WO2020216071A1 - 二聚或多聚体形式的突变型idh抑制剂 - Google Patents

二聚或多聚体形式的突变型idh抑制剂 Download PDF

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WO2020216071A1
WO2020216071A1 PCT/CN2020/084041 CN2020084041W WO2020216071A1 WO 2020216071 A1 WO2020216071 A1 WO 2020216071A1 CN 2020084041 W CN2020084041 W CN 2020084041W WO 2020216071 A1 WO2020216071 A1 WO 2020216071A1
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substituted
unsubstituted
group
compound
alkyl
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PCT/CN2020/084041
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French (fr)
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曾蜜
吴海平
朱卫星
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上海仕谱生物科技有限公司
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Priority to CN202080029908.9A priority Critical patent/CN114127060B/zh
Priority to JP2021562119A priority patent/JP2022531104A/ja
Priority to EP20794158.4A priority patent/EP3964508A4/en
Priority to US17/605,828 priority patent/US20220267309A1/en
Publication of WO2020216071A1 publication Critical patent/WO2020216071A1/zh

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    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and specifically relates to a mutant IDH inhibitor.
  • Isocitrate dehydrogenase is a key rate-limiting enzyme in the tricarboxylic acid cycle involved in cell energy metabolism, catalyzing the oxidative decarboxylation of isocitrate to ⁇ -ketoglutarate ( ⁇ -KG) and CO2.
  • the IDH enzyme family has two different subtypes, one of which uses NAD(+) as an electron acceptor, and the other uses NADP(+) as an electron acceptor. It has been reported that there are five isoenzymes in the IDH family, three of which are NAD(+)-dependent isocitrate dehydrogenase, which are located in the mitochondrial matrix; and two of them are NADP(+)-dependent isocitrate dehydrogenase.
  • Hydrogenase, isocitrate dehydrogenase 1 (IDH1) is located in the cytoplasm
  • isocitrate dehydrogenase 2 (IDH2) is located in the mitochondria.
  • IDH1 mutations have been found in a variety of tumors. Mutation of IDH1 (IDH1m) can cause loss of its normal function and convert ⁇ -KG into the carcinogenic metabolite 2-hydroxyglutarate (2-HG), allowing 2-HG to accumulate in the mutant tumor cells.
  • mutant IDH1 inhibitors can specifically bind to the catalytic domain of the mutant enzyme protein. Through allosteric inhibition, it can effectively inhibit the activity of mutant proteases and reduce the carcinogenic metabolite 2-HG in the body, thereby inducing Demethylation of histones and/or DNA can promote tumor cell differentiation and inhibit tumor development.
  • Ivosidenib AG-120
  • the only marketed drug Ivosidenib that inhibits the activity of mutant IDH1 is a new drug developed by Agios to treat relapsed or refractory acute myeloid leukemia in adults carrying IDH1 gene mutations.
  • the medication guideline of Ivosidenib states that it is 500mg per day, the dosage is large, and the clinical trials of patients with relapsed or progressing IDH1 mutant glioma carried out at this dosage have not achieved the desired effect.
  • Patients with IDH1 mutants are basically heterozygous mutations. Therefore, there is an urgent need for new, highly effective and low-toxic IDH1 inhibitors.
  • the purpose of the present invention is a new, high-efficiency and low-toxicity mutant IDH1 inhibitor.
