HK1246292B - 1, 3, 5-triazine derivative and method of using same - Google Patents
1, 3, 5-triazine derivative and method of using sameInfo
- Publication number
- HK1246292B HK1246292B HK18105822.3A HK18105822A HK1246292B HK 1246292 B HK1246292 B HK 1246292B HK 18105822 A HK18105822 A HK 18105822A HK 1246292 B HK1246292 B HK 1246292B
- Authority
- HK
- Hong Kong
- Prior art keywords
- alkyl
- formula
- trifluoromethyl
- pharmaceutically acceptable
- compound
- Prior art date
Links
Abstract
Disclosed are compounds having formulae I and II or pharmaceutically acceptable salts or hydrates thereof, a preparation method thereof and pharmaceutical compositions thereof. The compounds having formulae I and II possesses an isocitrate dehydrogenase 2 (IDH2) inhibitory activity and are capable of treating IDH2 mutation-induced cancers.
Description
Citation of Related Applications
This application claims the benefit of Chinese invention patent application No. 201510459126.X filed with the State Intellectual Property Office of the People's Republic of China on July 30, 2015, the entire contents of which are hereby incorporated by reference into this document in their entirety.
Technical Field
The present invention relates to the field of medicine, and more specifically to 1,3,5-triazine derivatives and methods of using the same.
Background Art
IDH, short for isocitrate dehydrogenase, is a key enzyme in the tricarboxylic acid cycle. It catalyzes the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate (i.e., α-ketoglutarate). Studies have found IDH mutations in various tumors, such as gliomas, sarcomas, and acute myeloid leukemia. The mutations occur at arginine residues located in the catalytic center (IDH1/R132H, IDH2/R140Q, and IDH2/R172K). These mutated IDHs acquire a novel ability to catalyze the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). Studies have shown that α-ketoglutarate and 2-HG share a similar structure, and 2-HG competes with α-KG, thereby reducing the activity of α-KG-dependent enzymes and leading to hypermethylation of chromatin. This hypermethylation is believed to interfere with normal cell differentiation, leading to excessive proliferation of immature cells and, consequently, cancer.
In 2013, Agios Pharmaceuticals reported the IDH2/R140Q inhibitor AGI-6780 (Science. 2013, 340, 622-626) and the IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630). WO2015017821 also disclosed another IDH2/R140Q inhibitor, AG-221. AGI-6780 and AGI-5198 inhibit 2-HG production in cells carrying the most common IDH2 and IDH1 mutants, respectively. In addition to inhibiting 2-HG production, these molecules also induced differentiation in abnormally proliferating human cancer cells in culture. Treatment of leukemia cells carrying IDH2 mutants with AGI-6780 and of glioma cells carrying IDH1 mutants with AGI-5198 both resulted in increased expression of maturation markers in the cells. Furthermore, the researchers demonstrated that AGI-5198 inhibited the growth rate of glioma cells, whether treated with AGI-5198 in cell culture or administered orally to mice with tumor transplants.
Summary of the Invention
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients.
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
Detailed Description of the Invention
In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, those skilled in the relevant art will recognize that embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.
Unless otherwise required in this application, throughout the specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, "including but not limited to".
Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
It should be understood that as used in this specification and the appended claims, the singular article "a," "an," and "the" includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a reaction including "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
definition
Unless otherwise indicated, the following terms and phrases used herein have the following meanings. The absence of a specific definition for a term or phrase should not be construed as indefinite or unclear, but rather as indicating its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted (such as CH2CH2F ), polysubstituted (such as CHFCH2F , CH2CHF2 , etc.), or fully substituted ( CF2CF3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
As used herein, Cmn means that the moiety has mn carbon atoms. For example, " C3-10 cycloalkyl" means that the cycloalkyl group has 3-10 carbon atoms. " C0-6 alkylene" means that the alkylene group has 0-6 carbon atoms. When the alkylene group has 0 carbon atoms, the group is a bond.
Numeric ranges herein refer to each integer in the given range. For example, " C1-10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.
When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), i.e., an atom other than carbon and hydrogen or a group containing these atoms, the heteroatom being independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, germanium, aluminum, and boron. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The term "halogen" or "halo" refers to any radical of fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to -OH.
The term "cyano" refers to -CN.
The term "amino" refers to -NH2 , -NH(alkyl) and -N(alkyl) 2 . Specific examples of amino include, but are not limited to, -NH2 , -NHCH3 , -NHCH( CH3 ) 2 , -N( CH3 ) 2 , -NHC2H5 , -N( CH3 ) C2H5 and the like.
The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The specific alkyl group includes all isomeric forms thereof, such as propyl, including -CH2CH2CH3 and -CH( CH3 ) 2 , and butyl, including -CH2CH2CH2CH3 , -CH(CH3)( CH2CH3 ), -C( CH3 ) 3 , and -CH2CH( CH3 ) 2 . The term " C1-8alkyl " refers to an alkyl group having 1 to 8 carbon atoms. The term " C1-6alkyl " refers to an alkyl group having 1 to 6 carbon atoms. The term " C1-4alkyl " refers to an alkyl group having 1 to 4 carbon atoms. The term " C1-3alkyl " refers to an alkyl group having 1 to 3 carbon atoms. The "alkyl", "C 1-8 alkyl", "C 1-6 alkyl", "C 1-4 alkyl" or "C 1-3 alkyl" may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.
The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, propenyl, 2-butenyl, and 3-hexenyl. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
The term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl groups.
The term "alkoxy" refers to an -O-alkyl group.
The term "heteroaromatic ring" refers to a monocyclic or fused ring having 5-12 ring atoms, for example 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, and the remaining ring atoms are C, and having a completely conjugated π-electron system.
The term "heteroaryl" refers to the group remaining after removing one hydrogen atom from a "heteroaromatic ring" molecule. The heteroaryl group can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrazolyl, triazinyl, pteridinyl, and the like.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable carrier" refers to a carrier that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound. A "pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for use in humans or animals (e.g., livestock) and approved by the State Food and Drug Administration. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle required to formulate an effective pharmaceutical composition.
With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms herein, an "effective amount" of an active substance in a pharmaceutical composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "patient" or "individual" includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).
General formula compound
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is provided:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, the compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein
X 1 is selected from O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1 or 2.
In one embodiment of the present application, a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein X1 is O; R1 is selected from a C1-6 alkyl group, which may be optionally substituted with one or more R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a C3-6 cycloalkyl group. More preferably, R1 is selected from a methyl group, an ethyl group, a propyl group, or a butyl group, and may be optionally substituted with one to two R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a cyclopropane group.
In one embodiment of the present application, a compound of Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; R2 is selected from phenyl, pyridyl, benzyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy, and may be optionally substituted with one or two R7 ; each R7 is independently selected from hydroxy, halogenated C1-3 alkyl, or C1-6 alkyl. More preferably, R2 is selected from phenyl, pyridyl, benzyl, propyl, butyl, ethoxy, and may be optionally substituted with one or more R7 ; each R7 is independently selected from hydroxy or trifluoromethyl.
In one embodiment of the present application, the compound represented by Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; n is 0 or 1; and R3 is a halogenated C1-3 alkyl group. More preferably, n is 0 or 1; and R3 is selected from trifluoromethyl.
In one embodiment of the present application, the following compounds are preferred:
and pharmaceutically acceptable salts or hydrates thereof.
Pharmaceutically acceptable salts of the compounds of Formula I or Formula II include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Non-limiting examples of salts with organic bases include, but are not limited to, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, and dicyclohexylamine. Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The compounds of Formula I or Formula II herein may exist in unsolvated or solvated forms, including hydrates. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention. The compounds of Formula I or Formula II herein may exist in polymorphic or amorphous forms.
The compounds of Formula I or Formula II of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present application.
The diagrammatic representations of racemates, ambiscalemic and scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration of a stereocenter. When compounds of Formula I or Formula II herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers, unless otherwise indicated. Likewise, all tautomeric forms are intended to be encompassed within the scope of this application.
The compounds of Formula I or Formula II herein may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are also within the scope of this application.
Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography known to those skilled in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., carbamate formation from an amine).
The compounds of Formula I or Formula II herein may contain unnatural proportions of atomic isotopes at one or more atoms comprising the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of Formula I or Formula II herein, whether radioactive or not, are encompassed within the scope of this application.
Pharmaceutical composition
In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present application may further contain one or more additional therapeutic agents.
The pharmaceutical composition of the present application can be prepared by combining the compound of general formula I or general formula II of the present application or a pharmaceutically acceptable salt or hydrate thereof with a suitable pharmaceutically acceptable carrier or excipient, and can be formulated into, for example, solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
Typical routes of administration of the compounds of Formula I or Formula II of the present application, or their pharmaceutically acceptable salts or hydrates, or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
The pharmaceutical composition of the present application can be prepared by methods known to those skilled in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
For oral administration, the pharmaceutical composition can be prepared by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with pharmaceutically acceptable carriers or excipients well known to those skilled in the art. These carriers or excipients enable the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.
Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to form a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; talc, starch, magnesium stearate, calcium stearate, or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, and cross-linked polyvinyl pyrrolidone. Dragee cores may optionally be coated according to methods generally known in the pharmaceutical art, in particular with an enteric coating.
The pharmaceutical compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable formulations for parenteral administration can be prepared using suitable excipients, such as fillers, buffers or surfactants.
Medical uses
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
In some embodiments of the present application, the cancer induced by IDH2 mutation is selected from: glioblastoma (neuroglioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL). In more specific embodiments, the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL), etc., preferably including acute myeloid leukemia (AML) or sarcoma.
The compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered by any suitable route and method, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered to a subject in need thereof. The dosage of the compounds of Formula I or Formula II can be from about 0.0001 to 20 mg/kg body weight/day, for example, from 0.001 to 10 mg/kg body weight/day.
The frequency of administration of the compound of Formula I or Formula II herein is determined by the individual patient's needs, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the compound of Formula I or Formula II over a period of several days, followed by a period of several or more days in which the patient does not receive a daily dose of the compound of Formula I or Formula II.
preparation
The compounds of general formula I or general formula II of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
The chemical reactions of the specific embodiments of this application are carried out in a suitable solvent, which must be compatible with the chemical transformations and the reagents and materials required. To obtain the compounds of Formula I or Formula II of this application, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.
The compounds of the general formula II of the present application can be prepared by those skilled in the art of organic synthesis using standard methods in the art via the following routes:
Compound 1-1 undergoes acylation to obtain 1-2; 1-2 reacts with biuret to obtain 1-3; 1-3 undergoes chlorination to obtain 1-4; 1-4 undergoes amination reaction with R2- substituted ammonia to obtain 1-5; 1-5 undergoes amination reaction with R2 - X1- substituted ammonia to obtain the compound of general formula II.
