400 MHz, CD OD): d .02-4.88 (m, 1H), 4.54-4.39 (m, 1H), 4.33-4.17 (m, 1H), 2.79-2.64 (m, 1H), 235 462.2 I-82 2.61-2.44 (m, 2H), 2.29-2.00 (m, 6H), 1.90-1.67 (m, 1H), 1.39-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d .05-4.91 (m, 1H), 4.31-4.20 (m, 1H), 2.86-2.60 (m, 2H), 2.59-2.43 (m, 1H), 238 398.0 I-16 2.24-2.04 (m, 2H), 1.38-1.31 (m, 3H), 0.78-0.66 (m, 2H), 0.57-0.44 (m, 2H).
H NMR (400 MHz, CD OD): d 4.98-4.90 (m, 1H), 4.32-4.19 (m, 1H), 3.38-3.23 (m, 2H), 2.80-2.61 (m, 1H), 248 400.0 I-18 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).
Compound 259 3-(4-((3,3-Difluorocyclobutyl)amino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)-2,6,6-trifluorocyclohexenol (A) (R)(3-((tert-butyldimethylsilyl)oxy)fluorocyclohexa-1,3-dienyl)-N -(3,3- difluorocyclobutyl)-N -(1,1,1-trifluoropropanyl)-1,3,5-triazine-2,4-diamine (B9) Under N , to a mixture of compound B8 (prepared according to Compound 39 using Intermediate I-9: 750 mg, 1.83 mmol) and Et N (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 Na SO condensed under reduced pressuer 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)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)-2,6-difluorocyclohexenone (B10) Under N , 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 reduece 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)(4-((3,3-difluorocyclobutyl)amino)((1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)-2,6,6-trifluorocyclohexenone (B11) Under N , 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 NH Cl aqueous solution was added to quench the reaction. The mixture was extracted with EtOAc. The organic layer was collected, condensed under reduece 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)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)-2,6,6-trifluorocyclohexenol Compound 259 was prepared according to the procedure of Compound 39, using compound B11 and corresponding reagents. MS (m/z): 448.0 [M+H] H NMR (400MHz, CD3OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 4.99-4.83 (m, 1H), 4.26-4.09 (m, 260 1H), 2.76-2.53 (m, 2H), 2.51-2.34 398.0 I-85 (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).
H NMR (400 MHz, CD OD): d 4.36-4.09 (m, 3H), 3.02-2.87 (m, 2H), 2.79-2.43 (m, 4H), 2.26-2.04 261 394.2 I-37 (m, 2H), 1.28-1.15 (m, 6H).
H NMR (400 MHz, CD OD) d 4.92-4.82 (m, 1H), 4.28-3.90 (m, 3H), 2.72-2.38 (m, 2H), 2.20-1.96 270 440.2 I-86 (m, 2H), 1.33-1.21 (m, 3H).
H NMR (400 MHz, CD OD): d 8.31-8.20 (m, 1H), 7.63-7.50 (m, 1H), 7.25-7.14 (m, 1H), 7.13-7.01 271 449.2 (m, 1H), 4.83-4.68 (m, 1H), I-87 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).
Compound 274 3-(4-((3,3-difluorocyclobutyl)amino)(isopropylamino)-1,3,5-triazinyl)-2,6,6-trifluorocy clohexenDol (A) 3-(4-((3,3-Difluorocyclobutyl)amino)(isopropylamino)-1,3,5-triazinyl)fluoro- cyclohexenone (B12) Under N , a mixture of Intermediate I-37 (4.17 g, 15.0 mmol), Intermediate I-88 (4.32 g, 18.0 mmol), Na PdCl (221 mg, 0.75 mmol), DTBPPS (402 mg, 1.5 mmol), K CO (5.18 g, 37.5 2 4 2 3 mmol), MeCN (40 mL) and H O (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)(isopropylamino)-1,3,5-triazinyl)-2,6- difluorocyclohexenone (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)(isopropylamino)-1,3,5-triazinyl)-2,6,6- trifluorocyclohexenone (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)(isopropylamino)-1,3,5-triazinyl)-2,6,6- trifluorocyclohexenDol Compound 274 was prepared according to the procedure of Step B of Compound 1, using Compound B14, NaBD and corresponding reagents. MS (m/z): 395.1 [M+H] H NMR (400MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 8.67-8.30 (m, 2H), 8.06-7.80 (m, 479.2 1H), 4.45-4.23 (m, 1H), 2.93-2.75 I-63 (m, 1H), 2.69-2.50 (m, 1H), 2.33- 2.06 (m, 2H), 1.42-1.20 (m, 9H).
H NMR (400 MHz, CD OD): d 8.67-8.32 (m, 2H), 8.08-7.80 (m, 276 480.2 1H), 2.91-2.75 (m, 1H), 2.69-2.52 I-63 (m, 1H), 2.32-2.08 (m, 2H), 1.42- 1.26 (m, 9H).
H NMR (400 MHz, CD OD): d .05-4.91 (m, 2H), 4.38-4.16 (m, 1H), 2.83-2.66 (m, 1H), 2.62-2.45 277 454.2 I-89 (m, 1H), 2.29-2.03 (m, 2H), 1.44- 1.26 (m, 6H).
H NMR (400 MHz, CD OD): d .14-4.92 (m, 1H), 2.88-2.64 (m, 2H), 2.59-2.43 (m, 1H), 2.32-1.99 278 399.2 I-85 (m, 2H), 1.45-1.28 (m, 3H), 0.82- 0.66 (m, 2H), 0.58-0.45 (m, 2H).
H NMR (400 MHz, CD3OD): d .13-4.93 (m, 1H), 2.90-2.64 (m, 2H), 2.61-2.41 (m, 1H), 2.33-1.99 279 399.0 I-16 (m, 2H), 1.49-1.24 (m, 3H), 0.86- 0.67 (m, 2H), 0.62-0.46 (m, 2H).
H NMR (400 MHz, CD OD): d 7.22-6.87 (m, 1H), 5.10-4.91 (m, 2H), 4.49-4.21 (m, 1H), 2.90-2.54 281 436.2 I-3 (m, 2H), 2.34-1.98 (m, 2H), 1.50- 1.20 (m, 6H).
H NMR (400 MHz, CD OD): d 7.22-6.87 (m, 1H), 5.10-4.91 (m, 2H), 2.90-2.54 (m, 2H), 2.34-1.98 282 437.2 I-3 (m, 2H), 1.50-1.20 (m, 6H).
H NMR (400 MHz, CD OD): d .05-4.90 (m, 2H), 4.40-4.19 (m, 1H), 2.84-2.66 (m, 1H), 2.62-2.45 283 454.0 I-32 (m, 1H), 2.30 -2.03 (m, 2H), 1.42-1.27 (m, 6H).
H NMR (400 MHz, CD OD): d .09-4.91 (m, 1H), 4.34-4.21 (m, 1H), 2.82-2.68 (m, 1H), 2.61-2.46 293 430.2 I-90 (m, 1H), 2.28-2.03 (m, 2H), 1.39- 1.34 (m, 3H), 1.29-1.26 (m, 9H).
H NMR (400 MHz, CD OD): d .09-4.91 (m, 1H), 4.34-4.21 (m, 1H), 2.82-2.68 (m, 1H), 2.61-2.46 294 430.2 I-91 (m, 1H), 2.28-2.03 (m, 2H), 1.39- 1.34 (m, 3H), 1.29-1.26 (m, 9H).
H NMR (400 MHz, CD OD): d .01-4.88 (m, 2H), 3.07-2.09 (m, 4H), 1.39-1.31 (m, 6H). 296 452.1 I-3 H NMR (400 MHz, CD3OD): d 8.77-8.34 (m, 2H), 8.01-7.69 (m, 1H), 4.47-4.17 (m, 1H), 3.81 (s, 3H), 298 437.1 I-92 2.89-2.73 (m, 1H), 2.67-2.52 (m, 1H), 2.30-2.06 (m, 2H).
Compound 297 2,6,6-Trifluoro(4-(methoxyamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenol (A) (R)(4-chloro((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6,6-trifluoro- cyclohexenone (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(4-(methoxyamino)((1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenone (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(4-(methoxyamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenol 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] H NMR (400MHz, CD OD): d 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(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6,6-trifluoro- cyclohexenol (A) (R)fluoro(4-((4-methoxyphenyl)amino)((1,1,1-trifluoropropanyl)amino)- 1,3,5-triazinyl)cyclohexenone (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)(4-amino((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)fluoro- cyclohexenone (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 NaHCO 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(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6,6- trifluorocyclohexenol Compound 280 was prepared according to the procedure of Compound 274, using Compound B19 and corresponding reagents. MS (m/z): 358.1 [M+H] ; H NMR (400MHz, CD OD): d 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-triazinyl)-2,6,6-trifluorocyclohexenol (A) 3-(4,6-Bis((3,5-dimethoxybenzyl)amino)-1,3,5-triazinyl)fluorocyclohexenone (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-triazinyl)fluorocyclohexenone (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-triazinyl)-2,6,6-trifluorocyclohex enone (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-triazinyl)-2,6,6-trifluorocyclohexenone (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-triazinyl)-2,6,6-trifluorocyclohexenol 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] H NMR (400MHz, CD OD): d 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-trifluoropropanyl)amino)-1,3,5-triazinyl)chlorofluoro- cyclohexenol (A) 3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)chlorofluoro- cyclohexenone (B24) To a sealed tube was added 3-(4,6-bis(((R)-1,1,1-trifluoropropanyl)amino)- 1,3,5-triazinyl)fluorocyclohexenone (prepared according to the procedure of Compound 1 using Intermediate I-3, 700 mg, 1.69 mmol), NCS (224 mg, 1.69 mmol), TsOH·H O (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-trifluoropropanyl)amino)-1,3,5-triazinyl)chlorofluoro- cyclohexenol Compound 99 was prepared according to the procedure of Compound 39 using Compound B24 and corresponding reagents. MS (m/z): 452.1 [M+H] H NMR (400MHz, CD OD): d 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)(4-(isopropylamino)((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)cyclohex enone To a flask were added Intermediate I-2 (500 mg, 1.76 mmol), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)cyclohexenone (391 mg, 1.76 mmol), Cs CO (1144 mg, 3.52 mmol), Pd(PPh ) (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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d .01-4.90 (m, 1H), 4.22-4.10 (m, 1H), 362.1 2.89-2.77 (m, 2H), 2.64-2.55 (m, 2H), I-2 2.12-2.02 (m, 2H), 1.39-1.32 (m, 3H), 1.23-1.17 (m, 6H).