  • Wa and Wb are each independently selected from the following group: none, O, S, NR a , CO, COO, SO, SO 2 , CO-NR a , NR a -CO, SO-N (R a ), N (R a ) -SO, NR a -COO, COO-NR a , NR a -SO 2 , SO 2 -NR a , CS-NR a , NR a -CS, or N(R a )-CO-NR a ;
  • R a is independently selected from the group consisting of: H, deuterium, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group (preferably the Is substituted by C1-C6 alkyl and/or halogen); preferably, each of Ra is independently selected from the following group: H, deuterium, -CH 3 , -C 2 H 5 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , cyclopropyl;
  • L is a linking group as shown in formula II
  • n is an integer of 1-50 (preferably an integer of 3-40);
  • Each X is the same or different, and each X is independently selected from the following group: O, S, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, CO, SO 2 , NR b , C(R c ) 2 , substituted or unsubstituted 4 to 10 membered carbocyclic ring (preferably 4 to 7 membered carbocyclic ring), substituted or unsubstituted 4 to 10 membered heterocyclic ring (preferably 4 to 7 membered heterocyclic ring), substituted or unsubstituted 6 to 12 membered aromatic ring (preferably 6 membered aromatic ring), substituted or unsubstituted 5 to 12 membered heterocyclic ring Aromatic ring (preferably a 5- to 7-membered heteroaromatic ring); or -Wc(T) k -
  • Each R d is independently none, or a divalent group selected from the following group: substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C1- C6 haloalkylene, substituted or unsubstituted C3-C6 cycloalkyl;
  • n is an integer of 1-50 (preferably an integer of 3-40);
  • Each Y is the same or different, and each Y is independently selected from the following group: O, S, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, CO, SO 2 , NR b , C(R c ) 2 , substituted or unsubstituted 4 to 10 membered carbocyclic ring (preferably 4 to 7 membered carbocyclic ring), substituted or unsubstituted 4 to 10 membered heterocyclic ring (preferably 4 to 7 membered heterocyclic ring), substituted or unsubstituted 6 to 12 membered aromatic ring (preferably 6 membered aromatic ring), substituted or unsubstituted or 5 to 12 membered Heteroaromatic ring (preferably 5-7 membered heteroaromatic ring);
  • Each R b is independently selected from the following group: H, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy;
  • Each R c is independently selected from the following group: H, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, OH, CN; (preferably H, deuterium, C1-C4 Alkyl, or halogen; more preferably H, deuterium, methyl, ethyl, propyl or isopropyl);
  • heterocyclic ring or heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from O, S or N;
  • the additional condition is that when the X is a substituted carbocyclic ring, substituted heterocyclic ring, substituted aromatic ring, or substituted heteroaryl group, the substitution on the carbocyclic ring, heterocyclic ring, aromatic ring or heteroaryl group
  • the base may optionally contain 1, 2 or 3 T, wherein T is as defined above;
  • substituted means that 1 to 5 hydrogens (preferably, 1 to 3) in the group are each independently substituted by a substituent selected from the following group: deuterium, halogen , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, -N(R b ) 2 , -C(R c ) 3 , -CN, -OH, -COOR f , -SO 2 R f , -NHC(O)R f ; wherein R f is each independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, R b And R c are as defined above;
  • D a , D b and D c are each independently an active group that inhibits the mutant IDH protein.
  • D a , D b and D c are each independently an active group that specifically inhibits the mutant IDH1 protein.
  • the mutant IDH protein is a mutant IDH1 protein.
  • the "specific inhibition” refers to no or substantially no inhibitory effect on IDH2 (such as mutant IDH2).
  • the mutant IDH1 is selected from the following group: IDH1/R132H, IDH1/R132C.
  • D a , D b and D c are all the same.
  • D a and D b are the same.
  • D a and D c are the same.
  • D b and D c are the same.
  • each Dc is the same.
  • the number of active groups in formula I is 2, 3, 4, or 5 (that is, the number of D c is 0, 1, 2, or 3).
  • the active group is a monovalent or divalent group derived from an active compound.
  • D a , D b and each D c are monovalent groups.
  • the active compound is selected from: the compound that inhibits mutant IDH protein disclosed in WO2013046136A1 (ie, the compound of formula (I) disclosed in WO2013046136A1).
  • the active compound is or,
  • the active compound is selected from: compounds 1-169, 170-212, 213-312, 313-442, 443a and 443b, 444-455, 456a and 456b, 457a and 457b, 458a and 458b, 459 disclosed in WO2013046136A1 -485, 486-507, 508, 509-513, 514, 515, 516-546, 547-550, 552-559, 560-562, 563, 564-565, 566-579, 580-582, 583-586 , 587-589, 590-604.
