WO2018014852A1 - 作为异柠檬酸脱氢酶抑制剂的化合物及其应用 - Google Patents

作为异柠檬酸脱氢酶抑制剂的化合物及其应用 Download PDF

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WO2018014852A1
WO2018014852A1 PCT/CN2017/093597 CN2017093597W WO2018014852A1 WO 2018014852 A1 WO2018014852 A1 WO 2018014852A1 CN 2017093597 W CN2017093597 W CN 2017093597W WO 2018014852 A1 WO2018014852 A1 WO 2018014852A1
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group
alkyl
amino
acyl
alkylamino
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PCT/CN2017/093597
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English (en)
French (fr)
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王勇
赵立文
刘晓蓉
张雁
黄丹丹
姜春环
史鑫生
古宏峰
庞司林
海维
葛冰洋
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南京圣和药业股份有限公司
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Priority to KR1020197000830A priority Critical patent/KR102232614B1/ko
Priority to CN201780029958.5A priority patent/CN109890806B/zh
Priority to CA3029343A priority patent/CA3029343C/en
Priority to EP17830486.1A priority patent/EP3489230B1/en
Priority to JP2019500677A priority patent/JP6772360B2/ja
Priority to US16/312,666 priority patent/US10961222B2/en
Publication of WO2018014852A1 publication Critical patent/WO2018014852A1/zh
Priority to HK18116073.6A priority patent/HK1257178A1/zh

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medical chemistry, and particularly relates to a compound as an inhibitor of isocitrate dehydrogenase 2 or an isomer thereof, a pharmaceutically acceptable salt, a crystal, a solvate or a prodrug thereof, a preparation method thereof and a Pharmaceutical compositions of these compounds and the use of these compounds or compositions for the treatment of cancer characterized by the presence of mutant isocitrate dehydrogenase 2.
  • Isocitrate dehydrogenase is the rate-limiting enzyme of the Krebs cycle. Its family includes three members, IDH1, IDH2 and IDH3. With NAD + (nicotinamide adenine dinucleotide, coenzyme I) Or NADP + (nicotinamide adenine dinucleotide phosphate, coenzyme II) as a cofactor to catalyze the oxidative decarboxylation of isocitrate to produce ⁇ -ketoglutarate ( ⁇ -KG), and simultaneously produce NADH (reduced coenzyme) I) or NADPH (reduced coenzyme II).
  • NAD + nicotinamide adenine dinucleotide, coenzyme I
  • NADP + nicotinamide adenine dinucleotide phosphate, coenzyme II
  • IDH isozymes have three forms: IDH1, which is dependent on the cytoplasm of NADP, and IDH2, which is mitochondria, and NAD-dependent mitochondrial IDH3.
  • the IDH1 gene is located on chromosome 2q33.3 and localizes in cytoplasm and peroxisomes; the IDH2 gene is located on chromosome 15q26.1 and localizes to cellular mitochondria.
  • IDH2 mutations have been identified in a variety of cancers such as glioma, glioblastoma multiforme, acute myeloid leukemia (AML) and the like. Mutations in IDH2 include R140 and R172, etc., which occur at or near the critical residues of the active site (see L. Dang et al, Nature, 2009, 462, 739-44). Studies have shown that mutations in IDH2 present in cancer cells result in the enzyme having a new ability to catalyze the NAPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). High levels of 2-HG have been detected in tumors containing mutations.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a carboxyl group, a nitro group and a cyano group, wherein the halogen, hydroxy group, alkyl group, cycloalkyl group, heterocyclic group, haloalkyl group, hydroxyalkane group Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carboxy, nitro and cyano are optionally one or a plurality of
  • X is selected from N(R 3 ), O, S and C(R 4 ), wherein R 3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl and aminodecylalkyl or R 3 and Y together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic group, and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, oxo, alkoxy a group, a carboxyl group, a cyano group, an amino group and an aminoalkyl group or R 4 and Y together with the carbon atom to which they are bonded form an optionally substituted carbocyclic or heterocyclic group, wherein the alkyl group, haloalkyl group, hydroxyalkyl group Aminoalkyl, mercaptoalkyl, aminoalky
  • Y is selected from optionally substituted alkyl, O(R 5 ), N(R 6 R 7 ), cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylamino
  • Y is selected from the group consisting of optionally substituted O(R 5 ) and N(R 6 R 7 ), and the dotted line between X and Y represents a single bond;
  • X is N(R 3 ) and R 3 is selected from the group consisting of alkyl, haloalkyl and hydroxyalkyl, mercaptoalkyl and aminodecylalkyl
  • Y is selected from optionally substituted alkyl, O(R 5 ) And N(R 6 R 7 ) and the dotted line between X and Y represents a single bond, or R 3 and Y together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic group;
  • Y is selected from optionally substituted alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylamino, alkyl acyl
  • An amino group, an alkyl acyl group, an amino acyl group and an alkylamino acyl group, and a dotted line between X and Y represents a single bond;
  • Y is selected from optionally substituted alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylamino, alkyl
  • An acylamino group, an alkyl acyl group, an aminoacyl group and an alkylamino acyl group, and a dotted line between X and Y represents a single bond, a double bond or a triple bond, or R 4 and Y together with the carbon atom to which they are bonded form an optionally substituted Carbocyclyl or heterocyclic group.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof.
  • a further object of the present invention is to provide a composition comprising a compound of the formula I of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a crystal, a solvate or a prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof and another or more IDH2 inhibitor.
  • the present invention provides a compound of the formula I or an isomer thereof, a pharmaceutically acceptable salt, a crystal, a solvate or a prodrug,
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a carboxyl group, a nitro group and a cyano group, wherein the halogen, hydroxy group, alkyl group, cycloalkyl group, heterocyclic group, haloalkyl group, hydroxyalkane group Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carboxy, nitro and cyano are optionally one or a plurality of
  • X is selected from N(R 3 ), O, S and C(R 4 ), wherein R 3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl and aminodecylalkyl or R 3 and Y together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic group, and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, oxo, alkoxy a group, a carboxyl group, a cyano group, an amino group and an aminoalkyl group or R 4 and Y together with the carbon atom to which they are bonded form an optionally substituted carbocyclic or heterocyclic group, wherein the alkyl group, haloalkyl group, hydroxyalkyl group Aminoalkyl, mercaptoalkyl, aminoalky
  • Y is selected from optionally substituted alkyl, O(R 5 ), N(R 6 R 7 ), cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylamino
  • Y is selected from the group consisting of optionally substituted O(R 5 ) and N(R 6 R 7 ), and the dotted line between X and Y represents a single bond;
  • X is N(R 3 ) and R 3 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl and aminodecylalkyl
  • Y is selected from optionally substituted alkyl, O.
  • Y is selected from optionally substituted alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylamino, alkyl acyl
  • An amino group, an alkyl acyl group, an amino acyl group and an alkylamino acyl group, and a dotted line between X and Y represents a single bond;
  • Y is selected from optionally substituted alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylamino, alkyl
  • An acylamino group, an alkyl acyl group, an aminoacyl group and an alkylamino acyl group and a dotted line between X and Y represents a single bond, a double bond or a triple bond, or R 4 and Y together with the carbon atom to which they are bonded form an optionally substituted carbon A cyclic or heterocyclic group.
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclic, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acyl Amino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, carboxy, nitro and cyano, wherein said halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl , hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, carboxy, nitro
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, halogenated C 1-3 alkane.
  • cyano group is optionally selected from one or more of halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-3 alkoxy, amino, C 1-3 alkylamino, C 1- a 3 -alkylacylamino group, a C 1-3 alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a carboxyl group, a nitro group and a cyano group, wherein the halogen, hydroxy group, alkyl group, cycloalkyl group, heterocyclic ring , haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkylacylamino, alkyl acyl, aminoacyl, alkylaminoacyl, carboxy, nitro and
  • the cyano group is optionally selected from one or more of halogen, hydroxy, C
  • each of R 1 and R 2 is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentane Base, cyclohexyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, trifluoromethoxy, trifluoroethoxy, hydroxymethoxy, Hydroxyethoxy, hydroxypropoxy, 2-hydroxypropoxy, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, Methyl ethylamino, methyl acylamino, ethyl acylamino, vinyl acylamino, methyl acyl
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • X is N(R 3 ), R 3 is hydrogen, Y is O(R 5 ), and R 5 is selected from C 1-12 alkyl, C 3-8 cycloalkyl and C 3-8 heterocyclic group, C 1-12 alkyl, C 3-8 cycloalkyl and C 3-8 heterocyclyl are optionally substituted by one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, Halogen, hydroxy, amino, carboxy, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl substituted;
  • X is N(R 3 ), R 3 is hydrogen, Y is O(R 5 ), and R 5 is selected from C 1-12 alkyl, C 3-8 cycloalkyl and C 3-8 heterocyclic ring
  • the C 1-12 alkyl group, the C 3-8 cycloalkyl group and the C 3-8 heterocyclic group are optionally one or more C 1-6 alkyl groups, C 3-8 cycloalkyl groups, C 3-8 heterocycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkyl acyl, amino acyl, C a 1-6 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • X is N(R 3 ), R 3 is hydrogen, Y is O(R 5 ), and R 5 is selected from C 1-6 alkyl, C 3-6 cycloalkyl and C 3-6 a cycloalkyl group, said C 1-6 alkyl group, C 3-6 cycloalkyl group and C 3-6 heterocyclic group optionally being one or more C 1-3 alkyl groups, C 3-6 cycloalkyl groups, C 3-6 heterocycloalkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, halogen, hydroxy, amino, carboxy, Nitro, cyano, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, sulfonyl, sulfinyl, decyl, phenyl or heteroaryl substituted.
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • X is N(R 3 ), R 3 is hydrogen, Y is N(R 6 R 7 ), and R 6 and R 7 are independently selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3- a heterocyclic group, said C 1-6 alkyl group, C 3-8 cycloalkyl group and C 3-8 heterocyclic group optionally being one or more alkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkane groups Oxyl, alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, alkyl acyl, amino acyl, alkylamino acyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl substituted;
  • X is N(R 3 ), R 3 is hydrogen, Y is N(R 6 R 7 ), and R 6 and R 7 are independently selected from C 1-6 alkyl, C 3-8 cycloalkyl And a C 3-8 heterocyclic group, the C 1-6 alkyl group, the C 3-8 cycloalkyl group and the C 3-8 heterocyclic group optionally being one or more C 1-6 alkyl groups, C 3 -8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkane a acyl group, an aminoacyl group, a C 1-6 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • X is N(R 3 ), R 3 is hydrogen, Y is N(R 6 R 7 ), and R 6 and R 7 are independently selected from C 1-3 alkyl, C 3-6 naphthenic And a C 3-6 heterocyclic group, said C 1-3 alkyl group, C 3-6 cycloalkyl group and C 3-6 heterocyclic group optionally being one or more C 1-3 alkyl groups, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, halogen A hydroxy group, an amino group, a carboxyl group, a nitro group, a cyano group, a C 1-3 alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a dec
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • X is N(R 3 ), R 3 is hydrogen, Y is N(R 6 R 7 ), and R 6 and R 7 together with the nitrogen atom to which they are bonded form a C 3-8 heterocyclic group, wherein the heterocyclic ring Further comprising one or more N, O or S heteroatoms, and said heterocyclyl is optionally substituted by one or more oxo groups, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkane a base amino group, a halogen, a hydroxyl group, an amino group, a carboxyl group, a nitro group, a cyano group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • X is N(R 3 ), R 3 is hydrogen, Y is N(R 6 R 7 ), and R 6 and R 7 together with the nitrogen atom to which they are bonded form a C 3-8 heterocyclic group, wherein
  • the heterocyclic group further comprises one or more N, O or S heteroatoms, and the heterocyclic group is optionally selected from one or more oxo groups, C 1-6 alkyl, C 3-8 naphthenes , C 3-8 heterocycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkyl acyl, amino An acyl group, a C 1-6 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • X is N(R 3 ), R 3 is hydrogen, Y is N(R 6 R 7 ), and R 6 and R 7 together with the nitrogen atom to which they are bonded form an azacyclopropyl group, Azetidinyl, tetrahydropyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridyl, pyrazolidinyl, dihydropyrazolyl, imidazolidinyl, dihydroimidazolyl, pyrazolyl, di Hydropyrazolyl, oxazolidinyl, dihydrooxazolyl, thiazolidinyl, dihydrothiazolyl, isoxazolidinyl, dihydroisoxazolyl, isothiazolidinyl, dihydroisothiazolyl, six Hydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, hexa
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • X is N(R 3 ), and R 3 is selected from C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, decyl C 1-6 alkane And an aminomethyl C 1-6 alkyl group
  • Y is selected from the group consisting of an optionally substituted C 1-6 alkyl group, O(R 5 ) and N(R 6 R 7 ), a cycloalkyl group, a heterocyclic group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, an alkylamino group, an alkylacylamino group, an alkyl acyl group, an aminoacyl group and an alkylamino acyl group, and R 5 , R 6 and R 7 are independently selected from C 1-6 alkane a C 3-8 cycloalkyl group and a C 3-8 heterocyclic group, said C
  • X is N(R 3 ), and R 3 is selected from C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, decyl C 1-6 alkyl and aminoindenyl C 1-6 alkyl, Y is selected from C 1-6 alkyl, O(R 5 ), N(R 6 R 7 ), C 3-8 cycloalkyl, C 3- 8 heterocyclyl, halo-C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 An alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group and a C 1-6 alkylamino acyl group, and R 5 , R 6 and R 7 are independently selected from a C 1-6 alkyl group, a C 3-8 cycloalkane And a C 3
  • X is N(R 3 ), and R 3 is selected from C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, decyl C 1-6 alkyl and amino fluorenyl C 1-6 alkyl, Y is selected from C 1-6 alkyl, O(R 5 ) and N(R 6 R 7 ), C 3-8 cycloalkyl, C 3 -8 heterocyclic group, halogenated C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkoxy group, C 1-6 alkylamino group, C 1- a 6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group and a C 1-6 alkylamino acyl group, and R 5 , R 6 and R 7 are independently selected from a C 1-6 alkyl group, a C 3-8
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • R 3 and Y together with the nitrogen atom to which they are bonded form a C 3-8 heterocyclic group, wherein the heterocyclic group further comprises one or more N, O or S heteroatoms, and the heterocyclic group is optionally One or more oxo groups, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, alkyl acyl, amino acyl, Alkanoyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl substituted;
  • the group is optionally selected from one or more oxo groups, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 alkoxy, C 1-6 alkane Alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl Base substitution
  • the compound of the present invention is a compound of Formula I, or an isomer thereof, a pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, wherein the compound of Formula I has the formula The structure of Ia:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carboxy, nitro and cyano, wherein said halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxy Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carboxy, nitro and cyano optionally Or a plurality of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo
  • Ring A is a heterocyclic group, preferably selected from the group consisting of a nitrogen heterocyclyl group, a nitrogen oxyheterocyclyl group, a nitrogen thioheterocyclyl group, and a dinitroheterocyclyl group;
  • R 8 is selected from the group consisting of hydrogen, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, halogen, hydroxy, One or more groups of amino, carboxyl, nitro, cyano, alkyl acyl, aminoacyl, alkanoyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl, wherein said oxo Group, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyanide a group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a s
  • the compound of the invention is a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclic, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acyl Amino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, carboxy, nitro and cyano, wherein said halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl , hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, carboxy, nitro
  • Ring A is selected from C 3-8 azetidin group, C 3-8 nitroxide heterocyclyl, C 3-8 sulfur, nitrogen, and heterocyclyl C 3-8 diazacycloalkyl group;
  • R 8 is selected from the group consisting of hydrogen, oxo group, C 1-6 alkyl group, halogenated C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group , C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, One or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group, wherein the oxo group , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy
  • the compound of the present invention is a compound of Formula Ia, or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, wherein Ring A is selected from the group consisting of azacyclopropyl, aza Cyclobutyl, tetrahydropyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridyl, pyrazolidinyl, dihydropyrazolyl, imidazolidinyl, dihydroimidazolyl, pyrazolyl, dihydropyridyl Azyl, oxazolidinyl, dihydrooxazolyl, thiazolidinyl, dihydrothiazolyl, isoxazolidinyl, dihydroisoxazolyl, isothiazolidinyl, dihydroisothiazolyl, hexahydropyrimidine , tetrahydropyrimidinyl, dihydr
  • the compound of the present invention is a compound of Formula I, or an isomer thereof, a pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, wherein the compound of Formula I has the formula The structure of Iaa:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carboxy, nitro and cyano, wherein said halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl, hydroxy Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carboxy, nitro and cyano optionally Or a plurality of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo
  • R 8 is selected from the group consisting of hydrogen, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, halogen, hydroxy, One or more groups of amino, carboxyl, nitro, cyano, alkyl acyl, aminoacyl, alkanoyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl, wherein said oxo Group, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyanide a group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a s
  • n 1, 2, 3, 4, 5 or 6.