H NMR (400 MHz, CD OD): d .00-4.88 (m, 2H), 2.91-2.78 (m, 2H), 295 416.2 I-3 2.62-2.53 (m, 2H), 2.11-2.00 (m, 2H), 1.40-1.30 (m, 6H).
Compound 124 3-(4-(Isopropylamino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)cyclohex enol To a flask were added Compound 122 (250 mg, 0.73 mmol), CeCl ·7H O (353 mg, 0.95 mmol) and EtOH (10 mL). The mixture was cooled to 0 C, NaBH (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 NH Cl 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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 6.88-6.70 (m, 1H), 5.07-4.87 (m, 2H), 125 4.23-4.08 (m, 1H), 2.90-2.77 (m, 1H), 332.0 I-2 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).
H NMR (400 MHz, CD OD): d 7.23-7.01 (m, 1H), 5.08-4.87 (m, 2H), 400.0 4.37-4.27 (m, 1H), 2.49-2.35 (m, 2H), I-3 1.98-1.82 (m, 2H), 1.68-1.53 (m, 2H), 1.39-1.32 (m, 6H).
H NMR (400 MHz, CD OD): d 7.22-6.93 (m, 1H), 4.36-4.19 (m, 3H), 388.1 2.97-2.87 (m, 4H), 2.69-2.50 (m, 4H), I-10 2.45-2.34 (m, 2H), 1.97-1.80 (m, 2H), 1.67-1.51 (m, 2H).
H NMR (400 MHz, CD OD): d 7.26-6.90 (m, 1H), 5.10-4.92 (m, 1H), 358.1 4.60-4.26 (m, 2H), 2.56- 2.23 (m, 4H), I-15 2.11-1.81 (m, 4H), 1.79-1.49 (m, 4H), 1.42-1.28 (m, 3H).
H NMR (400 MHz, CD OD): d 7.27-6.85 (m, 1H), 5.17-4.95 (m, 1H), 129 4.45-4.20 (m, 1H), 2.84-2.63 (m, 1H), 344.1 I-16 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).
H NMR (400 MHz, CD OD): d 7.22-6.89 (m, 1H), 5.09-4.92 (m, 1H), 372.1 4.41-4.18 (m, 2H), 2.54-2.31 (m, 2H), I-12 2.09-1.82 (m, 4H), 1.80-1.69 (m, 2H), 1.67-1.44 (m, 6H), 1.40-1.31 (m, 3H).
H NMR (400 MHz, CD3OD): d 7.24-6.95 (m, 1H), 5.12-4.90 (m, 1H), 131 4.43-4.25 (m, 1H), 3.53-3.37 (m, 2H), 376.1 I-7 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).
H NMR (400 MHz, CD OD): d 7.23-6.91 (m, 1H), 5.12-4.91 (m, 1H), 132 4.43-4.25 (m, 1H), 3.65-3.46 (m, 4H), 362.1 I-17 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).
H NMR (400 MHz, CD OD): d 7.02-6.87 (m, 1H), 5.11-4.90 (m, 1H), 133 4.40-4.23 (m, 1H), 3.40-3.30 (m, 2H), 346.1 I-18 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).
H NMR (400 MHz, CD3OD): d 7.23-6.90 (m, 1H), 5.14-4.89 (m, 1H), 134 4.45-4.21 (m, 1H), 3.25-3.07 (m, 2H), 360.1 I-13 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).
H NMR (400 MHz, CD OD): d 7.28-6.88 (m, 1H), 5.14-4.93 (m, 1H), 135 4.40-4.22 (m, 1H), 3.48-3.35 (m, 2H), 332.1 I-19 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).
H NMR (400 MHz, CD OD): d 7.22-6.92 (m, 1H), 5.11-4.88 (m, 1H), 136 4.41-4.26 (m, 1H), 3.95-3.72 (m, 1H), 386.1 I-20 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).
H NMR (400 MHz, CD OD): d 7.31-7.215 (m, 1H), 5.09-4.95 (m, 1H), 137 4.39-4.30 (m, 1H), 3.16-2.81 (m, 1H), 374.1 I-4 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).
Compound 138 (R)(3,3-difluorocyclohexenyl)-N -isopropyl-N -(1,1,1-trifluoropropanyl)-1,3,5- triazine-2,4-diamine 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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 7.12-6.83 (m, 1H), 5.07-4.92 (m, 1H), 4.64-4.41 (m, 1H), 4.03-3.88 (m, 2H), 394.0 3.87-3.76 (m, 1H), 3.72-3.60 (m, 1H), I-8 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).
Compound 140 6-(3-Methoxycyclohexenyl)-N ,N -bis((R)-1,1,1-trifluoropropanyl)-1,3,5-triazine- 2,4-diamine 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] ; H NMR (400MHz, CD OD): d 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)cyclohexenyl)-N ,N -bis((R)-1,1,1-trifluoropropanyl)-1,3,5- triazine-2,4-diamine To a solution of Compound 126 (50mg, 0.125mmol) in dry DCM (3 mL) was added SOCl (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] H NMR (400 MHz, CD3OD): d 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 H NMR (M+H) mediate H NMR (400MHz, CD OD): d 7.26-7.06 (m, 1H), 5.08-4.91 (m, 2H), 142 3.89-3.73 (m, 1H), 2.74-2.66 (m, 3H), Comp. 413.1 2.63-2.44 (m, 2H), 2.19-2.07(m, 1H), 126 2.02-1.92 (m, 1H), 1.76-1.57(m, 2H), 1.38-1.33 (m, 6H).
Compound 143 3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)(trifluoromethyl)- cyclohexenol To a solution of 3-(4,6-bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenone (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 NH Cl 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] ; H NMR (400 MHz, CD OD): d 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)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)cyclohex enol (A) (R)-N -isopropyl(1,4-dioxaspiro[4.5]decenyl)-N -(1,1,1-trifluoropropanyl)- 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(1,4-dioxaspiro[4.5]decenyl)-1,3,2-dioxaborolane (300 mg, 1.13 mmol), Cs CO (734 mg, 2.26 mmol), Pd(PPh ) (69 mg, 0.06 mmol), 1,4-dioxane (10 mL) 2 3 3 4 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)(4-(Isopropylamino)((1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl) cyclohexenone (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 NaHCO 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)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl) cyclohexenol Compound 144 was prepared according to the procedure of Compound 124 using Compound B26 and corresponding reagents. MS (m/z): 346.3 [M+H] H NMR (400MHz, CD3OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 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, 346.3 1H), 2.57-2.48 (m, 1H), 2.46-2.33 (m, I-2 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).
Compound 152 2-Fluoro(4-(((R)phenylethyl)amino)(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5- triazinyl)cyclohexenol To a sealed tube was added Intermediate I-1 (50 mg, 0.15 mmol), (R)phenylethanamine (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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 7.21-6.96 (m, 1H), 5.09-4.88 (m, 1H), 153 4.39-4.13 (m, 2H), 2.99-2.87 (m, 2H), 394.1 I-25 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).
H NMR (400 MHz, CD OD): d 7.26-7.03 (m, 1H), 5.07-4.90 (m, 1H), 386.1 4.38-4.26 (m, 1H), 4.21-4.02 (m, 2H), I-25 2.49-2.33 (m, 2H), 1.97-1.82 (m, 2H), 1.67-1.52 (m, 2H), 1.39-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d 7.21-6.89 (m, 1H), 5.07-4.87 (m, 1H), 360.1 4.36-4.24 (m, 1H), 2.48-2.33 (m, 2H), I-25 1.97-1.83 (m, 2H), 1.68-1.52 (m, 2H), 1.43 (s, 9H), 1.38-1.32 (m, 3H).
H NMR (400 MHz, CD OD): d 7.25-6.90 (m, 1H), 5.13-4.93 (m, 1H), 156 4.38-4.23 (m, 1H), 2.54-2.31 (m, 2H), 358.1 I-25 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).
H NMR (400 MHz, CD OD): d 7.40-7.15 (m, 5H), 5.23-4.62 (m, 2H), 426.4 4.34-4.18 (m, 1H), 2.62-2.24 (m, 2H), I-1 1.88-1.60 (m, 4H), 1.53-1.44 (m, 3H), 1.35-1.29 (m, 2H), 1.18-1.07 (m, 1H).
H NMR (400 MHz, CD OD): d 4.99-4.88 (m, 1H), 4.33-4.22 (m, 1H), 3.61- 3.40 (m, 1H), 2.65- 2.47 (m, 158 1H), 2.43-2.25 (m, 1H), 1.91-1.72 (m, 390.1 I-1 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).
H NMR (400 MHz, CD OD): d 4.97-4.88 (m, 1H), 4.35-4.13 (m, 2H), 416.3 2.60-2.47 (m, 1H), 2.44-2.26 (m, 3H), I-1 2.10-2.02 (m, 2H), 1.97-1.76 (m, 9H), 1.70-1.60 (m, 1H), 1.38-1.29 (m, 3H).
H NMR (400 MHz, CD OD): d 4.97-4.89 (s, 1H), 4.43-4.22 (m, 2H), 160 2.68-2.43 (m, 7H), 2.37-2.25 (m, 1H), 452.3 I-1 2.121-2.06 (m, 2H), 1.91-1.73 (m, 3H), 1.73-1.58 (m, 1H), 1.37-1.29 (m, H NMR (400 MHz, CD OD): d 4.97-4.88 (m, 1H), 4.78-4.71 (m, 2H), 418.3 4.64-4.55 (m, 2H), 4.37-4.14 (m, 2H), I-1 2.70-2.48 (m, 3H), 2.38-2.12 (m, 3H), 1.90-1.61 (m, 4H), 1.38-1.29 (m, 3H).