  • D a , D b and D c are each independently a group represented by formula III:
  • R 1 is a divalent linking group
  • R 21 and R 22 are each independently selected from the following group: hydrogen, deuterium, halogen, amino, cyano, substituted or unsubstituted C1-C6 alkyl, or R 21 , R 22 and the carbon atom to which they are connected together form a substitution Or unsubstituted C3-C5 cycloalkyl; wherein, the substitution means that one or more (preferably 1-3) H on the group is substituted by a substituent selected from the following group: deuterium, halogen, C1 -C6 alkyl;
  • R 23 is selected from the group consisting of NR 62 (preferably, R 23 is NH);
  • R 31 , R 32 , R 33 , and R 34 are each independently selected from the following group: N, CR 61 (preferably CH);
  • R 8 is selected from the following group: N, CR 61 (preferably, R 8 is N);
  • R 9 is C
  • R 10 is selected from the following group: O, S (preferably, R 10 is O);
  • R 41 and R 42 are each independently selected from the following group: O, S, C(R 53 ) 2 ;
  • R 51 is each independently selected from the following group: H, deuterium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted 5-7 member Heteroaryl, substituted or unsubstituted diphenylmethyl (ie -CH(C 6 H 5 ) 2 );
  • R 52 is selected from the following group: H, deuterium, C1-C6 alkyl;
  • R 51 and R 52 and the carbon atom to which they are connected together form a substituted or unsubstituted C1-C6 (preferably, C1-C4) cycloalkyl group, a substituted or unsubstituted 5- to 7-membered heterocyclic group;
  • R 53 is each independently selected from the following group: H, deuterium, substituted or unsubstituted C1-C6 alkyl, phenyl, benzyl; or two R 53 and the carbon atom connected to it together form a substituted or unsubstituted 3 -7 membered cycloalkyl or substituted or unsubstituted 4-7 membered heterocycle; in the R 53 group, the said substitution means that 1 to 3 hydrogens in the group are each independently substituted by a group selected from the following group Group substituted: deuterium, halogen, hydroxyl, C1-6 alkyl, C1-C6 haloalkyl, amino;
  • R 61 are each independently selected from the group consisting of hydrogen, deuterium, halogen (preferably, F, Cl, Br), C1-C6 alkyl, C1-C6 haloalkyl; and
  • R 62 is each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and C1-C6 haloalkyl.
  • R 21 and R 22 are each independently selected from the following group: hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl (preferably, one of R 21 and R 22 is hydrogen or Deuterium; and the other is a C1-C6 alkyl group); or, R 21 , R 22 and the carbon atom to which they are connected together form a C3-C5 cycloalkyl group.
  • R 31 is selected from the group consisting of CH and N.
  • R 32 is selected from the group consisting of CH and N.
  • R 33 is CR 61 ; preferably, R 33 is CH or CF.
  • R 34 is N.
  • R 41 is C(R 53 ) 2 ; preferably, R 41 is CH 2 .
  • R 42 is selected from the group consisting of O and S; preferably, R 42 is O.
  • R 51 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.
  • R 52 is selected from the group consisting of hydrogen and deuterium.
  • R 1 is -Ar 1 -L 1 -Ar 2 -L 2 -Ar 3 -, wherein,
  • Ar 1 , Ar 2 and Ar 3 are each independently selected from the following group: unsubstituted, substituted or unsubstituted C6-C20 aromatic ring, substituted or unsubstituted C3-C18 aromatic heterocyclic ring;
  • L 1 and L 2 are each independently none, -O-, C1-C3 alkylene, or C3-C6 cycloalkylene;
  • At least one of Ar 1 , Ar 2 and Ar 3 is not null;
  • the said substitution means that one or more (preferably 1-3) H on the ring is substituted by a substituent selected from the following group: halogen (preferably, F, Cl, Br), C1 -C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyloxy.