  • the compound of the invention is a compound of Formula Iaa, or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclic, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acyl Amino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, carboxy, nitro and cyano, wherein said halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, haloalkyl , hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, carboxy, nitro
  • R 8 is selected from the group consisting of hydrogen, oxo group, C 1-6 alkyl group, halogenated C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group , C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, One or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group, wherein the oxo group , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy
  • n 1, 2, 3, 4, 5 or 6.
  • the compound of the invention is a compound of Formula Iaa, or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, amino, C 1-3 alkylamino, C 1-3 alkyl acyl An amino group, a C 1-3 alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a carboxyl group, a nitro group and a cyano group, wherein the halogen, hydroxy group, alkyl group, cycloalkyl group, heterocyclic group, haloalkyl group , hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino, alkyl acylamino, alkyl
  • R 8 is selected from the group consisting of hydrogen, oxo group, C 1-3 alkyl group, halogenated C 1-3 alkyl group, hydroxy C 1-3 alkyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group , C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, C 1-3 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, One or more groups of C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl, wherein the oxo group , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, halogen, hydroxy, amino,
  • n 1, 2, 3, 4, 5 or 6.
  • the compound of the invention is a compound of Formula Iaa, or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein
  • R 8 is selected from the group consisting of hydrogen, oxo group, C 1-6 alkyl group, halogenated C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group , C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, One or more groups of a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group, wherein the oxo group , alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy
  • the compounds of the present invention is a compound of Formula Iaa or its isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein R 8 is selected from one of the following groups Or more: hydrogen, oxo group, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyano, amino, carboxyl , nitro, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, trifluoromethoxy, trifluoroethoxy, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, 2 - hydroxypropoxy, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, methylacy
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • X is selected from O and S
  • Y is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclic, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl and C 1-6 alkyl Aminoacyl group, said C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group, halogenated C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 Alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl and C 1-6 alkylamino acyl optionally By one or more alkyl, cycloalky
  • X is selected from the group consisting of O and S
  • Y is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclic, halogenated C 1-6 alkyl, hydroxy C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl and C 1 a -6 alkylamino group, said C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group, halogenated C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl and C 1-6 alkyl Aminoacyl is optional
  • X is selected from the group consisting of O and S
  • Y is selected from the group consisting of C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclic, halogenated C 1-3 alkyl, hydroxy C 1 -3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl And a C 1-3 alkylamino acyl group, said C 1-3 alkyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group, halogenated C 1-3 alkyl group, hydroxy C 1-3 Alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl and C 1-3 alkylaminoacyl
  • the inventors of the present invention have unexpectedly discovered that a compound of formula I, or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, according to the present invention, Wherein when X is O, that is, a compound represented by the following formula Ib, the compound of the present invention has a very excellent function of inhibiting mutant IDH2 enzyme activity and inhibiting the function of mutant IDH2 tumor cells,
  • the compound of the invention is a compound of Formula Ib, or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclic, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino Acyl, C 1-6 alkylamino acyl, carboxyl, nitro and cyano;
  • Y is selected from C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino A C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group and a C 1-6 alkylamino acyl group.
  • the compound of the present invention is a compound of Formula Ib or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, wherein Y is selected from the group consisting of methyl, ethyl, and C. Base, isopropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, 2,2,3,3,3-pentafluoropropyl.
  • the compound of the invention is a compound of formula I or an isomer, pharmaceutically acceptable salt, crystallization, solvate or prodrug thereof, wherein:
  • X is C(R 4 ), and R 4 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy, hydroxy C 1-6 alkyl, halogen, oxo group, C 1- 6 alkoxy group, carboxyl group, cyano group and amino group
  • Y is selected from C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group, halogenated C 1-6 alkyl group, hydroxyl group C 1 -6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl And a C 1-6 alkylamino acyl group, said C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 heterocyclic group, halogenated C 1-6 alkyl group, hydroxy C 1-6 Alkyl, C 1-6
  • X is C(R 4 ), and R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy, hydroxy C 1-6 alkyl, halogen, oxo group , C 1-6 alkoxy, carboxy, cyano and amino
  • Y is selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, halo C 1-6 alkyl , hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl
  • X is C(R 4 ), and R 4 is selected from the group consisting of hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy, hydroxy C 1-3 alkyl, halogen, oxo a group, C 1-3 alkoxy group, carboxyl group, cyano group and amino group
  • Y is selected from C 1-3 alkyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group, halogenated C 1-3 alkane Base, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkane a acyl group, an amino acyl group and a C 1-3 alkylamino acyl group, said C 1-3 alkyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group, halogenated C 1-3 alkyl group
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, Crystallization, solvate or prodrug, of which:
  • R 4 and Y together with the carbon atom to which they are bonded form a C 3-8 carbocyclic group or a C 3-8 heterocyclic group, wherein the heterocyclic group further comprises one or more N, O or S heteroatoms, and
  • the carbocyclic group and heterocyclic group are optionally selected from one or more oxo groups, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halogen, hydroxy, amino, carboxy, nitro a group, a cyano group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • R 4 and Y together with the carbon atom to which they are bound form a C 3-8 carbocyclic group or a C 3-8 heterocyclic group, wherein said heterocyclic group further comprises one or more N, O or S a hetero atom, and the carbocyclic group and heterocyclic group are optionally substituted by one or more oxo groups, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, sulfonyl Substituted with a sulfinyl, fluorenyl, aryl or heteroaryl group;
  • R 4 and Y together with the carbon atom to which they are bonded form a ring propyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, ring Hexenyl, aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, Dihydrofuranyl, dihydropyranyl, cyclothioethane, cyclobutane, tetrahydrothiophenyl, cyclopentyl sulfide, dihydrothienyl, pyrazolidinyl, dihydropyrazolyl, Imidazolidinyl, dihydrothienyl
  • a hexyl group wherein the group is optionally substituted by one or more oxo groups, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, Halogen C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, halogen, hydroxy, amino, carboxy, nitro, cyano, C 1- a 3 alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, a phenyl group or a heteroaryl group.
  • the present invention provides the following specific compounds:
  • the invention provides a process for the preparation of a compound of the formula of the invention, the process comprising the steps of:
  • a compound of the formula (1) is esterified with MOH under the action of a thionyl chloride to obtain a compound of the formula (2);
  • R 1 , R 2 , X and Y have the meanings in the formula I;
  • M represents an alkyl group, preferably a C 1-6 alkyl group, further preferably a C 1-3 alkyl group.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a crystal, a solvate or a prodrug.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or an isomer thereof, pharmaceutically acceptable a salt, crystal, solvate or prodrug, further comprising one or more selected from the group consisting of an IDH1 inhibitor, an IDH2 inhibitor, a tyrosine protease inhibitor, an EGFR inhibitor, a VEGFR inhibitor, Bcr-Abl Inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody, HIV protein kinase inhibitor, HMG-CoA reductase inhibitor Wait.
  • the invention provides a compound of the invention, or an isomer thereof, a pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, and a compound of the invention, or an isomer thereof, pharmaceutically acceptable
  • the compound of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for Oral or parenteral administration.
  • a pharmaceutically acceptable carrier diluent or excipient
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides the use of a compound of Formula I, or an isomer thereof, a pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, for example, for use as a new variant having 2-HG Use of an inhibitor of mutant IDH2.
  • the invention further provides a compound of formula I, or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, for use as a mutation at residue 140 or 172, such as R140Q, R140G, R172K, R172M, Use of inhibitors of IDH2 of R172S, R172G and R172W.
  • the treatment is a cancer associated with a mutant IDH2 having 2-HG neovariant activity.
  • the cancer is associated with a mutant IDH2 having a 2-HG novel variant activity having a mutation at residue R140 or 172, such as R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the present invention provides a compound of the formula I of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a crystal, a solvate or a prodrug thereof, or a pharmaceutical composition comprising the same, in the preparation of a treatment for the presence of a mutant IDH2
  • a medicament for the characteristic cancer wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, liver, kidney, bladder, prostate, breast and Cancers and sarcomas of the pancreas, as well as primary and recurrent solid tumors or leukemias of the skin, colon, thyroid, lungs and ovaries.
  • the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN), acute myeloid leukemia (AML) , sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma or angioimmunoblastic lymphoma.
  • glioblastoma glioma
  • MDS myelodysplastic syndrome
  • MPN myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • sarcoma melanoma
  • non-small cell lung cancer chondrosarcoma
  • cholangiocarcinoma cholangiocarcinoma
  • angioimmunoblastic lymphoma angioimmunoblastic lymphoma.
  • the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloid proliferative neoplasm (MPN), acute myeloid leukemia (AML) ), melanoma, chondrosarcoma, or vascular immunoblastic non-Hodgkin's lymphoma (NHL).
  • glioma myelodysplastic syndrome
  • MDS myeloid proliferative neoplasm
  • AML acute myeloid leukemia
  • melanoma chondrosarcoma
  • NHL vascular immunoblastic non-Hodgkin's lymphoma
  • the present invention relates to a method of treating cancer characterized by the presence of a mutant IDH2 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or an isomer thereof, pharmaceutically An acceptable salt, crystal, solvate or prodrug, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymph Cancer and sarcoma of the tumor, liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors or leukemia of the skin, colon, thyroid, lung and ovary.
  • the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymph Cancer and sarcoma of the tumor, liver, kidney, bladder, prostate, breast and pancreas,
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • alkyl group of the present invention means a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group having 1 to 6 carbon atoms, and more preferably a linear or branched chain having 1 to 3 carbon atoms.
  • Groups non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane Base, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like.
  • the alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • hydroxyalkyl group of the present invention means an alkyl group substituted with at least one hydroxyl group.
  • carbocyclic group of the present invention means a non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyl groups) and partially saturated ring systems.
  • cycloalkyl group of the present invention includes a saturated cyclic, bicyclic, tricyclic or polycyclic hydrocarbon group having 3 to 12 carbons. Any ring atom can be substituted (eg, substituted with one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
  • alkoxy group of the present invention means an -O-alkyl group.
  • alkylamino group of the present invention means -NH-alkyl or -N-(alkyl)(alkyl).
  • alkyl acyl group of the present invention means a -C(O)-alkyl group.
  • aminoacyl group of the present invention means -C(O)-NH 2
  • aminoacyl group of the present invention means -C(O)-NH 2
  • alkylaminoacyl means -C(O)-NH-alkyl or -C(O)-N-(alkyl) ( alkyl).
  • heterocyclic group of the present invention means a non-aromatic group having 1 to 3 hetero atoms if it is a monocyclic ring, 1 to 6 hetero atoms if it is a bicyclic ring or 1 to 9 hetero atoms if it is a tricyclic ring. a 3-10 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system of the family selected from O, N and S (or oxidized forms such as N + -O - , S(O) ) and S(O) 2 ).
  • the hetero atom can optionally be the point of attachment of a heterocyclyl substituent.
  • heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolinyl, pyrimidinyl, and pyrrolidinyl.
  • Heterocyclyl groups include fully saturated cyclic systems and partially saturated cyclic systems.
  • alkoxy group of the present invention means an -O-alkyl group.
  • alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like.
  • the alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • aryl group of the present invention means an aromatic system which may contain a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic group.
  • a system comprising from 6 to 18 carbon atoms, preferably from about 6 to about 14 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl.
  • heteroaryl of the present invention means an aryl group having at least one carbon atom replaced by a hetero atom, and the hetero atom is O, S, N.
  • Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.
  • the "C 3 -C 8 heterocyclic group" of the present invention means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total ring atom number containing at least one hetero atom of 3, 4, 5, 6, 7 or 8 is a heterocyclic group such as C 3-8 nitrogen heterocyclic, heterocyclyl C 3-8 nitrogen oxygen, sulfur, nitrogen C 3-8 heterocyclyl and C 3-8 cycloalkyl group means diazepin-substituted or Unsubstituted saturated, partially saturated and fully unsaturated nitrogen-containing heterocyclic group having 3, 4, 5, 6, 7 or 8 ring atoms, nitrogen-containing heterocyclic group, nitrogen-containing thioheterocyclic group and Azacyclic heterocyclic group.
  • a heterocyclic group such as C 3-8 nitrogen heterocyclic, heterocyclyl C 3-8 nitrogen oxygen, sulfur, nitrogen C 3-8 heterocyclyl and C 3-8 cycloalkyl group means diazepin-substituted or Unsubstituted saturated
  • C 3-10 heteroaryl group of the present invention means a heteroaryl group having a total number of ring atoms of 3, 4, 5, 6, 7, 8, 9 or 10 containing at least one hetero atom.
  • a C 3-6 heteroaryl group refers to a heteroaryl group having at least one hetero atom having a total number of ring atoms of 3, 4, 5 or 6.
  • the compounds of the present invention contain multiple asymmetric centers and, therefore, may be a single enantiomer, an enantiomer, a single enantiomeric mixture, a diastereomer, a mixture of diastereomers. And in the form of a single diastereomer.
  • "Isomers" of the present invention include, for example, tautomers, cis and trans isomers, enantiomers, and conformational forms. Thus, individual stereoisomers as well as enantiomeric, diastereomeric mixtures of the compounds of the invention are within the scope of the invention. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • Optionally substituted means a group such as alkyl, O(R 5 ), N(R 6 R 7 ), cycloalkyl, heterocyclyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, carbocyclyl, aminoalkyl, decylalkyl, aminoalkylalkyl may be unsubstituted or the group may be one or Substituted by a plurality of substituents as defined in formula I, for example by one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halogen, hydroxy, amino, carboxy, nitro , a cyano group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a sulfony
  • solvate of the invention is meant in the conventional sense a complex of a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water).
  • Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is often referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound converted by oxidation, reduction, hydrolysis or the like of an enzyme.
  • a compound of the compound of (I) and/or a compound which is converted into a compound of the formula (I) by a hydrolysis reaction such as gastric acid or the like.
  • composition a compound comprising any of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • the compositions are typically used in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by one or more kinases.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersing agents, and surfaces.
  • the active agent isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, and fibers And cellulose acetate; malt, gelatin and the like.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
  • New variant activity in the present invention means that the wild-type protein does not have a novel protein activity that is present or exhibited to a significant extent.
  • a new variant activity associated with a mutated form of IDH2 is the ability to reduce alpha-ketoglutarate to 2-hydroxyglutaric acid (i.e., 2-HG, particularly R-2-HG).
  • Wild type IDH2 does not have the ability to reduce alpha-ketoglutaric acid to 2-hydroxyglutaric acid (i.e., 2-HG, especially R-2-HG), or if it does have this ability, it does not produce A significant amount (ie, harmful or disease-causing) of 2-HG.
  • the present invention "treating a cancer characterized by the presence of mutant IDH2" means that the cancer having the IDH2 mutation, for example, having a mutation at the residue R140 or 172, can be improved, inhibiting the growth, development and/or metastasis of the cancer, or
  • a therapeutically and/or prophylactically effective amount of a compound of the invention is administered to a human or animal in need thereof to inhibit, slow or reverse the growth, progression or spread of cancer in the subject, thereby improving cancer.
  • cancer including bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervix Cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphoid, including, for example, leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; mesenchymal-derived tumors, including, for example, fibrosarcoma Rhabdomyosarcoma; hematopoietic tumors of the myeloid line, including, for example, acute and chronic myeloid leukemia, myelodysplastic syndrome
  • compositions of the present invention refer to salts of the compounds of the present invention which are safe and effective for use in mammals and which have the desired biological activity.
  • Haldrogen and “carbon” in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers, such as hydrogen isotopes including lanthanum and cerium, carbon isotopes including 13 C and 14 C, and oxygen isotopes including 16 O and 18 O, and the like.
  • Figure 1 shows the survival rate of mice in each group after inoculation with AM7577 cells in the NOD/SCID animal model of human acute myeloid leukemia, wherein the abscissa is the time after cell inoculation (days) and the ordinate is the percentage of survival (%).
  • Example 22B Groups of 15 mg/kg and 45 mg/kg And AG-221 15mg/kg and 45mg/kg group
  • 6-Trifluoromethylpyridine-2-carboxylic acid 25 g, 130.8 mmol was dissolved in 300 mL of methanol, and thionyl chloride (23.3 g, 196.2 mmol) was added dropwise, and the mixture was refluxed for 12 h. The reaction mixture was concentrated to dryness.
  • the biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, sodium hydride (42 g, 1053 mmol) was added portionwise, and stirred at 50 ° C for 1 h.
  • Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 ° C for 16 h.
  • the reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and then filtered to give the title compound.
  • 6-(6-(Trifluoromethyl)pyridin-2-yl)-1,3,5-triazine-2,4-(1H,3H)-dione 35 g, 135.6 mmol was dissolved in 200 mL of three To the phosphorus oxychloride, phosphorus pentachloride (100 g, 542.3 mmol) was added, and the mixture was heated at 105 ° C for 12 h. The reaction mixture was poured into water, EtOAc (EtOAc m.
