WO2017016513A1 - 1,3,5-三嗪衍生物及其使用方法 - Google Patents

1,3,5-三嗪衍生物及其使用方法 Download PDF

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Publication number
WO2017016513A1
WO2017016513A1 PCT/CN2016/092254 CN2016092254W WO2017016513A1 WO 2017016513 A1 WO2017016513 A1 WO 2017016513A1 CN 2016092254 W CN2016092254 W CN 2016092254W WO 2017016513 A1 WO2017016513 A1 WO 2017016513A1
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Prior art keywords
alkyl
cycloalkyl
group
pharmaceutically acceptable
compound
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PCT/CN2016/092254
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English (en)
French (fr)
Inventor
赵娜
王树龙
刘希杰
胡远东
张慧
罗鸿
彭勇
韩永信
张喜全
徐宏江
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
北京赛林泰医药技术有限公司
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Priority to CA2993687A priority Critical patent/CA2993687C/en
Priority to KR1020187005756A priority patent/KR102303011B1/ko
Priority to AU2016299092A priority patent/AU2016299092B2/en
Priority to JP2018504253A priority patent/JP6786086B2/ja
Priority to CN201680043893.5A priority patent/CN107922358B/zh
Priority to RU2018105614A priority patent/RU2724333C2/ru
Priority to ES16829878T priority patent/ES2881695T3/es
Priority to DK16829878.4T priority patent/DK3330258T3/da
Application filed by 正大天晴药业集团股份有限公司, 连云港润众制药有限公司, 北京赛林泰医药技术有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to BR112018001780-9A priority patent/BR112018001780B1/pt
Priority to EP16829878.4A priority patent/EP3330258B1/en
Priority to US15/748,795 priority patent/US10745383B2/en
Publication of WO2017016513A1 publication Critical patent/WO2017016513A1/zh
Priority to ZA2018/01301A priority patent/ZA201801301B/en
Priority to HK18105822.3A priority patent/HK1246292A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to the field of medicine, and more particularly to 1,3,5-triazine derivatives and methods of use thereof.
  • IDH the full name of isocitrate dehydrogenase, is the most important key enzyme in the intracellular tricarboxylic acid cycle. It can catalyze the oxidative decarboxylation of isocitrate to form 2-oxoglutarate (ie, a-ketoglutaric acid).
  • IDH mutations in various tumors (such as glioma, sarcoma, acute myeloid leukemia, etc.), and the mutation site is the arginine residue located in the catalytic center (IDH1/R132H, IDH2/R140Q, IDH2/R172K).
  • the mutated IDH acquires a new ability to catalyze the conversion of a-ketoglutarate (a-KG) to 2-hydroxyglutaric acid (2-HG).
  • a-ketoglutaric acid is similar in structure to 2-hydroxyglutaric acid, and 2-HG competes with a-KG, thereby reducing the activity of a-KG-dependent enzymes, resulting in hypermethylation of chromatin. This hypermethylation is thought to interfere with normal cell differentiation, leading to excessive proliferation of immature cells, leading to cancer.
  • AGI-6780 (Science. 2013, 340, 622-626) and the IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630), and WO2015017821 disclose another IDH2. /R140Q inhibitor AG-221.
  • AGI-6780 and AGI-5198 are capable of inhibiting the production of 2-HG in cells carrying the most common IDH2 and IDH1 mutants, respectively. In addition to inhibiting 2-HG production, these molecules also induce differentiation of abnormally proliferating human cancer cells in culture.
  • AGI-5198 inhibited the growth rate of glioma cells whether it was treated with AGI-5198 or a tumor-transplanted mouse.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl 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 alkyl, alkenyl, alkynyl or cycloalkyl is available The ground is replaced by 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 a 3-6 cycloalkyl group, and may be optionally substituted with one or more R 7 ;
  • Each R 3 is independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • R 4 and R 5 are independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl;
  • Each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or containing 1-2 selected from N, a 5-6 membered heteroaryl of a hetero atom of O or S, and said phenyl or heteroaryl group may be optionally substituted by one or more R 8 ;
  • Each R 7 and each R 8 are each independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • n 0, 1, 2 or 3.
  • the application provides a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof:
  • X 1 is selected from NH or O
  • X 2 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 alkyl, alkenyl, alkynyl or cycloalkyl is available The ground is replaced by 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 by one or more R 7 ;
  • Each R 3 is independently selected from halogen, hydroxy, amino, halo 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 contains from 1 to 2 heteroatoms selected from N, O or S. a 5-6 membered heteroaryl group, and the phenyl or heteroaryl group can be optionally substituted with one or more R 8 ;
  • Each R 7 and each R 8 are each independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • n 0, 1, 2 or 3.
  • the application provides a pharmaceutical composition
  • 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 an excipient.
  • the application provides a method of treating cancer induced by an IDH2 mutation, the method comprising administering a compound of formula I or a compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a medicament thereof, to a subject in need thereof combination.
  • the 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, for the manufacture of a medicament for the treatment of a cancer induced by an IDH2 mutation.
  • the application provides a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, for use in treating a cancer induced by an IDH2 mutation.
  • the IDH2 mutation is an IDH2/R140Q mutation or an IDH2/R172K mutation.
  • references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). 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 to exist and/or which cannot be synthesized is introduced.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • C 0-6 alkylene group means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same, and the hetero atom is independently selected from the group consisting of oxygen, nitrogen, sulfur, Phosphorus, silicon, germanium, aluminum, boron.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • halogen refers to any group of fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • amino refers to -NH 2 , -NH(alkyl) and -N(alkyl) 2 , and specific examples of the amino group include, but are not limited to, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , - N(CH 3 ) 2 , -NHC 2 H 5 , -N(CH 3 )C 2 H 5 and the like.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C 1-8 alkyl refers to an alkyl group having from 1 to 8 carbon atoms.
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having from 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 one Or a plurality of substituents selected from a hydroxyl group, a halogen or an amino group.
  • alkenyl refers to a straight or branched aliphatic hydrocarbon group containing from 2 to 12 carbon atoms and having one or more double bonds.
  • 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 attachment point of an alkenyl substituent.