  • R 1 is substituted or unsubstituted C6-C20 aryl (preferably, substituted or unsubstituted phenyl or naphthyl), substituted or unsubstituted C3-C18 heteroaryl ( Preferably substituted or unsubstituted pyridyl), substituted or unsubstituted C6-C20 aryl-L 1 -substituted or unsubstituted C6-C20 aryl (preferably, substituted or unsubstituted biphenyl ), substituted or unsubstituted C6-C20 aryl-L 1 -substituted or unsubstituted C3-C18 heteroaryl, or substituted or unsubstituted C3-C18 heteroaryl-L 1 -substituted or unsubstituted C3 -C18 heteroaryl.
  • C6-C20 aryl preferably, substituted or unsubstituted phenyl
  • R 1 is pyridyl
  • R 1 is a group represented by formula VI-A or formula VI-B,
  • R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from: N, CR 61 ;
  • R 16 are each independently selected from: N, CR 63 ;
  • R 63 is selected from the following group: deuterium, halogen (preferably, F, Cl), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl (preferably, fluoroalkyl) .
  • R 11 is selected from the following group: N, CR 61 (preferably CH); and R 12 , R 13 , R 14 and R 15 are CR 61 (preferably CH).
  • R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from: N, CH, CF, and CCl.
  • R 11 is N
  • R 12 , R 13 , R 14 and R 15 are each independently selected from the following group: N, CH, CF, and CCl.
  • R 1 is a substituted or unsubstituted divalent group selected from the following group:
  • D a , D b and D c are each independently a group represented by formula III-A or III-B:
  • R 21 , R 22 , R 23 , R 31 , R 32 , R 33 , R 34 , R 8 , R 9 , R 10 , R 41 , R 42 , R 51 , R 52 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are as defined above.
  • D a , D b and D c are each independently a group represented by formula III-C:
  • R 1 , R 21 , R 22 , R 31 , R 32 , R 33 and R 51 are as defined above.
  • D a , D b and D c are each independently a group represented by formula III-D or III-E:
  • R 21 , R 22 , R 51 , R 31 , R 32 , R 33 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are as defined above.
  • D a , D b and each D c are each independently a monovalent group selected from the following group:
  • D a , D b and D c are the same monovalent group.
  • D a , D b and D c are
  • D a and D b are the same monovalent group.
  • D a and D b are
  • the substituted phenyl group has 1-5 substituents selected from group (a):
  • the substituted benzyl group has 1-5 substituents selected from group (a).
  • each X is a divalent group.
  • the definition of X is the same as that of Y.
  • each X is independently selected from the following group: O, S, C1-C6 alkylene, NR b , C(R c ) 2 , substituted or unsubstituted 4 to 7-membered carbocyclic ring or hetero
  • the ring loses a divalent group formed by two hydrogens at any position.
  • each X is independently selected from the following group: O, S, NH, C1-C6 alkylene (preferably CH 2 , CH(CH 3 ), (CH 2 ) 2 , CH 2 CH (CH 3 ), (CH 2 ) 3 ).
  • each X is independently selected from the following group: O, NH, or C1-C6 alkylene.
  • each X is independently selected from the following group: O or CH 2 .
  • L is a linking group as shown in formula II-C
  • s is an integer of 1-15 (preferably an integer of 2-12; more preferably an integer of 3-9);
  • Y 1 , Y 2 and Y 3 are each independently selected from the following group: O, S, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, CO, SO 2 , NR b , or C(R b ) 2 , or, substituted or unsubstituted 4 to 10 membered carbocyclic ring (preferably 4 to 7 membered carbocyclic ring), 4 to 10 membered heterocyclic ring (preferably 4 to 7 membered heterocyclic ring), 6 to 12 membered aromatic ring (preferably 6 membered aromatic ring), or 5 to 12 membered heteroaromatic ring (preferably 5-7 membered heteroaromatic ring) loses two hydrogens at any position (including those on the same atom) Hydrogen or hydrogen on different atoms) to form a divalent group.
  • s is an integer of 2-10; preferably an integer of 3-7.
  • Y 1 , Y 2 and Y 3 are each independently selected from the following group: O, S, C1-C6 alkylene, NR b , or C(R c ) 2 , or substituted or unsubstituted
  • the 4 to 7-membered carbocyclic or heterocyclic ring is a divalent group formed by losing two hydrogens at any position; preferably, each is independently selected from the following group: none, O, or C1-C6 alkylene.