  • Step 5 4-(4,4-Difluoropiperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine- Preparation of 4-yl)-1,3,5-triazin-2-amine
  • Step 1 4-(Piperazine-4-carboxylic acid tert-butyl ester-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine Preparation of -4-yl)-1,3,5-triazin-2-amine
  • Step 2 4-(Piperazine-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1 Preparation of 3,5-triazin-2-amine
  • Example 12 4-(3-Cyanopiperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4 -yl)-1,3,5-triazin-2-amine
  • Step 2 4-(3-Aminopiperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridin-4-yl Preparation of-1,3,5-triazin-2-amine
  • Step 2 1-(4-(6-(Trifluoromethyl)pyridin-2-yl)-(6-(2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5- Preparation of triazin-2-yl)piperidine-3,4-diol
  • Step 2 4-(3-Fluoro-4,4-dihydroxypiperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) Of pyridyl-4-yl)-1,3,5-triazin-2-amine
  • Example 22 The product obtained in Example 22 was 4-(3-trifluoromethyl-3-hydroxypyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-( 2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (260 mg) was dissolved in 30 mL of methanol for preparative separation.
  • the preparative separation method was: Instrument: MGIIpreparative SFC (SFC-1), preparative column: ChiralCel OD, 250 x 30 mm ID, 5 ⁇ m., mobile phase: A: CO 2 , B: isopropanol (0.1% NH 3 H 2 O), gradient: B 30%, flow rate : 60 mL / min, pressure: 100 bar, column temperature: 38 ° C, detection wavelength: 220 nm.
  • Example 22 The product obtained in Example 22 was 4-(3-trifluoromethyl-3-hydroxypyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-( 2-(Trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (260 mg) was dissolved in 30 mL of methanol for preparative separation.
  • the preparative separation method was: Instrument: MGIIpreparative SFC (SFC-1), preparative column: ChiralCel OD, 250 x 30 mm ID, 5 ⁇ m., mobile phase: A: CO 2 , B: isopropanol (0.1% NH 3 H 2 O), gradient: B 30%, flow rate : 60 mL / min, pressure: 100 bar, column temperature: 38 ° C, detection wavelength: 220 nm.
  • Example 24 4-(Tetrahydropyrimidin-1(2H)-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4 -yl)-1,3,5-triazin-2-amine
  • Step 1 tert-Butyl 3-(4-(6-(trifluoromethyl)pyridin-2-yl)-(6-(2-(trifluoromethyl)pyridin-4-yl)amino)-1,3 Of 5-,3-triazin-2-yl)tetrahydropyrimidine-1(2H)-carboxylate
  • Step 2 4-(tetrahydropyrimidin-1(2H)-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine-4- Preparation of -1,3,5-triazin-2-amine
  • Methyl 1-tritylaziridine-2-carboxylate (500 mg, 1.45 mmol) was dissolved in 10 mL of tetrahydrofuran, and methyllithium was added. (2.91 mL, 2.91 mmol, 1 mol/L in THF), stirred at room temperature for 12 h. The reaction mixture was concentrated to give the title compound.
  • Step 3 4-(2-(2-propyl-2-ol)aziridine-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2- Preparation of (trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
  • Methyl 1-tert-butoxycarbonylazetidine-2-carboxylate 500 mg, 2.33 mmol was dissolved in 10 mL of tetrahydrofuran.
  • Methyl lithium (4.66 mL, 4.66 mmol, 1 mol/L in THF) was added and stirred at room temperature 12h. The reaction mixture was concentrated to give the title compound.
  • Step 3 4-(2-(2-propyl-2-ol)azetidin-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2 Preparation of -(trifluoromethyl)pyridin-4-yl)-1,3,5-triazin-2-amine
  • Example 54 4-(3-Hydroxy-3-cyanopyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl) Pyridin-4-yl)-1,3,5-triazin-2-amine
  • Step 2 4-(3-Hydroxy-3-cyanopyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine Preparation of -4-yl)-1,3,5-triazin-2-amine
  • the control compound is Compound 409 (see page 134) disclosed in WO 2013/102431, chemical name 2-methyl-l-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-( Trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2ylamino)propan-2-ol (AG-221), prepared by the method described in WO2013/102431 and identified by hydrogen spectroscopy and mass spectrometry.
  • each compound was formulated into 20 mM with DMSO, and sequentially diluted to 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, 1.52. nM, 0.51 nM.
  • Reagents 1 ⁇ reaction buffer (50 mM KH 2 PO 4 , 10% glycerol, 150 mM NaCl, 0.05% BSA, 2 mM 2-mercaptoethanol), prepared before use; IDH2 wild-type enzyme (IDH2-WT), purchased from BPS, Cat. No. 71074-1; IDH2-R140Q mutant enzyme (IDH2-R140Q), purchased from BPS, Cat. No. 71100-1; NADPH, purchased from Sigma, Cat. No. N5130 NADP, purchased from Sigma, Cat. No. N5755; dimethyl sulfoxide (DMSO), purchased from Sigma, USA; ⁇ -ketoglutarate, purchased from Sigma, Cat. No. K1875; Isocitrate, It was purchased from Sigma, USA, Cat. No. I1252; Diaphorase, available from Worthington Biochemical, Cat. No. LS004327.
  • IDH2 wild-type enzyme IDH2 wild-type enzyme (IDH2-WT)
  • the final concentration of IDH2-WT enzyme was 0.06 ng/ml
  • the final concentration of the reaction substrate Isocitrate was 150 ⁇ M
  • the final concentration of the reaction cofactor NADP was 25 ⁇ M.
  • the final concentration of IDH2-R140Q in the IDH2-R140Q reaction system Is 0.3ng/ml
  • the final concentration of the reaction substrate ⁇ -ketoglutarate was 4 mM
  • the final concentration of the reaction cofactor NADPH was 15 ⁇ M.
  • reaction buffer containing 2 ⁇ enzyme IDH2-WT or IDH2-R140Q
  • cofactor NADP or NADPH
  • the compound group was added with 20 ⁇ L of reaction buffer containing 4 ⁇ test compound per well.
  • the compound was prepared in 200 ⁇ mother liquor with 100% DMSO in advance, and the DMSO concentration was 0.5% in the final reaction system; 20 ⁇ L of DMSO was added to each well of the DMSO control group. Reaction buffer, the final reaction system, the concentration of DMSO is 0.5%;
  • the compound is mixed with the enzyme and its cofactor and pre-incubated at room temperature for 16 h;
  • reaction buffer containing 4 ⁇ reaction substrate 20 ⁇ L was added to each well, and the mixture was reacted at room temperature for 1 h.
  • 3 ⁇ stop detection solution prepared with reaction buffer, the final concentration of Diaphorase is 0.015 mg/mL, and the final concentration of Resazurin is 0.03 mM). Add 40 ⁇ L of 3 ⁇ stop detection solution to each well of the enzyme reaction system, mix and incubate for 10 min at room temperature. ;
  • Activity% (Measured data-Subtract background)/(DMSO Control-Subtract background) ⁇ 100, where Measured data is compound pre- The fluorescence value of the incubation well, Subtract background is the fluorescence value of the enzyme-free control well, and DMSO Control is the fluorescence value of the DMSO pre-incubation well.
  • the experimental results show that the IC 50 of the compound of the present invention is nM level, and the IC 50 value of some compounds is better than that of the control drug AG-221, and in particular, the enzyme activity of some compounds against the R140Q mutant enzyme can be more than three times.
  • Test compound The compound of the present invention prepared in the above partial examples, each compound was formulated into 20 mM with DMSO, and then diluted 3 times to 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM. , 4.57nM, 1.52nM.
  • human glioblastoma cell line U87-MG purchased from the American Type Culture Collection (ATCC);
  • the U87-MG cell line overexpressing the mutant IDH2 (R140Q) was constructed by Nanjing Kingsray Biotechnology Co., Ltd. using conventional molecular biology techniques, including the following brief steps:
  • MEM medium purchased from Invitrogen, USA;
  • Fetal bovine serum purchased from Invitrogen, USA;
  • Trypsin purchased from Invitrogen, USA;
  • Phenacetin standard (internal standard / IS): purchased from Sigma, purity ⁇ 98%;
  • Acetonitrile/methanol (chromatographically pure) was purchased from Merck;
  • the U87-MG cell line without transfection of IDH2 (R140Q) was used in the non-mutation control group, and the U87-MG cell line overexpressing mutant IDH2 (R140Q) was used in the compound group and the DMSO control group [U87-MG (IDH2-R140Q)] .
  • Cell resuscitation Cell line U87-MG (IDH2-R140Q) and U87-MG cells were dissolved in a 37 ° C water bath, then transferred to 15 mL of pre-warmed medium, centrifuged at 1000 rpm for 5 minutes, and the medium was discarded. The cells were resuspended in 15 mL of fresh medium, transferred to T75 flasks, and cultured in a 37 ° C, 5% CO 2 incubator. After 24 hours, the cells were replaced with fresh medium.
  • Cell passage Transfer the above-mentioned resuscitated cells to a 50 mL sterile centrifuge tube, centrifuge at 1000 rpm for 5 minutes, discard the medium, take a uniform cell count, adjust the appropriate cell concentration to 15 mL of fresh medium, and add to T75 culture.
  • the flask was placed in an incubator at 37 ° C, 5% CO 2 .
  • the cells were grown to a higher density in the culture dish, they were trypsinized, resuspended in medium (MEM + 10% FBS), and counted.
  • the resuspended cells were adjusted to a concentration and seeded in a 96-well plate at 5 x 10 3 cells per well. After inoculation, the cells were cultured for 24 hours until the cells adhered. The medium was aspirated, and the medium containing the gradient concentration compound was added, 100 ⁇ L per well, and the cells were further cultured for 72 hours. The cell supernatant was removed by 20 ⁇ L and placed in a 2 mL 96-well sample-processing plate. 480 ⁇ L of the dilution was added, shaken and mixed, centrifuged at 4500 rpm for 5 minutes, and the supernatant was transferred to 200 ⁇ L for LC-MS/MS injection analysis.
  • the atmospheric piezoelectric ionization source is selected, and the source parameters are set as: IonSpray Voltage/IS-4500V, Ion Source Gas 1/GS 1, N2 55Arb, Ion Source Gas 2/GS 2, N2) 55 Arb, auxiliary gas heating temperature (Temperature/TEM) 500 ° C, Curtain Gas (CUR) 25 Arb, collision gas (Collision Gas / CAD, N2) 8 Pa.
  • MRM Multiple ion reaction monitoring
  • the MRM parameters of 2-HG are: parent ion (Q 1Mass) is 146.9Da, daughter ion (Q 3Mass) is 129.0Da, de-clusting potential (DP) is -15.3V, collision voltage (Collision Energy/CE) It is -14.5 eV.
  • the internal standard (IS) MRM parameters are: parent ion (Q 1Mass) is 178.0Da, daughter ion (Q3Mass) is 149.0Da, decluster potential (DP) is -51V, collision voltage (Collision Energy/CE) It is -17eV.
  • Example 1 Compound IC 50 (nM) Compound IC 50 (nM) Example 1 15 Example 2 27 Example 3 twenty four Example 4 twenty one Example 27 31.2 Example 28 25.1 Example 29 17.1 Example 31 38.1 Example 32 36.1 Example 33 10.2 Example 34 17.1 Example 35 9.8 Example 38 59.1 Example 40 33.1
  • Example 41 10.1 Example 42 8.1 Example 43 9.6 Example 44 5.1 Example 45 10.2 Example 55 15.0 AG-221 30.2
  • the experimental results show that the IC 50 of the compound of the present invention is nM level, and the IC 50 value of some compounds is much better than that of the control drug AG-221, and has a very good ability to inhibit IDH2.
  • Test compound The compound of the present invention prepared in the above partial examples, each compound used in a solvent (2% absolute ethanol: 10%) : 88% physiological saline (v/v/v)) was formulated as the corresponding concentration solution.
  • mice BALB/c nude mice, 6-7 weeks old, female, 18-22 g, purchased from Nanjing Jinlaichang Company.
  • U87-MG (IDH2-R140Q) cells and U87-MG cells (wild type) were expanded, and tumor cells in the logarithmic growth phase were used for tumor inoculation in vivo. According to the amount of 2 ⁇ 10 6 cells/mouse (the volume ratio of cell suspension to Matrigel was 1:0.8), 16 mice were inoculated subcutaneously into the right lower back of the body.
  • the non-mutation control group used the U87-MG cell line inoculated nude mice, and the compound group and the vehicle control group used U87-MG (IDH2-R140Q) inoculated nude mice.
  • Each group was intragastrically administered with a corresponding concentration of the compound solution, the administration volume was 100 ⁇ L/10 g body weight, and the control group was given the same volume of blank vehicle.
  • mice were sacrificed, the tumor was exfoliated, homogenized, and the 2-HG content in the tumor was examined.
  • the 2-HG concentration of the tumor homogenate of each animal in each group was determined by LC-MS/MS, and the percentage (2-HG%) was calculated.
  • the calculation formula is as follows.
  • 2-HG% (intratumoral 2-HG concentration in the drug-administered group - intratumoral 2-HG concentration in the U87-MG control group)/(U87-MG(IDH2-R140Q) control group intratumoral 2-HG concentration-U87-MG Intratumoral 2-HG concentration in the control group) ⁇ 100%
  • the experimental results indicate that the compound of the present invention has a very good ability to inhibit high levels of 2-HG caused by IDH2 mutations in tumors in the U87-MG (IDH2-R140Q) mutant cell subcutaneous xenograft model, and some compounds such as the examples
  • the compounds of 22A, 22B, 45, 51, 55 have a significantly better ability to inhibit 2-HG levels than the positive compound AG-221.
  • the compounds of the present invention are expected to have a good effect of inhibiting the production and progression of tumors caused by IDH2 mutations.
  • Test compound The compound of the present invention prepared in the above partial examples, each compound used in a solvent (2% absolute ethanol: 10%) : 88% physiological saline (v/v/v)) was formulated as the corresponding concentration solution.
  • FITC anti-human CD45 purchased from Biolegend
  • NOD/SCID mice 3-4 weeks old, female, purchased from Beijing Huakang Biotechnology Co., Ltd.;
  • Each mouse was inoculated through the tail vein in an amount of 2 x 10 6 cells resuspended in 100 uL of PBS.
  • the mortality of the animals after administration and the survival of the surviving animals were observed.
  • the number of animals in each group after 14 days of administration is shown in Table 7.
  • the survival period of each group of animals after administration is shown in Fig. 1.
  • the results of the experiment showed that only 1 of the control animals survived after 14 days of administration, and 3 of the 4 animals in the high dose (45 mg/kg) of the positive compound AG-221 survived.
  • the positive compound AG-221 was low dose (15 mg/ Six of the 8 animals in the kg) group survived, while 7 animals in the low-dose group of the compounds of the invention survived.
  • the survival of the mice treated with the compounds of the present invention was significantly prolonged compared to the vehicle control group, and as the dose was increased, the efficacy of the compounds of the present invention was significantly better than that of the positive compound AG-221. Animal survival has increased significantly.
  • the compounds of the invention can significantly improve the survival rate and survival of tumor-bearing mice.