  • alkynyl refers to a straight or branched aliphatic hydrocarbon group containing from 2 to 12 carbon atoms and having one or more triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
  • One of the triple bond carbons may optionally be the attachment point of an alkynyl substituent.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, such as a cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the cycloalkyl group may be unsubstituted or substituted, and the substituent includes, but is not limited to, an alkyl group, an alkyloxy group, a cyano group, a carboxyl group, an aryl group, a heteroaryl group, an amino group, a halogen, a sulfonyl group. , sulfinyl group, phosphoryl group, hydroxyl group and the like.
  • alkoxy refers to an -O-alkyl group.
  • heteromatic ring refers to a monocyclic or fused ring having 5 to 12 ring atoms, for example 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, in which 1, 2, 3 are contained. Or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated ⁇ -electron system.
  • heteroaryl refers to a group remaining after the "heteroaryl ring" molecule has one hydrogen atom removed, and the heteroaryl group may be unsubstituted or substituted, including but not limited to alkyl, alkyl. Oxyl, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic groups, and the like.
  • Non-limiting examples of non-substituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazole Base, thiadiazolyl, fluorenyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl , quinolyl, isoquinolyl, triazolyl, tetrazolyl, triazinyl, acridinyl and the like.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, includes, but is not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of the carrier include carbon Calcium acid, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil and polyethylene glycol.
  • the carrier include carbon Calcium acid, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil and polyethylene glycol.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a pharmaceutical composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also on the particular active substance, and a suitable effective amount in a case can be determined by a person skilled in the art according to routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • patient or “individual” includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
  • mammals eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl 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 alkyl, alkenyl, alkynyl or cycloalkyl is available The ground is replaced by 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 a 3-6 cycloalkyl group, and may be optionally substituted with one or more R 7 ;
  • Each R 3 is independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • R 4 and R 5 are independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl;
  • Each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or containing 1-2 selected from N, a 5-6 membered heteroaryl of a hetero atom of O or S, and said phenyl or heteroaryl group may be optionally substituted by one or more R 8 ;
  • Each R 7 and each R 8 are each independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • n 0, 1, 2 or 3.
  • X 1 is selected from NH or O
  • X 2 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 alkyl, alkenyl, alkynyl or cycloalkyl is available The ground is replaced by 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 by one or more R 7 ;
  • Each R 3 is independently selected from halogen, hydroxy, amino, halo 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 contains from 1 to 2 heteroatoms selected from N, O or S. a 5-6 membered heteroaryl group, and the phenyl or heteroaryl group can be optionally substituted with one or more R 8 ;
  • Each R 7 and each R 8 are each independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • n 0, 1, 2 or 3.
  • a compound of Formula II or a pharmaceutically acceptable salt or hydrate thereof, is preferred, wherein
  • X 1 is selected from O;
  • X 2 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 alkyl, alkenyl, alkynyl or cycloalkyl is available The ground is replaced by 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 by one or more R 7 ;
  • Each R 3 is independently selected from halogen, hydroxy, amino, halo 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 contains from 1 to 2 heteroatoms selected from N, O or S. a 5-6 membered heteroaryl group, and the phenyl or heteroaryl group can be optionally substituted with one or more R 8 ;
  • Each R 7 and each R 8 are each independently selected from halogen, hydroxy, amino, halo C 1-3 alkyl, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;
  • n 0, 1 or 2.
  • a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof wherein X 1 is O; R 1 is selected from C 1-6 alkyl, which may be optionally One or more R 6 are substituted; each R 6 is independently selected from hydroxy, phenyl or C 3-6 cycloalkyl. More preferably, R 1 is selected from methyl, ethyl, propyl or butyl and may be optionally substituted by from 1 to 2 R 6 ; each R 6 is independently selected from hydroxy, phenyl or cyclopropyl .
  • R 2 is selected from the group consisting of phenyl, pyridyl, benzyl, propyl, butyl, ethoxy, and may be optionally substituted by one or more R 7 ; each R 7 is independently selected from hydroxy Or trifluoromethyl.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, or the like may be mentioned.
  • alkaline or A salt formed by an acidic amino acid or the like include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting a compound of the free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of formula I or formula II of the present application may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present application.
  • the compounds of formula I or formula II of the present application may exist in polymorph or amorphous form.
  • 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 included within the scope of this application.
  • the compounds of formula I or formula II of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the application. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are also included within the scope of the present application.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide purity. The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then known to those skilled in the art.
  • the diastereomeric resolution is carried out by fractional crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of Formula I or Formula II of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositions of the compounds of Formula I or Formula II of the present application, whether radioactive or not, are included within the scope of this application.
  • the application provides a pharmaceutical composition
  • 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 compositions of the present application may further comprise one or more additional therapeutic agents.
  • compositions of the present application can be prepared by combining a compound of Formula I or Formula II of the present application, or a pharmaceutically acceptable salt or hydrate thereof, with a suitable pharmaceutically acceptable carrier or excipient, for example, Can be formulated into 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, etc.
  • Typical routes of administration of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, of the present application include, but are not limited to, oral, rectal, transmucosal, enteral, Or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • compositions of the present application can be prepared by methods known to those skilled in the art, such as conventional mixing Legal, dissolution method, granulation method, sugar coating pill method, grinding method, emulsification method, freeze drying method, and the like.
  • the compound can be formulated by mixing a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or hydrate thereof, with a pharmaceutically acceptable carrier or excipient well known to those skilled in the art. combination.
  • a pharmaceutically acceptable carrier or excipient well known to those skilled in the art. combination.
  • These carriers or excipients enable the compound of Formula I or Formula II of the present application, or a pharmaceutically acceptable salt or hydrate thereof, to be formulated into tablets, pills, troches, dragees, capsules, liquids, condensates Glue, serum, suspension, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the compound of the formula I or formula II or a pharmaceutically acceptable salt or hydrate thereof with a solid excipient, optionally milling the resulting mixture, if If necessary, other suitable excipients are added and the mixture is processed into granules to give the core of the tablet or dragee.
  • suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone.
  • the core of the dragee can optionally be coated according to methods generally known in the pharmaceutical arts, especially enteric coatings.
  • compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • parenteral administration such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • Dosage forms suitable for parenteral administration can be prepared using suitable excipients such as fillers, buffers or surfactants.