H NMR (400 MHz, CD OD): d .10-4.89 (m, 1H), 4.33-4.20 (m, 1H), 162 2.79-2.67 (m, 1H), 2.64-2.48 (m, 1H), 362.3 I-1 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).
H NMR (400MHz, CD OD): d 4.98-4.89 (m, 1H), 4.33-4.22 (m, 1H), 163 4.00-3.86 (m, 1H), 2.62-2.47 (m, 1H), 392.3 I-1 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).
H NMR (400MHz, CD OD): d 4.97-4.90 (m, 1H), 4.34-4.22 (m, 1H), 4.03-3.91 (m, 1H), 2.63-2.48 (m, 1H), 378.3 2.40-2.24 (m, 1H), 1.90-1.73 (m, 3H), I-1 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).
H NMR (400MHz, CD OD): d 4.97-4.90 (m, 1H), 4.34-4.22 (m, 1H), 4.03-3.91 (m, 1H), 2.63-2.48 (m, 1H), 378.3 2.40-2.24 (m, 1H), 1.90-1.73 (m, 3H), I-1 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).
H NMR (400MHz,CD OD): d .02-4.95 (m, 1H), 4.78-4.57 (m, 1H), 166 426.3 4.41-4.22 (m, 1H), 2.57-2.52 (m, 1H), I-1 2.43-2.31 (m, 1H), 2.27-2.05 (m, 3H), 1.95-1.62 (m, 7H), 1.43-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d .00-4.93 (m, 1H), 4.36-4.23 (m, 1H), 4.04-3.90 (m, 1H), 2.64-2.50 (m, 1H), 167 392.4 I-1 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).
H NMR (400 MHz, CD OD): d 4.99-4.93 (m, 1H), 4.42-4.25 (m, 2H), 2.88-2.71 (m, 2H), 2.66-2.52 (m, 1H), 168 389.3 I-1 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).
H NMR (400 MHz, CD OD): d .01-4.92 (m, 1H), 4.51-4.26 (m, 4H), 169 382.2 2.64-2.49 (m, 1H), 2.39-2.25 (m, 1H), I-1 1.90-1.61 (m, 4H), 1.40-1.31 (m, 3H), 1.27-1.19 (m, 3H).
H NMR (400 MHz, CD OD): d .01-4.92 (m, 1H), 4.51-4.26 (m, 4H), 170 382.3 2.64-2.49 (m, 1H), 2.39-2.25 (m, 1H), I-1 1.90-1.61 (m, 4H), 1.40-1.31 (m, 3H), 1.27-1.19 (m, 3H).
H NMR (400 MHz, CD OD): d 4.99-4.91 (m, 1H), 4.34-4.24 (m, 1H), 3.67-3.44 (m, 2H), 3.19-3.03 (m, 1H), 171 426.3 I-1 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).
H NMR (400 MHz, CD3OD): d .02-4.93 (m, 1H), 4.33-4.26 (m, 1H), 172 394.3 2.63-2.55 (m, 1H), 2.34-2.28 (m, 1H), I-1 1.90-1.76 (m, 3H), 1.71-1.62 (m, 1H), 1.38-1.35 (m, 3H), 1.28 (s, 9H).
H NMR (400 MHz, CD OD): d 5.01- 4.90 (m, 1H), 4.58-4.43 (m, 1H), 173 405.2 4.35-4.25 (m, 1H), 3.00-2.84 (m, 1H), I-61 2.71-2.42 (m, 4H), 2.40-2.21 (m, 5H), 1.89-1.58 (m, 5H), 1.40-1.28 (m, 3H).
H NMR (400 MHz, CD OD): d 6.07-5.70 (m, 1H), 5.01-4.88 (m, 1H), 4.52-4.35 (m, 1H), 4.33-4.23 (m, 1H), 174 400.2 I-61 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).
H NMR (400 MHz, CD OD): d .03-4.89 (m, 1H), 4.69-4.51 (m, 1H), 4.35-4.22 (m, 1H), 2.68-2.50 (m, 1H), 175 414.2 I-61 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).
H NMR (400 MHz, CD OD): d 7.27-6.94 (m, 1H), 5.10-4.87 (m, 1H), 4.57-4.38 (m, 1H), 4.36-4.25 (m, 1H), 176 408.1 2.62-2.48 (m, 1H), 2.47-2.32 (m, 2H), I-26 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).
H NMR (400 MHz, CD OD): d 7.27-6.94 (m, 1H), 5.10-4.87 (m, 1H), 4.57-4.38 (m, 1H), 4.36-4.25 (m, 1H), 177 408.1 2.62-2.48 (m, 1H), 2.47-2.32 (m, 2H), I-27 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).
H NMR (400MHz, CD OD): d 7.17-6.98 (m, 1H), 5.18-4.90 (m, 2H), 4.90-4.86 (m, 2H), 4.66-4.59 (m, 2H), 178 360.0 I-27 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).
H NMR (400 MHz, CD OD): d 7.23-6.95 (m, 1H), 5.08-4.90 (m, 1H), 4.61-4.44 (m, 1H), 4.35-4.25 (m, 1H), 179 374 4.00-3.89 (m, 2H), 3.85-3.76 (m, 1H), I-27 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).
H NMR (400 MHz, CD OD): d 7.23-6.95 (m, 1H), 5.08-4.90 (m, 1H), 4.61-4.44 (m, 1H), 4.35-4.25 (m, 1H), 180 374 4.00-3.89 (m, 2H), 3.85-3.76 (m, 1H), I-27 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).
H NMR (400 MHz, CD OD): d 7.23-6.93 (m, 1H), 5.13-4.88 (m, 1H), 181 422.1 4.39-4.27 (m, 1H), 4.14-3.91 (m, 1H), I-27 2.53-2.35 (m, 2H), 2.14-1.81 (m, 8H), 1.73-1.51 (m, 4H), 1.40-1.30 (m, 3H).
H NMR (400MHz, CD OD): d 7.24-6.90 (m, 1H), 5.10-4.88 (m, 1H), 4.39-4.27 (m, 1H), 4.23-4.08 (m, 2H), 182 388.2 I-27 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).
H NMR (400 MHz, CD OD): d 7.20-6.93 (m, 1H), 5.07-4.89 (m, 1H), 4.37-4.19 (m, 2H), 3.48-3.41 (m, 1H), 183 376.3 I-27 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).
H NMR (400MHz, CD OD): d 7.19-6.91 (m, 1H), 5.06-4.90 (m, 1H), 4.35-4.07 (m, 2H), 3.63-3.48 (m, 2H), 184 362.2 I-27 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).
Compound 186 6-(Cyclohexenyl)-N ,N -bis((R)-1,1,1-trifluoropropanyl)-1,3,5-triazine-2,4-diamine Under nitrogen atmosphere, to a flask was added Intermediate I-3 (150 mg, 0.44 mmol), cyclohexenylboronic acid (85 mg, 0.66 mmol), Cs CO (290 mg, 0.88 mmol), Pd(PPh ) 2 3 3 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] H NMR (400 MHz, DMSO-d ): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 7.20-6.87 (m, 1H), 3.27-3.16 (m, 187 4H), 2.45-2.34 (m, 2H), 2.26-2.18 300.2 I-6 (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).
H NMR (400 MHz, CD OD): d 7.41-6.99 (m, 1H), 5.11-4.88 (m, 188 1H), 3.60-3.34 (m, 2H), 2.55-2.35 360.1 I-7 (m, 2H), 2.29-2.15 (m, 2H), 1.81-1.57 (m, 4H), 1.40-1.30 (m, 3H), 1.19 (s, 6H).
H NMR (400MHz, CD OD): d 6.96-6.78 (m, 1H), 5.06-4.87 (m, 1H), 4.25-4.07 (m, 1H), 2.72-2.62 189 316.1 I-2 (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).
Compound 190 (R)(cyclohexenyl)-N -isopropyl-N -(1,1,1-trifluoropropanyl)-1,3,5-triazine-2,4- diamine A mixture of Intermediate I-22 (85 mg, 0.33 mmol), (R)-1,1,1-trifluoropropanamine hydrochloride (201 mg, 1.34 mmol) and DIEA (0.47mL, 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] H NMR (400 MHz, CD OD): d 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 7.19-6.85 (m, 1H), 3.60-3.40 (m, 2H), 2.46-2.29 (m, 2H), 2.25-2.16 328.2 (m, 2H), 1.73-1.60 (m, 4H), 1.23 (d, J I-23 = 6.6 Hz, 6H), 0.97-0.85 (m, 2H), 0.53-0.30 (m, 6H), 0.23-0.15 (m, H NMR (400 MHz, CD OD): d 7.30-7.02 (m, 1H), 5.08-4.90 (m, 1H), 3.28-3.16 (m, 2H), 2.50-2.34 342.1 (m, 2H), 2.28-2.18 (m, 2H), I-24 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).
H NMR (400 MHz, CD3OD): d 7.25-6.82 (m, 1H), 3.28-3.13 (m, 193 2H), 2.89 (s, 3H), 2.47-2.33 (m, 2H), 260.1 I-24 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).
H NMR (400 MHz, CD OD): d 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), 194 288.2 I-24 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, H NMR (400 MHz, CD OD): d 7.26-6.89 (m, 1H), 3.45-3.35 (m, 2H), 3.27-3.16 (m, 2H), 2.45-2.35 195 318.2 (m, 2H), 2.26-2.19 (m, 2H), I-24 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).