Example
The following specific examples are intended to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the present invention, but rather as illustrative and representative examples thereof. Those skilled in the art will appreciate that other synthetic pathways exist for forming the compounds of the present invention, and the following examples are provided as non-limiting examples.
All operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise stated, the raw materials used in this application were purchased directly from the market and used directly without further purification.
Column chromatography used silica gel (200-300 mesh) manufactured by Qingdao Chemical Co., Ltd. Thin-layer chromatography used precast plates (Silica gel 60PF254, 0.25 mm) manufactured by E. Merck. Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H, 5 μm, 30°C). Nuclear magnetic resonance (NMR) chromatography was performed using a Varian VNMRS-400 NMR spectrometer; liquid chromatography-mass spectrometry (LC/MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX and an Agilent LC 1200 series (column: Waters Symmetry C18, 5 μm, 35°C) in ESI (+) ion mode.
Experimental part
Example 1: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
Under nitrogen, palladium acetate (74.0 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene (363.0 mg, 0.655 mmol), and triethylamine (0.92 g, 9.8 mmol) were added sequentially to a solution of 2-bromo-6-trifluoromethylpyridine (1.48 g, 6.55 mmol) in methanol (50.0 mL). The reaction mixture was allowed to react at 60°C under a 2 atmosphere carbon monoxide atmosphere for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to yield methyl 6-trifluoromethyl-pyridine-2-carboxylate (0.9 g, 67.0% yield).
Step 2: 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione
Under nitrogen, methyl 6-trifluoromethyl-pyridine-2-carboxylate (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol) were added sequentially to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL). The mixture was heated under reflux for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into water. The pH was adjusted to 7 with 6 mol/L hydrochloric acid. The resulting solid was filtered, the filter cake washed with water, and dried to yield 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, 47.5% yield).
Step 3: 2,4-Dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine
Under nitrogen, a mixture of 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (15.0 g, 58.1 mmol) and phosphorus oxychloride (200 mL) was reacted at 100°C for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under vacuum to yield 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (10.0 g, 58.3% yield).
Step 4: 4-Chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (5.0 g, 16.9 mmol) in tetrahydrofuran (100 mL) were added 4-amino-2-trifluoromethylpyridine (3.3 g, 20.3 mmol) and sodium bicarbonate (2.14 g, 25.3 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine (6.5 g, 91.2% yield).
Step 5: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (50.0 mg) in tetrahydrofuran (20 mL) were added ethoxylamine hydrochloride (12.0 mg, 0.18 mmol) and sodium bicarbonate (40.0 mg, 0.48 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to yield 4-(ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (40.0 mg). 1 H-NMR (400MHz, CDCl 3 ): δ = 8.66-8.58 (m, 2H), 8.49 (s, 1H), 8.32(s,1H),8.10(t,J＝7.9Hz,1H),7.94(s,1H),7.88(d,J＝7.8Hz,1H),7.62(d,J＝3.7Hz,1H), 4.19(q,J＝7.0Hz,2H),1.41(t,J＝7.1Hz,3H).
Example 2: 4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.35 (s, 1H), 10.85 (s, 1H), 8.66 (s, 1H), 8.56 (d, J = 5.6 Hz, 2H), 8.32 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 4.28-4.06 (m, 1H), 1.23 (d, J = 14.5 Hz, 6H).
Example 3: 4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.00 (s, 1H), 10.84 (s, 1H), 8.74 (s, 1H), 8.57 (t, J = 6.5 Hz, 2H), 8.31 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 1.28 (s, 9H).
Example 4: 4-((Cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-((cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-
(2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.4 (s, 1H), 10.9 (s, 1H), 8.61 (s, 1H), 8.57 (d, J=5.6 Hz, 2H), 8.32 (t, J=7.9 Hz, 1H), 8.17-8.09 (m, 2H), 3.77 (d, J=7.1 Hz, 2H), 3.15 (d, J=5.2 Hz, 1H), 0.87-0.76 (m, 2H), 0.57-0.47 (m, 2H).
Example 5: N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino)
N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino) was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.96 (s, 2H), 8.48 (d, J=7.8 Hz, 1H), 8.24 (t, J=7.9 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 3.90 (q, J=7.0 Hz, 4H), 1.30-1.06 (m, 6H).
Example 6: 2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol
2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, CDCl 3 ): δ=8.59 (dd, J=10.7, 6.7 Hz, 2H), 8.29 (s, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 4.00 (s, 2H), 1.62 (s, 1H), 1.32 (s, 6H).
Example 7: 2-Methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol
Referring to the synthetic method of Example 1, 2-methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol was prepared. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.80 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.29 (t, J=7.9 Hz, 3H), 8.08 (m, 2H), 5.38 (s, 1H), 4.56 (s, 1H), 3.54-3.39 (m, 2H), 1.27-1.10 (m, 6H).
Example 8: 4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.52 (s, 1H), 10.91 (s, 1H), 8.60 (s, 2H), 8.56 (d, J=5.4 Hz, 1H), 8.36 (t, J=7.9 Hz, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.52 (s, 2H), 7.47-7.35 (m, 3H), 5.04 (s, 2H).
Example 9: 4-(2-methylhydrazine)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(2-methylhydrazinyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.76 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.30 (t, J=7.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.93 (s, 1H), 5.39 (s, 1H), 5.21 (s, 1H), 3.40 (s, 3H).
Example 10: 4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.59 (d, 2H), 8.59 (m, 1H), 8.55 (m, 1H), 8.32 (m, 2H), 8.00 (m, 1H), 7.56 (m, 3H), 1.41-0.95 (m, 9H).
Example 11: 1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol
1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.29 (d, 2H), 8.53 (d, J=7.9 Hz, 1H), 8.28 (t, J=7.9 Hz, 1H), 8.13-8.03 (m, 1H), 4.86 (s, 1H), 3.39 (m, 2H), 1.27 (m, 9H), 1.07 (m, 6H).
Example 12: 4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1H), 10.12 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.31 (t, J = 7.8 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.99 (m, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 1.29 (s, 9H).
Example 13: N-Benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
N-benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.26 (s, 2H), 8.50 (dd, J = 13.2, 5.0 Hz, 2H), 8.33 - 8.18 (m, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.31 (dd, J = 10.1, 4.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 1.18 (s, 9H).
Example 14: 4-(tert-Butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-(tert-butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-
1,3,5-Triazine-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.16 (s, 2H), 8.49 (d, J=8.1 Hz, 1H), 8.04 (d, J=7.4 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 4.16 (m, 1H), 1.24 (m, 9H), 1.18 (m, 6H).
Experimental Example 1: Determination of IDH2 inhibitory activity
The present application adopts the following method to determine the inhibitory activity of the compounds of the present application on IDH2 (R172K, 40-end). The inhibitory activity is represented by the indicator IC50 , which is the concentration of the compound when the activity of IDH2 is inhibited by 50%.
Materials and methods:
The inhibitory activity of the compounds against IDH2 (R172K, 40-end) was determined by depletion of the cofactor NADPH. The compounds were pre-incubated with the enzyme and NADPH, and the reaction was initiated by the addition of α-KG and allowed to react for 120 minutes under linear conditions. The reaction was then terminated by the addition of diaphorase (lipoamide dehydrogenase) and the corresponding substrate, resazurin (resazurin). Lipoamide dehydrogenase terminates the IDH2m reaction by depleting the available cofactor NADPH, oxidizing NADPH to NADP and reducing resazurin to the highly fluorescent resorufin. The amount of cofactor NADPH remaining after a specific reaction time was quantified using an easily detectable fluorescent group.
Specifically, 2.5 μl of a 3x serial dilution of the compound was added to a 384-well plate, followed by 5 μl of reaction buffer (20 mM Tris-HCl, pH 7.5; 150 mM NaCl; 10 mM MgCl2; 10 mM MnCl2; 0.4 mg/ml BSA; and 2 mM DTT) containing 80 nM IDH2 (R172K, 40-end) and 40 μM NADPH. The assay mixture was then incubated at 23°C for 120 minutes, after which the reaction was initiated by the addition of 2.5 μl of reaction buffer containing 4 mM α-KG. After incubation at room temperature for 120 minutes, 5 μl of a stop mix (0.4 U/ml diaphorase and 40 μM resazurin) prepared in reaction buffer was added to convert resazurin to resorufin, allowing measurement of residual NADPH. After incubation at 23°C for 10 minutes, fluorescence was measured using a Flexstation 3 using Ex535/Em595.
The IDH2 inhibitory activities of the example compounds are shown in Table 1:
Table 1
| Example No. | |
| 1 | 22.40 |
| 2 | 28.79 |
| 3 | 31.69 |
| 4 | 38.19 |
| 6 | 46.85 |
| 7 | 153.6 |
| 8 | 239.3 |
| 10 | 51.42 |
Experimental Example 2: Determination of pharmacokinetic parameters
The present application uses the following methods to determine the pharmacokinetic parameters of the compounds of the present application:
The study used healthy male adult rats aged 7-9 weeks. Each group of animals (3 male rats) received a single oral administration of 5 mg/kg. The animals in the oral administration group fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration.
Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the retinal venous plexus and placed in a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis.
Plasma sample analysis was performed using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight) software. A non-compartmental model was used for concentration analysis, and the pharmacokinetic parameters of the compounds were calculated, as shown in Table 2. The compound of Example 3 has a good in vivo metabolism level and a long half-life, and at the same dose, its blood concentration is higher than that of the IDH2 inhibitor AG-221.
Table 2
| Example | 3 | AG-221 |
| Dosage (mg/kg) | 5 | 5 |
| 12.0 | 3.73 | |
| 5.0 | 4.00 | |
| 589 | 479 | |
| 10838 | 5385 |
Citation of Related Applications
This application claims the benefit of Chinese invention patent application No. 201510459126.X filed with the State Intellectual Property Office of the People's Republic of China on July 30, 2015, the entire contents of which are hereby incorporated by reference into this document in their entirety.
Technical Field
The present invention relates to the field of medicine, and more specifically to 1,3,5-triazine derivatives and methods of using the same.
Background Art
IDH, short for isocitrate dehydrogenase, is a key enzyme in the tricarboxylic acid cycle. It catalyzes the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate (i.e., α-ketoglutarate). Studies have found IDH mutations in various tumors, such as gliomas, sarcomas, and acute myeloid leukemia. The mutations occur at arginine residues located in the catalytic center (IDH1/R132H, IDH2/R140Q, and IDH2/R172K). These mutated IDHs acquire a novel ability to catalyze the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). Studies have shown that α-ketoglutarate and 2-HG share a similar structure, and 2-HG competes with α-KG, thereby reducing the activity of α-KG-dependent enzymes and leading to hypermethylation of chromatin. This hypermethylation is believed to interfere with normal cell differentiation, leading to excessive proliferation of immature cells and, consequently, cancer.