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Abstract

一类作为异柠檬酸脱氢酶抑制剂的化合物及其应用，属于医药化学领域，具体为式I所示的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物的应用。所述化合物具有非常好的抑制突变型IDH2酶活性及抑制突变型IDH2肿瘤细胞的功能，可用于预防和/或治疗以突变型IDH2的存在为特征的肿瘤。

Description

作为异柠檬酸脱氢酶抑制剂的化合物及其应用 技术领域
本发明属于医药化学领域，具体涉及一类作为异柠檬酸脱氢酶2抑制剂的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗以突变型异柠檬酸脱氢酶2的存在为特征的癌症的用途。
背景技术
异柠檬酸脱氢酶(isocitrate dehydrogenase，IDH)是三羧酸循环的限速酶，其家族包括IDH1、IDH2和IDH3三个成员，借助NAD+(烟酰胺腺嘌呤二核苷酸，辅酶I)或NADP+(烟酰胺腺嘌呤二核苷酸磷酸，辅酶II)作为辅助因子，催化异柠檬酸的氧化脱羧反应生成α-酮戊二酸(α-KG)，同时分别生成NADH(还原型辅酶I)或NADPH(还原型辅酶II)。IDH同工酶有以下三种形式：依赖NADP的胞质的IDH1和线粒体的IDH2，依赖NAD的线粒体IDH3。IDH1基因位于染色体2q33.3，定位于细胞质和过氧化物酶体中；IDH2基因位于染色体15q26.1，定位于细胞线粒体。
已经在多种癌症中鉴别出IDH2突变，所述癌症例如神经胶质瘤、多形性成胶质细胞瘤、急性髓性白血病(AML)等。IDH2的突变包括R140和R172等，这些突变发生在活性位点的关键残基处或附近(参见L.Dang等人,Nature,2009,462,739-44)。研究表明存在于癌细胞中的IDH2的突变导致所述酶具有催化α-酮戊二酸NAPH-依赖性还原为R(-)-2-羟基戊二酸(2-HG)的新的能力。已经在包含突变的肿瘤中检测到高水平的2-HG。例如，已经在患有含突变IDH的AML的患者的血浆中检测到高水平的2-HG(参见S.Gross等人,J.Exp.Med.,2010,207(2),339)。认为IDH2突变导致的高水平2-HG的产生促成癌症的形成和发展(参见L.Dang等人,Nature,2009,462,739-44)。因此，对突变型IDH2及其新生活性的抑制作为以突变型IDH2的存在为特征的癌症治疗进入药物研究人员视野。研制一种安全有效的IDH抑制剂成为治疗癌症的重要方式。
目前，抑制突变型IDH2以用于治疗癌症的药物研究已经取得了一些成功。不过，仍然需要开发更优异的IDH2抑制剂，从而用于治疗与IDH2介导的事件相关的疾病。
发明内容
本发明的一个目的是提供通式I所示的一类具有IDH2抑制活性的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，
Figure PCTCN2017093597-appb-000001
其中，
R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
X选自N(R3)、O、S和C(R4)，其中R3选自氢、烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基和氨基巯基烷基或者R3和Y与它们所结合的氮原子一起形成任选取代的杂环基，R4选自氢、烷基、烯基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基和氨基烷基或者R4和Y与它们所结合的碳原子一起形成任选取代的碳环基或杂环基，其中所述烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基、氨基巯基烷基、烯基、羟基、卤素、氧代基团、烷氧基、羧基、氰基、氨基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
Y选自任选取代的烷基、O(R5)、N(R6R7)、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，其中R5、R6和R7独立地选自任选取代的烷基、环烷基和杂环基，或者R6和R7与它们所结合的氮原子一起形成杂环基；且
当X为N(R3)，且R3为氢时，则Y选自任选取代的O(R5)和N(R6R7)，且X和Y间的虚线代表单键；
当X为N(R3)，且R3选自烷基、卤代烷基和羟基烷基、巯基烷基和氨基巯基烷基时，则Y选自任选取代的烷基、O(R5)和N(R6R7)且X和Y间的虚线代表单键，或者R3和Y与它们所结合的氮原子一起形成任选取代的杂环基；
当X选自O和S时，则Y选自任选取代的烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，且X和Y间的虚线代表单键；
当X为C(R4)时，则Y选自任选取代的烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、 卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，且X和Y间的虚线代表单键、双键或三键，或者R4和Y与它们所结合的碳原子一起形成任选取代的碳环基或杂环基。
本发明的另一个目的是提供制备本发明的通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药和药学可接受的载体的组合物，以及包含本发明的通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药和另一种或多种IDH2抑制剂的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药治疗以突变型IDH2的存在为特征的癌症的方法，以及本发明的通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药在制备用于治疗以突变型IDH2的存在为特征的癌症的药物中的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供通式I所示的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，
Figure PCTCN2017093597-appb-000002
其中，
R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
X选自N(R3)、O、S和C(R4)，其中R3选自氢、烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基和氨基巯基烷基或者R3和Y与它们所结合的氮原子一起形成任选取代的杂环基，R4选自氢、烷基、烯基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基和氨基烷基或者R4和Y与它们所结合的碳原子一起形成任选取代的碳环基或杂环基，其中所述烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基、氨基巯基烷基、烯基、羟基、卤素、氧代基团、烷氧基、羧基、氰 基、氨基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
Y选自任选取代的烷基、O(R5)、N(R6R7)、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，其中R5、R6和R7独立地选自任选取代的烷基、环烷基和杂环基，或者R6和R7与它们所结合的氮原子一起形成杂环基；且
当X为N(R3)，且R3为氢时，则Y选自任选取代的O(R5)和N(R6R7)，且X和Y间的虚线代表单键；
当X为N(R3)，且R3选自烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基和氨基巯基烷基时，则Y选自任选取代的烷基、O(R5)和N(R6R7)且X和Y间的虚线代表单键，或者R3和Y与它们所结合的氮原子一起形成任选取代的杂环基；
当X选自O和S时，则Y选自任选取代的烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，且X和Y间的虚线代表单键；
当X为C(R4)时，则Y选自任选取代的烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基且X和Y间的虚线代表单键、双键或三键，或者R4和Y与它们所结合的碳原子一起形成任选取代的碳环基或杂环基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
R1、R2各自独立地选自氢、卤素、羟基、C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
进一步优选地，R1、R2各自独立地选自氢、卤素、羟基、C1-3烷基、C3-6环烷基、C3-6杂环基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、氨基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟 基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和C3-10杂芳基取代；
更进一步优选地，R1、R2各自独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、三氟甲氧基、三氟乙氧基、羟甲氧基、羟乙氧基、羟丙氧基、2-羟基丙氧基、甲氧基、乙氧基、丙氧基、异丙氧基、氨基、甲氨基、二甲氨基、乙氨基、二乙氨基、甲基乙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、羧基、硝基和氰基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
X为N(R3)，R3为氢，Y为O(R5)，R5选自C1-12烷基、C3-8环烷基和C3-8杂环基，所述的C1-12烷基、C3-8环烷基和C3-8杂环基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，X为N(R3)，R3为氢，Y为O(R5)，R5选自C1-12烷基、C3-8环烷基和C3-8杂环基，所述的C1-12烷基、C3-8环烷基和C3-8杂环基任选被一个或多个C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，X为N(R3)，R3为氢，Y为O(R5)，R5选自C1-6烷基、C3-6环烷基和C3-6杂环基，所述的C1-6烷基、C3-6环烷基和C3-6杂环基任选被一个或多个C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
X为N(R3)，R3为氢，Y为N(R6R7)，R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，X为N(R3)，R3为氢，Y为N(R6R7)，R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、 氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，X为N(R3)，R3为氢，Y为N(R6R7)，R6和R7独立地选自C1-3烷基、C3-6环烷基和C3-6杂环基，所述的C1-3烷基、C3-6环烷基和C3-6杂环基任选被一个或多个C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
X为N(R3)，R3为氢，Y为N(R6R7)，R6和R7与它们所结合的氮原子一起形成C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述杂环基任选被一个或多个氧代基团、烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，X为N(R3)，R3为氢，Y为N(R6R7)，R6和R7与它们所结合的氮原子一起形成C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述杂环基任选被一个或多个氧代基团、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，X为N(R3)，R3为氢，Y为N(R6R7)，R6和R7与它们所结合的氮原子一起形成选自氮杂环丙基、氮杂环丁基、四氢吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡唑烷基、二氢吡唑基、咪唑烷基、二氢咪唑基、吡唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、噻唑烷基、二氢噻唑基、异噁唑烷基、二氢异噁唑基、异噻唑烷基、二氢异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吗啉基、硫代吗啉基和牛磺胺基的基团，其中所述基团任选被一个或多个氧代基团、C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
X为N(R3)，R3选自C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、巯基C1-6烷基和氨基巯基C1-6烷基，Y选自任选取代的C1-6烷基、O(R5)和N(R6R7)、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，R5、R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、卤代C1-6烷基、羟 基C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，X为N(R3)，R3选自C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、巯基C1-6烷基和氨基巯基C1-6烷基，Y选自C1-6烷基、O(R5)、N(R6R7)、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，R5、R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，X为N(R3)，R3选自C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、巯基C1-6烷基和氨基巯基C1-6烷基，Y选自C1-6烷基、O(R5)和N(R6R7)、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，R5、R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
R3和Y与它们所结合的氮原子一起形成C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述杂环基任选被一个或多个氧代基团、烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，R3和Y与它们所结合的氮原子一起形成C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述杂环基任选被一个或多个氧代基团、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，R3和Y与它们所结合的氮原子一起形成氮杂环丙基、氮杂环丁基、四氢吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡唑烷基、二氢吡唑基、咪唑烷基、二氢咪唑基、吡唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、噻唑烷基、二氢噻唑基、异噁唑烷基、二氢异噁唑基、异噻唑 烷基、二氢异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吗啉基、硫代吗啉基和牛磺胺基的基团，其中所述基团任选被一个或多个氧代基团、C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述通式I的化合物具有如下式Ia的结构：
Figure PCTCN2017093597-appb-000003
其中R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
环A为杂环基，优选选自氮杂环基、氮氧杂环基、氮硫杂环基和二氮杂环基；
R8选自氢、氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代。
在一些实施方案中，本发明的化合物为通式Ia的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中
R1、R2各自独立地选自氢、卤素、羟基、C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷 基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和C3-10杂芳基取代；
环A选自C3-8氮杂环基、C3-8氮氧杂环基、C3-8氮硫杂环基和C3-8二氮杂环基；
R8选自氢、氧代基团、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-8环烷基、C3-8杂环基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和C3-10杂芳基取代。
在一些实施方案中，本发明的化合物为通式Ia的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中环A选自氮杂环丙基、氮杂环丁基、四氢吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡唑烷基、二氢吡唑基、咪唑烷基、二氢咪唑基、吡唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、噻唑烷基、二氢噻唑基、异噁唑烷基、二氢异噁唑基、异噻唑烷基、二氢异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吗啉基、硫代吗啉基和牛磺胺基的基团，其中所述基团任选被一个或多个氧代基团、C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述通式I的化合物具有如下式Iaa的结构：
Figure PCTCN2017093597-appb-000004
其中R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧 基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
R8选自氢、氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
m为1、2、3、4、5或6。
在一些实施方案中，本发明的化合物为通式Iaa的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中
R1、R2各自独立地选自氢、卤素、羟基、C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基、C1-6烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和杂芳基取代；
R8选自氢、氧代基团、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-8环烷基、C3-8杂环基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、 杂环基、芳基和杂芳基取代；
m为1、2、3、4、5或6。
在一些实施方案中，本发明的化合物为通式Iaa的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中
R1、R2各自独立地选自氢、卤素、羟基、C1-3烷基、C3-6环烷基、C3-6杂环基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、氨基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基、C1-3烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和C3-10杂芳基取代；
R8选自氢、氧代基团、C1-3烷基、卤代C1-3烷基、羟基C1-3烷基、C3-6环烷基、C3-6杂环基、C1-3烷氧基、卤代C1-3烷氧基、羟基C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和C3-10杂芳基取代；
m为1、2、3、4、5或6。
在一些实施方案中，本发明的化合物为通式Iaa的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中
基团
Figure PCTCN2017093597-appb-000005
选自氮杂环丙基、氮杂环丁基、四氢吡咯基和哌啶基；和
R8选自氢、氧代基团、C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-8环烷基、C3-8杂环基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、C1-6烷基、卤代C1-6烷基、 羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷氧基、硝基、羧基、氰基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、C3-8环烷基、C3-8杂环基、C6-10芳基和C3-10杂芳基取代。
在一些具体的实施方案中，本发明的化合物为通式Iaa的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中R8选自以下基团中的一个或多个：氢、氧代基团、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、氰基、氨基、羧基、硝基、羟甲基、羟乙基、羟丙基、2-羟基丙基、三氟甲氧基、三氟乙氧基、羟甲氧基、羟乙氧基、羟丙氧基、2-羟基丙氧基、甲氧基、乙氧基、丙氧基、异丙氧基、氨基、甲氨基、二甲氨基、乙氨基、二乙氨基、甲基乙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基和环己基。在一些具体的实施方案中，本发明的化合物为通式Iaa的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中基团
Figure PCTCN2017093597-appb-000006
选自
Figure PCTCN2017093597-appb-000007
Figure PCTCN2017093597-appb-000008
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
X选自O和S，Y选自C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6 烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，所述的C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，X选自O和S，Y选自C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，所述的C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基任选被一个或多个C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，X选自O和S，Y选自C1-3烷基、C3-6环烷基、C3-6杂环基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基和C1-3烷基氨基酰基，所述的C1-3烷基、C3-6环烷基、C3-6杂环基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基和C1-3烷基氨基酰基任选被一个或多个C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
不希望被现有理论所束缚，本发明的发明人意料不到地发现，根据本发明的通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中当X为O时，即为以下通式Ib所示的化合物时，本发明的化合物具有非常优异的抑制突变型IDH2酶活性以及抑制突变型IDH2肿瘤细胞的功能，
Figure PCTCN2017093597-appb-000009
在一些实施方案中，本发明的化合物为通式Ib的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中
R1、R2各自独立地选自氢、卤素、羟基、C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、氨基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰 基、氨基酰基、C1-6烷基氨基酰基、羧基、硝基和氰基；
Y选自C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基。在一些具体的实施方案中，本发明的化合物为通式Ib的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中Y选自甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、三氟丙基、三氟异丙基、2,2,3,3,3-五氟丙基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