Compounds 206 and 207 3-(5-Fluoro-4,6-bis(((R)-1,1,1-trifluoropropanyl)amino)pyrimidinyl)cyclohexen ol and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropanyl)amino)pyrimidinyl)cyclohexenol (A) A mixture of 2-chlorofluoro-N ,N -bis((R)-1,1,1-trifluoropropanyl)pyrimidine- 4,6-diamine and 6-chlorofluoro-N ,N -bis((R)-1,1,1-trifluoropropanyl)pyrimidine- 2,4-diamine Under nitrogen atmosphere, a mixture of 2,4,6-trichlorofluoropyrimidine (1.12 g, 5.6 mmol), (R)-1,1,1-trifluoropropanamine hydrochloride (2.51g, 16.8 mmol), DIEA (4.22g, 56mmol) 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-trifluoropropanyl)amino) pyrimidinyl) cyclohexenone and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropanyl)amino) pyrimidinyl)cyclohexenone Under nitrogen atmosphere, a mixture of the product obtained in step (A) (80mg, 0.23 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclohexenone (50mg, 0.23 mmol), Cs2CO3 (150mg, 0.46mmol) , 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-trifluoropropanyl)amino)pyrimidinyl) cyclohex enol and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoropropanyl)amino)pyrimidinyl) cyclohexenol 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-trifluoropropanyl)amino) pyrimidinyl)cyclohex- 2-enone and 3-(5-fluoro-2,6-bis(((R)-1,1,1-trifluoro propanyl)amino)pyrimidinyl) cyclohexenoneobtained 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] . H NMR (400 MHz, CD OD): d 6.97-6.89 (m, 1H), .21-5.03 (m, 2H), 4.38-4.26 (m, 1H), 2.55-2.34 (m, 2H), 1.96-1.82 (m, 2H), 1.68-1.52 (m, 2H), 1.42-1.32 (m, 6H).
Compound 207, MS (m/z): 417.0 [M+H] . H NMR (400 MHz, CD OD): d 6.47-6.40 (m, 1H), .10-4.97(m, 1H), 4.82-4.72 (m, 1H), 4.35-4.26(m, 1H), 2.50-2.30 (m, 2H), 1.99-1.85 (m, 2H), 1.71-1.56 (m, 2H), 1.38 (d, J = 7.1 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H).
The compounds 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 H NMR (M+H) mediate H NMR (400 MHz, CD OD): d 8.54-8.35 (m, 2H), 7.98-7.78 (m, 1H), 4.37-4.24 (m, 1H), 4.10-3.94 212 451.2 I-93 (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).
H NMR (400 MHz, CD OD): d 8.50-8.31 (m, 2H), 8.00-7.88 (m, 1H), 4.41-4.24 (m, 1H), 3.78 (d, J = 213 477.2 7.2 Hz, 2H), 2.90-2.73 (m, 1H), I-94 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).
H NMR (400 MHz, CD OD): d 8.92-8.76 (m, 1H), 8.73-8.64 (m, 214 480.0 1H), 4.40- 4.26 (m, 1H), 2.93-2.77 I-95 (m, 1H), 2.71-2.55 (m, 1H), 2.34-2.07 (m, 2H), 1.31 (s, 9H).
H NMR (400 MHz, CD OD): d 8.05-7.88 (m, 2H), 7.47-7.43 (m, 215 429.2 1H), 4.34-4.30 (m, 1H), 2.85-2.77 I-65 (m, 1H), 2.65-2.55 (m, 1H), 2.31-2.06 (m, 2H), 1.32 (s, 9H).
H NMR (400 MHz, CD OD): d 8.31 (s, 1H), 8.13-8.02 (m, 1H), 7.64-7.47 (m, 1H), 4.38-4.23 (m, 216 445.0 I-96 1H), 2.89-2.71 (m, 1H), 2.66-2.50 (m, 1H), 2.32-2.03 (m, 2H), 1.32 (s, H NMR (400 MHz, CD OD): d 8.61-8.28 (m, 2H), 8.07-7.76 (m, 1H), 4.42-4.16 (m, 1H), 4.03-3.82 217 465.2 (m, 2H), 2.88-2.72 (m, 1H), 2.67- I-97 2.50 (m, 1H), 2.31-2.06 (m, 2H), 1.80-1.63 (m, 2H), 1.10-0.90 (m, H NMR (400 MHz, CD OD): d 8.61-8.26 (m, 2H), 7.91-7.74 (m, 218 497.2 1H), 4.45-4.21 (m, 1H), 3.98-3.77 I-98 (m, 4H), 2.90-2.75 (m, 1H), 2.65- 2.41 (m, 3H), 2.30-2.05 (m, 2H).
H NMR (400 MHz, CD OD): d 8.77-7.63 (m, 2H), 7.68 (s, 1H), 4.39-4.18 (m, 1H), 3.27-3.16 (m, 220 501.1 I-99 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).
H NMR (400 MHz, CD OD): d 8.50-8.37 (m, 2H), 7.88-7.80 (m, 221 483.2 1H), 4.60-4.40 (m, 4H), 4.34-4.27 I-100 (m, 1H), 2.85-2.75 (m, 1H), 2.65- 2.55 (m, 1H), 2.31-2.05 (m, 2H).
H NMR (400 MHz, CD3OD): d .03-4.86 (m, 1H), 4.49-4.34 (m, 243 434.0 4H), 4.30-4.20 (m, 1H), 2.75-2.65 I-101 (m, 1H), 2.55-2.45 (m, 1H), 2.27- 2.02 (m, 2H), 1.45-1.33 (m, 3H).
H NMR (400 MHz, CD OD): d .01-4.90 (br, 1H), 4.37-4.20 (m, 244 400.0 1H), 4.19-4.03 (m, 1H), 2.85-2.39 I-2 (m, 2H), 2.32-2.02 (m, 2H), 1.43- 1.29 (m, 3H), 1.23-1.09 (m, 6H).
H NMR (400 MHz, CD OD): d .04-4.86 (m, 1H), 4.50-4.34 (m, 299 434.0 4H), 4.31-4.20 (m, 1H), 2.78-2.65 I-102 (m, 1H), 2.59-2.44 (m, 1H), 2.29- 1.98 (m, 2H), 1.41-1.31 (m, 3H).
H NMR (400 MHz, CD OD): d 8.60-8.47 (m, 1H), 8.43-8.38 (m, 1H), 7.86-7.70 (m, 1H), 4.38-4.23 300 545.1 I-103 (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).
H NMR (400 MHz, CD OD): d 8.51-8.43 (m, 1H), 8.42-8.38 (m, 1H), 7.91-7.84 (m, 1H), 4.40-4.29 301 533.1 I-104 (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).
Compounds 197 and 198 3-(4,6-Bis(((R)-1,1,1-trifluoropropanyl)amino)-1,3,5-triazinyl)-2,6,6-trifluorocyclohex- 2-enol, optically pure diastereoisomers 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(250mm*30mm, 5um); 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 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: H NMR (400 MHz, CD OD): d 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: H NMR (400 MHz, CD OD): d 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 H NMR Purity (M+H) (min) Condition separation H NMR (400 MHz, CD OD): d .00-4.89 (m, 1H), 4.33-4.24 (m, 1H), 4.21-4.06 (m, 1H), 2.63-2.47 (m, 1H), ee%= Column: OJ-H 100 364.1 1.230 2.41-2.47 (br, 1H), 1.93-1.71 (m, 3H), 100% (0.46 cm I.D. × 1.70-1.61 (m, 1H), 1.40-1.30 (m, 3H), 15 cm L); 1.21-1.15 (m, 6H). Mobile phase: H NMR (400 MHz, CD OD): d n-heptane/ .01-4.90 (m, 1H), 4.34-4.24 (m, 1H), isopropanol 4.20-4.06 (m, 1H), 2.65-2.48 (m, 1H), ee%= (0.1% Et NH) 101 364.1 1.316 = 90/10 2.43-2.23 (m, 1H), 1.92-1.72 (m,3H), 100% 1.68-1.59 (m, 1H), 1.40-1.31 (m, 3H), 1.21-1.14 (m, 6H).
H NMR (400 MHz, CD OD): d .03-4.88 (m, 2H), 4.34-4.25 (m, 1H), Column: AD-H 102 418.0 2.68-2.51 (m, 1H), 2.41-2.26 (m, 1H), 1.899 (0.46 cm I.D. × 1.90-1.74 (m, 3H), 1.70-1.58 (m, 1H), 15 cm L); 1.37-1.31 (m, 6H) Mobile phase: H NMR (400 MHz, CD OD): d n-heptane/ isopropanol .02-4.87 (m, 2H), 4.34-4.24 (m, 1H), 103 418.1 2.64-2.50 (m, 1H), 2.45-2.32 (m, 1H), 2.263 (0.1% Et NH) 1.91-1.71 (m, 3H), 1.69-1.71 (m, 1H), = 80/20 1.38-1.30 (m, 6H).
H NMR (400 MHz, CD OD): d 3 Column: AD-H 4.37-4.22 (m, 3H), 3.02-2.86 (m, 4H), ee%= (0.46 cm I.D. × 104 406.3 3.608 2.73-2.50 (m, 5H), 2.41-2.25 (m, 1H), 100% 15 cm L); 1.91-1.72 (m, 3H), 1.72-1.62 (m, 1H). Mobile phase: n-heptane/ H NMR (400 MHz, CD OD): d isopropanol 4.37-4.22 (m, 3H), 3.02-2.86 (m, 4H), ee%= 105 406.3 3.871 (0.1% Et2NH) 2.73-2.50 (m, 5H), 2.41-2.25 (m, 1H), 100% = 70/30 1.91-1.72 (m, 3H), 1.72-1.62 (m, 1H).
H NMR (400 MHz, CD OD): d .02-4.89 (m, 2H), 4.53-4.41 (m, 1H), de% = Column: AS-H 106 432.1 2.77-2.62 (m, 1H), 2.40-2.27 (m, 1H), 10.540 97.79% (0.46 cm I.D. × 2.02-1.83 (m, 3H), 1.74-1.61 (m, 3H), cm L); 1.39-1.32 (m, 6H) Mobile phase: H NMR (400 MHz, CD3OD): d n-heptane/ .02-4.89 (m, 2H), 4.53-4.41 (m, 1H), isopropanol = de% = 107 432.2 2.77-2.62 (m, 1H), 2.40-2.27 (m, 1H), 18.120 97.84% 90/10 2.02-1.83 (m, 3H), 1.74-1.61 (m, 3H), 1.39-1.32 (m, 6H) H NMR (400 MHz, CD OD): d Column: AD-H 4.38-4.15 (m, 2H), 3.05-2.85 (m, 4H), de% = 108 407.1 4.596 (0.46 cm I.D. × 2.72-2.48 (m, 5H), 2.40-2.26 (m, 1H), 99.8% cm L); 1.90-1.61 (m, 4H) Mobile phase: H NMR (400 MHz, CD OD): d n-heptane/ 4.38-4.15 (m, 2H), 3.05-2.85 (m, 4H), de% = 109 407.1 4.897 isopropanol = 2.72-2.48 (m, 5H), 2.40-2.26 (m, 1H), 99.32% 70/30 1.90-1.61 (m, 4H).