In 2013, Agios Pharmaceuticals reported the IDH2/R140Q inhibitor AGI-6780 (Science. 2013, 340, 622-626) and the IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630). WO2015017821 also disclosed another IDH2/R140Q inhibitor, AG-221. AGI-6780 and AGI-5198 inhibit 2-HG production in cells carrying the most common IDH2 and IDH1 mutants, respectively. In addition to inhibiting 2-HG production, these molecules also induced differentiation in abnormally proliferating human cancer cells in culture. Treatment of leukemia cells carrying IDH2 mutants with AGI-6780 and of glioma cells carrying IDH1 mutants with AGI-5198 both resulted in increased expression of maturation markers in the cells. Furthermore, the researchers demonstrated that AGI-5198 inhibited the growth rate of glioma cells, whether treated with AGI-5198 in cell culture or administered orally to mice with tumor transplants.
Summary of the Invention
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients.
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
Detailed Description of the Invention
In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, those skilled in the relevant art will recognize that embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.
Unless otherwise required in this application, throughout the specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, "including but not limited to".
Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
It should be understood that as used in this specification and the appended claims, the singular article "a," "an," and "the" includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a reaction including "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
definition
Unless otherwise indicated, the following terms and phrases used herein have the following meanings. The absence of a specific definition for a term or phrase should not be construed as indefinite or unclear, but rather as indicating its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted (such as CH2CH2F ), polysubstituted (such as CHFCH2F , CH2CHF2 , etc.), or fully substituted ( CF2CF3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
As used herein, Cmn means that the moiety has mn carbon atoms. For example, " C3-10 cycloalkyl" means that the cycloalkyl group has 3-10 carbon atoms. " C0-6 alkylene" means that the alkylene group has 0-6 carbon atoms. When the alkylene group has 0 carbon atoms, the group is a bond.
Numeric ranges herein refer to each integer in the given range. For example, " C1-10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.
When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), i.e., an atom other than carbon and hydrogen or a group containing these atoms, the heteroatom being independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, germanium, aluminum, and boron. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The term "halogen" or "halo" refers to any radical of fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to -OH.
The term "cyano" refers to -CN.
The term "amino" refers to -NH2 , -NH(alkyl) and -N(alkyl) 2 . Specific examples of amino include, but are not limited to, -NH2 , -NHCH3 , -NHCH( CH3 ) 2 , -N( CH3 ) 2 , -NHC2H5 , -N( CH3 ) C2H5 and the like.
The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The specific alkyl group includes all isomeric forms thereof, such as propyl, including -CH2CH2CH3 and -CH( CH3 ) 2 , and butyl, including -CH2CH2CH2CH3 , -CH(CH3)( CH2CH3 ), -C( CH3 ) 3 , and -CH2CH( CH3 ) 2 . The term " C1-8alkyl " refers to an alkyl group having 1 to 8 carbon atoms. The term " C1-6alkyl " refers to an alkyl group having 1 to 6 carbon atoms. The term " C1-4alkyl " refers to an alkyl group having 1 to 4 carbon atoms. The term " C1-3alkyl " refers to an alkyl group having 1 to 3 carbon atoms. The "alkyl", "C 1-8 alkyl", "C 1-6 alkyl", "C 1-4 alkyl" or "C 1-3 alkyl" may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.
The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, propenyl, 2-butenyl, and 3-hexenyl. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
The term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl groups.
The term "alkoxy" refers to an -O-alkyl group.
The term "heteroaromatic ring" refers to a monocyclic or fused ring having 5-12 ring atoms, for example 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, and the remaining ring atoms are C, and having a completely conjugated π-electron system.
The term "heteroaryl" refers to the group remaining after removing one hydrogen atom from a "heteroaromatic ring" molecule. The heteroaryl group can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrazolyl, triazinyl, pteridinyl, and the like.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable carrier" refers to a carrier that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound. A "pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for use in humans or animals (e.g., livestock) and approved by the State Food and Drug Administration. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle required to formulate an effective pharmaceutical composition.
With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms herein, an "effective amount" of an active substance in a pharmaceutical composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "patient" or "individual" includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).
General formula compound
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is provided:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, the compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein
X 1 is selected from O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1 or 2.
In one embodiment of the present application, a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein X1 is O; R1 is selected from a C1-6 alkyl group, which may be optionally substituted with one or more R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a C3-6 cycloalkyl group. More preferably, R1 is selected from a methyl group, an ethyl group, a propyl group, or a butyl group, and may be optionally substituted with one to two R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a cyclopropane group.
In one embodiment of the present application, a compound of Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; R2 is selected from phenyl, pyridyl, benzyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy, and may be optionally substituted with one or two R7 ; each R7 is independently selected from hydroxy, halogenated C1-3 alkyl, or C1-6 alkyl. More preferably, R2 is selected from phenyl, pyridyl, benzyl, propyl, butyl, ethoxy, and may be optionally substituted with one or more R7 ; each R7 is independently selected from hydroxy or trifluoromethyl.
In one embodiment of the present application, the compound represented by Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; n is 0 or 1; and R3 is a halogenated C1-3 alkyl group. More preferably, n is 0 or 1; and R3 is selected from trifluoromethyl.
In one embodiment of the present application, the following compounds are preferred:
and pharmaceutically acceptable salts or hydrates thereof.
Pharmaceutically acceptable salts of the compounds of Formula I or Formula II include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Non-limiting examples of salts with organic bases include, but are not limited to, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, and dicyclohexylamine. Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The compounds of Formula I or Formula II herein may exist in unsolvated or solvated forms, including hydrates. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention. The compounds of Formula I or Formula II herein may exist in polymorphic or amorphous forms.
The compounds of Formula I or Formula II of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present application.
The diagrammatic representations of racemates, ambiscalemic and scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration of a stereocenter. When compounds of Formula I or Formula II herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers, unless otherwise indicated. Likewise, all tautomeric forms are intended to be encompassed within the scope of this application.
The compounds of Formula I or Formula II herein may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are also within the scope of this application.
Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography known to those skilled in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., carbamate formation from an amine).
The compounds of Formula I or Formula II herein may contain unnatural proportions of atomic isotopes at one or more atoms comprising the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of Formula I or Formula II herein, whether radioactive or not, are encompassed within the scope of this application.
Pharmaceutical composition
In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present application may further contain one or more additional therapeutic agents.
The pharmaceutical composition of the present application can be prepared by combining the compound of general formula I or general formula II of the present application or a pharmaceutically acceptable salt or hydrate thereof with a suitable pharmaceutically acceptable carrier or excipient, and can be formulated into, for example, solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
Typical routes of administration of the compounds of Formula I or Formula II of the present application, or their pharmaceutically acceptable salts or hydrates, or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
The pharmaceutical composition of the present application can be prepared by methods known to those skilled in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
For oral administration, the pharmaceutical composition can be prepared by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with pharmaceutically acceptable carriers or excipients well known to those skilled in the art. These carriers or excipients enable the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.
Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to form a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; talc, starch, magnesium stearate, calcium stearate, or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, and cross-linked polyvinyl pyrrolidone. Dragee cores may optionally be coated according to methods generally known in the pharmaceutical art, in particular with an enteric coating.
The pharmaceutical compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable formulations for parenteral administration can be prepared using suitable excipients, such as fillers, buffers or surfactants.
Medical uses
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
In some embodiments of the present application, the cancer induced by IDH2 mutation is selected from: glioblastoma (neuroglioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL). In more specific embodiments, the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL), etc., preferably including acute myeloid leukemia (AML) or sarcoma.
The compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered by any suitable route and method, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered to a subject in need thereof. The dosage of the compounds of Formula I or Formula II can be from about 0.0001 to 20 mg/kg body weight/day, for example, from 0.001 to 10 mg/kg body weight/day.
The frequency of administration of the compound of Formula I or Formula II herein is determined by the individual patient's needs, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the compound of Formula I or Formula II over a period of several days, followed by a period of several or more days in which the patient does not receive a daily dose of the compound of Formula I or Formula II.
preparation
The compounds of general formula I or general formula II of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
The chemical reactions of the specific embodiments of this application are carried out in a suitable solvent, which must be compatible with the chemical transformations and the reagents and materials required. To obtain the compounds of Formula I or Formula II of this application, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.
The compounds of the general formula II of the present application can be prepared by those skilled in the art of organic synthesis using standard methods in the art via the following routes:
Compound 1-1 undergoes acylation to obtain 1-2; 1-2 reacts with biuret to obtain 1-3; 1-3 undergoes chlorination to obtain 1-4; 1-4 undergoes amination reaction with R2- substituted ammonia to obtain 1-5; 1-5 undergoes amination reaction with R2 - X1- substituted ammonia to obtain the compound of general formula II.
Example
The following specific examples are intended to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the present invention, but rather as illustrative and representative examples thereof. Those skilled in the art will appreciate that other synthetic pathways exist for forming the compounds of the present invention, and the following examples are provided as non-limiting examples.
All operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise stated, the raw materials used in this application were purchased directly from the market and used directly without further purification.
Column chromatography used silica gel (200-300 mesh) manufactured by Qingdao Chemical Co., Ltd. Thin-layer chromatography used precast plates (Silica gel 60PF254, 0.25 mm) manufactured by E. Merck. Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H, 5 μm, 30°C). Nuclear magnetic resonance (NMR) chromatography was performed using a Varian VNMRS-400 NMR spectrometer; liquid chromatography-mass spectrometry (LC/MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX and an Agilent LC 1200 series (column: Waters Symmetry C18, 5 μm, 35°C) in ESI (+) ion mode.
Experimental part
Example 1: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
Under nitrogen, palladium acetate (74.0 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene (363.0 mg, 0.655 mmol), and triethylamine (0.92 g, 9.8 mmol) were added sequentially to a solution of 2-bromo-6-trifluoromethylpyridine (1.48 g, 6.55 mmol) in methanol (50.0 mL). The reaction mixture was allowed to react at 60°C under a 2 atmosphere carbon monoxide atmosphere for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to yield methyl 6-trifluoromethyl-pyridine-2-carboxylate (0.9 g, 67.0% yield).
Step 2: 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione
Under nitrogen, methyl 6-trifluoromethyl-pyridine-2-carboxylate (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol) were added sequentially to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL). The mixture was heated under reflux for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into water. The pH was adjusted to 7 with 6 mol/L hydrochloric acid. The resulting solid was filtered, the filter cake washed with water, and dried to yield 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, 47.5% yield).