  • the application provides a method of treating cancer induced by an IDH2 mutation, the method comprising administering a compound of formula I or a compound of formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a medicament thereof, to a subject in need thereof combination.
  • the 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, for the manufacture of a medicament for the treatment of a cancer induced by an IDH2 mutation.
  • the application provides a compound of Formula I or a compound of Formula II, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition thereof, for use in treating a cancer induced by an IDH2 mutation.
  • the IDH2 mutation is an IDH2/R140Q mutation or IDH2/R172K mutation.
  • the cancer induced by the IDH2 mutation is selected from the group consisting of: glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN) ), acute myeloid leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or vascular immunoblastic non-Hodgkin's lymphoma (NHL).
  • glioblastoma glioma
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • sarcoma melanoma
  • non-small cell lung cancer chondrosarcoma
  • cholangiocarcinoma cholangiocarcinoma
  • NHL vascular immunoblastic non-Hodgkin's lymphoma
  • the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN), acute myeloid leukemia (AML), melanoma, chondrosarcoma Or angioimmunoblastic non-Hodgkin's lymphoma (NHL) or the like, preferably including acute myeloid leukemia (AML) or sarcoma.
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • melanoma chondrosarcoma
  • chondrosarcoma angioimmunoblastic non-Hodgkin's lymphoma
  • AML acute myeloid leukemia
  • sarcoma preferably including acute myeloid leukemia (AML) or sarcoma.
  • the compound of Formula I or Formula II described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be administered by any suitable route and method, for example by oral or parenteral (eg, intravenous) Dosing.
  • a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, is administered to a subject in need thereof in a therapeutically effective amount.
  • the compound of Formula I or Formula II can be administered at a dose of from about 0.0001 to 20 mg/kg body weight per day, such as from 0.001 to 10 mg/kg body weight per day.
  • the frequency of administration of the compound of Formula I or Formula II of the present application is determined by the needs of the individual patient, for example, once or twice daily, or more times per day. Administration can be intermittent, for example, wherein during a period of several days, the patient receives a daily dose of a compound of Formula I or Formula II, followed by a patient for a period of several days or more. Or a daily dose of a compound of formula II.
  • the compounds of Formula I or 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 set forth below, combinations thereof with other chemical synthesis methods, and Equivalent alternatives well known to those skilled in the art, including, but not limited to, the embodiments of the present application.
  • Compound 1-1 is acylated to give 1-2; 1-2 is reacted with biuret to give 1-3; 1-3 is chlorinated to give 1-4; 1-4 and R 2 substituted by ammonia The amination reaction occurs to give 1-5; 1-5 is aminated with an amine substituted with an R 2 -X 1 group to give a compound of the formula II.
  • Nuclear magnetic resonance chromatography was measured using a Varian VNMR S-400 nuclear magnetic resonance spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18, Mm, 5 microns, 35 ° C), using ESI (+) ion mode.
  • Example 1 4-(ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1 ,3,5-triazin-2-amine
  • Methyl 6-trifluoromethyl-pyridine-2-carboxylate (10.0 g, 48.7 mmol) and biuret (4.2) were added sequentially to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL). g, 40.7 mmol). The mixture was heated to reflux for 2 hours and then cooled to room temperature.
  • reaction solution was concentrated under reduced pressure in vacuo, and the residue was poured into water, and the pH was adjusted to 7 with 6 mol/L hydrochloric acid solution, and the obtained solid was filtered, and the filter cake was washed with water and dried to give 6-(6-trifluoromethylpyridine- 2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, yield 47.5%).
  • Step 4 4-Chloro-6-(6-trifluoromethylpyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1,3,5-triazine- 2-amine
  • Step 4 4-(ethoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1, 3,5-triazin-2-amine
  • Example 2 4-(Isopropylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1 ,3,5-triazin-2-amine
  • Example 4 4-((Cyclopropylmethoxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4 -yl)-1,3,5-triazin-2-amine
  • N,N'-(6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-diyl) was obtained.
  • Example 8 4-((Benzyloxy)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazin-2-amine
  • Example 9 4-(2-methylindolyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl) -1,3,5-triazin-2-amine
  • N-benzyl-4-(tert-butoxyamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-1,3,5-triazine was obtained.
  • This application is determined by the following method of application of the compounds of the present IDH2 (R172K, 40-end) inhibitory activity, the inhibitory activity of IC 50 uses the indicators to represent, 50% of the active compound IC 50 is suppressed i.e. IDH2 concentration.
  • the inhibitory activity of the compound on IDH2 was determined by subtraction of the cofactor NADPH.
  • the compound was pre-incubated with the enzyme and NADPH, then the reaction was initiated by the addition of a-KG and reacted under linear conditions for 120 minutes.
  • the reaction was then terminated by the addition of Diaphorase (lipoamide dehydrogenase) and the corresponding substrate Resazurin (Resazurin).
  • Diaphorase lipoamide dehydrogenase
  • Resazurin Resazurin
  • the lipoamide dehydrogenase terminates the IDH2m reaction by attenuating the available cofactor NADPH, which oxidizes NADPH to NADP and reduces resazurin to a highly fluorescent resorufin, quantified by readily detectable fluorophores.
  • the amount of cofactor NADPH remaining after a specific reaction time was determined by subtraction of the cofactor NADPH.
  • reaction buffer (20 mM Tris-HCl, pH 7.5; containing 80 nM IDH2 (R172K, 40-end) and 40 ⁇ M NADPH; 150 mM NaCl; 10 mM MgCl2; 10 mM MnCl2; 0.4 mg/ml BSA and 2 mM DTT).
  • the test mixture was then incubated at 23 ° C for 120 minutes, after which 2.5 ⁇ l of reaction buffer containing 4 mM a-KG was added to initiate the reaction.
  • the IDH2 inhibitory activity of the example compounds is shown in Table 1:
  • the present application employs the following method to determine the pharmacokinetic parameters of the compounds of the present application:
  • the dose was 5 mg/kg, and the animals in the gavage administration group were fasted overnight before the experiment, and the fasting time 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 anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube. The sample was centrifuged at 4 ° C, 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in a -80 °C is saved until analysis.