X为C(R4)，R4选自氢、C1-6烷基、卤代C1-6烷基、羟基、羟基C1-6烷基、卤素、氧代基团、C1-6烷氧基、羧基、氰基和氨基，Y选自C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，所述的C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，X为C(R4)，R4选自氢、C1-6烷基、卤代C1-6烷基、羟基、羟基C1-6烷基、卤素、氧代基团、C1-6烷氧基、羧基、氰基和氨基，Y选自C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，所述的C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基任选被一个或多个C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，X为C(R4)，R4选自氢、C1-3烷基、卤代C1-3烷基、羟基、羟基C1-3烷基、卤素、氧代基团、C1-3烷氧基、羧基、氰基和氨基，Y选自C1-3烷基、C3-6环烷基、C3-6杂环基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基和C1-3烷基氨基酰基，所述的C1-3烷基、C3-6环烷基、C3-6杂环基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3烷基氨基、C1-3烷基酰基氨基、C1-3烷基酰基、氨基酰基和C1-3烷基氨基酰基任选被一个或多个C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、 结晶、溶剂化物或前药，其中：
R4和Y与它们所结合的碳原子一起形成C3-8碳环基或C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述碳环基和杂环基任选被一个或多个氧代基团、烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
进一步优选地，R4和Y与它们所结合的碳原子一起形成C3-8碳环基或C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述碳环基和杂环基任选被一个或多个氧代基团、C1-6烷基、C3-8环烷基、C3-8杂环烷基、C1-6烷氧基、C1-6烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-6烷基酰基、氨基酰基、C1-6烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；
更进一步优选地，R4和Y与它们所结合的碳原子一起形成选自环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、环氧丙烷基、四氢呋喃基、四氢吡喃基、二氢呋喃基、二氢吡喃基、环硫乙烷基、硫化环丁烷基、四氢噻吩基、硫化环戊烷基、二氢噻吩基、吡唑烷基、二氢吡唑基、咪唑烷基、二氢咪唑基、吡唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、噻唑烷基、二氢噻唑基、异噁唑烷基、二氢异噁唑基、异噻唑烷基、二氢异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吗啉基、硫代吗啉基、二氧六环基、二硫六环基、牛磺胺基、双环[2.2.1]庚烷基和氧代双环[3.1.0]己烷基的基团，其中所述基团任选被一个或多个氧代基团、C1-3烷基、C3-6环烷基、C3-6杂环烷基、卤代C1-3烷基、羟基C1-3烷基、C1-3烷氧基、C1-3烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、C1-3烷基酰基、氨基酰基、C1-3烷氨基酰基、磺酰基、亚磺酰基、巯基、苯基或杂芳基取代。
本发明提供了以下具体化合物：
Figure PCTCN2017093597-appb-000010
Figure PCTCN2017093597-appb-000011
Figure PCTCN2017093597-appb-000012
Figure PCTCN2017093597-appb-000013
另一方面，本发明提供本发明的通式化合物的制备方法，该方法包括以下步骤：
Figure PCTCN2017093597-appb-000014
a)式(1)的化合物在二氯亚砜作用下与MOH发生酯化反应，制得式(2)的化合物；
b)式(2)的化合物与式(3)的化合物在强碱的作用下反应，制得式(4)的化合物；
c)式(4)的化合物与五氯化磷反应制得式(5)的化合物；
d)式(5)的化合物与式(6)的化合物反应制得式(7)的化合物；
e)式(7)的化合物与式(8)的化合物或式(8)的盐经常规反应制得式(I)的化合物。
其中，R1、R2、X和Y具有通式I中的含义；M表示烷基，优选为C1-6烷基，进一步优选为C1-3烷基。
第三方面，本发明提供药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药。
在一些实施方案中，本发明提供药物组合物，其包含本发明的化合物或其异构体、药学上可接受 的盐、结晶、溶剂化物或前药，还包含选自下列组成的一种或多种：IDH1抑制剂、IDH2抑制剂、酪氨酸蛋白酶抑制剂、EGFR抑制剂、VEGFR抑制剂、Bcr-Abl抑制剂、c-kit抑制剂、c-Met抑制剂、Raf抑制剂、MEK抑制剂、组蛋白去乙酰酶抑制剂、VEGF抗体、EGF抗体、HIV蛋白激酶抑制剂、HMG-CoA还原酶抑制剂等。
在一些实施方案中，本发明提供本发明的化合物或其或其异构体、药学上可接受的盐、结晶、溶剂化物或前药及包含本发明的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药的药物组合物，所述化合物或药物组合物用于治疗以突变型IDH2的存在为特征的癌症。
可以将本发明的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
第四方面，本发明提供通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药在治疗中的用途，例如用作具有2-HG新变体活性的突变IDH2的抑制剂的用途。本发明还提供通式I的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药用作在残基140或172处具有突变，例如R140Q、R140G、R172K、R172M、R172S、R172G和R172W的IDH2的抑制剂的用途。在一些实施方案中，所述治疗是与具有2-HG新变体活性的突变IDH2相关的癌症。在另一些实施方案中，癌症与具有在残基R140或172处具有突变，例如R140Q、R140G、R172K、R172M、R172S、R172G和R172W的2-HG新变体活性的突变IDH2相关。本发明提供本发明通式I所示的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，或包含其的药物组合物在制备治疗以突变型IDH2的存在为特征的癌症的药物中的用途，其中所述的癌症选自黑素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、肺癌、恶性淋巴肿瘤，肝、肾、膀胱、前列腺、乳腺和胰腺的癌和肉瘤，以及皮肤、结肠、甲状腺、肺和卵巢的原发和复发性实体瘤或者白血病等。在具体的实施方案中，待治疗的癌症是成胶质细胞瘤(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淋巴瘤。在更具体的实施方案中，待治疗的癌症是成胶质细胞瘤(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)、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)。在一些实施方案中，本发明涉及一种治疗以突变型IDH2的存在为特征的癌症的方法，其包括给予所需患者治疗有效量的通式I所示的化合物或其异构体、药学上 可接受的盐、结晶、溶剂化物或前药，或包含其的药物组合物，其中所述的癌症选自黑素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、肺癌、恶性淋巴肿瘤，肝、肾、膀胱、前列腺、乳腺和胰腺的癌和肉瘤，以及皮肤、结肠、甲状腺、肺和卵巢的原发和复发性实体瘤或者白血病等。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明“卤素”是指氟、氯、溴、碘。
本发明“烷基”指直链或支链的饱和脂肪烃基团，优选含1至6个碳原子的直链或支链基团，进一步优选含有1至3个碳原子的直链或支链基团，非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。本发明的“卤代烷基”是指至少被一个卤素取代的烷基。本发明的“羟基烷基”是指至少被一个羟基取代的烷基。本发明的“碳环基”是指非芳族的单环、双环或三环烃环系统。碳环基包括完全饱和的环状系统(例如环烷基)和部分饱和的环状系统。
本发明的“环烷基”包括具有3-12个碳的饱和的环状、双环、三环或多环烃基。任何环原子可以是取代的(例如被一个或多个取代基取代)。环烷基部分的实例包括但不限于环丙基、环己基、甲基环己基、金刚烷基和降冰片烷基。
本发明的“烷氧基”是指-O-烷基。
本发明的“烷基氨基”是指-NH-烷基或-N-(烷基)(烷基)。
本发明的“烷基酰基”是指-C(O)-烷基。
本发明的“氨基酰基”是指-C(O)-NH2，术语“烷氨基酰基”是指-C(O)-NH-烷基或-C(O)-N-(烷基)(烷基)。
本发明的“杂环基”是指如果为单环则具有1-3个杂原子、如果为双环则具有1-6个杂原子或如果为三环则具有1-9个杂原子的非芳族的3-10元单环、8-12元双环或11-14元三环环状系统，所述杂原子选自O、N和S(或氧化形式例如N+-O-、S(O)和S(O)2)。杂原子可任选为杂环基取代基的连接点。杂环基的实例包括但不限于四氢呋喃基、四氢吡喃基、哌啶基、吗啉基、吡咯啉基、嘧啶基和吡咯烷基。杂环基包括完全饱和的环状系统和部分饱和的环状系统。
本发明的“烷氧基”是指-O-烷基。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、正丙氧基、异丙氧基、异丁氧基、仲丁氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“芳基”是指可以包含单环或稠合多环的芳香体系，优选包含单环或稠合双环的芳香体 系，其含有6个至18个碳原子，优选含有约6至约14个碳原子。合适的芳基包括但不限于苯基、萘基、蒽基、四氢萘基、芴基、茚满基。
本发明的“杂芳基”是指至少有一个碳原子被杂原子替代的芳基，所述的杂原子为O、S、N。合适的杂芳基包括但不限于咪唑基、苯并咪唑基、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基等。
本发明的“C3-C8杂环基”是指含有至少一个杂原子的取代或未取代的饱和、部分饱和和完全不饱和的总环原子数为3、4、5、6、7或8的杂环基团，例如C3-8氮杂环基、C3-8氮氧杂环基、C3-8氮硫杂环基和C3-8二氮杂环基是指取代或未取代的饱和、部分饱和和完全不饱和的总环原子数为3、4、5、6、7或8的含氮杂环基、含氮氧杂环基、含氮硫杂环基和二氮杂环基。
本发明的“C3-10杂芳基”是指含有至少一个杂原子的总环原子数为3、4、5、6、7、8、9或10的杂芳基。类似地，C3-6杂芳基是指含有至少一个杂原子的总环原子数为3、4、5或6的杂芳基。
本发明的化合物含有多个不对称中心，因此，可以以单一对映异构体、对映异构体、单一对映异构体混合物、非对映异构体、非对映异构体混合物和单一非对映异构体的形式存在。本发明的“异构体”包括例如互变异构体、顺反异构体、对映异构体、构象异构体形式。因此，本发明的化合物的单个立体异构体以及对映异构体、非对映异构体混合物均在本发明的范围内。除非另外指明，本发明化合物的全部互变异构体形式在本发明的范围内。“任选取代”表示基团如烷基、O(R5)、N(R6R7)、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、碳环基、氨基烷基、巯基烷基、氨基巯基烷基可以是未取代的或者所述基团可以被一个或多个如通式I中所定义的取代基取代，例如被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代。
本发明“溶剂化物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂化物通常被称作水合物，例如一水合物、二水合物、三水合物等。
本发明的“前药”是指在生物体中的生理条件下，由于与酶、胃酸等反应而转化成式(Ⅰ)的化合物的化合物，即通过酶的氧化、还原、水解等转化成式(I)的化合物的化合物和/或通过胃酸等的水解反应等转化成式(I)的化合物的化合物等。
本发明“药物组合物”是指包含任何一种本文所述的化合物，包括对应的异构体、前药、溶剂化物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。药用组合物的目的是促进化合物对生物体的给药。所述组合物通常用于制备治疗和/或预防由一种或多种激酶介导的疾病的药物。
本发明“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含所有的溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为 药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。
本发明“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。
本发明中的“新变体活性”指野生型蛋白质没有以显著程度具有或呈现的新的蛋白质活性。例如，与IDH2的突变形式相关的新变体活性是将α-酮戊二酸还原为2-羟基戊二酸(即2-HG、特别是R-2-HG)的能力。野生型IDH2不具有将α-酮戊二酸还原为2-羟基戊二酸(即2-HG、特别是R-2-HG)的能力，或者，如果它确实具有该能力，则它不产生显著量(即有害的或引起疾病的)的2-HG。
本发明“治疗以突变型IDH2的存在为特征的癌症”是指可以使具有IDH2突变，例如在残基R140或172处具有突变的癌症得到改善，抑制癌症的生长、发展和/或转移，或降低患癌症的风险，主要向所需要的人或动物给予治疗和/或预防有效量的本发明的化合物以抑制、减慢或逆转受治疗者中癌症的生长、发展或扩散，使癌症得到改善，或降低患病风险，所述的肿瘤包括癌，例如包括膀胱癌、乳腺癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌)；淋巴系的造血肿瘤，例如包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤；间充质细胞来源的肿瘤，例如包括纤维肉瘤、横纹肌肉瘤；髓系的造血肿瘤，例如包括急慢性骨髓性白血病、骨髓增生异常综合征和前髓细胞白血病；中枢和周围神经系统肿瘤，例如包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤；和其它肿瘤，例如包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、色性干皮病、角化棘皮瘤、甲状腺滤泡癌和卡波济氏肉瘤。
本发明“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物中的“氢”、“碳”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子，例如氢的同位素包括氚和氘，碳的同位素包括13C和14C，氧的同位素包括16O和18O等。
附图说明
图1为人急性髓性白血病NOD/SCID动物模型中接种AM7577细胞后随时间进展各组小鼠的存活率，其中横坐标为细胞接种后的时间(天)，纵坐标为存活百分率(％)，包括对照组
Figure PCTCN2017093597-appb-000015
实施例22B 15mg/kg和45mg/kg组
Figure PCTCN2017093597-appb-000016
及AG-221 15mg/kg和45mg/kg组
Figure PCTCN2017093597-appb-000017
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1 4-(4,4-二氟哌啶-1-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 PCTCN2017093597-appb-000018
步骤1 6-(三氟甲基)-吡啶甲酸甲酯的制备
Figure PCTCN2017093597-appb-000019
将6-三氟甲基吡啶-2-甲酸(25g,130.8mmol)溶入300mL甲醇中，滴加氯化亚砜(23.3g,196.2mmol)，滴毕加热回流反应12h。反应液浓缩干，加入饱和碳酸氢钠溶液调节pH，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得标题化合物。
步骤2 6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2,4-(1H,3H)-二酮的制备
Figure PCTCN2017093597-appb-000020
将缩二脲(13g,126.3mmol)溶入300mL乙二醇二甲醚中，分批加入氢化钠(42g,1053mmol)，加热50℃搅拌1h。加入6-(三氟甲基)-吡啶甲酸甲酯(21.6g,105.3mmol)，加热85℃反应16h。反应液倒入水中，用浓盐酸调节pH，过滤，滤饼烘干，得标题化合物。
步骤3 2,4-二氯-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪的制备
Figure PCTCN2017093597-appb-000021
将6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪-2,4-(1H,3H)-二酮(35g,135.6mmol)溶入200mL三氯氧磷中，加入五氯化磷(100g,542.3mmol)，加热105℃反应12h。反应液倒入水中，二氯甲烷萃取，无水硫酸钠干燥，浓缩得标题化合物。
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-胺的制备
Figure PCTCN2017093597-appb-000022
将2,4-二氯-6-(6-(三氟甲基)吡啶-2-基)-1,3,5-三嗪(7g,23.72mmol)溶入50mL四氢呋喃中，加入2-(三氟甲基)-吡啶-4-胺(4.2g,26.1mmol)，碳酸钠(3.8g,35.6mmol)，加热回流72h。反应液过滤，滤液柱层析纯化得标题化合物。
步骤5 4-(4,4-二氟哌啶-1-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-胺的制备
Figure PCTCN2017093597-appb-000023
将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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入4,4-二氟哌啶(15mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.80(s,1H),8.59-8.70(m,3H),8.32(s,1H),8.11-8.13(m,1H),7.93(s,1H),4.01-4.11(m,4H),2.15(s,4H).ES:m/z506.1[M+H]+。
实施例2 4-(3,3-二氟哌啶-1-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 PCTCN2017093597-appb-000024
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3,3-二氟哌啶(15mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.69-10.71(m,1H),8.58-8.68(m,3H),8.30-8.35(m,1H),8.11-8.13(m,1H),7.89-7.98(m,1H),4.19-4.33(m,1.5H),3.63(s,1H),3.31-3.49(m,1.5H),1.86-1.95(m,2H),1.54-1.56(m,2H).ES:m/z506.1[M+H]+。
实施例3 4-(3-羟基哌啶-1-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 PCTCN2017093597-appb-000025
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3-羟基哌啶(12mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.84(s,1H),8.59-8.71(m,3H),8.31-8.34(m,1H),8.11-8.13(m,1H),7.83-7.90(m,1H),4.22-4.36(m,2H),3.95-4.06(m,2H),2.18-2.22(m,2H),1.83(s,2H).ES:m/z 486.1[M+H]+。
实施例4 4-吗啉基-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 PCTCN2017093597-appb-000026
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入吗啉(10mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.74(s,1H),8.56-8.67(m,3H),8.27-8.30(m,1H),8.08-8.10(m,1H),7.94(s,1H),3.74-3.96(m,8H).ES:m/z 472.2[M+H]+。
实施例5 4-(哌嗪-1-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 PCTCN2017093597-appb-000027
步骤1 4-(哌嗪-4-甲酸叔丁酯-1-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-胺的制备
Figure PCTCN2017093597-appb-000028
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入哌嗪-1-甲酸叔丁酯(22mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液浓缩干得标题化合物。
步骤2 4-(哌嗪-1-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-胺的制备
Figure PCTCN2017093597-appb-000029
将叔丁基4-(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)哌嗪(45mg,0.08mmol)溶入5mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌12h。反应液倒入水中，饱和碳酸氢钠溶液调节pH，二氯甲烷萃取，无水硫酸钠干燥，浓缩有机相得粗品，柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.72(br,1H),8.54-8.66(m,3H),8.25-8.30(m,1H),8.07-8.10(m,1H),7.88-7.89(m,1H),3.78-3.89(m,4H),2.80(s,4H).ES:m/z 471.1[M+H]+。
实施例6 4-(4-甲基哌嗪-1-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 PCTCN2017093597-appb-000030
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入N-甲基哌嗪(12mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.75(s,1H),8.59-8.70(m,3H),8.30-8.33(m,1H),8.12-8.13(m,1H),7.92-7.93(m,1H),3.90-4.00(m,4H),2.48(s,4H),2.28(s,3H).ES:m/z 485.2[M+H]+。
实施例7 4-(3-(三氟甲基)哌啶-1-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 PCTCN2017093597-appb-000031
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3-三氟甲基哌啶(18mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.76(s,1H),8.52-8.64(m,3H),8.26-8.30(m,1H),8.08-8.09(m,1H),7.86-7.87(m,1H),4.48-4.92(m,2H), 3.11-3.24(m,2H),2.61(s,1H),2.01-2.02(m,1H),1.83-1.85(m,1H),1.57-1.65(m,2H).ES:m/z538.2[M+H]+。
实施例8 4-(1,2,4-噻二烷-1,1-二氧代-4-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 PCTCN2017093597-appb-000032