Step 3: 2,4-Dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine
Under nitrogen, a mixture of 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (15.0 g, 58.1 mmol) and phosphorus oxychloride (200 mL) was reacted at 100°C for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under vacuum to yield 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (10.0 g, 58.3% yield).
Step 4: 4-Chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (5.0 g, 16.9 mmol) in tetrahydrofuran (100 mL) were added 4-amino-2-trifluoromethylpyridine (3.3 g, 20.3 mmol) and sodium bicarbonate (2.14 g, 25.3 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine (6.5 g, 91.2% yield).
Step 5: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (50.0 mg) in tetrahydrofuran (20 mL) were added ethoxylamine hydrochloride (12.0 mg, 0.18 mmol) and sodium bicarbonate (40.0 mg, 0.48 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to yield 4-(ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (40.0 mg). 1 H-NMR (400MHz, CDCl 3 ): δ = 8.66-8.58 (m, 2H), 8.49 (s, 1H), 8.32(s,1H),8.10(t,J＝7.9Hz,1H),7.94(s,1H),7.88(d,J＝7.8Hz,1H),7.62(d,J＝3.7Hz,1H), 4.19(q,J＝7.0Hz,2H),1.41(t,J＝7.1Hz,3H).
Example 2: 4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.35 (s, 1H), 10.85 (s, 1H), 8.66 (s, 1H), 8.56 (d, J = 5.6 Hz, 2H), 8.32 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 4.28-4.06 (m, 1H), 1.23 (d, J = 14.5 Hz, 6H).
Example 3: 4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.00 (s, 1H), 10.84 (s, 1H), 8.74 (s, 1H), 8.57 (t, J = 6.5 Hz, 2H), 8.31 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 1.28 (s, 9H).
Example 4: 4-((Cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-((cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-
(2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.4 (s, 1H), 10.9 (s, 1H), 8.61 (s, 1H), 8.57 (d, J=5.6 Hz, 2H), 8.32 (t, J=7.9 Hz, 1H), 8.17-8.09 (m, 2H), 3.77 (d, J=7.1 Hz, 2H), 3.15 (d, J=5.2 Hz, 1H), 0.87-0.76 (m, 2H), 0.57-0.47 (m, 2H).
Example 5: N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino)
N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino) was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.96 (s, 2H), 8.48 (d, J=7.8 Hz, 1H), 8.24 (t, J=7.9 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 3.90 (q, J=7.0 Hz, 4H), 1.30-1.06 (m, 6H).
Example 6: 2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol
2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, CDCl 3 ): δ=8.59 (dd, J=10.7, 6.7 Hz, 2H), 8.29 (s, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 4.00 (s, 2H), 1.62 (s, 1H), 1.32 (s, 6H).
Example 7: 2-Methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol
Referring to the synthetic method of Example 1, 2-methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol was prepared. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.80 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.29 (t, J=7.9 Hz, 3H), 8.08 (m, 2H), 5.38 (s, 1H), 4.56 (s, 1H), 3.54-3.39 (m, 2H), 1.27-1.10 (m, 6H).
Example 8: 4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.52 (s, 1H), 10.91 (s, 1H), 8.60 (s, 2H), 8.56 (d, J=5.4 Hz, 1H), 8.36 (t, J=7.9 Hz, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.52 (s, 2H), 7.47-7.35 (m, 3H), 5.04 (s, 2H).
Example 9: 4-(2-methylhydrazine)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(2-methylhydrazinyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.76 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.30 (t, J=7.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.93 (s, 1H), 5.39 (s, 1H), 5.21 (s, 1H), 3.40 (s, 3H).
Example 10: 4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.59 (d, 2H), 8.59 (m, 1H), 8.55 (m, 1H), 8.32 (m, 2H), 8.00 (m, 1H), 7.56 (m, 3H), 1.41-0.95 (m, 9H).
Example 11: 1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol
1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.29 (d, 2H), 8.53 (d, J=7.9 Hz, 1H), 8.28 (t, J=7.9 Hz, 1H), 8.13-8.03 (m, 1H), 4.86 (s, 1H), 3.39 (m, 2H), 1.27 (m, 9H), 1.07 (m, 6H).
Example 12: 4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1H), 10.12 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.31 (t, J = 7.8 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.99 (m, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 1.29 (s, 9H).
Example 13: N-Benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
N-benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.26 (s, 2H), 8.50 (dd, J = 13.2, 5.0 Hz, 2H), 8.33 - 8.18 (m, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.31 (dd, J = 10.1, 4.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 1.18 (s, 9H).
Example 14: 4-(tert-Butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-(tert-butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-
1,3,5-Triazine-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.16 (s, 2H), 8.49 (d, J=8.1 Hz, 1H), 8.04 (d, J=7.4 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 4.16 (m, 1H), 1.24 (m, 9H), 1.18 (m, 6H).
Experimental Example 1: Determination of IDH2 inhibitory activity
The present application adopts the following method to determine the inhibitory activity of the compounds of the present application on IDH2 (R172K, 40-end). The inhibitory activity is represented by the indicator IC50 , which is the concentration of the compound when the activity of IDH2 is inhibited by 50%.
Materials and methods:
The inhibitory activity of the compounds against IDH2 (R172K, 40-end) was determined by depletion of the cofactor NADPH. The compounds were pre-incubated with the enzyme and NADPH, and the reaction was initiated by the addition of α-KG and allowed to react for 120 minutes under linear conditions. The reaction was then terminated by the addition of diaphorase (lipoamide dehydrogenase) and the corresponding substrate, resazurin (resazurin). Lipoamide dehydrogenase terminates the IDH2m reaction by depleting the available cofactor NADPH, oxidizing NADPH to NADP and reducing resazurin to the highly fluorescent resorufin. The amount of cofactor NADPH remaining after a specific reaction time was quantified using an easily detectable fluorescent group.
Specifically, 2.5 μl of a 3x serial dilution of the compound was added to a 384-well plate, followed by 5 μl of reaction buffer (20 mM Tris-HCl, pH 7.5; 150 mM NaCl; 10 mM MgCl2; 10 mM MnCl2; 0.4 mg/ml BSA; and 2 mM DTT) containing 80 nM IDH2 (R172K, 40-end) and 40 μM NADPH. The assay mixture was then incubated at 23°C for 120 minutes, after which the reaction was initiated by the addition of 2.5 μl of reaction buffer containing 4 mM α-KG. After incubation at room temperature for 120 minutes, 5 μl of a stop mix (0.4 U/ml diaphorase and 40 μM resazurin) prepared in reaction buffer was added to convert resazurin to resorufin, allowing measurement of residual NADPH. After incubation at 23°C for 10 minutes, fluorescence was measured using a Flexstation 3 using Ex535/Em595.
The IDH2 inhibitory activities of the example compounds are shown in Table 1:
Table 1
| Example No. | |
| 1 | 22.40 |
| 2 | 28.79 |
| 3 | 31.69 |
| 4 | 38.19 |
| 6 | 46.85 |
| 7 | 153.6 |
| 8 | 239.3 |
| 10 | 51.42 |
Experimental Example 2: Determination of pharmacokinetic parameters
The present application uses the following methods to determine the pharmacokinetic parameters of the compounds of the present application:
The study used healthy male adult rats aged 7-9 weeks. Each group of animals (3 male rats) received a single oral administration of 5 mg/kg. The animals in the oral administration group fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration.
Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the retinal venous plexus and placed in a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis.
Plasma sample analysis was performed using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight) software. A non-compartmental model was used for concentration analysis, and the pharmacokinetic parameters of the compounds were calculated, as shown in Table 2. The compound of Example 3 has a good in vivo metabolism level and a long half-life, and at the same dose, its blood concentration is higher than that of the IDH2 inhibitor AG-221.
Table 2
| Example | 3 | AG-221 |
| Dosage (mg/kg) | 5 | 5 |
| 12.0 | 3.73 | |
| 5.0 | 4.00 | |
| 589 | 479 | |
| 10838 | 5385 |
Citation of Related Applications
This application claims the benefit of Chinese invention patent application No. 201510459126.X filed with the State Intellectual Property Office of the People's Republic of China on July 30, 2015, the entire contents of which are hereby incorporated by reference into this document in their entirety.
Technical Field
The present invention relates to the field of medicine, and more specifically to 1,3,5-triazine derivatives and methods of using the same.
Background Art
IDH, short for isocitrate dehydrogenase, is a key enzyme in the tricarboxylic acid cycle. It catalyzes the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate (i.e., α-ketoglutarate). Studies have found IDH mutations in various tumors, such as gliomas, sarcomas, and acute myeloid leukemia. The mutations occur at arginine residues located in the catalytic center (IDH1/R132H, IDH2/R140Q, and IDH2/R172K). These mutated IDHs acquire a novel ability to catalyze the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). Studies have shown that α-ketoglutarate and 2-HG share a similar structure, and 2-HG competes with α-KG, thereby reducing the activity of α-KG-dependent enzymes and leading to hypermethylation of chromatin. This hypermethylation is believed to interfere with normal cell differentiation, leading to excessive proliferation of immature cells and, consequently, cancer.
In 2013, Agios Pharmaceuticals reported the IDH2/R140Q inhibitor AGI-6780 (Science. 2013, 340, 622-626) and the IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630). WO2015017821 also disclosed another IDH2/R140Q inhibitor, AG-221. AGI-6780 and AGI-5198 inhibit 2-HG production in cells carrying the most common IDH2 and IDH1 mutants, respectively. In addition to inhibiting 2-HG production, these molecules also induced differentiation in abnormally proliferating human cancer cells in culture. Treatment of leukemia cells carrying IDH2 mutants with AGI-6780 and of glioma cells carrying IDH1 mutants with AGI-5198 both resulted in increased expression of maturation markers in the cells. Furthermore, the researchers demonstrated that AGI-5198 inhibited the growth rate of glioma cells, whether treated with AGI-5198 in cell culture or administered orally to mice with tumor transplants.
Summary of the Invention
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients.
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
Detailed Description of the Invention
In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, those skilled in the relevant art will recognize that embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.
Unless otherwise required in this application, throughout the specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, "including but not limited to".
Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
It should be understood that as used in this specification and the appended claims, the singular article "a," "an," and "the" includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a reaction including "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
definition
Unless otherwise indicated, the following terms and phrases used herein have the following meanings. The absence of a specific definition for a term or phrase should not be construed as indefinite or unclear, but rather as indicating its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted (such as CH2CH2F ), polysubstituted (such as CHFCH2F , CH2CHF2 , etc.), or fully substituted ( CF2CF3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
As used herein, Cmn means that the moiety has mn carbon atoms. For example, " C3-10 cycloalkyl" means that the cycloalkyl group has 3-10 carbon atoms. " C0-6 alkylene" means that the alkylene group has 0-6 carbon atoms. When the alkylene group has 0 carbon atoms, the group is a bond.