  • Plasma sample analysis was performed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Plasma concentration-time data for individual animals were analyzed using WinNonlin (Professional Edition, Version 6.3; Pharsight) software, non-room The chamber model was used for concentration analysis to calculate the pharmacokinetic parameters of the compounds, as shown in Table 2: The compound of Example 3 has better in vivo metabolic levels and longer half-lives, and at the same dose, its blood concentration Higher than the IDH2 inhibitor AG-221.

Abstract

一种通式I和通式II的化合物或其药学上可接受的盐或水合物、其制备方法及其药物组合物。所述通式I和通式II的化合物具有异柠檬酸脱氢酶2（IDH2）抑制活性，能治疗IDH2突变诱发的癌症。

Description

1,3,5-三嗪衍生物及其使用方法
相关申请的引用
本申请要求于2015年07月30日向中华人民共和国国家知识产权局提交的第201510459126.X号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及医药领域，更具体而言涉及1,3,5-三嗪衍生物及其使用方法。
背景技术
IDH全称异柠檬酸脱氢酶，是细胞内三羧酸循环过程中最主要的关键酶，它们能够催化异柠檬酸氧化脱羧生成2-氧化戊二酸酯(即，a-酮戊二酸)。研究发现多种肿瘤(如神经胶质瘤、肉瘤、急性粒细胞白血病等)存在IDH突变，突变位点是位于催化中心的精氨酸残基(IDH1/R132H、IDH2/R140Q、IDH2/R172K)。突变后的IDH获得一种新的能力，即催化a-酮戊二酸(a-KG)转化为2-羟基戊二酸(2-HG)。研究表明，a-酮戊二酸与2-羟基戊二酸的结构相似，2-HG与a-KG竞争，由此降低了a-KG依赖性酶的活性，导致染色质高度甲基化，这种超甲基化被认为干扰了正常的细胞分化，导致未成熟细胞过度增殖，从而引发癌症。
2013年Agios Pharmaceuticals报道了IDH2/R140Q抑制剂AGI-6780(Science.2013,340,622-626)和IDH1/R132H抑制剂AGI-5198(Science.2013,340,626-630)，以及WO2015017821公开了另一种IDH2/R140Q抑制剂AG-221。AGI-6780和AGI-5198能够分别抑制携带最常见IDH2和IDH1突变体的细胞中2-HG的生成。除能抑制2-HG生成，这些分子还诱导了培养物中异常增殖的人类癌细胞的分化。用AGI-6780治疗携带IDH2突变体的白血病细胞，用AGI-5198治疗携带IDH1突变体的神经胶质瘤细胞，均导致细胞中的成熟标记物表达增高。此外，研究人员证实不论是用AGI-5198处理细胞培养物，还是口服给药肿瘤移植小鼠，AGI-5198均可抑制神经胶质瘤细胞生长速率。
发明内容
一方面，本申请提供通式Ⅰ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092254-appb-000001
其中，
环A选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环；
X1选自NH或O；
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
R2选自苯基、含有1-2个选自N、O或S的杂原子的5-6元杂芳基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
R4和R5独立地选自H、C1-6烷基或C3-6环烷基；
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
n为0，1，2或3。
另一方面，本申请提供通式Ⅱ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092254-appb-000002
其中，
X1选自NH或O；
X2选自N或CH；
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
每个R6独立地选自卤素、羟基、氨基、CF3、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
n为0，1，2或3。
另一方面，本申请提供了药物组合物，其包含治疗有效量的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。
另一方面，本申请提供了治疗由IDH2突变诱发的癌症的方法，所述方法包括给予有需要的个体通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
另一方面，本申请提供了通式Ⅰ或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
另一方面，本申请提供了用于治疗由IDH2突变诱发的癌症的通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
在本申请的一些实施方案中，所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
发明详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节， 而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在整个说明书和其后的权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
定义
除非另有说明，本文所用的下列术语和短语具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而是应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文所用的Cm-n指该部分中具有m-n个碳原子。例如，“C3-10环烷基”指该环烷基具有3-10个碳原子。“C0-6亚烷基”指该亚烷基具有0-6个碳原子，当亚烷基具有0个碳原子时，该基团为键。
本文中的数字范围是指给定范围中的各个整数。例如“C1-10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代，酮取代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，即碳和氢以外的原子或含有这些原子的原子团，杂原子独立地选自氧、氮、硫、磷、硅、锗、铝、硼。在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的部分或全部彼此不同。
术语“卤素”或“卤代”是指氟、氯、溴或碘的任何基团。
术语“羟基”指-OH。
术语“氰基”指-CN。
术语“氨基”是指-NH2、-NH(烷基)和-N(烷基)2，氨基的具体例子包括但不限于-NH2、-NHCH3、-NHCH(CH3)2、-N(CH3)2、-NHC2H5、-N(CH3)C2H5等。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和脂肪烃基团，例如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基等。所述特定烷基包括其所有同分异构体形式，例如丙基包括-CH2CH2CH3、-CH(CH3)2，例如丁基包括-CH2CH2CH2CH3、-CH(CH3)(CH2CH3)、-C(CH3)3、-CH2CH(CH3)2。术语“C1-8烷基”指具有1-8个碳原子的烷基。术语“C1-6烷基”指具有1-6个碳原子的烷基。术语“C1-4烷基”指具有1-4个碳原子的烷基。术语“C1-3烷基”指具有1-3个碳原子的烷基。所述“烷基”、“C1-8烷基”、“C1-6烷基”、“C1-4烷基”或“C1-3烷基”可以是非取代的或是被一个或多个选自羟基、卤素或氨基的取代基取代。
术语“烯基”是指含有2至12个碳原子并且具有一个或多个双键的直链或支链的脂肪烃基。烯基的实例包括但不限于乙烯基、烯丙基、丙烯基、2-丁烯基以及 3-己烯基。双键碳之一可任选地为烯基取代基的附接点。
术语“炔基”是指含有2至12个碳原子并且具有一个或多个三键的直链或支链的脂肪烃基。炔基的实例包括但不限于乙炔基、炔丙基以及3-己炔基。三键碳之一可任选地为炔基取代基的附接点。
术语“环烷基”是指仅由碳原子和氢原子组成的单环的饱和的脂肪烃基团，如C3-20环烷基，优选为C3-6环烷基，例如环丙基、环丁基、环戊基、环己基等。所述环烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基等。