H NMR (400 MHz, CD OD): d Column: AD-H .02-4.87 (m, 2H), 2.68-2.51 (m, 1H), de% = 110 419.1 10.090 (0.46 cm I.D. × 2.44-2.28 (m, 1H), 1.92-1.63 (m, 4H), 100% cm L); 1.42-1.30 (m, 6H) Mobile phase: 18 H NMR (400 MHz, CD3OD): d n-heptane/ .02-4.87 (m, 2H), 2.68-2.51 (m, 1H), de% = isopropanol = 111 419.1 16.800 2.44-2.28 (m, 1H), 1.92-1.63 (m, 4H), 100% 90/10 1.42-1.30 (m, 6H) H NMR (400 MHz, CD OD): d Column: AD-H .00-4.87 (m, 2H), 2.63-2.53 (m, 1H), de% = 112 421.1 5.500 (0.46 cm I.D. × 2.37-2.26 (m, 1H), 1.81-1.69 (m, 1H), 100% cm L); 1.67-1.60 (m, 1H), 1.37-1.31 (m, 6H) Mobile phase: 83 H NMR (400 MHz, CD3OD): d n-heptane .00-4.87 (m, 2H), 2.63-2.53 (m, 1H), de% = /isopropanol = 113 421.1 7.420 2.37-2.26 (m, 1H), 1.81-1.69 (m, 1H), 97.54% 80/20 1.67-1.60 (m, 1H), 1.37-1.31 (m, 6H) H NMR (400 MHz, CD OD): d 4.98-4.89 (m, 1H), 4.35-4.13 (m, 1H), de% = Column: AD-H 114 415.1 3.02-2.81 (m, 2H), 2.75-2.46 (m, 3H), 5.960 (0.46 cm I.D. × 2.44-2.24 (m, 1H), 1.82-1.71 (m, 1H), cm L); 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H) Mobile phase: 90 H NMR (400 MHz, CD3OD): d n-heptane/ 4.98-4.89 (m, 1H), 4.35-4.13 (m, 1H), isopropanol = de% = 115 415.1 3.02-2.81 (m, 2H), 2.75-2.46 (m, 3H), 7.800 98.30% 80/20 2.44-2.24 (m, 1H), 1.82-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.38-1.28 (m, 3H) H NMR (400 MHz, CD OD): d Column: AD-H 4.36-4.14 (m, 2H), 2.98-2.85 (m, 4H), de% = 116 409.1 10.170 (0.46 cm I.D. × 2.67-2.46 (m, 5H), 2.39-2.22 (m, 1H), 100% cm L); 1.82-1.71 (m, 1H), 1.68-1.57 (m, 1H) Mobile phase: 91 H NMR (400 MHz, CD OD): d n-heptane/ 4.36-4.14 (m, 2H), 2.98-2.85 (m, 4H), de% = 117 409.1 13.590 isopropanol = 99.16% 2.67-2.46 (m, 5H), 2.39-2.22 (m, 1H), 80/20 1.82-1.71 (m, 1H), 1.68-1.57 (m, 1H) H NMR (400 MHz, CD OD): d .00-4.89 (m, 1H), 4.36-4.25 (m, 1H), de% = Column: AS-H 118 364.1 4.19-4.08 (m, 1H), 2.68-2.50 (m, 1H), 1.334 97.56% (0.46 cm I.D. × 2.40-2.24 (m, 1H), 1.96-1.57 (m, 4H), cm L); 1.41-1.29 (m, 3H), 1.23-1.12 (m, 6H) Mobile phase: 33 H NMR (400 MHz, CD OD): d n-heptane/ .01-4.89 (m, 1H), 4.32-4.25 (m, 1H), de% = isopropanol = 119 364.1 4.20-4.07 (m, 1H), 2.64-2.48 (m, 1H), 1.403 100% 90/10 2.42-2.26 (m, 1H), 1.93-1.59 (m, 4H), 1.38-1.31 (m, 3H), 1.22-1.15 (m, 6H) H NMR (400 MHz, CD OD): d Column: OJ-H .05-4.89 (m, 1H), 4.41-4.13 (m, 2H), de% = (0.46 cm I.D. × 3.08-2.80 (m, 2H), 2.78-2.24 (m, 4H), 120 412.0 2.589 cm L); 2.01-1.60 (m, 4H), 1.47-1.24 (m, 3H) Mobile phase: n-heptane/ H NMR (400 MHz, CD OD): d isopropanol .07-4.88 (m, 1H), 4.39-4.13 (m, 2H), de% = (0.1% Et NH) 121 412.0 3.189 2 3.06-2.83 (m, 2H), 2.77-2.23 (m, 4H), 100% = 90/10 1.95-1.60 (m, 4H), 1.45-1.28 (m, 3H) H NMR (400 MHz, CD OD): d 7.21-6.90 (m, 1H), 5.03-4.92 (m, 1H), 4.36-4.26 (m, 1H), 4.22-4.07 (m, 1H), de% = 146 346.1 1.526 Column: AS-H 2.48-2.34 (m, 2H), 1.96-1.83 (m, 2H), 100% (0.46 cm I.D. × 1.66-1.54 (m, 2H), 1.37-1.31 (m, 3H), cm L); 1.26-1.13 (m, 6H) Mobile phase: 124 H NMR (400 MHz, CD OD): d n-heptane/ 7.18-6.93 (m, 1H), 5.06-4.91 (m, 1H), isopropanol = 4.37-4.25 (m, 1H), 4.24-4.06 (m, 1H), de% = 147 346.1 1.995 80/20 99.774% 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) H NMR (400 MHz, CD OD): d 7.22-7.03 (m, 1H), 5.06-4.87 (m, 2H), Column: AS-H de% = 148 400.1 4.36-4.26 (m, 1H), 2.50-2.34 (m, 2H), 1.169 (0.46 cm I.D. × 1.99-1.81 (m, 2H), 1.68-1.50 (m, 2H), 15 cm L); 1.38-1.31 (m, 6H) Mobile phase: H NMR (400 MHz, CD OD): d n-heptane/ isopropanol 7.22-7.03 (m, 1H), 5.06-4.87 (m, 2H), de% = 149 400.1 4.36-4.26 (m, 1H), 2.50-2.34 (m, 2H), 2.443 (0.1% Et NH) 1.99-1.81 (m, 2H), 1.68-1.50 (m, 2H), = 80/20 1.38-1.31 (m, 6H) H NMR (400 MHz, CD OD): d 7.22-6.93 (m, 1H), 4.36-4.19 (m, 3H), ee% = Column: AS-H 150 388.1 2.97-2.87 (m, 4H), 2.69-2.50 (m, 4H), 2.492 (0.46 cm I.D. × 2.45-2.34 (m, 2H), 1.97-1.80 (m, 2H), cm L); 1.67-1.51 (m, 2H) Mobile phase: 127 H NMR (400 MHz, CD3OD): d n-heptane/ 7.22-6.93 (m, 1H), 4.36-4.19 (m, 3H), isopropanol = ee% = 151 388.1 2.97-2.87 (m, 4H), 2.69-2.50 (m, 4H), 3.658 100% 70/30 2.45-2.34 (m, 2H), 1.97-1.80 (m, 2H), 1.67-1.51 (m, 2H) H NMR (400 MHz, CD OD): d 8.93-8.78 (m, 2H), 7.98-7.93 (m, 1H), 7.84-7.77 (m, 1H), 4.37-4.30 (m, 1H), ee% = 222 431.0 5.097 Column: IC-H 2.70-2.61 (m, 1H), 2.48-2.36 (m, 1H), 99.89% (0.46 cm I.D. × 1.92-1.86 (m, 2H), 1.85-1.76 (m, 1H), cm L); 1.73-1.65 (m, 1H), 1.33 (s, 9H) Mobile phase: 34 H NMR (400 MHz, CD OD): d n-heptane/ 8.93-8.75 (m, 2H), 7.98-7.93 (m, 1H), isopropanol = 7.83-7.77 (m, 1H), 4.37-4.30 (m, 1H), ee% = 223 431.0 6.651 60/40 2.71-2.61 (m, 1H), 2.48-2.36 (m, 1H), 97.67% 1.92-1.86 (m, 2H), 1.85-1.77 (m, 1H), 1.73-1.66 (m, 1H), 1.33 (s, 9H) H NMR (400 MHz, CD OD): d Column: AD-H 4.41-4.08 (m, 3H), 3.01-2.82 (m, 4H), (0.46 cm ee% = 236 442.2 4.121 2.74-2.43 (m, 6H), 2.25-2.02 (m, 2H) I.D.