Numeric ranges herein refer to each integer in the given range. For example, " C1-10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.
When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), i.e., an atom other than carbon and hydrogen or a group containing these atoms, the heteroatom being independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, germanium, aluminum, and boron. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The term "halogen" or "halo" refers to any radical of fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to -OH.
The term "cyano" refers to -CN.
The term "amino" refers to -NH2 , -NH(alkyl) and -N(alkyl) 2 . Specific examples of amino include, but are not limited to, -NH2 , -NHCH3 , -NHCH( CH3 ) 2 , -N( CH3 ) 2 , -NHC2H5 , -N( CH3 ) C2H5 and the like.
The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The specific alkyl group includes all isomeric forms thereof, such as propyl, including -CH2CH2CH3 and -CH( CH3 ) 2 , and butyl, including -CH2CH2CH2CH3 , -CH(CH3)( CH2CH3 ), -C( CH3 ) 3 , and -CH2CH( CH3 ) 2 . The term " C1-8alkyl " refers to an alkyl group having 1 to 8 carbon atoms. The term " C1-6alkyl " refers to an alkyl group having 1 to 6 carbon atoms. The term " C1-4alkyl " refers to an alkyl group having 1 to 4 carbon atoms. The term " C1-3alkyl " refers to an alkyl group having 1 to 3 carbon atoms. The "alkyl", "C 1-8 alkyl", "C 1-6 alkyl", "C 1-4 alkyl" or "C 1-3 alkyl" may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.
The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, propenyl, 2-butenyl, and 3-hexenyl. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
The term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl groups.
The term "alkoxy" refers to an -O-alkyl group.
The term "heteroaromatic ring" refers to a monocyclic or fused ring having 5-12 ring atoms, for example 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, and the remaining ring atoms are C, and having a completely conjugated π-electron system.
The term "heteroaryl" refers to the group remaining after removing one hydrogen atom from a "heteroaromatic ring" molecule. The heteroaryl group can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrazolyl, triazinyl, pteridinyl, and the like.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable carrier" refers to a carrier that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound. A "pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for use in humans or animals (e.g., livestock) and approved by the State Food and Drug Administration. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle required to formulate an effective pharmaceutical composition.
With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms herein, an "effective amount" of an active substance in a pharmaceutical composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "patient" or "individual" includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).
General formula compound
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is provided:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, the compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein
X 1 is selected from O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1 or 2.
In one embodiment of the present application, a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein X1 is O; R1 is selected from a C1-6 alkyl group, which may be optionally substituted with one or more R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a C3-6 cycloalkyl group. More preferably, R1 is selected from a methyl group, an ethyl group, a propyl group, or a butyl group, and may be optionally substituted with one to two R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a cyclopropane group.
In one embodiment of the present application, a compound of Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; R2 is selected from phenyl, pyridyl, benzyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy, and may be optionally substituted with one or two R7 ; each R7 is independently selected from hydroxy, halogenated C1-3 alkyl, or C1-6 alkyl. More preferably, R2 is selected from phenyl, pyridyl, benzyl, propyl, butyl, ethoxy, and may be optionally substituted with one or more R7 ; each R7 is independently selected from hydroxy or trifluoromethyl.
In one embodiment of the present application, the compound represented by Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; n is 0 or 1; and R3 is a halogenated C1-3 alkyl group. More preferably, n is 0 or 1; and R3 is selected from trifluoromethyl.
In one embodiment of the present application, the following compounds are preferred:
and pharmaceutically acceptable salts or hydrates thereof.
Pharmaceutically acceptable salts of the compounds of Formula I or Formula II include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Non-limiting examples of salts with organic bases include, but are not limited to, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, and dicyclohexylamine. Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The compounds of Formula I or Formula II herein may exist in unsolvated or solvated forms, including hydrates. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention. The compounds of Formula I or Formula II herein may exist in polymorphic or amorphous forms.
The compounds of Formula I or Formula II of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present application.
The diagrammatic representations of racemates, ambiscalemic and scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration of a stereocenter. When compounds of Formula I or Formula II herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers, unless otherwise indicated. Likewise, all tautomeric forms are intended to be encompassed within the scope of this application.
The compounds of Formula I or Formula II herein may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are also within the scope of this application.
Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography known to those skilled in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., carbamate formation from an amine).
The compounds of Formula I or Formula II herein may contain unnatural proportions of atomic isotopes at one or more atoms comprising the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of Formula I or Formula II herein, whether radioactive or not, are encompassed within the scope of this application.
Pharmaceutical composition
In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present application may further contain one or more additional therapeutic agents.
The pharmaceutical composition of the present application can be prepared by combining the compound of general formula I or general formula II of the present application or a pharmaceutically acceptable salt or hydrate thereof with a suitable pharmaceutically acceptable carrier or excipient, and can be formulated into, for example, solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
Typical routes of administration of the compounds of Formula I or Formula II of the present application, or their pharmaceutically acceptable salts or hydrates, or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
The pharmaceutical composition of the present application can be prepared by methods known to those skilled in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
For oral administration, the pharmaceutical composition can be prepared by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with pharmaceutically acceptable carriers or excipients well known to those skilled in the art. These carriers or excipients enable the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.
Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to form a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; talc, starch, magnesium stearate, calcium stearate, or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, and cross-linked polyvinyl pyrrolidone. Dragee cores may optionally be coated according to methods generally known in the pharmaceutical art, in particular with an enteric coating.
The pharmaceutical compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable formulations for parenteral administration can be prepared using suitable excipients, such as fillers, buffers or surfactants.
Medical uses
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
In some embodiments of the present application, the cancer induced by IDH2 mutation is selected from: glioblastoma (neuroglioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL). In more specific embodiments, the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL), etc., preferably including acute myeloid leukemia (AML) or sarcoma.
The compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered by any suitable route and method, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered to a subject in need thereof. The dosage of the compounds of Formula I or Formula II can be from about 0.0001 to 20 mg/kg body weight/day, for example, from 0.001 to 10 mg/kg body weight/day.
The frequency of administration of the compound of Formula I or Formula II herein is determined by the individual patient's needs, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the compound of Formula I or Formula II over a period of several days, followed by a period of several or more days in which the patient does not receive a daily dose of the compound of Formula I or Formula II.
preparation
The compounds of general formula I or general formula II of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
The chemical reactions of the specific embodiments of this application are carried out in a suitable solvent, which must be compatible with the chemical transformations and the reagents and materials required. To obtain the compounds of Formula I or Formula II of this application, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.
The compounds of the general formula II of the present application can be prepared by those skilled in the art of organic synthesis using standard methods in the art via the following routes:
Compound 1-1 undergoes acylation to obtain 1-2; 1-2 reacts with biuret to obtain 1-3; 1-3 undergoes chlorination to obtain 1-4; 1-4 undergoes amination reaction with R2- substituted ammonia to obtain 1-5; 1-5 undergoes amination reaction with R2 - X1- substituted ammonia to obtain the compound of general formula II.
Example
The following specific examples are intended to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the present invention, but rather as illustrative and representative examples thereof. Those skilled in the art will appreciate that other synthetic pathways exist for forming the compounds of the present invention, and the following examples are provided as non-limiting examples.
All operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise stated, the raw materials used in this application were purchased directly from the market and used directly without further purification.
Column chromatography used silica gel (200-300 mesh) manufactured by Qingdao Chemical Co., Ltd. Thin-layer chromatography used precast plates (Silica gel 60PF254, 0.25 mm) manufactured by E. Merck. Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H, 5 μm, 30°C). Nuclear magnetic resonance (NMR) chromatography was performed using a Varian VNMRS-400 NMR spectrometer; liquid chromatography-mass spectrometry (LC/MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX and an Agilent LC 1200 series (column: Waters Symmetry C18, 5 μm, 35°C) in ESI (+) ion mode.
Experimental part
Example 1: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
Under nitrogen, palladium acetate (74.0 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene (363.0 mg, 0.655 mmol), and triethylamine (0.92 g, 9.8 mmol) were added sequentially to a solution of 2-bromo-6-trifluoromethylpyridine (1.48 g, 6.55 mmol) in methanol (50.0 mL). The reaction mixture was allowed to react at 60°C under a 2 atmosphere carbon monoxide atmosphere for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to yield methyl 6-trifluoromethyl-pyridine-2-carboxylate (0.9 g, 67.0% yield).
Step 2: 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione
Under nitrogen, methyl 6-trifluoromethyl-pyridine-2-carboxylate (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol) were added sequentially to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL). The mixture was heated under reflux for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into water. The pH was adjusted to 7 with 6 mol/L hydrochloric acid. The resulting solid was filtered, the filter cake washed with water, and dried to yield 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, 47.5% yield).
Step 3: 2,4-Dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine
Under nitrogen, a mixture of 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (15.0 g, 58.1 mmol) and phosphorus oxychloride (200 mL) was reacted at 100°C for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under vacuum to yield 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (10.0 g, 58.3% yield).
Step 4: 4-Chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (5.0 g, 16.9 mmol) in tetrahydrofuran (100 mL) were added 4-amino-2-trifluoromethylpyridine (3.3 g, 20.3 mmol) and sodium bicarbonate (2.14 g, 25.3 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine (6.5 g, 91.2% yield).
Step 5: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (50.0 mg) in tetrahydrofuran (20 mL) were added ethoxylamine hydrochloride (12.0 mg, 0.18 mmol) and sodium bicarbonate (40.0 mg, 0.48 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to yield 4-(ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (40.0 mg). 1 H-NMR (400MHz, CDCl 3 ): δ = 8.66-8.58 (m, 2H), 8.49 (s, 1H), 8.32(s,1H),8.10(t,J＝7.9Hz,1H),7.94(s,1H),7.88(d,J＝7.8Hz,1H),7.62(d,J＝3.7Hz,1H), 4.19(q,J＝7.0Hz,2H),1.41(t,J＝7.1Hz,3H).
Example 2: 4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.35 (s, 1H), 10.85 (s, 1H), 8.66 (s, 1H), 8.56 (d, J = 5.6 Hz, 2H), 8.32 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 4.28-4.06 (m, 1H), 1.23 (d, J = 14.5 Hz, 6H).
Example 3: 4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.00 (s, 1H), 10.84 (s, 1H), 8.74 (s, 1H), 8.57 (t, J = 6.5 Hz, 2H), 8.31 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 1.28 (s, 9H).