  • Y 1 , Y 2 and Y 3 are each independently selected from the following group: O or CH 2 (not adjacent to each other being O).
  • L is -(CH 2 -CH 2 -O) s -; wherein, s is an integer of 2-10 (more preferably, s is 3, 4, 5, 6 or 7).
  • At least one X is a trivalent group, a tetravalent group, or a pentavalent group.
  • At least one X is a trivalent group.
  • L is a group represented by formula II-D
  • Z is -Wc(T) k -;
  • p is an integer of 0-50
  • q is an integer of 0-50
  • p is an integer of 1-30
  • q is an integer of 1-30
  • 2 ⁇ p+q ⁇ 50 is another preferred example.
  • p is an integer of 3-30
  • q is an integer of 3-30
  • the chain length of the main chain is 3-50 chain atoms (excluding H atoms); preferably 6-40 chain atoms; more preferably 9-30 chain atoms, Optimally 9-21 chain atoms.
  • Wa and Wb are each independently selected from the following group: none, O, S, CO, COO, NH, CO-NH, or NH-CO.
  • Wa and Wb are each independently selected from the following group: none, or O.
  • the compound is a compound represented by formula IV,
  • R 1 , R 21 , R 22 , R 31 , R 32 , R 33 , R 51 , Wa, Wb, and L are as defined above.
  • R 1 , R 21 , R 22 , R 31 , R 32 , and R 51 are as defined above.
  • the compound is a compound selected from the following group:
  • composition comprising; (i) the compound as described in the first aspect, and (ii) a pharmaceutically acceptable carrier.
  • R 7 is selected from: F, Cl, Br, I (preferably, R 7 is Br or Cl); R 1 , R 21 , R 22 , R 31 , R 32 , R 33 , R 51 and The definition of s is as before.
  • the fifth aspect of the present invention there is provided a use of the compound as described in the first aspect for preparing (i) for inhibiting the activity of mutant IDH; and/or (ii) for treating and/or preventing mutations Type IDH-mediated disease drugs.
  • a method for treating and/or preventing a disease mediated by mutant IDH comprising the step of: administering the compound of the first aspect or a pharmaceutically acceptable compound thereof to a subject in need , Or the pharmaceutical composition as described in the second aspect.
  • the subject is a human or non-human mammal; preferably a human.
  • the IDH is IDH1.
  • the disease mediated by the mutant IDH includes cancer.
  • the cancer is selected from: glioma, glioblastoma, paraneuronoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, bile duct epithelial cancer, peripheral T Cell leukemia, melanoma, or a combination thereof.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-8 represents 1-8 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. .
  • alkenyl refers to an unsaturated alkyl group having one or more double bonds.
  • alkynyl refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1, 4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologues and isomers.
  • cycloalkyl refers to a hydrocarbon ring that has the specified number of ring atoms (eg, C 3-6 cycloalkyl) and is fully saturated or has no more than one double bond between the ring tops.
  • Cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and the like.
  • heterocycloalkyl refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Ammonium.
  • the heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system.
  • heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, Piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc.
  • the heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom.
  • cycloalkylalkyl and heterocycloalkylalkyl it is meant that the cycloalkyl or heterocycloalkyl is attached to the rest of the molecule through an alkyl or alkylene linker.
  • cyclobutylmethyl- is a cyclobutyl ring attached to the methylene linker of the rest of the molecule.
  • alkylene by itself or as part of another substituent refers to a divalent group derived from an alkane, such as -CH 2 CH 2 CH 2 CH 2 -.
  • Alkyl groups (or alkylene groups) generally have 1 to 24 carbon atoms, with those groups having 10 or less carbon atoms being preferred in the present invention.
  • “Lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, usually having 4 or fewer carbon atoms.
  • alkenylene or “alkynylene” refers to an unsaturated form of "alkylene” having a double bond or a triple bond, respectively.