术语“烷氧基”是指-O-烷基基团。
术语“杂芳环”是指具有5-12个环原子的单环或稠合环，例如5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。
术语“杂芳基”是指“杂芳环”分子去掉1个氢原子后余下的基团，杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基等。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噻二唑基、吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并咪唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、喹啉基、异喹啉基、三唑基、四唑基、三嗪基、喋啶基等。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成分一同给药的、有利于活性成分给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳 酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要的载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本申请中的口服剂型，药物组合物中的一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“患者”或“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
通式化合物
一方面，本申请提供通式Ⅰ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092254-appb-000003
其中，
环A选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环；
X1选自NH或O；
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
R2选自苯基、含有1-2个选自N、O或S的杂原子的5-6元杂芳基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
R4和R5独立地选自H、C1-6烷基或C3-6环烷基；
每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
n为0，1，2或3。
在本申请的一个实施方案中，提供通式Ⅱ的化合物或其药学上可接受的盐或水合物：
Figure PCTCN2016092254-appb-000004
其中，
X1选自NH或O；
X2选自N或CH；
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
每个R6独立地选自卤素、羟基、氨基、CF3、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可 任选地被一个或多个R8取代；
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
n为0，1，2或3。
在本申请的一个实施方案中，优选通式Ⅱ的化合物或其药学上可接受的盐或水合物，其中
X1选自O；
X2选自N或CH；
R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并且可任选地被一个或多个R7取代；
每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
每个R6独立地选自卤素、羟基、氨基、CF3、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
n为0，1或2。
在本申请的一个实施方案中，优选通式Ⅱ的化合物或其药学上可接受的盐或水合物，其中X1为O；R1选自C1-6烷基，其可任选地被一个或多个R6取代；每个R6独立地选自羟基、苯基或C3-6环烷基。更优选地，R1选自甲基、乙基、丙基或丁基，并可任选地被1-2个R6取代；每个R6独立地选自羟基、苯基或环丙烷基。
在本申请的一个实施方案中，优选通式Ⅱ的化合物或其药学上可接受的盐或水合物，其中X1为O；R2选自苯基、吡啶基、苄基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基，并可任选地被1个或2个R7取代；每个R7独立地选自羟基、卤代C1-3烷基或C1-6烷基。更优选地，R2选自苯基、吡啶基、苄基、丙基、丁基、乙氧基，并可任选地被一个或多个R7取代；每个R7独立地 选自羟基或三氟甲基。
在本申请的一个实施方案中，优选通式Ⅱ所示的化合物或其药学上可接受的盐或水合物，其中X1为O；n为0或1；R3为卤代C1-3烷基。更优选地，n为0或1；R3选自三氟甲基。
在本申请的一个实施方案中，优选下述化合物：
Figure PCTCN2016092254-appb-000005
及其药学上可接受的盐或水合物。
作为通式Ⅰ或通式Ⅱ的化合物的药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者 酸性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐，例如钠盐、钾盐等；碱土金属的盐，例如钙盐、镁盐、钡盐等；铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺等形成的盐。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。与碱性氨基酸形成的盐的非限制性实例包括但不限于与精氨酸、赖氨酸、鸟氨酸等形成的盐。与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、谷氨酸等形成的盐。
本申请的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本申请的通式Ⅰ或通式Ⅱ的化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本申请的范围之内。本申请的通式Ⅰ或通式Ⅱ的化合物可以以多晶型物或无定形形式存在。
本申请的通式Ⅰ或通式Ⅱ的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本申请的范围之内。
本申请中的消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本申请所述的通式Ⅰ或通式Ⅱ的化合物含有烯双键或其它几何不对称中心，除非另有规定，它们包括E和Z几何异构体。同样地，所有的互变异构形式均包括在本申请的范围之内。
本申请的通式Ⅰ或通式Ⅱ的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本 申请的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物也均包括在本申请的范围之内。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某一化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域技术人员已知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请的通式Ⅰ或通式Ⅱ的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本申请的通式Ⅰ或通式Ⅱ的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
药物组合物
另一方面，本申请提供了药物组合物，其包含通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。本申请的药物组合物可以进一步含有一种或多种另外的治疗剂。
本申请的药物组合物可通过将本申请的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物与适宜的药学上可接受的载体或赋形剂组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
本申请的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物或其药物组合物的典型的给药途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
可以采用本领域技术人员已知的方法制备本申请的药物组合物，如常规的混 合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