Example 4: 4-((Cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-((cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-
(2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.4 (s, 1H), 10.9 (s, 1H), 8.61 (s, 1H), 8.57 (d, J=5.6 Hz, 2H), 8.32 (t, J=7.9 Hz, 1H), 8.17-8.09 (m, 2H), 3.77 (d, J=7.1 Hz, 2H), 3.15 (d, J=5.2 Hz, 1H), 0.87-0.76 (m, 2H), 0.57-0.47 (m, 2H).
Example 5: N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino)
N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino) was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.96 (s, 2H), 8.48 (d, J=7.8 Hz, 1H), 8.24 (t, J=7.9 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 3.90 (q, J=7.0 Hz, 4H), 1.30-1.06 (m, 6H).
Example 6: 2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol
2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, CDCl 3 ): δ=8.59 (dd, J=10.7, 6.7 Hz, 2H), 8.29 (s, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 4.00 (s, 2H), 1.62 (s, 1H), 1.32 (s, 6H).
Example 7: 2-Methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol
Referring to the synthetic method of Example 1, 2-methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol was prepared. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.80 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.29 (t, J=7.9 Hz, 3H), 8.08 (m, 2H), 5.38 (s, 1H), 4.56 (s, 1H), 3.54-3.39 (m, 2H), 1.27-1.10 (m, 6H).
Example 8: 4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.52 (s, 1H), 10.91 (s, 1H), 8.60 (s, 2H), 8.56 (d, J=5.4 Hz, 1H), 8.36 (t, J=7.9 Hz, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.52 (s, 2H), 7.47-7.35 (m, 3H), 5.04 (s, 2H).
Example 9: 4-(2-methylhydrazine)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(2-methylhydrazinyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.76 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.30 (t, J=7.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.93 (s, 1H), 5.39 (s, 1H), 5.21 (s, 1H), 3.40 (s, 3H).
Example 10: 4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.59 (d, 2H), 8.59 (m, 1H), 8.55 (m, 1H), 8.32 (m, 2H), 8.00 (m, 1H), 7.56 (m, 3H), 1.41-0.95 (m, 9H).
Example 11: 1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol
1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.29 (d, 2H), 8.53 (d, J=7.9 Hz, 1H), 8.28 (t, J=7.9 Hz, 1H), 8.13-8.03 (m, 1H), 4.86 (s, 1H), 3.39 (m, 2H), 1.27 (m, 9H), 1.07 (m, 6H).
Example 12: 4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1H), 10.12 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.31 (t, J = 7.8 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.99 (m, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 1.29 (s, 9H).
Example 13: N-Benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
N-benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.26 (s, 2H), 8.50 (dd, J = 13.2, 5.0 Hz, 2H), 8.33 - 8.18 (m, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.31 (dd, J = 10.1, 4.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 1.18 (s, 9H).
Example 14: 4-(tert-Butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-(tert-butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-
1,3,5-Triazine-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.16 (s, 2H), 8.49 (d, J=8.1 Hz, 1H), 8.04 (d, J=7.4 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 4.16 (m, 1H), 1.24 (m, 9H), 1.18 (m, 6H).
Experimental Example 1: Determination of IDH2 inhibitory activity
The present application adopts the following method to determine the inhibitory activity of the compounds of the present application on IDH2 (R172K, 40-end). The inhibitory activity is represented by the indicator IC50 , which is the concentration of the compound when the activity of IDH2 is inhibited by 50%.
Materials and methods:
The inhibitory activity of the compounds against IDH2 (R172K, 40-end) was determined by depletion of the cofactor NADPH. The compounds were pre-incubated with the enzyme and NADPH, and the reaction was initiated by the addition of α-KG and allowed to react for 120 minutes under linear conditions. The reaction was then terminated by the addition of diaphorase (lipoamide dehydrogenase) and the corresponding substrate, resazurin (resazurin). Lipoamide dehydrogenase terminates the IDH2m reaction by depleting the available cofactor NADPH, oxidizing NADPH to NADP and reducing resazurin to the highly fluorescent resorufin. The amount of cofactor NADPH remaining after a specific reaction time was quantified using an easily detectable fluorescent group.
Specifically, 2.5 μl of a 3x serial dilution of the compound was added to a 384-well plate, followed by 5 μl of reaction buffer (20 mM Tris-HCl, pH 7.5; 150 mM NaCl; 10 mM MgCl2; 10 mM MnCl2; 0.4 mg/ml BSA; and 2 mM DTT) containing 80 nM IDH2 (R172K, 40-end) and 40 μM NADPH. The assay mixture was then incubated at 23°C for 120 minutes, after which the reaction was initiated by the addition of 2.5 μl of reaction buffer containing 4 mM α-KG. After incubation at room temperature for 120 minutes, 5 μl of a stop mix (0.4 U/ml diaphorase and 40 μM resazurin) prepared in reaction buffer was added to convert resazurin to resorufin, allowing measurement of residual NADPH. After incubation at 23°C for 10 minutes, fluorescence was measured using a Flexstation 3 using Ex535/Em595.
The IDH2 inhibitory activities of the example compounds are shown in Table 1:
Table 1
| Example No. | |
| 1 | 22.40 |
| 2 | 28.79 |
| 3 | 31.69 |
| 4 | 38.19 |
| 6 | 46.85 |
| 7 | 153.6 |
| 8 | 239.3 |
| 10 | 51.42 |
Experimental Example 2: Determination of pharmacokinetic parameters
The present application uses the following methods to determine the pharmacokinetic parameters of the compounds of the present application:
The study used healthy male adult rats aged 7-9 weeks. Each group of animals (3 male rats) received a single oral administration of 5 mg/kg. The animals in the oral administration group fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration.
Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the retinal venous plexus and placed in a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis.
Plasma sample analysis was performed using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight) software. A non-compartmental model was used for concentration analysis, and the pharmacokinetic parameters of the compounds were calculated, as shown in Table 2. The compound of Example 3 has a good in vivo metabolism level and a long half-life, and at the same dose, its blood concentration is higher than that of the IDH2 inhibitor AG-221.
Table 2
| Example | 3 | AG-221 |
| Dosage (mg/kg) | 5 | 5 |
| 12.0 | 3.73 | |
| 5.0 | 4.00 | |
| 589 | 479 | |
| 10838 | 5385 |
Citation of Related Applications
This application claims the benefit of Chinese invention patent application No. 201510459126.X filed with the State Intellectual Property Office of the People's Republic of China on July 30, 2015, the entire contents of which are hereby incorporated by reference into this document in their entirety.
Technical Field
The present invention relates to the field of medicine, and more specifically to 1,3,5-triazine derivatives and methods of using the same.
Background Art
IDH, short for isocitrate dehydrogenase, is a key enzyme in the tricarboxylic acid cycle. It catalyzes the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate (i.e., α-ketoglutarate). Studies have found IDH mutations in various tumors, such as gliomas, sarcomas, and acute myeloid leukemia. The mutations occur at arginine residues located in the catalytic center (IDH1/R132H, IDH2/R140Q, and IDH2/R172K). These mutated IDHs acquire a novel ability to catalyze the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). Studies have shown that α-ketoglutarate and 2-HG share a similar structure, and 2-HG competes with α-KG, thereby reducing the activity of α-KG-dependent enzymes and leading to hypermethylation of chromatin. This hypermethylation is believed to interfere with normal cell differentiation, leading to excessive proliferation of immature cells and, consequently, cancer.
In 2013, Agios Pharmaceuticals reported the IDH2/R140Q inhibitor AGI-6780 (Science. 2013, 340, 622-626) and the IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630). WO2015017821 also disclosed another IDH2/R140Q inhibitor, AG-221. AGI-6780 and AGI-5198 inhibit 2-HG production in cells carrying the most common IDH2 and IDH1 mutants, respectively. In addition to inhibiting 2-HG production, these molecules also induced differentiation in abnormally proliferating human cancer cells in culture. Treatment of leukemia cells carrying IDH2 mutants with AGI-6780 and of glioma cells carrying IDH1 mutants with AGI-5198 both resulted in increased expression of maturation markers in the cells. Furthermore, the researchers demonstrated that AGI-5198 inhibited the growth rate of glioma cells, whether treated with AGI-5198 in cell culture or administered orally to mice with tumor transplants.
Summary of the Invention
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients.
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
Detailed Description of the Invention
In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, those skilled in the relevant art will recognize that embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.
Unless otherwise required in this application, throughout the specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, "including but not limited to".
Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that the particular referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
It should be understood that as used in this specification and the appended claims, the singular article "a," "an," and "the" includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a reaction including "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
definition
Unless otherwise indicated, the following terms and phrases used herein have the following meanings. The absence of a specific definition for a term or phrase should not be construed as indefinite or unclear, but rather as indicating its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted (such as CH2CH2F ), polysubstituted (such as CHFCH2F , CH2CHF2 , etc.), or fully substituted ( CF2CF3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
As used herein, Cmn means that the moiety has mn carbon atoms. For example, " C3-10 cycloalkyl" means that the cycloalkyl group has 3-10 carbon atoms. " C0-6 alkylene" means that the alkylene group has 0-6 carbon atoms. When the alkylene group has 0 carbon atoms, the group is a bond.
Numeric ranges herein refer to each integer in the given range. For example, " C1-10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.
When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatom group (i.e., a group containing heteroatoms), i.e., an atom other than carbon and hydrogen or a group containing these atoms, the heteroatom being independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, germanium, aluminum, and boron. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The term "halogen" or "halo" refers to any radical of fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to -OH.
The term "cyano" refers to -CN.
The term "amino" refers to -NH2 , -NH(alkyl) and -N(alkyl) 2 . Specific examples of amino include, but are not limited to, -NH2 , -NHCH3 , -NHCH( CH3 ) 2 , -N( CH3 ) 2 , -NHC2H5 , -N( CH3 ) C2H5 and the like.
The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. The specific alkyl group includes all isomeric forms thereof, such as propyl, including -CH2CH2CH3 and -CH( CH3 ) 2 , and butyl, including -CH2CH2CH2CH3 , -CH(CH3)( CH2CH3 ), -C( CH3 ) 3 , and -CH2CH( CH3 ) 2 . The term " C1-8alkyl " refers to an alkyl group having 1 to 8 carbon atoms. The term " C1-6alkyl " refers to an alkyl group having 1 to 6 carbon atoms. The term " C1-4alkyl " refers to an alkyl group having 1 to 4 carbon atoms. The term " C1-3alkyl " refers to an alkyl group having 1 to 3 carbon atoms. The "alkyl", "C 1-8 alkyl", "C 1-6 alkyl", "C 1-4 alkyl" or "C 1-3 alkyl" may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.
The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, propenyl, 2-butenyl, and 3-hexenyl. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
The term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group containing 2 to 12 carbon atoms and having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl, and hydroxyl groups.
The term "alkoxy" refers to an -O-alkyl group.