×15 cm L); Mobile phase: n-heptane/ H NMR (400 MHz, CD OD): d isopropanol ee% = 4.41-4.08 (m, 3H), 3.01-2.82 (m, 4H), 237 442.2 4.453 (0.1% Et NH) 2.74-2.43 (m, 6H), 2.25-2.02 (m, 2H) = 80/20 H NMR (400 MHz, CD OD): d Column: AD-H .03-4.87 (m, 2H), 2.82-2.66 (m, 1H), de% = (0.46 cm I.D. × 249 455.2 2.293 2.62-2.45 (m, 1H), 2.27-2.02 (m, 2H), cm L); 1.40-1.29 (m, 6H) Mobile phase: 1 n-heptane/ H NMR (400 MHz, CD OD): d isopropanol .03-4.87 (m, 2H), 2.82-2.66 (m, 1H), de% = 250 455.2 2.898 (0.1% Et NH) 2.62-2.45 (m, 1H), 2.27-2.02 (m, 2H), 100% = 80/20 1.40-1.29 (m, 6H) H NMR (400 MHz, CD OD): d .14-4.92 (m, 1H), 4.33-4.19 (m, 1H), de% = Column: OJ-H 251 398.0 2.81-2.60 (m, 2H), 2.60-2.41 (m, 1H), 2.179 (0.46 cm I.D. × 2.25-2.05 (m, 2H), 1.38-1.32 (m, 3H), cm L); 0.77-0.69 (m, 2H), 0.55-0.48 (m, 2H) Mobile phase: 238 H NMR (400 MHz, CD OD): d n-heptane/ .04-4.94 (m, 1H), 4.32-4.19 (m, 1H), isopropanol = de% = 252 398.0 2.83-2.61 (m, 2H), 2.58-2.42 (m, 1H), 2.465 99.76% 90/10 2.23-2.05 (m, 2H), 1.39-1.32 (m, 3H), 0.77-0.69 (m, 2H), 0.57-0.47 (m, 2H) H NMR (400 MHz, CD OD): d .04-4.89 (m, 1H), 4.38-4.16 (m, 2H), de% = Column: OJ-H 253 448.0 3.225 3.05-2.85 (m, 2H), 2.81-2.43 (m, 4H), 100% (0.46 cm I.D. × 2.31 -1.96 (m, 2H), 1.42-1.30 (m, 3H) cm L); Mobile phase: H NMR (400 MHz, CD OD): d n-heptane/ .05-4.92 (m, 1H), 4.34-4.14 (m, 2H), de% = 254 448.0 3.790 ethanol = 80/20 3.02-2.85 (m, 2H), 2.80-2.45 (m, 4H), 100% 2.29 -2.01 (m, 2H), 1.43-1.29 (m, 3H) H NMR (400 MHz, CD OD): d Column: OJ-H 4.97-4.83 (m, 1H), 4.29-3.90 (m, 3H), de% = 255 440.0 3.119 (0.46 cm I.D. × 2.77-2.58 (m, 1H), 2.51-2.37 (m, 1H), cm L); 2.26-1.93 (m, 2H), 1.37-1.20 (m, 3H) Mobile phase: 245 H NMR (400 MHz, CD OD): d n-heptane/ .03-4.82 (m, 1H), 4.27 -3.84 (m, 3H), de% = isoproanol = 256 440.0 3.644 2.75-2.58 (m, 1H), 2.52-2.35 (m 1H), 100% 80/20 2.21-1.95 (m, 2H), 1.39-1.23 (m, 3H) H NMR (400 MHz, CD OD): d 4.90-4.81 (m, 1H), 4.24-4.11 (m, 1H), 3.33-3.14 (m, 2H), 2.70-2.55 (m, 1H), de% = 257 400.0 3.436 Column: AD-H 99.24% 2.48-2.34 (m, 1H), 2.17-2.96 (m, 2H), (0.46 cm I.D. × 1.56- 1.44 (m, 2H), 1.29-1.23 (m, 3H), cm L); 0.88-0.80 (m, 3H) Mobile phase: 248 H NMR (400 MHz, CD OD): d n-heptane/ 4.90-4.83 (m, 1H), 4.25-4.10 (m, 1H), isopropanol = 3.34-3.13 (m, 2H), 2.70-2.54 (m, 1H), de% = 258 400.0 4.005 80/20 2.54-2.33 (m, 1H), 2.19-1.96 (m, 2H), 99.74% 1.56- 1.44 (m, 2H), 1.29-1.22 (m, 3H), 0.89-0.81 (m, 3H) H NMR (400 MHz, CD OD): d Column: AD-H .04-4.95 (m, 1H), 4.42-4.14 (m, 2H), de% = 262 447.9 3.388 (0.46 cm I.D. × 3.04-2.87 (m, 2H), 2.84-2.45 (m, 4H), 100% cm L); 2.31-2.06 (m, 2H), 1.45-1.33 (m, 3H) Mobile phase: 259 H NMR (400 MHz, CD OD): d n-heptane/ 4.92-4.83 (m, 1H), 4.31-4.04 (m, 2H), de% = 263 448.0 3.968 isopropanol = 2.94-2.73 (m, 2H), 2.72-2.34 (m, 4H), 99.48% 80/20 2.18-1.91 (m, 2H), 1.32-1.21 (m, 3H) H NMR (400 MHz, CD OD): d .00-4.83 (m, 1H), 4.26-4.09 (m, 1H), de% = Column: AD-H 264 398.0 2.73-2.53 (m, 2H), 2.53-2.34 (m, 1H), 3.524 99.56% (0.46 cm I.D. × 2.17-1.94 (m, 2H), 1.31-1.22 (m, 3H), cm L); 0.70-0.58 (m, 2H), 0.47-0.39 (m, 2H) Mobile phase: 260 H NMR (400 MHz, CD OD): d n-heptane/ .03-4.83 (m, 1H), 4.26-4.10 (m, 1H), de% = isopropanol = 265 398.0 2.78-2.54 (m, 2H), 2.52-2.32 (m, 1H), 3.737 99.58% 80/20 2.19-1.94 (m, 2H), 1.32-1.22 (m, 3H), 0.71-0.53 (m, 2H), 0.51-0.35 (m, 2H) H NMR (400 MHz, CD OD): d Column: AD-H 4.36-4.09 (m, 3H), 3.02-2.87 (m, 2H), ee% = 272 394.1 4.176 (0.46 cm I.D. × 2.79-2.43 (m, 4H), 2.26-2.04 (m, 2H), 100% cm L); 1.28-1.15 (m, 6H) Mobile phase: 261 H NMR (400 MHz, CD OD): d n-heptane/ 4.36-4.09 (m, 3H), 3.02-2.87 (m, 2H), ee% = isopropanol = 273 394.0 4.696 2.79-2.43 (m, 4H), 2.26-2.04 (m, 2H), 70/30 1.28-1.15 (m, 6H) H NMR (400 MHz, CD3OD): d 8.67-8.30 (m, 2H), 8.06-7.80 (m, 1H), ee% = Column: AD-H 285 479.2 4.45-4.23 (m, 1H), 2.93-2.75 (m, 1H), 3.399 100% (0.46 cm I.D. × 2.69-2.50 (m, 1H), 2.33-2.06 (m, 2H), cm L); 1.42-1.20 (m, 9H) Mobile phase: 275 H NMR (400 MHz, CD OD): d n-heptane/ 8.67-8.30 (m, 2H), 8.06-7.80 (m, 1H), ee% = isopropanol = 286 479.2 4.45-4.23 (m, 1H), 2.93-2.75 (m, 1H), 4.089 100% 70/30 2.69-2.50 (m, 1H), 2.33-2.06 (m, 2H), 1.42-1.20 (m, 9H) H NMR (400 MHz, CD OD): d Column: AD-H 8.67-8.32 (m, 2H), 8.08-7.80 (m, 1H), ee% = 287 480.2 3.400 (0.46 cm I.D. × 2.91-2.75 (m, 1H), 2.69-2.52 (m, 1H), 100% cm L); 2.32-2.08 (m, 2H), 1.42-1.26 (m, 9H) Mobile phase: 276 H NMR (400 MHz, CD OD): d n-heptane/ 8.67-8.32 (m, 2H), 8.08-7.80 (m, 1H), ee% = 288 480.2 4.086 isopropanol = 2.91-2.75 (m, 1H), 2.69-2.52 (m, 1H), 100% 70/30 2.32-2.08 (m, 2H), 1.42-1.26 (m, 9H) H NMR (400 MHz, CD OD): d .00-4.92 (m, 1H), 4.38-4.18 (m, 1H), de% = Column: AD-H 289 358.2 3.506 2.80-2.61 (m, 1H), 2.61-2.44 (m, 1H), (0.46 cm I.D. × 2.31-2.10 (m, 2H), 1.50-1.23 (m, 3H) cm L); 1 Mobile phase: 280 H NMR (400 MHz, CD OD): d n-heptane/ .00-4.92 (m, 1H), 4.38-4.18 (m, 1H), de% = isopropanol = 2.80-2.61 (m, 1H), 2.61-2.44 (m, 1H), 290 358.1 3.754 80/20 2.31-2.10 (m, 2H), 1.50-1.23 (m, 3H) H NMR (400 MHz, CD OD): d 7.22-6.87 (m, 1H), 5.10-4.91 (m, 2H), de% = Column: AD-H 291 436.2 2.376 4.49-4.21 (m, 1H), 2.90-2.54 (m, 2H), (0.46 cm I.D. × 2.34-1.98 (m, 2H), 1.50-1.20 (m, 6H) cm L); Mobile phase: 281 H NMR (400 MHz, CD OD): d n-heptane/ 7.22-6.87 (m, 1H), 5.10-4.91 (m, 2H), de% = isopropanol = 4.49-4.21 (m, 1H), 2.90-2.54 (m, 2H), 292 436.2 3.321 80/20 2.34-1.98 (m, 2H), 1.50-1.20 (m, 6H) 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% 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 Dhydroxyglutarate 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 6×10 /mL per well in a 96-well plate a.
The plate was incubated at 37°C with 5% CO 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 tranfered 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 tranfered 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 IC 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) x 100%.
The followings are the activity values of some of the compounds of the invention determined in this example.