  • heteroalkyl by itself or in combination with other terms refers to a stable linear or branched or cyclic hydrocarbon group or a combination thereof, consisting of a specified number of carbon atoms and 1 to 3 selected from O , N, Si and S heteroatoms, and wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms can be optionally quaternized.
  • the heteroatoms O, N and S can be located in any internal position of the heteroalkyl group.
  • the heteroatom Si can be located in any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule.
  • Up to two heteroatoms can be continuous, such as -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkenyl and “heteroalkynyl” by themselves or in combination with another term refer to alkenyl or alkynyl, respectively, which contain the specified number of carbons and 1 to 3 options, respectively.
  • nitrogen heteroatoms may optionally be quaternized.
  • the heteroatoms O, N and S can be located in any internal position of the heteroalkyl group.
  • heteroatoms may also occupy either or two of the chain ends (for example, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense and refer to the attachment to the molecule via an oxygen atom, an amino group or a sulfur atom, respectively The rest of those alkyl groups.
  • dialkylamino groups the alkyl moieties can be the same or different, and can also be combined with the nitrogen atom connected to each alkyl group to form a 3-7 membered ring. Therefore, the group represented by -NR a R b includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
  • halo or halogen by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl or polyhaloalkyl.
  • C 1-4 haloalkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.
  • aryl means a polyunsaturated (usually aromatic) hydrocarbon group, which may be a single ring or multiple rings (up to three rings) fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized .
  • the heteroaryl group can be attached to the rest of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, Quinoxalinyl, quinazolinyl, cinnoline, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benziso Oxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzene And thiazolyl, benzofuranyl, benzothienyl, indolyl, quinoliny
  • aryl when used in combination with other terms (eg, aryloxy, arylthio, aralkyl), it includes aryl and heteroaryl rings as defined above.
  • aralkyl refers to those groups (e.g., benzyl, phenethyl, pyridylmethyl, etc.) in which the aryl group is attached to an alkyl group attached to the rest of the molecule.
  • the aforementioned terms will include both substituted and unsubstituted forms of the specified groups.
  • the preferred substituents for each type of group are provided below.
  • aryl and heteroaryl will refer to the substituted or unsubstituted forms as provided below, while the term “alkyl” and related aliphatic groups refer to the unsubstituted form, unless substituted is indicated .
  • R'and R" are attached to the same nitrogen atom, they can be The nitrogen atoms combine to form a 3-, 4-, 5-, 6- or 7-membered ring.
  • -NR'R" means to include 1-pyrrolidinyl and 4-morpholinyl.
  • acyl used alone or as part of another group, refers to where the group is closest to the point of attachment
  • substituent for example, -C(O)CH 3 , -C(O)CH 2 CH 2 OR', etc.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).
  • the bond from the substituent (usually the R group) to the center of the aromatic ring will be understood to mean a bond that provides a connection at any available vertex of the aromatic ring.
  • the description also includes connections to rings fused to aromatic rings.
  • the bond drawn to the center of the indolebenzene moiety will represent the bond connected to any available vertex of the six- or five-membered ring portion of the indole.
  • each chiral carbon atom may optionally be R configuration or S configuration, or a mixture of R configuration and S configuration.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (for example, separated enantiomers) Body) should be included in the scope of the present invention.
  • the compounds provided herein have a defined stereochemistry (represented as R or S, or indicated by a dashed or wedge-shaped bond)
  • those skilled in the art will understand that those compounds are substantially free of other isomers (e.g., at least 80% , 90%, 95%, 98%, 99% and up to 100% free of other isomers).
  • substituted means that one or more hydrogen atoms on the group are substituted by a substituent selected from the following group: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-OH, unsubstituted or halogenated, -CN.
  • the term “comprising”, “comprising” or “including” means that various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms “mainly consisting of” and “consisting of” are included in the term “containing”.
  • pharmaceutically acceptable ingredients refers to substances that are suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, substances that have a reasonable benefit/risk ratio.