The term "heteroaromatic ring" refers to a monocyclic or fused ring having 5-12 ring atoms, for example 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, and the remaining ring atoms are C, and having a completely conjugated π-electron system.
The term "heteroaryl" refers to the group remaining after removing one hydrogen atom from a "heteroaromatic ring" molecule. The heteroaryl group can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrazolyl, triazinyl, pteridinyl, and the like.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable carrier" refers to a carrier that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound. A "pharmaceutically acceptable carrier" refers to an inert substance that is administered together with the active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for use in humans or animals (e.g., livestock) and approved by the State Food and Drug Administration. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle required to formulate an effective pharmaceutical composition.
With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms herein, an "effective amount" of an active substance in a pharmaceutical composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "patient" or "individual" includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).
General formula compound
In one aspect, the present application provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:
in,
Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O or S;
X 1 is selected from NH or O;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
R4 and R5 are independently selected from H, C1-6 alkyl or C3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is provided:
in,
X 1 is selected from NH or O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1, 2 or 3.
In one embodiment of the present application, the compound of formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein
X 1 is selected from O;
X2 is selected from N or CH;
R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl or cycloalkyl may be optionally substituted with one or more R 6 ;
R 2 is selected from phenyl, pyridyl, benzyl, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl, and may be optionally substituted with one or more R 7 ;
Each R 3 is independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
Each R 6 is independently selected from halogen, hydroxy, amino, CF 3 , C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or a 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, and the phenyl or heteroaryl may be optionally substituted with one or more R 8 ;
Each R 7 and each R 8 are independently selected from halogen, hydroxy, amino, halogenated C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; and
n is 0, 1 or 2.
In one embodiment of the present application, a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein X1 is O; R1 is selected from a C1-6 alkyl group, which may be optionally substituted with one or more R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a C3-6 cycloalkyl group. More preferably, R1 is selected from a methyl group, an ethyl group, a propyl group, or a butyl group, and may be optionally substituted with one to two R6 groups; each R6 group is independently selected from a hydroxyl group, a phenyl group, or a cyclopropane group.
In one embodiment of the present application, a compound of Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; R2 is selected from phenyl, pyridyl, benzyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy, and may be optionally substituted with one or two R7 ; each R7 is independently selected from hydroxy, halogenated C1-3 alkyl, or C1-6 alkyl. More preferably, R2 is selected from phenyl, pyridyl, benzyl, propyl, butyl, ethoxy, and may be optionally substituted with one or more R7 ; each R7 is independently selected from hydroxy or trifluoromethyl.
In one embodiment of the present application, the compound represented by Formula II or a pharmaceutically acceptable salt or hydrate thereof is preferred, wherein X1 is O; n is 0 or 1; and R3 is a halogenated C1-3 alkyl group. More preferably, n is 0 or 1; and R3 is selected from trifluoromethyl.
In one embodiment of the present application, the following compounds are preferred:
and pharmaceutically acceptable salts or hydrates thereof.
Pharmaceutically acceptable salts of the compounds of Formula I or Formula II include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; and aluminum salts. Non-limiting examples of salts with organic bases include, but are not limited to, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, and dicyclohexylamine. Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The compounds of Formula I or Formula II herein may exist in unsolvated or solvated forms, including hydrates. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention. The compounds of Formula I or Formula II herein may exist in polymorphic or amorphous forms.
The compounds of Formula I or Formula II of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present application.
The diagrammatic representations of racemates, ambiscalemic and scalemic, or enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, wedge-shaped and dashed bonds are used to represent the absolute configuration of a stereocenter. When compounds of Formula I or Formula II herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers, unless otherwise indicated. Likewise, all tautomeric forms are intended to be encompassed within the scope of this application.
The compounds of Formula I or Formula II herein may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are also within the scope of this application.
Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography known to those skilled in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., carbamate formation from an amine).
The compounds of Formula I or Formula II herein may contain unnatural proportions of atomic isotopes at one or more atoms comprising the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of Formula I or Formula II herein, whether radioactive or not, are encompassed within the scope of this application.
Pharmaceutical composition
In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of the present application may further contain one or more additional therapeutic agents.
The pharmaceutical composition of the present application can be prepared by combining the compound of general formula I or general formula II of the present application or a pharmaceutically acceptable salt or hydrate thereof with a suitable pharmaceutically acceptable carrier or excipient, and can be formulated into, for example, solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
Typical routes of administration of the compounds of Formula I or Formula II of the present application, or their pharmaceutically acceptable salts or hydrates, or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
The pharmaceutical composition of the present application can be prepared by methods known to those skilled in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
For oral administration, the pharmaceutical composition can be prepared by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with pharmaceutically acceptable carriers or excipients well known to those skilled in the art. These carriers or excipients enable the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.
Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to form a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; talc, starch, magnesium stearate, calcium stearate, or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, and cross-linked polyvinyl pyrrolidone. Dragee cores may optionally be coated according to methods generally known in the pharmaceutical art, in particular with an enteric coating.
The pharmaceutical compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable formulations for parenteral administration can be prepared using suitable excipients, such as fillers, buffers or surfactants.
Medical uses
On the other hand, the present application provides a method for treating cancer induced by IDH2 mutation, which comprises administering to a subject in need thereof a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof.
On the other hand, the present application provides the use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer induced by IDH2 mutation.
On the other hand, the present application provides a compound of formula I or formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof for treating cancer induced by IDH2 mutation.
In some embodiments of the present application, the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
In some embodiments of the present application, the cancer induced by IDH2 mutation is selected from: glioblastoma (neuroglioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL). In more specific embodiments, the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL), etc., preferably including acute myeloid leukemia (AML) or sarcoma.
The compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered by any suitable route and method, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compounds of Formula I or Formula II described herein, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, can be administered to a subject in need thereof. The dosage of the compounds of Formula I or Formula II can be from about 0.0001 to 20 mg/kg body weight/day, for example, from 0.001 to 10 mg/kg body weight/day.
The frequency of administration of the compound of Formula I or Formula II herein is determined by the individual patient's needs, for example, once or twice a day, or more times a day. Administration can be intermittent, for example, wherein the patient receives a daily dose of the compound of Formula I or Formula II over a period of several days, followed by a period of several or more days in which the patient does not receive a daily dose of the compound of Formula I or Formula II.
preparation
The compounds of general formula I or general formula II of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
The chemical reactions of the specific embodiments of this application are carried out in a suitable solvent, which must be compatible with the chemical transformations and the reagents and materials required. To obtain the compounds of Formula I or Formula II of this application, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.
The compounds of the general formula II of the present application can be prepared by those skilled in the art of organic synthesis using standard methods in the art via the following routes:
Compound 1-1 undergoes acylation to obtain 1-2; 1-2 reacts with biuret to obtain 1-3; 1-3 undergoes chlorination to obtain 1-4; 1-4 undergoes amination reaction with R2- substituted ammonia to obtain 1-5; 1-5 undergoes amination reaction with R2 - X1- substituted ammonia to obtain the compound of general formula II.
Example
The following specific examples are intended to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the present invention, but rather as illustrative and representative examples thereof. Those skilled in the art will appreciate that other synthetic pathways exist for forming the compounds of the present invention, and the following examples are provided as non-limiting examples.
All operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise stated, the raw materials used in this application were purchased directly from the market and used directly without further purification.
Column chromatography used silica gel (200-300 mesh) manufactured by Qingdao Chemical Co., Ltd. Thin-layer chromatography used precast plates (Silica gel 60PF254, 0.25 mm) manufactured by E. Merck. Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H, 5 μm, 30°C). Nuclear magnetic resonance (NMR) chromatography was performed using a Varian VNMRS-400 NMR spectrometer; liquid chromatography-mass spectrometry (LC/MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX and an Agilent LC 1200 series (column: Waters Symmetry C18, 5 μm, 35°C) in ESI (+) ion mode.
Experimental part
Example 1: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
Under nitrogen, palladium acetate (74.0 mg, 0.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene (363.0 mg, 0.655 mmol), and triethylamine (0.92 g, 9.8 mmol) were added sequentially to a solution of 2-bromo-6-trifluoromethylpyridine (1.48 g, 6.55 mmol) in methanol (50.0 mL). The reaction mixture was allowed to react at 60°C under a 2 atmosphere carbon monoxide atmosphere for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to yield methyl 6-trifluoromethyl-pyridine-2-carboxylate (0.9 g, 67.0% yield).
Step 2: 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione
Under nitrogen, methyl 6-trifluoromethyl-pyridine-2-carboxylate (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol) were added sequentially to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL). The mixture was heated under reflux for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into water. The pH was adjusted to 7 with 6 mol/L hydrochloric acid. The resulting solid was filtered, the filter cake washed with water, and dried to yield 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, 47.5% yield).
Step 3: 2,4-Dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine
Under nitrogen, a mixture of 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (15.0 g, 58.1 mmol) and phosphorus oxychloride (200 mL) was reacted at 100°C for 2 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated under vacuum to yield 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (10.0 g, 58.3% yield).
Step 4: 4-Chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 2,4-dichloro-6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine (5.0 g, 16.9 mmol) in tetrahydrofuran (100 mL) were added 4-amino-2-trifluoromethylpyridine (3.3 g, 20.3 mmol) and sodium bicarbonate (2.14 g, 25.3 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine (6.5 g, 91.2% yield).
Step 5: 4-(Ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
To a solution of 4-chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (50.0 mg) in tetrahydrofuran (20 mL) were added ethoxylamine hydrochloride (12.0 mg, 0.18 mmol) and sodium bicarbonate (40.0 mg, 0.48 mmol). The mixture was reacted at 70°C for 8 hours and then cooled to room temperature. The reaction solution was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography to yield 4-(ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (40.0 mg). 1 H-NMR (400MHz, CDCl 3 ): δ = 8.66-8.58 (m, 2H), 8.49 (s, 1H), 8.32(s,1H),8.10(t,J＝7.9Hz,1H),7.94(s,1H),7.88(d,J＝7.8Hz,1H),7.62(d,J＝3.7Hz,1H), 4.19(q,J＝7.0Hz,2H),1.41(t,J＝7.1Hz,3H).
Example 2: 4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.35 (s, 1H), 10.85 (s, 1H), 8.66 (s, 1H), 8.56 (d, J = 5.6 Hz, 2H), 8.32 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 4.28-4.06 (m, 1H), 1.23 (d, J = 14.5 Hz, 6H).
Example 3: 4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine-2-amine
4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.00 (s, 1H), 10.84 (s, 1H), 8.74 (s, 1H), 8.57 (t, J = 6.5 Hz, 2H), 8.31 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 1.28 (s, 9H).