IC IC 50 50 Compound Compound Compound IC (µM) Compound IC (µM) 50 50 (µM) (µM) 1 0.097 73 0.064 148 1.558 221 0.487 2 0.137 74 0.034 149 0.177 222 0.065 3 0.866 75 0.218 150 0.541 224 0.137 4 0.080 78 0.069 151 0.039 225 0.036 0.093 79 0.106 152 0.300 226 0.361 6 0.115 80 0.079 153 0.099 227 0.048 7 0.087 81 0.099 154 0.202 228 0.417 8 0.216 82 0.075 155 0.319 229 0.383 9 0.571 83 0.203 156 0.657 230 0.658 0.113 84 0.048 157 0.141 231 0.037 11 0.284 85 0.035 158 0.278 232 0.040 12 0.199 86 0.021 159 0.205 233 0.368 13 0.373 87 0.205 160 0.180 234 0.078 14 0.230 89 0.057 162 0.177 235 0.130 0.259 90 0.065 163 0.162 236 0.045 16 0.326 91 0.058 164 0.176 237 1.492 17 1.616 92 0.143 165 0.198 238 0.139 18 0.110 94 0.131 166 0.180 239 0.046 19 0.083 95 0.043 167 0.327 240 0.984 0.232 96 0.675 169 0.738 241 0.100 21 0.099 97 0.052 170 1.382 242 0.802 22 0.336 98 0.344 171 0.268 243 1.175 23 0.192 99 0.553 172 0.344 244 0.053 24 0.197 100 2.905 174 0.096 245 0.102 0.665 101 0.080 175 0.291 248 0.093 27 0.148 102 0.051 176 0.612 249 0.072 28 0.123 103 1.002 177 0.046 250 2.473 29 0.177 104 2.079 178 0.934 252 0.050 0.228 105 0.040 179 0.598 254 0.025 31 0.110 106 0.106 180 0.531 255 0.078 32 0.080 107 0.554 181 0.177 257 0.056 34 0.145 108 2.226 182 1.231 259 0.057 0.591 109 0.057 183 0.507 260 0.094 36 0.181 110 0.070 184 3.779 261 0.094 37 1.911 111 2.257 186 0.677 262 0.056 38 1.619 112 0.098 187 0.742 263 1.394 39 0.164 113 2.059 188 5.015 264 0.084 40 0.106 114 1.716 189 1.415 266 0.033 41 0.297 115 0.059 190 0.413 267 1.327 42 0.152 116 2.620 191 0.999 268 0.349 43 0.328 117 0.095 192 0.314 269 0.137 44 3.149 118 0.106 196 0.094 270 0.109 47 0.059 119 3.393 197 0.041 272 0.051 49 0.210 120 2.397 198 0.845 273 1.228 50 0.072 121 0.068 199 1.504 274 0.084 51 0.125 122 1.340 200 0.632 275 0.062 52 0.229 124 0.137 201 0.045 276 0.081 53 0.131 125 1.671 202 0.383 277 0.156 54 0.015 126 0.086 203 0.098 278 0.148 55 0.103 127 0.064 204 0.209 279 0.170 56 0.093 128 0.092 205 0.803 280 >10 57 2.180 129 0.171 207 0.564 281 0.690 58 0.169 130 0.067 208 0.102 282 0.343 59 0.221 131 2.798 209 0.078 283 0.174 60 0.590 133 0.174 210 0.093 285 0.034 61 0.170 134 0.100 211 0.097 286 0.165 62 1.343 135 0.336 212 0.063 287 0.095 64 1.628 136 0.296 213 0.038 288 0.035 65 0.152 137 1.540 214 0.108 291 0.201 67 2.374 138 0.504 215 0.079 292 3.456 68 0.435 139 2.505 216 0.082 293 0.637 69 0.173 140 2.390 217 0.069 294 0.425 70 0.112 144 2.748 218 0.381 296 0.423 71 0.050 146 0.999 219 0.707 297 2.660 72 0.042 147 0.067 220 0.059 298 0.620 Example 4 Fluorescent Determination of 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 Compound IC (µM) Compound IC (µM) Compound IC (µM) 50 50 50 2 0.365 94 1.144 198 1.893 245 1.499 4 0.750 95 0.317 199 >10 248 4.338 0.869 96 2.703 200 >10 249 0.134 6 0.670 97 0.047 201 0.109 250 2.480 7 1.503 98 0.254 202 1.101 252 2.621 8 1.221 99 0.938 203 0.733 254 0.262 11 1.016 101 1.141 204 >10 255 0.715 13 2.076 102 0.232 205 >10 257 1.380 14 1.326 103 2.501 207 1.510 259 0.213 0.619 105 0.351 208 1.499 260 >10 18 0.219 106 0.272 209 1.763 261 2.231 19 0.421 107 1.751 210 4.338 262 0.182 21 0.234 109 0.279 211 0.175 263 3.513 24 0.769 110 0.160 212 >10 264 >10 31 0.280 118 2.141 213 >10 266 0.043 32 0.610 119 >10 214 >10 267 3.566 34 >10 121 0.186 215 >10 268 0.939 39 1.913 124 0.658 216 8.519 269 0.296 40 0.450 126 0.289 217 >10 270 2.853 41 1.627 127 0.203 218 >10 272 2.086 47 5.636 130 0.733 219 3.232 273 >10 51 6.042 134 2.472 220 2.878 274 3.284 52 2.245 136 1.342 221 >10 275 8.017 54 1.683 147 0.372 222 >10 276 8.367 60 >10 149 0.693 224 4.650 277 1.030 61 >10 151 0.256 225 0.917 278 >10 62 2.703 152 2.008 226 5.123 279 9.426 64 >10 153 0.447 227 0.081 280 >10 65 >10 155 2.245 228 0.705 281 0.455 67 >10 157 4.350 229 >10 282 0.444 71 3.054 158 1.520 230 >10 283 1.319 73 >10 159 2.717 231 1.528 285 3.587 74 7.441 163 0.809 232 0.070 286 >10 75 >10 166 1.347 233 0.628 287 >10 78 1.407 167 3.171 234 1.763 288 2.695 79 1.296 169 9.464 235 0.246 291 0.179 80 2.695 170 6.933 236 0.252 292 3.639 81 3.571 171 1.575 238 7.355 293 >10 82 0.181 174 0.343 239 0.344 294 9.184 83 0.282 175 0.495 240 >10 296 1.135 84 0.268 177 0.094 241 2.060 297 >10 85 0.207 181 0.476 242 3.523 298 >10 87 0.781 196 0.210 243 >10 89 2.957 197 0.120 244 1.082 Example 5 Metabolic Stability Test in Liver Microsomes Materials: Male CD1 mouse liver microsomes was supplied by Research Institute for Liver Diseases (Shanghai) Co., Ltd.. Male SD rat liver microsomes was supplied by BioreclamationIVT in US.
Phenacetin, glucosephosphate (GP), glucosephosphate dehydrogenase (GPD), and nicotinamide adenine dinucleotide phosphate (NADP) were supplied by Sigma-Aldrich (Missouri, USA).
Solution preparation: 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 GP and 100 U/mL GPDH were mixed and diluted with ultrapure water to provide the NADPH regenerating system containing 1 mM NADP, 5 mM GP and 1U/mL GPD, which was pre-incubated at 37 °? 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 MgCl (concentration of EDTA and MgCl 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 Mouse liver Rat liver Mouse liver Compound microsome microsome Compound microsome microsome stability stability stability stability 1 73.8% 83.5% 124 74.1% 44.1% 2 99.0% 83.8% 126 79.8% 58.2% 4 62.9% 82.1% 127 49.8% 28.7% 76.8% 58.6% 128 34.0% 15.9% 6 70.0% 76.3% 147 65.0% 48.1% 7 50.3% 49.8% 149 66.8% 59.7% 11 87.6% 80.3% 153 41.7% 46.9% 18 91.5% 82.7% 177 45.9% 31.0% 19 83.8% 66.2% 196 100.0% 95.2% 82 92.9% 93.1% 197 99.5% 98.4% 83 96.6% 83.7% 201 91.6% 79.3% 84 67.8% 78.9% 202 94.2% 96.4% 85 78.1% 64.0% 203 92.1% 91.3% 87 97.9% 88.5% 211 98.8% 99.7% 90 82.4% 80.9% 227 88.8% 81.4% 91 86.6% 70.5% 232 86.6% 76.3% 94 82.6% 65.4% 235 89.0% 75.5% 95 74.8% 80.1% 236 91.3% 83.9% 97 98.5% 89.5% 239 93.0% 91.8% 98 99.2% 83.7% 249 98.0% 100.0% 101 88.0% 84.6% 254 100.0% 90.9% 102 92.7% 86.2% 259 95.1% 86.9% 103 89.7% 78.5% 262 98.3% 92.2% 105 84.0% 67.3% 266 98.2% 91.5% 109 85.4% 58.8% 291 100.0% 98.9% Example 6 Determination of solubility 1. Preparation of sample solution 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 1mg 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 1mg 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 5u 4.6*150mm 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 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: Compound Solubility (mg/mL) Compound Solubility (mg/mL) pH 2.1 pH 7.4 pH 2.1 pH 7.4 3 >1.000 0.716 125 0.448 0.019 9 >1.000 0.085 219 0.190 0.060 0.570 0.062 223 0.060 0.016 68 0.141 <0.005 243 0.055 <0.005 71 0.064 0.055 249 0.036 0.011 82 0.146 0.037 262 0.237 0.013 97 0.077 0.021 271 0.974 0.124 102 0.729 <0.005 284 0.789 0.818

Claims (23)

1. A compound of formula (I): and/or a pharmaceutically acceptable salt thereof, and/or solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein A is , 10 R is chosen from H, -OH, halo, C alkyl, C alkoxyl, -NH , -NH(C alkyl), -N(C alkyl) , 1 1-6 1-6 2 1-4 1-4 2 oxo, or C cycloalkyl; each of R is independently chosen from H, deuterium, halo, -OH, -NH , -CN, -SH, C alkyl, 2 2 1-6 C alkenyl, C alkynyl, C haloalkyl, C cycloalkyl, oxo, -OR , -OCOR , -NHR , -N(R )(C 2-6 2-6 1-6 3-8 5 5 5 5 1-4 alkyl), -COR , -NHCOR , or 3-8 membered heterocyclyl containing one or more heteroatoms 15 independently chosen from N, O, and S; in which each of said C alkyl, C alkenyl, C alkynyl, 1-6 2-6 2-6 C cycloalkyl or 3-8 membered heterocyclyl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more groups chosen from deuterium, halo, -CN, -OH, -SH, -NH , -NH(C alkyl), -N(C alkyl) , or C alkoxyl; or two R , which 2 1-4 1-4 2 1-6 2 attach to the same carbon atom, together with the carbon atom they are attached to form a 3-5 20 membered cycloalkyl which is optionally substituted with one or more halo or deuterium; R ’ and R ’ are both H; R and R are independently chosen from H, C alkyl, C alkenyl, C alkynyl, C 3 4 1-6 2-6 2-6 3-12 cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently chosen 25 from N, O, and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, -C(O)R , -OR , or -NHR , in which each of said C alkyl, 5 5 5 1-6 C alkenyl, C alkynyl, C cycloalkyl, 3-12 membered heterocyclyl containing one or more 2-6 2-6 3-12 heteroatoms independently chosen from N, O, and S, phenyl, or 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more R ; provided that R and R are not H simultaneously; provided that 6 3 4 when one of R and R is optionally substituted phenyl or optionally substituted 5-6 membered 5 heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, the other one is -OR or -NHR ; or R and R ’ are independently chosen from H, C alkyl, C alkenyl, C alkynyl, C 3 3 1-6 2-6 2-6 3-12 cycloalkyl, 3-12 membered heterocyclyl containing one or more heteroatoms independently chosen from N, O, and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms 10 independently chosen from N, O, and S, -C(O)R , -OR , or -NHR , in which each of said C alkyl, 5 5 5 1-6 C alkenyl, C alkynyl, C cycloalkyl, 3-12 membered heterocyclyl containing one or more 2-6 2-6 3-12 heteroatoms independently chosen from N, O, and S, phenyl, or 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more R ; R and R ’ together with the N atom they are attached to form a 6 4 4 15 3-8 membered heterocycyl containing one or more heteroatoms independently chosen from N, O, and S optionally substituted by one or more R ; R is chosen from C alkyl or C cycloalkyl, each of which is optionally substituted with one 5 1-6 3-8 or more groups independently chosen from halo, -CN, -OH, -SH, -NH , or C alkoxyl; 2 1-6 each of R is independently chosen from deuterium, halo, -CN, -OH, -SH, -NH , C alkoxyl, 6 2 1-6 20 C alkyl, C haloalkyl, C cycloalkyl, 3-8 membered heterocyclyl containing one or more 1-6 1-6 3-8 heteroatoms independently chosen from N, O, and S, phenyl, or 5-6 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, in which each of said C alkoxyl, C alkyl, C cycloalkyl, 3-8 membered heterocyclyl containing one or more 1-6 1-6 3-8 heteroatoms independently chosen from N, O, and S, phenyl, or 5-6 membered heteroaryl 25 containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more groups independently chosen from halo, -CN, -OH, -SH, -NH , C 2 1-6 alkoxyl, C alkynyl, or C alkyl; 2-6 1-6 m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, or 2; 30 wherein the term “cycloalkyl” as used herein refers to saturated or partially unsaturated cyclic hydrocarbon radical, which may have one or more rings.