  • the term "therapeutically effective dose” refers to any amount of the drug as described below, when used alone or in combination with another therapeutic agent, the amount of the drug can promote the regression of the disease, which is manifested as disease symptoms Reduce the severity of the disease, increase the frequency and duration of the asymptomatic period, or prevent obstacles or disability caused by the disease.
  • the "therapeutically effective dose” of the drug of the present invention also includes the “preventively effective dose”.
  • the “preventively effective dose” is any amount of the drug as described below, when the amount of the drug is administered alone or in combination with another therapeutic agent When a subject is at risk of developing a disease or suffering from a recurrence of the disease, the occurrence or recurrence of the disease can be suppressed.
  • the present invention provides compounds for inhibiting mutant IDH.
  • the compounds of the invention are inhibitors in dimeric or multimeric form.
  • compounds of the present invention refers to compounds having the structure of Formula I, pharmaceutically acceptable salts, prodrugs, optical isomers, racemates, solvates,
  • each group is defined as described in the first aspect.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • the present invention also provides compounds in prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir containing a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compound of the invention.
  • One type of preferred prodrug is the ester form.
  • the compound of the present invention may be amorphous, crystalline, or a mixture thereof.
  • Certain compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated form is usually equivalent to the unsolvated form and should be included in the scope of the present invention.
  • Certain compounds of the invention may exist in polymorphic or amorphous forms. Generally, as far as the application considered in the present invention is concerned, all physical forms are equivalent and should be included in the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the isotopic atoms constituting such compounds.
  • the unnatural proportion of a certain isotope can be defined as the amount from the naturally found amount of the atom in question to 100% of that atom.
  • the compound can incorporate radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H) or carbon-13 ( 13 C ).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C)
  • non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C ).
  • such isotopic variants may provide additional uses.
  • isotopic variants of the compounds of the invention may have additional uses, including, but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents.
  • isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby helping to increase safety, tolerability or efficacy during treatment. Regardless of whether it is radioactive or not, all isotopic variants of the compounds of the present invention should be included within the scope of the present invention.
  • the active groups (or corresponding active compounds) used to inhibit mutant IDH proteins such as D a , D b and D c can be prepared or purchased with reference to the prior art.
  • a typical method for preparing the compound of the present invention uses the following process:
  • R 7 is selected from: F, Cl, Br, I (preferably, R 7 is Br or Cl); R 1 , R 21 , R 22 , R 31 , R 32 , R 33 , R 51 and The definition of s is as before.
  • step (i) usually in a solvent (such as acetonitrile), under alkaline conditions, at room temperature or heating, react for 4 hours or more (such as 4-20 hours) to obtain the formula V-C Compound.
  • a solvent such as acetonitrile
  • step (i) usually in a solvent (such as acetonitrile), under alkaline conditions, at room temperature or heating, react for 4 hours or more (such as 4-20 hours) to obtain the formula V-C Compound.
  • the compound of formula V-C can be isolated or used directly in the next step.
  • step (ii) usually in a solvent (such as methanol), under acidic conditions, at room temperature or heating, react for 2 hours or more (such as 2-10 hours) to obtain the compound of formula V.
  • a solvent such as methanol
  • step (iii) usually in a solvent (such as DMSO), under alkaline conditions, at room temperature or under heating, react for 2 hours or more to obtain the compound of formula V.
  • a solvent such as DMSO
  • the compound of the present invention has excellent inhibitory activity against mutant IDH1 (for example, IDH1/R132H and IDH1/R132C), the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or Solvates and pharmaceutical compositions containing the compound of the present invention as the main active ingredients can be used to treat, prevent and alleviate diseases mediated by mutant IDH1.
  • mutant IDH1 for example, IDH1/R132H and IDH1/R132C
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or Solvates and pharmaceutical compositions containing the compound of the present invention as the main active ingredients can be used to treat, prevent and alleviate diseases mediated by mutant IDH1.
  • the compounds of the invention can be used to treat cancer.