Example 4: 4-((Cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-((cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-
(2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.4 (s, 1H), 10.9 (s, 1H), 8.61 (s, 1H), 8.57 (d, J=5.6 Hz, 2H), 8.32 (t, J=7.9 Hz, 1H), 8.17-8.09 (m, 2H), 3.77 (d, J=7.1 Hz, 2H), 3.15 (d, J=5.2 Hz, 1H), 0.87-0.76 (m, 2H), 0.57-0.47 (m, 2H).
Example 5: N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino)
N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl)bis(O-ethoxyamino) was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.96 (s, 2H), 8.48 (d, J=7.8 Hz, 1H), 8.24 (t, J=7.9 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 3.90 (q, J=7.0 Hz, 4H), 1.30-1.06 (m, 6H).
Example 6: 2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol
2-Methyl-1-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, CDCl 3 ): δ=8.59 (dd, J=10.7, 6.7 Hz, 2H), 8.29 (s, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 4.00 (s, 2H), 1.62 (s, 1H), 1.32 (s, 6H).
Example 7: 2-Methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol
Referring to the synthetic method of Example 1, 2-methyl-2-(((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)oxy)propan-1-ol was prepared. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.80 (s, 1H), 8.54 (d, J=5.8 Hz, 1H), 8.29 (t, J=7.9 Hz, 3H), 8.08 (m, 2H), 5.38 (s, 1H), 4.56 (s, 1H), 3.54-3.39 (m, 2H), 1.27-1.10 (m, 6H).
Example 8: 4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=11.52 (s, 1H), 10.91 (s, 1H), 8.60 (s, 2H), 8.56 (d, J=5.4 Hz, 1H), 8.36 (t, J=7.9 Hz, 1H), 8.15 (d, J=7.7 Hz, 2H), 7.52 (s, 2H), 7.47-7.35 (m, 3H), 5.04 (s, 2H).
Example 9: 4-(2-methylhydrazine)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(2-methylhydrazinyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.76 (s, 1H), 8.67 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.30 (t, J=7.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.93 (s, 1H), 5.39 (s, 1H), 5.21 (s, 1H), 3.40 (s, 3H).
Example 10: 4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-6-phenyl-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.59 (d, 2H), 8.59 (m, 1H), 8.55 (m, 1H), 8.32 (m, 2H), 8.00 (m, 1H), 7.56 (m, 3H), 1.41-0.95 (m, 9H).
Example 11: 1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol
1-((4-(tert-Butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-yl)amino)-2-methylpropan-2-ol was prepared by referring to the synthesis method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.29 (d, 2H), 8.53 (d, J=7.9 Hz, 1H), 8.28 (t, J=7.9 Hz, 1H), 8.13-8.03 (m, 1H), 4.86 (s, 1H), 3.39 (m, 2H), 1.27 (m, 9H), 1.07 (m, 6H).
Example 12: 4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
4-(tert-Butoxyamino)-N-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1H), 10.12 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.31 (t, J = 7.8 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.99 (m, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 1.29 (s, 9H).
Example 13: N-Benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
N-benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine was prepared by referring to the synthetic method of Example 1. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.26 (s, 2H), 8.50 (dd, J = 13.2, 5.0 Hz, 2H), 8.33 - 8.18 (m, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.0 Hz, 1H), 7.31 (dd, J = 10.1, 4.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 1.18 (s, 9H).
Example 14: 4-(tert-Butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazin-2-amine
Referring to the synthesis method of Example 1, 4-(tert-butoxyamino)-N-isopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-
1,3,5-Triazine-2-amine. 1 H-NMR (400 MHz, DMSO-d 6 ): δ=10.16 (s, 2H), 8.49 (d, J=8.1 Hz, 1H), 8.04 (d, J=7.4 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 4.16 (m, 1H), 1.24 (m, 9H), 1.18 (m, 6H).
Experimental Example 1: Determination of IDH2 inhibitory activity
The present application adopts the following method to determine the inhibitory activity of the compounds of the present application on IDH2 (R172K, 40-end). The inhibitory activity is represented by the indicator IC50 , which is the concentration of the compound when the activity of IDH2 is inhibited by 50%.
Materials and methods:
The inhibitory activity of the compounds against IDH2 (R172K, 40-end) was determined by depletion of the cofactor NADPH. The compounds were pre-incubated with the enzyme and NADPH, and the reaction was initiated by the addition of α-KG and allowed to react for 120 minutes under linear conditions. The reaction was then terminated by the addition of diaphorase (lipoamide dehydrogenase) and the corresponding substrate, resazurin (resazurin). Lipoamide dehydrogenase terminates the IDH2m reaction by depleting the available cofactor NADPH, oxidizing NADPH to NADP and reducing resazurin to the highly fluorescent resorufin. The amount of cofactor NADPH remaining after a specific reaction time was quantified using an easily detectable fluorescent group.
Specifically, 2.5 μl of a 3x serial dilution of the compound was added to a 384-well plate, followed by 5 μl of reaction buffer (20 mM Tris-HCl, pH 7.5; 150 mM NaCl; 10 mM MgCl2; 10 mM MnCl2; 0.4 mg/ml BSA; and 2 mM DTT) containing 80 nM IDH2 (R172K, 40-end) and 40 μM NADPH. The assay mixture was then incubated at 23°C for 120 minutes, after which the reaction was initiated by the addition of 2.5 μl of reaction buffer containing 4 mM α-KG. After incubation at room temperature for 120 minutes, 5 μl of a stop mix (0.4 U/ml diaphorase and 40 μM resazurin) prepared in reaction buffer was added to convert resazurin to resorufin, allowing measurement of residual NADPH. After incubation at 23°C for 10 minutes, fluorescence was measured using a Flexstation 3 using Ex535/Em595.
The IDH2 inhibitory activities of the example compounds are shown in Table 1:
Table 1
| Example No. | |
| 1 | 22.40 |
| 2 | 28.79 |
| 3 | 31.69 |
| 4 | 38.19 |
| 6 | 46.85 |
| 7 | 153.6 |
| 8 | 239.3 |
| 10 | 51.42 |
Experimental Example 2: Determination of pharmacokinetic parameters
The present application uses the following methods to determine the pharmacokinetic parameters of the compounds of the present application:
The study used healthy male adult rats aged 7-9 weeks. Each group of animals (3 male rats) received a single oral administration of 5 mg/kg. The animals in the oral administration group fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration.
Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After isoflurane anesthesia using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the retinal venous plexus and placed in a heparinized tube. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis.
Plasma sample analysis was performed using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS). Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight) software. A non-compartmental model was used for concentration analysis, and the pharmacokinetic parameters of the compounds were calculated, as shown in Table 2. The compound of Example 3 has a good in vivo metabolism level and a long half-life, and at the same dose, its blood concentration is higher than that of the IDH2 inhibitor AG-221.
Table 2
| Example | 3 | AG-221 |
| Dosage (mg/kg) | 5 | 5 |
| 12.0 | 3.73 | |
| 5.0 | 4.00 | |
| 589 | 479 | |
| 10838 | 5385 |
Claims (13)
1. A compound of general formula II or a pharmaceutically acceptable salt thereof.
in,
X 1 is selected from O;
X 2 is selected from N;
R1 is selected from C1-6 alkyl groups, wherein the alkyl group may optionally be substituted by one or more R6 groups;
R2 is selected from pyridinyl and may optionally be substituted by one or more R7 ;
Each R3 is independently selected from a halogenated C1-3 alkyl group;
Each R6 is independently selected from hydroxyl, C3-6 cycloalkyl, or phenyl;
Each R 7 is independently selected from halogenated C1-3 alkyl groups; and
n is 1.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is O; R1 is selected from methyl, ethyl, propyl or butyl and may optionally be substituted by 1-2 R6 ; and each R6 is independently selected from hydroxy, phenyl or cyclopropane.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is O; R2 is selected from pyridyl and may optionally be substituted by one or two R7s ; and each R7 is independently selected from a halogenated C1-3 alkyl group.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is O; R2 is selected from pyridyl and may optionally be substituted by one or more R7 ; and each R7 is independently selected from trifluoromethyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is 0; n is 1, and R3 is selected from trifluoromethyl.
6. The following compounds or their pharmaceutically acceptable salts.
7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating cancer induced by IDH2 mutation.
9. The use according to claim 8, wherein the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
10. The use according to claim 8 or 9, wherein the cancer induced by the IDH2 mutation is selected from: glioblastoma, myelodysplastic syndrome, bone marrow proliferative vegetation, acute myeloid leukemia, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic non-Hodgkin's lymphoma.
11. A compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 7, for the treatment of cancer induced by IDH2 mutation.
12. The compound of claim 11 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
13. The compound of claim 11 or 12 or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the cancer induced by the IDH2 mutation is selected from: glioblastoma, myelodysplastic syndrome, myeloid hyperplasia, acute myeloid leukemia, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma or angioimmunoblastic non-Hodgkin's lymphoma.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510459126 | 2015-07-30 | ||
| CN201510459126.X | 2015-07-30 | ||
| PCT/CN2016/092254 WO2017016513A1 (en) | 2015-07-30 | 2016-07-29 | 1, 3, 5-triazine derivative and method of using same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1246292A1 HK1246292A1 (en) | 2018-09-07 |
| HK1246292B true HK1246292B (en) | 2022-03-11 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107922358B (en) | 1,3,5-triazine derivatives and methods of using the same | |
| US8575221B2 (en) | Derivatives of dimethylcurcumin | |
| WO2023232069A1 (en) | Azaquinolinone derivative, preparation method therefor and use thereof | |
| US20170273961A1 (en) | Novel iminonitrile derivatives | |
| JP2026027279A (en) | Thyroid hormone receptor beta agonist compounds | |
| TW201443001A (en) | Bicyclic analgesic compound | |
| KR20220066290A (en) | PERK inhibitory pyrrolopyrimidine compounds | |
| US20220098152A1 (en) | Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide | |
| CN107922375B (en) | Antitumor compounds targeting IDH2 mutations and methods of use | |
| JPWO2009041559A1 (en) | Indazole acrylic acid amide compound | |
| CN111925368A (en) | Pyrimidone derivatives, preparation method thereof and application thereof in resisting mycobacterium tuberculosis infection | |
| WO2022002100A1 (en) | Novel benzimidazole compound | |
| TW202446392A (en) | Pharmaceutical compositions of pyridopyrazole derivatives and their application in medicine | |
| EP4501926A1 (en) | N-substituted quinolinone compound, preparation method therefor and use thereof | |
| WO2022228509A1 (en) | Pyrrolopyrimidine derivative, preparation method therefor and use thereof | |
| US20210122714A1 (en) | Crystal forms of oxypyridine amide derivative and preparation method therefor | |
| HK40019697A (en) | Novel benzimidazolone compound and pharmaceutical use thereof |