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入牛磺胺(16mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.94(s,1H),8.59-8.74(m,3H),8.31-8.34(m,1H),8.12-8.14(m,1H),7.93(s,1H),7.60-7.68(m,1H),5.20-5.31(m,2H),4.37-4.47(m,2H),3.29(s,2H).ES:m/z 521.1[M+H]+。
实施例9 4-((R)-3-羟基哌啶-1-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 PCTCN2017093597-appb-000033
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(R)-3-羟基哌啶(12mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.70(br,1H),8.55-8.66(m,3H),8.26-8.33(m,1H),8.08-8.11(m,1H),7.85-7.96(m,1H),4.97-4.98(m,1H),4.16-4.49(m,2H),3.26-3.60(m,3H),1.83-1.92(m,2H),1.51-1.54(m,2H).ES:m/z 486.1[M+H]+。
实施例10 4-((S)-3-羟基哌啶-1-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 PCTCN2017093597-appb-000034
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(S)-3-羟基哌啶(12mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.70(br,1H),8.55-8.66(m,3H),8.26-8.33(m,1H),8.08-8.11(m,1H),7.85-7.96(m,1H),4.97-4.98(m,1H),4.16-4.49(m,2H),3.26-3.60(m,3H),1.83-1.92(m,2H),1.51-1.54(m,2H).ES:m/z 486.1[M+H]+。
实施例11 4-(3-氟哌啶-1-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 PCTCN2017093597-appb-000035
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3-氟哌啶(12mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.76(s,1H),8.57-8.68(m,3H),8.28-8.33(m,1H),8.10-8.12(m,1H),7.87-7.89(m,1H),4.23-4.99(m,3H),3.54-3.89(m,2H),1.67-1.98(m,4H).ES:m/z 488.1[M+H]+。
实施例12 4-(3-氰基哌啶-1-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 PCTCN2017093597-appb-000036
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3-氰基哌啶(13mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.81(s,1H),8.57-8.68(m,3H),8.28-8.39(m,1H),8.09-8.12(m,1H),7.87(s,1H),3.77-4.37(m,4H),3.23(s,1H),2.00(s,2H),1.72(s,2H).ES:m/z 495.2[M+H]+。
实施例13 4-(哌啶-2-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 PCTCN2017093597-appb-000037
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL二氧六环中，加入哌啶-2-硼酸频哪醇酯(21mg,0.10mmol)，1,1'-双二苯基膦二茂铁二氯化钯(7mg,0.01mmol)，碳酸钠(16mg,0.15mmol)，加热100℃反应12h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.70(s,1H),8.55-8.68(m,3H),8.27-8.32(m,1H),8.09-8.11(m,1H),7.86-7.87(m,1H),3.87-3.96(m,3H),1.63-1.69(m,6H).ES:m/z470.2[M+H]+。
实施例14 4-(3-氨基哌啶-1-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 PCTCN2017093597-appb-000038
步骤1 叔丁基(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)-3-哌啶基)氨基甲酸酯的制备
Figure PCTCN2017093597-appb-000039
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入哌啶-3-氨基甲酸叔丁酯(24mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液浓缩干得标题化合物。
步骤2 4-(3-氨基哌啶-1-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-胺的制备
Figure PCTCN2017093597-appb-000040
将叔丁基(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)-3-哌啶基)氨基甲酸酯(45mg,0.08mmol)溶入5mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌12h。反应液倒入水中，饱和碳酸氢钠溶液调节pH，二氯甲烷萃取，无水硫酸钠干燥，浓缩有机相得粗品，柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.75-10.81(m,1H),8.56-8.76(m,2H), 7.86-8.33(m,4H),4.11-4.62(m,2H),3.57-3.76(m,2H),3.35(s,1H),2.06(s,1H),1.64-1.85(m,3H).ES:m/z485.1[M+H]+。
实施例15 4-(3,3-二氟吡咯-1-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 PCTCN2017093597-appb-000041
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3,3-二氟吡咯(13mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.90(s,1H),8.58-8.74(m,3H),8.30-8.35(m,1H),8.13-8.15(m,1H),8.00-8.01(m,1H),4.05-4.18(m,2H),3.89-3.98(m,2H),2.61-2.67(m,2H).ES:m/z 492.2[M+H]+。
实施例16 4-(3,4-二羟基哌啶-1-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 PCTCN2017093597-appb-000042
步骤1 3,4-二羟基哌啶的制备
Figure PCTCN2017093597-appb-000043
将7-氧杂-3-氮杂双环[4.1.0]庚烷-3-羧酸叔丁酯(100mg,0.50mmol)溶入5mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌12h。反应液浓缩干得标题化合物。
步骤2 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)哌啶-3,4-二醇的制备
Figure PCTCN2017093597-appb-000044
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3,4-二羟基哌啶(14mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6): δ10.70(br,1H),8.55-8.66(m,3H),8.27-8.32(m,1H),8.09-8.11(m,1H),7.86-7.92(m,1H),4.93-5.03(m,2H),4.20-4.37(m,2H),3.45-3.55(m,2H),1.94-1.98(m,1H),1.44-1.48(m,1H).ES:m/z 502.2[M+H]+。
实施例17 4-((R)-3-羟基吡咯-1-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 PCTCN2017093597-appb-000045
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(R)-3-羟基吡咯(10mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.70(s,1H),8.53-8.71(m,3H),8.25-8.30(m,1H),8.06-8.09(m,1H),7.95(s,1H),5.10(br,1H),4.42-4.43(m,1H),3.55-3.84(m,4H),1.94-2.10(m,2H).ES:m/z 472.2[M+H]+。
实施例18 4-((S)-3-羟基吡咯-1-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 PCTCN2017093597-appb-000046
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(S)-3-羟基吡咯(10mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.70(s,1H),8.53-8.71(m,3H),8.25-8.30(m,1H),8.06-8.09(m,1H),7.95(s,1H),5.10(br,1H),4.42-4.43(m,1H),3.55-3.84(m,4H),1.94-2.10(m,2H).ES:m/z 472.2[M+H]+。
实施例19 4-(4-氟哌啶-1-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 PCTCN2017093597-appb-000047
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL四氢呋喃中，加入4-氟哌啶(12mg，0.12mmol)，碳酸钠(16mg，0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6): δ10.71(s,1H),8.54-8.66(m,3H),8.25-8.30(m,1H),8.07-8.09(m,1H),7.87-7.89(m,1H),4.90-5.06(m,1H),3.93-4.03(m,4H),1.83-2.07(m,4H).ES:m/z 488.2[M+H]+。
实施例20 4-(3-氟-4,4-二羟基哌啶-1-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 PCTCN2017093597-appb-000048
步骤1 3-氟-4,4-二羟基哌啶的制备
Figure PCTCN2017093597-appb-000049
将3-氟-4,4-二羟基哌啶-1-甲酸叔丁酯(200mg,0.85mmol)溶入5mL二氯甲烷中，加入5mL三氟乙酸，室温搅拌12h。反应液浓缩干得标题化合物。
步骤2 4-(3-氟-4,4-二羟基哌啶-1-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-胺的制备
Figure PCTCN2017093597-appb-000050
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL四氢呋喃中，加入实施例20步骤1中制得的3-氟-4,4-二羟基哌啶(16mg，0.12mmol)，碳酸钠(16mg，0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ8.64-8.67(m,2H),8.54-8.56(m,1H),8.27-8.30(m,1H),8.07-8.09(m,1H),7.78-7.80(m,1H),4.37-5.11(m,3H),3.28-3.59(m,2H),1.75-1.90(m,2H).ES:m/z520.1[M+H]+。
实施例21 4-(4-三氟甲基-4-羟基哌啶-1-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 PCTCN2017093597-appb-000051
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL四氢呋喃中，加入4-(三氟甲基)哌啶-4-醇(20mg，0.12mmol)，碳酸钠(16mg，0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.74(s,1H),8.54-8.67(m,3H),8.25-8.30(m,1H),8.07-8.09(m,1H),7.85-7.88(m,1H),6.21(s,1H),4.87-4.91(m,1H),4.62-4.66(m,1H),3.25-3.32(m,2H),1.73-1.86(m,4H).ES:m/z554.2[M+H]+。
实施例22 4-(3-三氟甲基-3-羟基吡咯-1-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 PCTCN2017093597-appb-000052
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL四氢呋喃中，加入3-三氟甲基吡咯-3-醇(19mg，0.12mmol)，碳酸钠(16mg，0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.81(s,1H),8.55-8.81(m,3H),8.27-8.32(m,1H),8.08-8.11(m,1H),7.81-8.00(m,1H),6.67(s,1H),3.73-4.11(m,4H),2.18-2.38(m,2H).ES:m/z 540.2[M+H]+。
实施例22A (R)-4-(3-三氟甲基-3-羟基吡咯-1-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 PCTCN2017093597-appb-000053
将实施例22中制得的产物4-(3-三氟甲基-3-羟基吡咯-1-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(260mg)溶解在30mL甲醇中进行制备性分离，制备性分离方法为：仪器：MGⅡpreparative SFC(SFC-1)，制备柱：ChiralCel OD,250×30mm I.D.,5μm.，流动相：A： CO2、B：异丙醇(0.1％NH3H2O)，梯度：B 30％，流速：60mL/min,，压力：100bar，柱温：38℃，检测波长：220nm。经制备性分离后，将先流出物经过40℃水浴真空旋干，得到标题化合物(115.4mg，保留时间为4.76min)，ee＝99.6％，1H NMR(500MHz,DMSO-d6):δ10.81(s,1H),8.55-8.81(m,3H),8.27-8.32(m,1H),8.08-8.11(m,1H),7.81-8.00(m,1H),6.67(s,1H),3.73-4.11(m,4H),2.18-2.38(m,2H),ES:m/z 540.2[M+H]+.
实施例22B (S)-4-(3-三氟甲基-3-羟基吡咯-1-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 PCTCN2017093597-appb-000054
将实施例22中制得的产物4-(3-三氟甲基-3-羟基吡咯-1-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(260mg)溶解在30mL甲醇中进行制备性分离，制备性分离方法为：仪器：MGⅡpreparative SFC(SFC-1)，制备柱：ChiralCel OD,250×30mm I.D.,5μm.，流动相：A：CO2、B：异丙醇(0.1％NH3H2O)，梯度：B 30％，流速：60mL/min,，压力：100bar，柱温：38℃，检测波长：220nm。经制备性分离后，将后流出物经过40℃水浴真空旋干，得到标题化合物(135.0mg，保留时间为5.09min)，ee＝99.7％，1H NMR(500MHz,DMSO-d6):δ10.81(s,1H),8.55-8.81(m,3H),8.27-8.32(m,1H),8.08-8.11(m,1H),7.81-8.00(m,1H),6.67(s,1H),3.73-4.11(m,4H),2.18-2.38(m,2H),ES:m/z 540.2[M+H]+。
实施例23 4-((3S,4S)-3-羟基-4-氟吡咯-1-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 PCTCN2017093597-appb-000055
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL四氢呋喃中，加入(3S,4S)-4-氟吡咯-3-醇(13mg，0.12mmol)，碳酸钠(16mg，0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.79(s,1H),8.56-8.70(m,3H),8.28-8.33(m,1H),8.09-8.11(m,1H),7.97-8.02(m,1H),5.68-5.72(m,1H),5.06-5.27(m,1H),4.43(s,1H),3.77-4.07(m,4H).ES:m/z 490.2[M+H]+。
实施例24 4-(四氢嘧啶-1(2H)-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 PCTCN2017093597-appb-000056
步骤1 叔丁基3-(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)四氢嘧啶-1(2H)-羧酸酯的制备
Figure PCTCN2017093597-appb-000057
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL四氢呋喃中，加入四氢嘧啶-1(2H)-羧酸叔丁酯(22mg，0.12mmol)，碳酸钠(16mg，0.15mmol)，加热回流16h。反应液过滤，滤液浓缩干得标题化合物。
步骤2 4-(四氢嘧啶-1(2H)-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-胺的制备
Figure PCTCN2017093597-appb-000058
将叔丁基3-(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)四氢嘧啶-1(2H)-羧酸酯(45mg,0.08mmol)溶入5mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌12h。反应液倒入水中，饱和碳酸氢钠溶液调节pH，二氯甲烷萃取，无水硫酸钠干燥，浓缩有机相得粗品，柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.98(s,1H),9.14(br,1H),8.54-9.12(m,3H),8.28-8.36(m,1H),8.08-8.15(m,1H),7.92(s,1H),5.16-5.31(m,2H),4.04-4.15(m,2H),3.33-3.51(m,2H),1.89(s,2H).ES:m/z 471.1[M+H]+。
实施例25 4-(4,4-二氟环己基-1-烯-1-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 PCTCN2017093597-appb-000059
将实施例1步骤4中制得的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(43mg，0.10mmol)溶入5mL二氧六环中，加入2-(4,4-二氟环己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊烷(24.4mg，0.01mmol)，1,1'-双二苯基膦二茂铁二氯化钯(7mg，0.01mmol)，碳酸钠(16mg，0.15mmol)，加热100℃反应12h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.68(s,1H),8.54-8.71(m,3H),8.15-8.28(m,1H),7.82-8.10(m,1H),7.85-7.87(m,1H),5.93-6.05(m,1H),1.85-2.34(m,6H).ES:m/z 503.1[M+H]+。
实施例26 4-(4,4-二氟环己基)-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 PCTCN2017093597-appb-000060
将实施例25中制得的4-(4,4-二氟环己基-1-烯-1-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(15mg,0.03mmol)溶入5mL甲醇中，加入10mg 10％的钯碳，常温常压加氢2h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.68(s,1H),8.54-8.71(m,3H),8.15-8.28(m,1H),7.82-8.10(m,1H),7.85-7.87(m,1H),2.65-2.73(m,1H),1.61-2.30(m,8H).ES:m/z 505.2[M+H]+。
实施例27 6-(6-(三氟甲氧基)吡啶-2-基)-N2-(2-(三氟甲氧)吡啶-4-基)-N4-(异丙氧基)-1,3,5-三嗪-2,4-二胺
Figure PCTCN2017093597-appb-000061
将实施例1步骤4中制得的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(430mg，1.02mmol)加入到10mL四氢呋喃中，然后加入2-(氨基氧基)丙烷盐酸盐(136mg，1.22mmol)和碳酸钠(212mg,2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ11.28(s,1H),10.81(s,1H),8.65(s,1H),8.58(d,2H),8.33(t,1H),8.12(d,1H),8.05(d,1H),4.23-4.15(d,1H),1.27(d,6H).ES:m/z 460.1[M+H]+。
实施例28 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 PCTCN2017093597-appb-000062
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入O-叔丁基羟基L胺盐酸(153mg，1.22 mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.95(s,1H),10.81(s,1H),8.72(s,1H),8.59(d,2H),8.33(t,1H),8.12(d,1H),8.05(d,1H),1.31(s,9H).ES:m/z 474.1[M+H]+。
实施例29 4-(2,2-二甲基肼基)-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 PCTCN2017093597-appb-000063
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入1,1-二甲基肼盐酸盐(117.8mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.84(s,1H),9.35(s,1H),8.90(s,1H),8.56(d,2H),8.32(t,1H),8.11(d,1H),7.94(d,1H),2.62(s,6H).ES:m/z 445.1[M+H]+。
实施例30 N2-吗啉基-6-(6-(三氟甲基)吡啶-2-基)-N4-(2-(三氟甲基)吡啶-4-基)-1,3,5-三嗪-2-胺
Figure PCTCN2017093597-appb-000064
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入4-氨基吗啉(124.4mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.79(s,1H),9.50(s,1H),8.87(s,1H),8.56(d,2H),8.35-8.30(t,1H),8.12(d,1H),7.98(d,1H),3.72(m,4H),2.89(s,4H).ES:m/z 487.1[M+H]+。