对于口服给药，可以通过将通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物与本领域技术人员熟知的药学上可接受的载体或赋形剂混合来配制该药物组合物。这些载体或赋形剂能使本申请的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的通式I或通式Ⅱ的化合物或其药学上可接受的盐或水合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预胶化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据药剂领域中通常公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
本申请的药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂来制备适于肠胃外给药的剂型。
医药用途
另一方面，本申请提供了治疗由IDH2突变诱发的癌症的方法，所述方法包括给予有需要的个体通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
另一方面，本申请提供了通式Ⅰ或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
另一方面，本申请提供了用于治疗由IDH2突变诱发的癌症的通式Ⅰ化合物或通式Ⅱ化合物或其药学上可接受的盐或水合物或其药物组合物。
在本申请的一些实施方案中，所述IDH2突变为IDH2/R140Q突变或 IDH2/R172K突变。
在本申请的一些实施方案中，所述的由IDH2突变诱发的癌症选自：成胶质细胞瘤(神经胶质瘤)、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)。在更具体的实施方案中，待治疗的癌症是神经胶质瘤、骨髓增生异常综合征(MDS)、骨髓组织增殖性赘生物(MPN)、急性骨髓性白血病(AML)、黑色素瘤、软骨肉瘤、或血管免疫母细胞性非霍奇金氏淋巴瘤(NHL)等，优选地包括急性骨髓性白血病(AML)或肉瘤。
本申请所述的通式Ⅰ或通式Ⅱ的化合物或其药学上可接受的盐或其药物组合物可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。本申请所述的通式Ⅰ或通式Ⅱ的化合物或其药学上可接受的盐或其药物组合物以治疗有效量给予所述有需要的个体。通式Ⅰ或通式Ⅱ化合物的给药剂量可以为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
本申请的通式Ⅰ或通式Ⅱ化合物的给药频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受通式Ⅰ或通式Ⅱ化合物的每日剂量，接着在若干天或更多天的期间，患者不接受通式Ⅰ或通式Ⅱ化合物的每日剂量。
制备
本申请的通式Ⅰ或通式Ⅱ的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方案以及本领域技术上人员所熟知的等同替换方式，优选的实施方案均包括但不限于本申请的实施例。
本申请的具体实施方案的化学反应是在合适的溶剂中完成的，所述的溶剂必须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的通式Ⅰ或通式Ⅱ的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本申请的通式Ⅱ的化合物可以由有机合成领域技术人员通过如下路线用本领域的标准方法来制备：
Figure PCTCN2016092254-appb-000006
化合物1-1发生成酰化反应得到1-2；1-2与缩二脲反应得到1-3；1-3发生氯化反应得到1-4；1-4与R2基团取代的氨发生氨化反应得到1-5；1-5与R2-X1基团取代的氨发生氨化反应得到通式Ⅱ的化合物。
实施例
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请化合物的其它合成途径，下面提供的是非限制性的实施例。
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本申请使用的原料都是市场上直接买到未经进一步纯化直接使用的。
柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60PF254,0.25毫米)。手性化合物分离和对 映体过量值(ee)测定使用Agilent LC 1200series(柱子：CHIRALPAK AD-H,
Figure PCTCN2016092254-appb-000007
Figure PCTCN2016092254-appb-000008
毫米，5微米，30℃)。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定；液质连用(LC/MS)使用FINNIGAN Thermo LCQ Advantage MAX，Agilent LC 1200series(柱子：Waters Symmetry C18,
Figure PCTCN2016092254-appb-000009
毫米，5微米，35℃)，采用ESI(+)离子模式。
实验部分
实施例1：4-(乙氧基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000010
步骤1：6-三氟甲基-吡啶-2-甲酸甲酯
Figure PCTCN2016092254-appb-000011
氮气保护下，向2-溴-6-三氟甲基吡啶(1.48g,6.55mmol)的甲醇(50.0mL)溶液中依次加入醋酸钯(74.0mg,0.33mmol)、1,1'-双(二苯基膦)二茂铁(363.0mg,0.655mmol)和三乙胺(0.92g,9.8mmol)。该反应液在60℃、2个大气压的一氧化碳气氛下反应18小时。反应结束后，将反应液冷却到室温，过滤，滤液真空减压浓缩，所得残留物经硅胶柱色谱纯化得6-三氟甲基-吡啶-2-甲酸甲酯(0.9g,收率67.0％)。
步骤2：6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪-2,4(1H,3H)-二酮
Figure PCTCN2016092254-appb-000012
氮气保护下，向乙醇钠(11.2g,165.0mmol)的乙醇(200mL)溶液中依次加入6-三氟甲基-吡啶-2-甲酸甲酯(10.0g,48.7mmol)和缩二脲(4.2g,40.7mmol)。将该混合物加热回流2小时后冷却到室温。将反应液真空减压浓缩，所得残留物倒入水中，用6mol/L盐酸溶液调节pH值到7，所得固体过滤，滤饼用水洗涤，干燥后得6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪-2,4(1H,3H)-二酮(5.0g,收率47.5％)。
步骤3：2,4-二氯-6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪
Figure PCTCN2016092254-appb-000013
氮气保护下，将6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪-2,4(1H,3H)-二酮(15.0g,58.1mmol)和三氯氧磷(200mL)的混合液于100℃反应2小时后冷却到室温。将反应液真空减压浓缩，所得残留物倒入饱和碳酸氢钠水溶液中，用乙酸乙酯萃取(2×100mL)，有机相用无水硫酸钠干燥。过滤，滤液真空浓缩得2,4-二氯-6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪(10.0g,收率58.3％)。
步骤4：4-氯-6-(6-三氟甲基吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000014
向2,4-二氯-6-(6-三氟甲基吡啶-2-基)-1,3,5-三嗪(5.0g,16.9mmol)的四氢呋喃(100mL)溶液中加入4-氨基-2-三氟甲基吡啶(3.3g,20.3mmol)和碳酸氢钠(2.14g,25.3mmol)。将该混合物在70℃反应8小时后冷却到室温。将反应液真空减压浓缩，所得残留物用硅胶色谱柱纯化得4-氯-6-(6-三氟甲基吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺(6.5g,收率91.2％)。
步骤4：4-(乙氧基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000015
向4-氯-6-(6-三氟甲基吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺(50.0mg,mmol)的四氢呋喃(20mL)溶液中加入乙氧基胺盐酸盐(12.0mg,0.18mmol)和碳酸氢钠(40.0mg,0.48mmol)。将该混合物在70℃反应8小时后冷却到室温。将反应液真空减压浓缩，所得残留物用硅胶色谱柱纯化得4-(乙氧基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺(40.0mg,收率80.0％)。1H-NMR(400MHz,CDCl3):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)。
实施例2：4-(异丙基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000016