2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, R is chosen from H, -OH or halo.
3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salts 5 thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, R is -OH.
4.The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, 10 wherein, each of R is independently chosen from H, deuterium, halo, -OH, -NH , -CN, -SH, C 2 2 1-6 alkyl, C alkenyl, C alkynyl, C haloalkyl, C cycloalkyl, oxo, -OR , -OCOR , -NHR , 2-6 2-6 1-6 3-8 5 5 5 -N(R )(C alkyl), -NHCOR , or 3-8 membered heterocyclyl containing one or more heteroatoms
5.1-4 5 independently chosen from N, O, and S. 15 5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, each of R is independently chosen from H, deuterium, halo, C alkyl, or C haloalkyl. 2 1-6 1-6
6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts 20 thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, R and R are independently chosen from C alkyl, C cycloalkyl, 3-12 membered 3 4 1-6 3-12 heterocyclyl containing one or more heteroatoms independently chosen from N, O, and S, phenyl, 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, -C(O)R , -OR , or -NHR , in which each of said C alkyl, C cycloalkyl, 3-12 membered 5 5 5 1-6 3-12 25 heterocyclyl containing one or more heteroatoms independently chosen from N, O, and S, phenyl, or 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more R .
7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salts 30 thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, R3 and R4 are independently chosen from C1-6 alkyl substituted with one or more halo, 5-12 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S substituted with C haloalkyl, or -OR . 1-6 5
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, R and R are independently chosen from C alkyl substituted with one or more halo. 4 1-6 5
9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, R is C alkyl optionally substituted with one or more halo. 5 1-6
10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts 10 thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, each of R is independently chosen from deuterium, halo, -CN, -OH, -NH , C alkoxyl, 6 2 1-6
11.C alkyl, C haloalkyl, C cycloalkyl, 3-8 membered heterocyclyl containing one or more 1-6 1-6 3-8 heteroatoms independently chosen from N, O, and S, phenyl, or 5-6 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S, in which each of said 15 C alkoxyl, C alkyl, C cycloalkyl, 3-8 membered heterocyclyl containing one or more 1-6 1-6 3-8 heteroatoms independently chosen from N, O, and S, phenyl, or 5-6 membered heteroaryl containing one or more heteroatoms independently chosen from N, O, and S is optionally substituted with one or more halo. 20 11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, n is 1.
12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salts 25 thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, R is chosen from H, C alkyl optionally substituted by C haloalkyl, or 5-12 membered 3 1-6 1-6 heteroaryl containing one or more heteroatoms independently chosen from N, O, and S optionally substituted by C haloalkyl; R ’is H; R and R ’ together with the N atom they are attached to form 1-6 3 4 4 a 3-8 membered heterocyclyl containing one or more heteroatoms independently chosen from N, O, 30 and S optionally substituted by one or more groups chosen from halo, -OH, or C haloalkyl.
13. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and tautomers thereof, wherein, the compound of formula (I) has the structure of formula (I-1) ( I-1)
14. The compound of formula (I) according to any one of claims 1-12, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, and 5 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; (II). 10
15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salts thereof, and/or solvates, racemic mixture, enantiomers, diastereomers, 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;
16. The compound of formula (I) according to claim 1, which is selected from: Compound Structure Compound Structure (RS)\ 1 152 CF3 n N CF3 N' '¦N | (R) N N (R) (R) ' N-W1- H H ¦OH .OH (RS)\ (RS)\ N ^N r-J CF3 N N CF, cf3 (ft) N H H H H .OH OH (RS)\ (RS)\ CF3 N ' N i—\ CF3 n N ' ^N^N-P° (R) N cf3 (R) N H H H (RS)\ CF3 N^ N CF3 N N I xNXrF 'fRSjN N N (R) N .OH OH (RS)\ (RS)\ CF3 N N ^-7 ' -V^H^ (R) N (RS)\ (RS)\ F\.f 157 CF3 n N CF3 N (R) N N N (S) (R) N N (RS) OH OH (RS)\ cf3 n N cf3 n N N (R) (R) N (R) N H H H H OH .OH (RS)\ (RS)\ cf3 n cf3 n (R) N (R)H (RS)\ CF3 N '¦N I cf3 n ¦ -V-H^ (R) ¦ NAA, (R) N H H H H 14 165 15 166 16 167 17 168 18 169 19 170 20 171 21 172 22 173 23 174 24 175 25 176 26 177 27 178 28 179 29 180 30 181 31 182 32 183 33 184 34 186 35 187 36 188 37 189 38 190 39 191 41 193 42 194 43 195 44 196 45 197 & 198 47 199 N N N N N N 201 & 202 51 203 52 204 N N N N N N 53 205 55 207 56 208 59 211 60 212 61 213 62 214 63 215 64 \ 216 N N ''N 65 217 N~n n I N N N N ^ (RSj\ 67 219 ,N'N^ OF, N ' n cf3 N^N^N ¦ W^- (R) N N CF3 N'^'N^N'^h cf3 n '¦n cf3 N IS) 222 & 223 .OH .OH r^^N^N^N'0^< cf3 n (R) N 73 225 75 227 CF N N N N N 76 228 CF N N N N N 77 229 230 & 80 232 81 233 cf3 n N cf3 N (Ft) N (R) N'VA CF3 N'5' 'n cf3 (Ft) N (RSj\ f/?sj d 83 235 F FUf cf3 n cf3 n n cf3 (R) N'V' (R) N CF3 N ^N -^.rVv^ 236 & 237 OH >OH ¦bjarh CF3 N' '¦'N a JU JL Fv .F * (RSj\ 87 239 CF3 N ^N cf3 n cf3 N (S) -irV- ' 89 240 cf3 n N N N N (R) N N N CF3 N H N B'V (RS)rD 90 241 f^n^n^n cf3 n v n OH .0 fRS^o 91 242 CF3 N' ''N cf3 ¦Kk'^' (R) N (RS)\"d 92 243 F3a-N^N^N cf3 n ' V-N (R) N 93 244 cf3 n CF3 N' ''N I fRJ'N^N^NHz Fv .F CF3 N' '¦N I (R) N CF3 N '-N I CF3 N' cf3 ¦ -V-A ' -V-H^ (R) N (R) N 246 & 95 & 96 OH .0 CF3 N' "N I CF3 N' "'N cf3 H H H H 249 & 251 & 100 & 101 253 & 102 & 103 255 & 104 & 105 257 & 106 & 107 108 & 109 110 & 111 262 & 112 & 113 264 & 114 & 115 116 & 117 118 & 119 120 & 121 272 & 273 123 274 125 276 126 277 127 278 128 279 129 280 130 281 131 282 132 283 133 284 285 & 287 & 289 & 291 & 142 293 143 294 144 295 145 296 146 & 147 148 & 149 299 150 & 151 or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound of any one of claims 1-16, or a 5 pharmaceutically acceptable salt thereof, and optionally comprising at least one pharmaceutically acceptable excipient.
18. A pharmaceutical composition for treating a disease induced by IDH mutation, comprising the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition 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. 15
20. The pharmaceutical composition 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 selected from: and . 5
22. The compound according to any one of claims 1-16 and 21, substantially as herein described, with reference to any example thereof and with reference to the appended figures.
23. The pharmaceutical composition according to any one of claims 17-20, substantially as herein described, with reference to any example thereof and with reference to the appended figures.
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