实施例31 1-(乙基(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)-2-甲基丙-2-醇
Figure PCTCN2017093597-appb-000065
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入1-乙氨基-2-甲基异丙醇(142.7mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.78(s,1H),8.75(s,1H),8.56(d,2H),8.32(t, 1H),8.11(d,1H),7.95(d,1H),4.59(s,1H),3.80-3.74(m,4H),1.17-1.15(m,9H).ES:m/z 502.1[M+H]+。
实施例32 1-(4-(6-(三氟甲基)吡啶-2-基)-6-(2-(三氟甲基)吡啶-4-基-1,3,5-三嗪-2-基))氮杂环丁烷-3-醇
Figure PCTCN2017093597-appb-000066
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入氮杂环丁烷-3-醇的盐酸盐(133.6mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.79(s,1H),8.77(d,1H),8.61(d,1H),8.56(d,1H),8.31(t,1H),8.12(d,1H),7.92(d,1H),5.88-5.87(m,1H),4.67-4.64(m,1H),4.48-4.41(m,2H),3.98-3.95(m,2H).ES:m/z 458.1[M+H]+。
实施例33 3-甲基-1-(4-(6-(三氟甲基)吡啶-2-基)-6-(2-(三氟甲基)吡啶-4-基-1,3,5-三嗪-2-基))氮杂环丁烷-3-醇
Figure PCTCN2017093597-appb-000067
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入3-甲基-3-吖啶醇的盐酸盐(150.7mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.77(s,1H),8.74(s,1H),8.61(d,1H),8.56(d,1H),8.31(t,1H),8.11(d,1H),7.94(d,1H),5.80(s,1H)4.15-4.05(m,4H),1.49(s,3H).ES:m/z472.1[M+H]+。
实施例34 3-三氟甲基-1-(4-(6-(三氟甲基)吡啶-2-基)-6-(2-(三氟甲基)吡啶-4-基-1,3,5-三嗪-2-基))氮杂环丁烷-3-醇
Figure PCTCN2017093597-appb-000068
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入3-三氟甲基-3-吖啶醇盐酸盐(143mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅 胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.89(s,1H),8.66(d,2H),8.58(d,1H),8.33(t,1H),8.12(d,1H),7.99(d,1H),7.60(s,1H),4.50(d,2H),4.27(d,2H).ES:m/z 526.1[M+H]+。
实施例35 4-(3,3-二氟氮杂环丁烷-1-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 PCTCN2017093597-appb-000069
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入3,3-二氟氮杂环丁烷盐酸盐(158mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.89(s,1H),8.65(d,2H),8.58(d,1H),8.34(t,1H),8.13(d,1H),7.80(d,1H),4.26(d,2H),4.12(d,2H).ES:m/z 478.1[M+H]+。
实施例36 (3R,4R)-1-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)吡咯-3,4-二醇
Figure PCTCN2017093597-appb-000070
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入(3R,4R)-吡咯-3,4-二醇(126mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.89(s,1H),8.64(d,2H),8.57(d,1H),8.31(t,1H),8.11(d,1H),7.99(d,1H),5.11(s,2H),3.55-3.38(m,6H).ES:m/z 488.1[M+H]+。
实施例37 (R)-2-(1-(4-(6-(三氟甲基)吡啶-2-基)-6-((2--(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)吡咯-2-基)异丙-2-醇
Figure PCTCN2017093597-appb-000071
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入D-脯氨酸甲酯盐酸盐(201.2mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h，降温，反应液抽滤，滤液加入硅胶制 砂，柱层析得中间体(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-D-脯氨酸甲酯。
将中间体(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-D-脯氨酸甲酯(257mg，0.5mmol)加入到10mL四氢呋喃中，降温至0℃，然后加入浓度为1M的甲基溴化镁溶液3mL，搅拌1h，然后升至室温搅拌1h，反应液加入硅胶制砂，柱层析后得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.89(s,1H),8.65(d,2H),8.58(d,1H),8.32(t,1H),8.12(d,1H),7.98(d,1H),4.69(s,1H),3.31-3.32(m,2H),3.11(t,1H),1.64-1.58(m,4H),1.33(s,6H).ES:m/z 514.2[M+H]+。
实施例38 4-(三氟甲基)-1-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)哌啶-4-醇
Figure PCTCN2017093597-appb-000072
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入4-(三氟甲基)哌啶-4-醇盐酸盐(250mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流反应16h，降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.89(s,1H),8.65(d,2H),8.58(d,1H),8.32(t,1H),8.12(d,1H),7.98(d,1H),7.59(s,1H),3.31-3.26(m,4H),1.86-1.70(m,4H).ES:m/z554.1[M+H]+。
实施例39 2-甲基-4-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-3-丁炔-2-醇
Figure PCTCN2017093597-appb-000073
将实施例1步骤4中制得的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(1.0g，2.37mmol)加入到30mL四氢呋喃中，然后依次加入2-甲基-3-丁炔-2-醇(240mg，2.85mmol)、四(三苯基膦)钯(275mg，0.237mmol)、碘化亚铜(45mg，0.237mmol)和N,N-二异丙基乙胺(768mg，2.5mmol)，在氩气氛围下升温至40℃反应5h，冷却至室温，向反应液中加入30mL水淬灭反应乙酸乙酯(30mL×3)萃取，无水硫酸钠干燥，浓缩制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ11.44(s,1H),8.71(d,1H),8.65(d,1H),8.37(t,1H),8.19(d,1H),7.94(d,1H),7.50(d,1H),5.86(s,1H),1.54(s,6H).ES:m/z 469.0[M+H]+。
实施例40 2-甲基-4-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-3-丁烯-2-醇
Figure PCTCN2017093597-appb-000074
将实施例39中得到的化合物2-甲基-4-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-3-丁炔-2-醇(468mg，1mmol)溶入15mL甲醇中，加入100mg Pd/CaCO3，氢气置换三次，室温反应2h。反应液制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ11.35(s,1H),8.83(d,1H),8.68(d,1H),8.35(t,1H),8.18(d,1H),7.94(d,1H),7.50(d,1H),6.81(d,1H),6.66(d,1H),4.35(s,1H),1.48(s,6H).ES:m/z 471.1[M+H]+。
实施例41 2-甲基-4-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-3-丁-2-醇
Figure PCTCN2017093597-appb-000075
将实施例39中得到的化合物2-甲基-4-(4-(6-(三氟甲基)吡啶-2-基)-6-((2-(三氟甲基)吡啶-4-基)胺基)-1,3,5-三嗪-2-基)-3-丁炔-2-醇(410mg，0.88mmol)加入到15mL甲醇中，然后加入10％Pd/C(94mg，0.088mmol)，在氢气氛围下室温反应过夜，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ11.24(s,1H),8.80(s,1H),8.73(d,1H),8.62(d,1H),8.36(t,1H),8.17(d,1H),7.96(d,1H),4.35(s,1H),2.96(t,2H),1.96(t,2H),1.19(s,6H).ES:m/z 473.1[M+H]+。
实施例42 4-异丙氧基-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 PCTCN2017093597-appb-000076
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，搅拌溶解配置成溶液1。在另一反应瓶中加入异丙醇(91mg，1.5mmol)和5mL四氢呋喃，降温至0℃，分批加入60％的NaH(200mg，5mmol)，加完后搅拌10min，然后将配置好的溶液1慢慢滴加，0℃反应1h，室温反应1h，反应结束后，慢慢加入1g碎冰淬灭反应，反应液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ11.21(s,1H),8.65(t,3H),8.35(t,1H),8.15(d,1H),7.97(d,1H),5.46-5.38(m,1H),1.14(s,6H).ES:m/z 445.1[M+H]+。
实施例43 4-(2,2,2-三氟乙氧基)-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 PCTCN2017093597-appb-000077
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，搅拌溶解配置成溶液1。在另一反应瓶中加入三氟乙醇(150mg，1.5mmol)和5mL四氢呋喃，降温至0℃，分批加入60％的NaH(200mg，5mmol)，加完后搅拌10min，然后将配置好的溶液1慢慢滴加，0℃反应1h，室温反应1h，反应结束后，慢慢加入1g碎冰淬灭反应，反应液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ11.41(s,1H),8.78(d,2H),8.66(d,1H),8.37(t,1H),8.18(d,1H),7.99(s,1H),5.28-5.23(m,2H).ES:m/z485.1[M+H]+。
实施例44 4-(6-(三氟甲基)吡啶-2-基)-N-(2-(三氟甲基)吡啶-4-基)-6-((1,1,1-三氟异丙-2-基)氧基)-1,3,5-三嗪-2-胺
Figure PCTCN2017093597-appb-000078
将实施例1步骤4中制得的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(420mg,1.00mmol)加入到10mL四氢呋喃中,搅拌溶解配置成溶液1。在另一反应瓶中加入三氟异丙醇(171mg，1.5mmol)和5mL四氢呋喃,降温至0℃，分批加入60％的NaH(200mg，5mmol),加完后搅拌10min,然后将配置好的溶液1慢慢滴加，0℃反应1h，室温反应1h，反应结束后，慢慢加入1g碎冰淬灭反应，反应液加入硅胶制砂，柱层析得标题化合物。1HNMR(300MHz,DMSO-d6):δ11.41(s,1H),8.78(d,2H),8.66(d,1H),8.37(t,1H),8.18(d,1H),7.99(s,1H),5.77-5.81(m,1H),1.48(d,3H).ES:m/z 499.1[M+H]+。
实施例45 4-(2,2,3,3,3-五氟丙氧基)-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 PCTCN2017093597-appb-000079
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，搅拌溶解配置成溶液1。在另一反应瓶中加入五氟丙醇(225mg，1.5mmol)和5mL四氢呋喃，降温至0℃，分批加入60％的NaH(200mg，5mmol),加完后搅拌10min，然后将配置好的溶液1慢慢滴加，0℃反应1h，室温反应1h，反应结束后，慢慢加入1g碎冰淬灭反应，反应液加入硅胶制砂，柱层析得标题化合物。1HNMR(300MHz,DMSO-d6):δ11.41(s,1H),8.78(d,2H),8.65(d,1H),8.36(t,1H),8.18(d,1H),7.99(s,1H),5.22-5.16(m,2H).ES:m/z535.1[M+H]+。
实施例46 4-(吡咯烷-2-酮-1-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 PCTCN2017093597-appb-000080
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL二氧六环中，加入2-吡咯烷酮(8.5mg,0.10mmol)，1,1'-双二苯基膦二茂铁二氯化钯(7mg,0.01mmol)，醋酸钾(15mg,0.15mmol)，加热100℃反应12h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.82(s,1H),8.51-8.65(m,3H),8.27-8.32(m,1H),8.08-8.11(m,1H),7.95-8.00(m,1H),3.70-3.85(m,2H),2.25-2.41(m,2H),1.86-2.01(m,2H).ES:m/z 470.1[M+H]+。
实施例47 4-(2-(2-丙基-2-醇)氮杂环丙烷-1-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 PCTCN2017093597-appb-000081
步骤1 2-(1-三苯甲基氮杂环丙烷-2-基)丙-2-醇的制备
Figure PCTCN2017093597-appb-000082
将1-三苯甲基氮杂环丙烷-2-甲酸甲酯(500mg,1.45mmol)溶入10mL四氢呋喃中，加入甲基锂 (2.91mL,2.91mmol,1mol/L in THF)，室温搅拌12h。反应液浓缩干得标题化合物。
步骤2 2-(氮杂环丙烷-2-基)丙-2-醇的制备
Figure PCTCN2017093597-appb-000083
将2-(1-三苯甲基氮杂环丙烷-2-基)丙-2-醇(100mg,0.29mmol)溶入5mL二氯甲烷中，加入5mL三氟乙酸，室温搅拌12h。反应液浓缩干得标题化合物。
步骤3 4-(2-(2-丙基-2-醇)氮杂环丙烷-1-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-胺的制备
Figure PCTCN2017093597-appb-000084
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入2-(氮杂环丙烷-2-基)丙-2-醇(12mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.71(br,1H),8.53-8.75(m,3H),8.23-8.30(m,1H),8.07-8.11(m,1H),7.92-7.95(m,1H),4.58(s,1H),4.07-4.23(m,3H),1.18(s,6H).ES:m/z 486.2[M+H]+。
实施例48 4-(3-(2-丙基-2-醇)氮杂环丁烷-1-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 PCTCN2017093597-appb-000085
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入2-(氮杂环丁烷-3-基)丙-2-醇(14mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。
1H NMR(500MHz,DMSO-d6):δ10.63(br,1H),8.53-8.73(m,3H),8.25-8.30(m,1H),8.06-8.09(m,1H),7.93-7.94(m,1H),4.62(s,1H),4.09-4.15(m,4H),2.69-2.79(m,1H),1.09(s,6H).ES:m/z 500.2[M+H]+。
实施例49 4-(2-(2-丙基-2-醇)氮杂环丁烷-1-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 PCTCN2017093597-appb-000086
步骤1 2-(2-羟基丙-2-基)氮杂环丁烷-1-甲酸叔丁酯的制备
Figure PCTCN2017093597-appb-000087
将1-叔丁氧羰基氮杂环丁烷-2-甲酸甲酯(500mg,2.33mmol)溶入10mL四氢呋喃中，加入甲基锂(4.66mL,4.66mmol,1mol/L in THF)，室温搅拌12h。反应液浓缩干得标题化合物。
步骤2 2-(氮杂环丁烷-2-基)丙-2-醇的制备
Figure PCTCN2017093597-appb-000088
将2-(2-羟基丙-2-基)氮杂环丁烷-1-甲酸叔丁酯(100mg,0.46mmol)溶入5mL二氯甲烷中，加入5mL三氟乙酸，室温搅拌12h。反应液浓缩干得标题化合物。
步骤3 4-(2-(2-丙基-2-醇)氮杂环丁烷-1-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-胺的制备
Figure PCTCN2017093597-appb-000089
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入2-(氮杂环丁烷-2-基)丙-2-醇(14mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。
1H NMR(500MHz,DMSO-d6):δ10.62(br,1H),8.53-8.74(m,3H),8.25-8.30(m,1H),8.07-8.09(m,1H),7.92-7.95(m,1H),4.60(s,1H),4.05-4.25(m,3H),2.01-2.30(m,2H),1.10(s,6H).ES:m/z 500.2[M+H]+。
实施例50 4-(哌啶-1-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 PCTCN2017093597-appb-000090
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入哌啶(10mg,0.12mmol)，碳酸钠(16mg,0.15 mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.58(br,1H),8.54-8.72(m,3H),8.26-8.30(m,1H),8.07-8.09(m,1H),7.92-7.94(m,1H),3.69-3.93(m,4H),1.50-1.70(m,6H).ES:m/z 470.1[M+H]+。
实施例51 4-((S)-3-氰基吡咯-1-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 PCTCN2017093597-appb-000091
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(S)-3-氰基吡咯(11.5mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.71(s,1H),8.52-8.69(m,3H),8.25-8.31(m,1H),8.07-8.11(m,1H),7.92-7.96(m,1H),4.12-4.15(m,1H),3.58-3.89(m,4H),1.91-2.09(m,2H).ES:m/z 481.1[M+H]+。
实施例52 4-((R)-3-氰基吡咯-1-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 PCTCN2017093597-appb-000092
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(R)-3-氰基吡咯(11.5mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.71(s,1H),8.52-8.69(m,3H),8.25-8.31(m,1H),8.07-8.11(m,1H),7.92-7.96(m,1H),4.12-4.15(m,1H),3.58-3.89(m,4H),1.91-2.09(m,2H).ES:m/z 481.1[M+H]+。
实施例53 4-((3S,4S)-3-羟基-4-氰基吡咯-1-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 PCTCN2017093597-appb-000093
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入(3S,4S)-3-羟基-4-氰基吡咯(13.4mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.75(s,1H),8.55-8.75(m,3H),8.23-8.35(m,1H),8.10-8.11(m,1H),7.97-8.00(m,1H),5.40-5.53(m,1H),5.07-5.30(m,1H),4.32(s,1H),3.65-3.97(m,4H).ES:m/z497.1[M+H]+。
实施例54 4-(3-羟基-3-氰基吡咯-1-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 PCTCN2017093597-appb-000094
步骤1 3-羟基-3-氰基吡咯的制备
Figure PCTCN2017093597-appb-000095
将3-羟基-3-氰基吡咯-1-甲酸叔丁酯(200mg,0.94mmol)溶入5mL二氯甲烷中，加入5mL三氟乙酸，室温搅拌12h。反应液浓缩干得标题化合物。
步骤2 4-(3-羟基-3-氰基吡咯-1-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-胺的制备
Figure PCTCN2017093597-appb-000096
将实施例1步骤4中制得的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(43mg,0.10mmol)溶入5mL四氢呋喃中，加入3-羟基-3-氰基吡咯(13.4mg,0.12mmol)，碳酸钠(16mg,0.15mmol)，加热回流16h。反应液过滤，滤液柱层析纯化得标题化合物。1H NMR(500MHz,DMSO-d6):δ10.60(s,1H),8.53-8.83(m,3H),8.21-8.30(m,1H),8.07-8.13(m,1H),7.76-8.01(m,1H),6.55(s,1H),3.77-4.21(m,4H),2.12-2.39(m,2H).ES:m/z 497.1[M+H]+。
实施例55 4-(3,3,4,4-四氟吡咯-1-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 PCTCN2017093597-appb-000097