参照实施例1的合成方法，制得4-(异丙基氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝11.35(s,1H),10.85(s,1H),8.66(s,1H),8.56(d,J＝5.6Hz,2H),8.32(t,J＝7.9Hz,1H),8.11(d,J＝7.6Hz,1H),8.03(s,1H),4.28-4.06(m,1H),1.23(d,J＝14.5Hz,6H)。
实施例3：4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000017
参照实施例1的合成方法，制得4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ ＝11.00(s,1H),10.84(s,1H),8.74(s,1H),8.57(t,J＝6.5Hz,2H),8.31(t,J＝7.9Hz,1H),8.11(d,J＝7.7Hz,1H),7.99(s,1H),1.28(s,9H)。
实施例4：4-((环丙基甲氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000018
参照实施例1的合成方法，制得4-((环丙基甲氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-
(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝11.4(s,1H),10.9(s,1H),8.61(s,1H),8.57(d,J＝5.6Hz,2H),8.32(t,J＝7.9Hz,1H),8.17-8.09(m,2H),3.77(d,J＝7.1Hz,2H),3.15(d,J＝5.2Hz,1H),0.87-0.76(m,2H),0.57-0.47(m,2H)。
实施例5：N,N'-(6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2,4-二基)双(O-乙氧氨基)
Figure PCTCN2016092254-appb-000019
参照实施例1的合成方法，制得N,N'-(6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2,4-二基)双(O-乙氧氨基)。1H-NMR(400MHz,DMSO-d6):δ＝10.96(s,2H),8.48(d,J＝7.8Hz,1H),8.24(t,J＝7.9Hz,1H),8.04(d,J＝7.7Hz,1H),3.90(q,J＝7.0Hz,4H),1.30-1.06(m,6H)。
实施例6：2-甲基-1-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-2-醇
Figure PCTCN2016092254-appb-000020
参照实施例1的合成方法，制得2-甲基-1-(((4-(6-(三氟甲基)吡啶-2- 基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-2-醇。1H-NMR(400MHz,CDCl3):δ＝8.59(dd,J＝10.7,6.7Hz,2H),8.29(s,1H),8.09(t,J＝7.8Hz,1H),7.87(d,J＝7.8Hz,1H),7.73(s,1H),4.00(s,2H),1.62(s,1H),1.32(s,6H)。
实施例7：2-甲基-2-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-1-醇
Figure PCTCN2016092254-appb-000021
参照实施例1的合成方法，制得2-甲基-2-(((4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)氨基)-1,3,5-三嗪-2-基)氨基)氧基)异丙-1-醇。1H-NMR(400MHz,DMSO-d6):δ＝10.80(s,1H),8.54(d,J＝5.8Hz,1H),8.29(t,J＝7.9Hz,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)。
实施例8：4-((苄氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000022
参照实施例1的合成方法，制得4-((苄氧基)氨基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝11.52(s,1H),10.91(s,1H),8.60(s,2H),8.56(d,J＝5.4Hz,1H),8.36(t,J＝7.9Hz,1H),8.15(d,J＝7.7Hz,2H),7.52(s,2H),7.47-7.35(m,3H),5.04(s,2H)。
实施例9：4-(2-甲基肼基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000023
参照实施例1的合成方法，制得4-(2-甲基肼基)-6-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝10.76(s,1H),8.67(s,1H),8.56(d,J＝5.5Hz,1H),8.30(t,J＝7.9Hz,1H),8.11(d,J＝7.7Hz,2H),7.93(s,1H),5.39(s,1H),5.21(s,1H),3.40(s,,3H)。
实施例10：4-(叔丁氧氨基)-6-苯基-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000024
参照实施例1的合成方法，制得4-(叔丁氧氨基)-6-苯基-N-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):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)。
实施例11：1-((4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-基)氨基)-2-甲基丙-2醇
Figure PCTCN2016092254-appb-000025
参照实施例1的合成方法，制得1-((4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-基)氨基)-2-甲基丙-2醇。1H-NMR(400MHz,DMSO-d6):δ＝10.29(d,2H),8.53(d,J＝7.9Hz,1H),8.28(t,J＝7.9Hz,1H),8.13-8.03(m,1H),4.86(s,1H),3.39(m,2H),1.27(m,9H),1.07(m,6H)。
实施例12：4-(叔丁氧氨基)-N-苯基-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000026
参照实施例1的合成方法，制得4-(叔丁氧氨基)-N-苯基-6-(6-(三氟甲基)吡啶 -2-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝10.62(s,1H),10.12(s,1H),8.57(d,J＝7.9Hz,1H),8.31(t,J＝7.8Hz,1H),8.10(d,J＝7.2Hz,1H),7.99(m,2H),7.32(t,J＝7.9Hz,2H),7.03(t,J＝7.4Hz,1H),1.29(s,9H)。
实施例13：N-苄基-4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000027
参照实施例1的合成方法，制得N-苄基-4-(叔丁氧氨基)-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝10.26(s,2H),8.50(dd,J＝13.2,5.0Hz,2H),8.33-8.18(m,1H),8.05(d,J＝7.8Hz,1H),7.37(d,J＝7.0Hz,1H),7.31(dd,J＝10.1,4.8Hz,2H),7.22(t,J＝7.2Hz,1H),4.55(d,J＝6.2Hz,2H),1.18(s,9H)。
实施例14：4-(叔丁氧氨基)-N-异丙基-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2-胺
Figure PCTCN2016092254-appb-000028
参照实施例1的合成方法，制得4-(叔丁氧氨基)-N-异丙基-6-(6-(三氟甲基)吡啶-2-基)-
1,3,5-三嗪-2-胺。1H-NMR(400MHz,DMSO-d6):δ＝10.16(s,2H),8.49(d,J＝8.1Hz,1H),8.04(d,J＝7.4Hz,1H),7.83(d,J＝7.9Hz,1H),4.16(m,1H),1.24(m,9H),1.18(m,6H)。
实验例1：IDH2抑制活性的测定
本申请采用以下方法来测定本申请的化合物对IDH2(R172K,40-end)的抑制活性，该抑制活性采用IC50这一指标来表示，IC50即IDH2的活性被抑制50％时的化合物的浓度。
材料和方法：