将实施例1步骤4中制得的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(420mg，1.00mmol)加入到10mL四氢呋喃中，然后加入3,3,4,4-四氟吡咯烷盐酸盐(219mg，1.22mmol)和碳酸钠(212mg，2.02mmol)，加热至回流，反应16h降温，反应液抽滤，滤液加入硅胶制砂，柱层析得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.88(s,1H),8.65(d,2H),8.57(d,1H),8.31(t,1H),8.10(d,1H),7.99(d,1H),3.85-3.61(m,4H).ES:m/z 528.1[M+H]+。
实验例1 化合物体外抑制酶活性评价
1.实验材料
对照化合物为WO2013/102431中公开的化合物409(参见说明书第134页)，化学名为2-methyl-l-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2ylamino)propan-2-ol(AG-221)，参照WO2013/102431中描述的方法制备并通过氢谱和质谱鉴定。
化合物：以上部分实施例制备的本发明的化合物，每个化合物用DMSO配制成20mM后，依次稀释至10μM、3.33μM、1.11μM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、1.52nM、0.51nM。
试剂：1×反应缓冲液(50mM KH2PO4,10％glycerol,150mM NaCl,0.05％BSA,2mM 2-巯基乙醇)，临用前配制；IDH2野生型酶(IDH2-WT)，购自于BPS公司，Cat.No.71074-1；IDH2-R140Q突变型酶(IDH2-R140Q)，购自于BPS公司，Cat.No.71100-1；NADPH，购自于Sigma公司,Cat.No.N5130；NADP，购自于Sigma公司，Cat.No.N5755；二甲基亚砜(DMSO)，购自于美国Sigma公司；α-ketoglutarate，购自于美国Sigma公司，Cat.No.K1875；Isocitrate，购自于美国Sigma公司，Cat.No.I1252；Diaphorase，购自于Worthington Biochemical公司，Cat.No.LS004327。
仪器：SpectraMax M3Multi-Mode Microplate Reader，购自于Molecular Devices公司。
2.实验方法
2.1.酶反应体系
IDH2-WT反应体系中，IDH2-WT酶终浓度为0.06ng/ml，反应底物Isocitrate终浓度为150μM，反应辅因子NADP终浓度为25μM；IDH2-R140Q反应体系中，IDH2-R140Q酶终浓度为0.3ng/ml， 反应底物α-ketoglutarate终浓度为4mM，反应辅因子NADPH终浓度为15μM。
2.2.酶反应操作步骤
96孔板中，化合物组和DMSO对照组每孔分别加入40μL含2×酶(IDH2-WT或IDH2-R140Q)与辅因子(NADP或NADPH)的反应缓冲液，无酶对照组每孔中加入40μL含2×辅因子(NADP或NADPH)的反应缓冲液；
化合物组每孔加入20μL含4×待测化合物的反应缓冲液，化合物预先用100％DMSO配制成200×母液，最终反应体系中，DMSO浓度为0.5％；DMSO对照组每孔中加入20μL含DMSO的反应缓冲液，最终反应体系中，DMSO浓度为0.5％；
化合物与酶及其辅因子混匀后室温预孵育16h；
每孔分别加入20μL含4×反应底物的反应缓冲液，混匀后室温反应1h。
2.3.终止反应操作步骤
配制3×终止检测液(用反应缓冲液配制，Diaphorase终浓度为0.015mg/mL，Resazurin终浓度为0.03mM)，每孔酶反应体系中加入40μL 3×终止检测液，混匀后室温孵育10min；
每孔各吸取40μL混合物至384孔板中，吸取两次，置于Microplate Reader上读取荧光值(Ex/Em＝544/590nm)。
2.4.数据处理步骤
读取两副孔荧光值取平均值，并计算活性率(Activity％)，计算公式为Activity％＝(Measured data-Subtract background)/(DMSO Control-Subtract background)×100，其中Measured data为化合物预孵育孔的荧光值，Subtract background为无酶对照孔的荧光值，DMSO Control为DMSO预孵育孔的荧光值。数据经GraphPad Prism v5.0software处理，拟合得IC50。实验数据见表1。
表1
Figure PCTCN2017093597-appb-000098
Figure PCTCN2017093597-appb-000099
实验结果表明，本发明的化合物的IC50为nM水平，部分化合物的IC50值好于对照药AG-221，尤其部分化合物针对R140Q突变酶的酶活可提高三倍以上。
实验例2 化合物体外细胞活性评价
1.实验材料
1.1受试化合物：以上部分实施例制备的本发明的化合物，每个化合物用DMSO配制成20mM，然后依次3倍稀释为10μM、3.33μM、1.11μM、370.37nM、123.46nM、41.15nM、13.72nM、4.57nM、1.52nM。
1.2细胞：人胶质母细胞瘤细胞株U87-MG，购于美国典型培养物保藏中心(ATCC)；
过表达突变型IDH2(R140Q)的U87-MG细胞株，由南京金斯瑞生物科技有限公司使用常规的分子生物学技术构建，所述方法包括以下简要步骤：
(1)将野生型IDH2亚克隆入Lenti-Puro载体(购自GenScript’s MGC library，Slot:IRAU-112-d-10；IRAT-17-b-7)，通过点突变获得IDH2(R140Q)突变体，制备转染级携带有IDH2(R140Q)的重组慢病毒载体；
(2)检测病毒的滴度；
(3)使用构建的重组慢病毒载体转导U87-MG宿主细胞，使用嘌呤霉素筛选稳定细胞，并通过qPCR和蛋白印迹确证IDH2(R140Q)的表达；
(4)通过有限稀释获得单克隆，并通过qPCR和蛋白印迹以及使用LC-MS检测2-羟基戊二酸(2-HG)含量来确认。
1.3试剂：MEM培养基，购自于美国Invitrogen公司；
胎牛血清(FBS)，购自于美国Invitrogen公司；
胰蛋白酶，购自于美国Invitrogen公司；
2-羟基戊二酸(D-α-Hydroxyglutaric acid disodium salt,2-HG)标准品，购自于Sigma公司， Cat.No.SLBD 8946V，纯度≥95％；
非那西汀标准品(内标/IS)：购自于Sigma公司，纯度≥98％；
乙腈/甲醇(色谱纯)购自Merck公司；
其余试剂均为市售分析纯。
1.4仪器：AB SCIEX API4500液质联用仪(LC-MS/MS)，配有日本岛津超高效液相色谱系统(LC-30A)、美国AB质谱系统(API4500)、电喷雾离子源及Analyst 1.6.2工作站；
Milli-Q超纯水机(Millipore Inc)；
TARGIN VX-II振荡器；
HITACHI CF16RXII台式高速冷冻离心机；
Thermo电动移液器。
2.实验方法
2.1细胞培养：
无突变对照组使用没有转染IDH2(R140Q)的U87-MG细胞株，化合物组和DMSO对照组使用过表达突变型IDH2(R140Q)的U87-MG细胞株[U87-MG(IDH2-R140Q)]。
细胞复苏：将细胞株U87-MG(IDH2-R140Q)和U87-MG细胞置于37℃水浴中溶解，然后转移到15mL已预热的培养基中，1000rpm离心5分钟，弃去培养基，用15mL新鲜培养基重悬细胞，转移至T75培养瓶中，置于37℃，5％CO2的培养箱中培养，24小时后细胞更换新鲜培养基。
细胞传代：将上述复苏的细胞分别转移到50mL无菌离心管中，1000rpm离心5分钟，弃去培养基，取分散均匀的细胞计数，调整合适的细胞浓度到15mL新鲜培养基，加入到T75培养瓶中，置于37℃，5％CO2的培养箱中培养。
2.2实验步骤：
细胞在培养皿中长至较高密度后，使用胰蛋白酶消化，用培养基(MEM+10％FBS)重悬，并计数。将重悬的细胞调整浓度后接种于96孔板中，每孔5×103个细胞。接种后细胞培养24h至细胞贴壁，吸出培养基，加入含梯度浓度化合物的培养基，每孔100μL，继续培养72h，移取细胞上清液20μL，置于2mL 96孔样品处理板中，再加入480μL稀释液，震荡混匀，4500rpm离心5分钟，转移上清200μL用于LC-MS/MS进样分析。
2.3LC-MS/MS分析条件
2.3.1色谱条件
色谱柱：Shim-pack XR-ODS 30L*2.0；流动相：乙腈-0.2％氨水，5mM乙酸铵水溶液；柱温：30℃；流速：0.4mL/min；梯度洗脱条件如下表2：
表2色谱洗脱条件
Figure PCTCN2017093597-appb-000100
Figure PCTCN2017093597-appb-000101
保留时间：t R,2-HG≈0.21min；t R,IS≈1.41min。
2.3.2质谱条件
选用大气压电离离子源(APCI)，设定源参数分别为：喷雾电压(IonSpray Voltage/IS)-4500V，辅助气1(Ion Source Gas 1/GS 1，N2)55Arb，辅助气2(Ion Source Gas 2/GS 2，N2)55Arb，辅助气加热温度(Temperature/TEM)500℃，气帘气(Curtain Gas/CUR)25Arb，碰撞气(Collision Gas/CAD，N2)8Pa。
选用负离子模式(Negative)下多重离子反应监测(MRM)。2-HG的MRM参数为：母离子(Q 1Mass)为146.9Da，子离子(Q 3Mass)为129.0Da，去簇电压(Declustering Potential/DP)为-15.3V，碰撞电压(Collision Energy/CE)为-14.5eV。内标(IS)的MRM参数为：母离子(Q 1Mass)为178.0Da，子离子(Q3Mass)为149.0Da，去簇电压(Declustering Potential/DP)为-51V，碰撞电压(Collision Energy/CE)为-17eV。
2.4数据处理
经LC-MS/MS测得每孔细胞培养上清液中2-HG含量，计算细胞突变酶酶活率(2-HG remaining compared to untreated％)，计算公式为2-HG remaining compared to untreated％＝(Measured 2-HG level–U87-MG control 2-HG level)/(Untreated 2-HG level–U87-MG control 2-HG level)×100，其中Measured 2-HG level为化合物孵育的U87-MG(IDH2-R140Q)孔的培养基上清中2-HG含量，U87-MG control 2-HG level为U87-MG孔的培养基上清中2-HG含量，Untreated 2-HG level为等浓度DMSO预孵育的U87-MG(IDH2-R140Q)孔的培养基上清中2-HG含量。数据经GraphPad Prism v5.0software处理，拟合得IC50。IC50为可抑制50％细胞中突变酶酶活所对应的化合物浓度。部分化合物的IC50结果见表3。
表3
化合物 IC50(nM) 化合物 IC50(nM)
实施例1 15 实施例2 27
实施例3 24 实施例4 21
实施例27 31.2 实施例28 25.1
实施例29 17.1 实施例31 38.1
实施例32 36.1 实施例33 10.2
实施例34 17.1 实施例35 9.8
实施例38 59.1 实施例40 33.1
实施例41 10.1 实施例42 8.1
实施例43 9.6 实施例44 5.1
实施例45 10.2 实施例55 15.0
AG-221 30.2    
实验结果表明，本发明的化合物的IC50为nM水平，部分化合物的IC50值远好于对照药AG-221，具有非常好的抑制IDH2的能力。
实验例3 U87-MG(IDH2-R140Q)突变细胞皮下移植瘤体内药效评价
1.实验材料
1.1受试化合物：以上部分实施例制备的本发明的化合物，每个化合物用溶媒(2％无水乙醇:10％
Figure PCTCN2017093597-appb-000102
:88％生理盐水(v/v/v))配制为相应浓度溶液。
1.2细胞和试剂：参见实施例2实验材料部分。
1.2动物：
BALB/c nude mice，6-7周龄，雌性，18-22g，购自南京金莱畅公司。
1.3细胞、试剂和仪器：参见实施例2实验材料部分。
2.实验方法
2.1动物接种：
扩增U87-MG(IDH2-R140Q)细胞和U87-MG细胞(野生型)，将处于对数生长期的肿瘤细胞用于体内肿瘤接种。按2×106细胞量/小鼠(细胞悬液体积与Matrigel体积比为1：0.8)，分别接种至16只小鼠身体右侧腰背部皮下。
2.2分组及给药：
无突变对照组使用U87-MG细胞株接种的裸鼠，化合物组和溶媒对照组使用U87-MG(IDH2-R140Q)接种的裸鼠。
各组分别灌胃给予相应浓度的化合物溶液，给药体积为100μL/10g体重，对照组均给予相同体积的空白溶媒。
给药10天后，处死小鼠，剥离肿瘤，匀浆，检测瘤中2-HG含量。
2.3LC-MS/MS分析条件
色谱及质谱条件参见实施例2实验方法部分。
2.4数据处理
经LC-MS/MS测得每组中各只动物肿瘤匀浆液2-HG浓度，计算百分比(2-HG％)，计算公式如下，
2-HG％＝(给药组瘤内2-HG浓度-U87-MG对照组瘤内2-HG浓度)/(U87-MG(IDH2-R140Q)对照组瘤内2-HG浓度-U87-MG对照组瘤内2-HG浓度)×100％
部分化合物给药后小鼠肿瘤内2-HG的相对百分含量(均值)如表5所示。
表5给药10天后瘤内2-HG％
组别 剂量(mg/kg) 2-HG(％)
U87-MG对照组 - 0
U87-MG(IDH2-R140Q)对照组 - 100
AG-221 25 -4
AG-221 12.5 9
AG-221 6.25 58
实施例1 25 22
实施例2 12.5 14
实施例3 12.5 22
实施例22A 6.25 31
实施例22B 6.25 -2
实施例23 6.25 67
实施例34 12.5 24
实施例45 6.25 17
实施例51 6.25 38
实施例55 6.25 1
实验结果表明，在U87-MG(IDH2-R140Q)突变型细胞皮下移植瘤模型中，本发明的化合物具有非常好的抑制肿瘤内因IDH2突变导致的高水平2-HG的能力，部分化合物例如实施例22A、22B、45、51、55的化合物具有明显优于阳性化合物AG-221的抑制2-HG水平的能力。预计本发明的化合物具有好的抑制IDH2突变导致的促成肿瘤的生成和进展的作用。
实验例4 人急性髓性白血病NOD/SCID动物模型
1.实验材料
1.1受试化合物：以上部分实施例制备的本发明的化合物，每个化合物用溶媒(2％无水乙醇:10％
Figure PCTCN2017093597-appb-000103
:88％生理盐水(v/v/v))配制为相应浓度溶液。
1.2细胞：人急性髓性白血病细胞AM7577，由中美冠科生物技术(北京)有限公司提供；
1.3试剂：FITC anti-human CD45，购自Biolegend；
1.4动物：
NOD/SCID小鼠，3-4周龄，雌性，购自北京华阜康生物科技股份有限公司；
1.5仪器：流式细胞仪FACSCalibur，BD；
2.实验方法
2.1动物接种：
每只小鼠按照100uL PBS中重悬2×106个细胞的量通过尾静脉接种。
2.2分组及给药：
每周取动物眼眶血，标记人CD45，检测阳性百分比，当外周血CD45+细胞比例达到5％后分组。 在接种后第40天外周血CD45+细胞比例达到5％。分组后，每日一次灌胃给药，给药时间为14天。分组及给药情况如表6所示。
表6
组别 动物数量 给药组 剂量(mg/kg)*
1 8 vehicle -
2 4 AG-221 45
3 8 AG-221 15
4 8 实施例22B 45
5 8 实施例22B 15
*注：动物的给药体积按照10μL/g体重进行调整。
2.3存活率和生存期的观察：
观察给药后动物的死亡率以及存活动物的生存期。给药14天后各组动物存活数量如表7所示。给药后各组动物的生存期如图1所示。
表7
组别 给药组 剂量(mg/kg) 动物数量 存活动物数
1 vehicle - 8 1
2 AG-221 45 4 3
3 AG-221 15 8 6
4 实施例22B 45 8 7
5 实施例22B 15 8 7
实验结果表明，给药14天后，对照组动物仅有1只存活，阳性化合物AG-221高剂量(45mg/kg)组4只动物中有3只存活，阳性化合物AG-221低剂量(15mg/kg)组8只动物中有6只存活，而本发明化合物的低高剂量组均有7只动物存活。从图1可以看出，与溶媒对照组相比，使用本发明的化合物治疗的小鼠生存期明显延长，且随着剂量的增加，本发明的化合物的疗效明显优于阳性化合物AG-221，动物存活期显著增加。本发明化合物可显著提高荷瘤小鼠的生存率和生存期。
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。

Claims (10)

  1. 一种通式I所示的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药：
    Figure PCTCN2017093597-appb-100001
    其中，
    R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
    X选自N(R3)、O、S和C(R4)，其中R3选自氢、烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基和氨基巯基烷基或者R3和Y与它们所结合的氮原子一起形成任选取代的杂环基，R4选自氢、烷基、烯基、卤代烷基、羟基、羟基烷基、卤素、氧代基团、烷氧基、羧基、氰基、氨基和氨基烷基或者R4和Y与它们所结合的碳原子一起形成任选取代的碳环基或杂环基，其中所述烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基、氨基巯基烷基、烯基、羟基、卤素、氧代基团、烷氧基、羧基、氰基、氨基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
    Y选自任选取代的烷基、O(R5)、N(R6R7)、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，其中R5、R6和R7独立地选自任选取代的烷基、环烷基和杂环基，或者R6和R7与它们所结合的氮原子一起形成杂环基；且
    当X为N(R3)，且R3为氢时，则Y选自任选取代的O(R5)和N(R6R7)，且X和Y间的虚线代表单键；
    当X为N(R3)，且R3选自烷基、卤代烷基、羟基烷基、氨基烷基、巯基烷基和氨基巯基烷基时，则Y选自任选取代的烷基、O(R5)和N(R6R7)且X和Y间的虚线代表单键，或者R3和Y与它们所结合的氮原子一起形成任选取代的杂环基；
    当X选自O和S时，则Y选自任选取代的烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧 基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基，且X和Y间的虚线代表单键；
    当X为C(R4)时，则Y选自任选取代的烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基且X和Y间的虚线代表单键、双键或三键，或者R4和Y与它们所结合的碳原子一起形成任选取代的碳环基或杂环基。
  2. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述通式I具有如下通式Ia的结构：
    Figure PCTCN2017093597-appb-100002
    其中R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
    环A为杂环基，优选选自氮杂环基、氮氧杂环基、氮硫杂环基和二氮杂环基，进一步优选选自C3-8氮杂环基，C3-8氮氧杂环基、C3-8氮硫杂环基和C3-8二氮杂环基；
    R8选自氢、氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代。
  3. 根据权利要求2所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中环A选自氮杂环丙基、氮杂环丁基、四氢吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡唑烷基、二氢吡唑基、咪唑烷基、二氢咪唑基、吡唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、噻唑烷基、二 氢噻唑基、异噁唑烷基、二氢异噁唑基、异噻唑烷基、二氢异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吗啉基、硫代吗啉基和牛磺胺基的基团。
  4. 根据权利要求2所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述通式I具有如下通式Iaa的结构：
    Figure PCTCN2017093597-appb-100003
    其中R1和R2独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基，其中所述卤素、羟基、烷基、环烷基、杂环基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、羧基、硝基和氰基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；
    R8选自氢、氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基中的一个或多个基团，其中所述氧代基团、烷基、卤代烷基、羟基烷基、环烷基、杂环基、烷氧基、卤代烷氧基、羟基烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基任选被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基、环烷基、杂环基、芳基和杂芳基取代；和
    m为1、2、3、4、5或6。
  5. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述通式I具有如下通式Ib的结构：
    Figure PCTCN2017093597-appb-100004
    其中Y选自烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基和烷基氨基酰基。
  6. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中X为N(R3)，R3为氢时，Y选自O(R5)和N(R6R7)，其中R5选自C1-12烷基、C3-8环烷基和C3-8杂环基，其中所述的C1-12烷基、C3-8环烷基和C3-8杂环基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；或者R6和R7与它们所结合的氮原子一起形成C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述杂环基任选被一个或多个氧代基团、烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代。
  7. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中：
    X为N(R3)，R3选自C1-6烷基、卤代C1-6烷基和羟基C1-6烷基，Y选自C1-6烷基、O(R5)和N(R6R7)，其中R5、R6和R7独立地选自C1-6烷基、C3-8环烷基和C3-8杂环基，所述的C1-6烷基、卤代C1-6烷基、羟基C1-6烷基、C3-8环烷基和C3-8杂环基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；或者
    X为C(R4)，R4选自氢、C1-6烷基、卤代C1-6烷基、羟基、羟基C1-6烷基、卤素、氧代基团、C1-6烷氧基、羧基、氰基和氨基，Y选自C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基，所述的C1-6烷基、C3-8环烷基、C3-8杂环基、卤代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基酰基氨基、C1-6烷基酰基、氨基酰基和C1-6烷基氨基酰基任选被一个或多个烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、 硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代；或者R4和Y与它们所结合的碳原子一起形成C3-8碳环基或C3-8杂环基，其中所述杂环基进一步包含一个或多个N、O或S杂原子，且所述碳环基和杂环基任选被一个或多个氧代基团、烷基、环烷基、杂环烷基、烷氧基、烷基氨基、卤素、羟基、氨基、羧基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基取代。
  8. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药，其中所述化合物为选自以下的化合物：
    Figure PCTCN2017093597-appb-100005
    Figure PCTCN2017093597-appb-100006
    Figure PCTCN2017093597-appb-100007
  9. 一种药物组合物，其包含权利要求1至8之任一项所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药和可药用载体。
  10. 权利要求1-8之任一项所述的化合物或其异构体、药学上可接受的盐、结晶、溶剂化物或前药或权利要求9所述的药物组合物在制备用于治疗以突变型IDH2的存在为特征的癌症的药物中的应用。
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