通过辅助因子NADPH的消减来测定化合物对IDH2(R172K,40-end)的抑制活性。将化合物与酶和NADPH进行预孵育，然后通过添加a-KG启动反应，线性条件下反应120分钟。之后通过添加Diaphorase(硫辛酰胺脱氢酶)和相应的底物Resazurin(刃天青)终止反应。硫辛酰胺脱氢酶通过消减可供使用的辅助因子NADPH而终止IDH2m反应，它将NADPH氧化成NADP，并且将刃天青还原成高荧光的试卤灵，通过易于检测的荧光基团来量化在特定反应时间之后剩余的辅助因子NADPH的量。
具体地说，将2.5μl 3×梯度稀释的化合物加到384孔板中，接着添加5μl含有80nM IDH2(R172K，40-end)和40μM NADPH的反应缓冲液(20mM Tris-HCl,PH7.5；150mM NaCl；10mM MgCl2；10mM MnCl2；0.4mg/ml BSA和2mM DTT)。然后将上述测试混合物在23℃孵育120分钟，之后添加2.5μl含有4mM a-KG的反应缓冲液启动反应。室温孵育120分钟后，加入5μl用反应缓冲液配制的终止混合物(0.4U/ml Diaphorase和40μM Resazurin)，使刃天青转化成试卤灵来测量剩余的NADPH。23℃孵育10分钟后，通过Flexstation 3在Ex535/Em595下进行荧光值测定。
实施例化合物的IDH2抑制活性如表1所示：
表1
实施例编号 IC50(nM)
1 22.40
2 28.79
3 31.69
4 38.19
6 46.85
7 153.6
8 239.3
10 51.42
实验例2：药代动力学参数的测定
本申请采用以下方法来测定本申请的化合物的药代动力学参数：
研究使用7-9周龄健康雄性成年大鼠，每组动物(3只雄性大鼠)单次灌胃 给药，剂量为5mg/kg，灌胃给药组的动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。
在给药后0.25、0.5、1、2、4、6、8和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。
血浆样品分析使用已确证的液相色谱-串联质谱联用方法(LC-MS/MS)，个体动物的血浆浓度-时间数据用WinNonlin(专业版，版本6.3；Pharsight公司)软件进行分析，非房室模型被用于浓度分析，计算化合物的药代动力学参数，如表2所示:实施例3化合物具有较好的体内代谢水平和较长的半衰期，并在同等剂量下，其血药浓度高于IDH2抑制剂AG-221。
表2
实施例 3 AG-221
剂量(mg/kg) 5 5
T1/2(hr) 12.0 3.73
Tmax(hr) 5.0 4.00
Cmax(ng/mL) 589 479
AUC0-inf(hr*ng/mL) 10838 5385

Claims (17)

  1. 通式Ⅰ的化合物或其药学上可接受的盐或水合物
    Figure PCTCN2016092254-appb-100001
    其中，
    环A选自苯环或含有1-2个选自N、O或S的杂原子的5-6元杂芳环；
    X1选自NH或O；
    R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
    R2选自苯基、含有1-2个选自N、O或S的杂原子的5-6元杂芳基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
    每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
    R4和R5独立地选自H、C1-6烷基或C3-6环烷基；
    每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
    每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
    n为0，1，2或3。
  2. 通式Ⅱ的化合物或其药学上可接受的盐或水合物
    Figure PCTCN2016092254-appb-100002
    其中，
    X1选自NH或O；
    X2选自N或CH；
    R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
    R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
    每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；
    每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
    每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
    n为0，1，2或3。
  3. 权利要求1或2所述的化合物或其药学上可接受的盐或水合物，其中
    X1选自O；
    X2选自N或CH；
    R1选自H、C1-6烷基、C2-6烯基、C2-6炔基或C3-6环烷基，其中所述烷基、烯基、炔基或环烷基可任选地被一个或多个R6取代；
    R2选自苯基、吡啶基、苄基、C1-6烷基、C1-6烷氧基或C3-6环烷基，并可任选地被一个或多个R7取代；
    每个R3独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或 C3-6环烷基；
    每个R6独立地选自卤素、羟基、氨基、卤代C1-3烷基、C1-6烷基、C3-6环烷基、苯基或含有1-2个选自N、O或S的杂原子的5-6元杂芳基，并且所述苯基或杂芳基可任选地被一个或多个R8取代；
    每个R7和每个R8分别独立地选自卤素、羟基、氨基、卤代C1-3烷基、氰基、C1-6烷基或C3-6环烷基；以及
    n为0，1或2。
  4. 权利要求1-3中任一项所述的化合物或其药学上可接受的盐或水合物，其中X1为O；R1选自C1-6烷基并可任选地被一个或多个R6取代；以及每个R6选自羟基、苯基或C3-6环烷基；优选地，R1选自甲基、乙基、丙基或丁基并可任选地被1-2个R6取代；以及每个R6独立地选自羟基、苯基或环丙烷基。
  5. 权利要求1-4中任一项所述的化合物或其药学上可接受的盐或水合物，其中X1为O；R2选自苯基、吡啶基、苄基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基，并可任选地被1个或2个R7取代；以及每个R7独立地选自羟基、卤代C1-3烷基或C1-6烷基；优选地，R2选自苯基、吡啶基、苄基、丙基、丁基、乙氧基，并可任选地被一个或多个R7取代；以及每个R7独立地选自羟基或三氟甲基。
  6. 权利要求1-5中任一项所述的化合物或其药学上可接受的盐或水合物，其中X1为O；n为0或1；以及R3为卤代C1-3烷基；优选地，n为0或1，以及R3选自三氟甲基。
  7. 如权利要求1或2所述的化合物，其选自如下化合物或其药学上可接受的盐或水合物
    Figure PCTCN2016092254-appb-100003
    Figure PCTCN2016092254-appb-100004
  8. 药物组合物，其包含权利要求1-7中任一项所述的化合物或其药学上可接受的盐或水合物和一种或多种药学上可接受的载体或赋形剂。
  9. 治疗由IDH2突变诱发的癌症的方法，所述方法包括给予有需要的个体权利要求1-7中任一项所述的化合物或其药学上可接受的盐或水合物或权利要求8所述的药物组合物。
  10. 权利要求9所述的方法，其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
  11. 权利要求9或10的所述的方法，其中所述由IDH2突变诱发的癌症选自成胶质细胞瘤、骨髓增生异常综合征、骨髓组织增殖性赘生物、急性骨髓性白血 病、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤。
  12. 权利要求1-7中任一项所述的化合物或其药学上可接受的盐或水合物或权利要求8所述的药物组合物在制备用于治疗由IDH2突变诱发的癌症的药物中的用途。
  13. 权利要求12所述的用途，其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
  14. 权利要求12或13所述的用途，其中所述由IDH2突变诱发的癌症选自：成胶质细胞瘤、骨髓增生异常综合征、骨髓组织增殖性赘生物、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤。
  15. 用于治疗由IDH2突变诱发的癌症的权利要求1-7中任一项所述的化合物或其药学上可接受的盐或水合物或权利要求8所述的药物组合物。
  16. 权利要求15所述的化合物或其药学上可接受的盐或水合物或药物组合物，其中所述IDH2突变为IDH2/R140Q突变或IDH2/R172K突变。
  17. 权利要求15或16所述的化合物或其药学上可接受的盐或水合物或药物组合物，其中所述由IDH2突变诱发的癌症选自：成胶质细胞瘤、骨髓增生异常综合征、骨髓组织增殖性赘生物、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、软骨肉瘤、胆管癌或血管免疫母细胞性非霍奇金氏淋巴瘤。
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