  • Representative cancers include (but are not limited to): glioma, glioblastoma, paraneuronoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, bile duct epithelial cancer, peripheral T cells Leukemia, melanoma, or a combination thereof.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, more preferably, contains 10-500 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and gly
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily The dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the compound of the present invention is highly effective, non-toxic, and has high inhibitory activity.
  • control compound of this example is AG-120, CAS: 1448347-49-6, commercially available, and the structural formula is as follows:
  • AG-120 (Ivosidenib) is an orally active IDH1 inhibitor with potential anti-tumor activity.
  • Some of the compounds used in the present invention can be obtained from commercial and/or public compound libraries.
  • some of the compounds of the present invention are purchased from Shanghai Bi De Pharmaceutical Technology Co., Ltd. or Beijing Yinuo Kai Technology Co., Ltd. or Shanghai Chaolan Chemical Technology Center Or Shanghai Aladdin Biochemical Technology Co., Ltd. or Tixiai (Shanghai) Chemical Industry Development Co., Ltd. or Shaoyuan Chemical Technology (Shanghai) Co., Ltd. or Shanghai Yunguan Electromechanical Equipment Co., Ltd.
  • 2-Hydroxyglutarate dehydrogenase (2HGDH) can reduce NAD+ to NADH in the presence of 2-HG.
  • the latter can be quantitatively determined by diaphorase and its substrate Resazurin (resazurin).
  • Glioma cells U87MG overexpressing IDH1/R132H mutations were cultured in 1% sodium pyruvate high-sugar MEM, 10% FBS, and placed in a CO 2 incubator (37°C, 5% CO 2 , 95% air) .
  • the cells were trypsinized and seeded in a 96-well plate at a density of 1 ⁇ 10 4 with a medium of 200 ⁇ L and cultured overnight in a 37°C incubator.
  • the test compound was added the next day, and the final concentration of DMSO was 0.1%.
  • draw 100 ⁇ L of medium and use 10KD The ultrafiltration tube (purchased from PALL) was centrifuged at 14000g for 10 minutes to filter the protein and other components that may interfere with the results in the medium, and use the subsequent method to detect the content of 2-HG.
  • reaction buffer 50mM Tris pH7.5, 100mM NaCl, 20mM MgCl 2 , 0.05% BSA
  • the final concentration of NAD+ is 40 ⁇ M
  • the final concentration of 2HGDH is 20nM
  • the test sample is added to 5 ⁇ L of culture medium;
  • the reaction solution was mixed and centrifuged, and reacted for 1 hour at 25°C in the dark;
  • color development buffer 50mM Tris pH7.5, 100mM NaCl, 20mM MgCl 2 , 0.05% BSA
  • the final concentration of diaphorase is 36 ⁇ g/mL
  • the final concentration of resazurin sodium It is 3 ⁇ M
  • 2-HG standard curve preparation Dilute the 2-HG stock solution to 20 ⁇ M with reaction buffer, and then perform a 2-fold gradient dilution for a total of 6 points. Then, the above-mentioned 2-HG was measured according to the extracellular 2-HG measurement system, and a standard curve was calculated and drawn.
  • the fluorescence value obtained in the extracellular 2-HG assay system was calculated using the 2-HG standard curve to calculate the content of 2-HG in the culture medium, and DMSO was used as a negative control to calculate the compound's inhibition of IDH1/R132H mutation to 2-HG activity.
  • test results are shown in Table 1.
  • "-" means that the inhibitory activity range of IDH1/R132H is IC 50 ⁇ 10 ⁇ M
  • “+” means that the inhibitory activity range of IDH1/R132H is 500nM ⁇ IC 50 ⁇ 10 ⁇ M
  • the inhibitory activity range of /R132H is 5nM ⁇ IC 50 ⁇ 500nM
  • +++ means the inhibitory activity range of IDH1/R132H is IC 50 ⁇ 5nM.
  • the experimental procedure is the same as in Example 3, except that the fibrosarcoma cell HT-1080 containing the IDH1/R132C mutation is used to replace the glioma cell U87MG that overexpresses the IDH1/R132H mutation.
  • the experimental operation is the same as in Example 7, but the difference is that the glioma cell U87MG overexpressing the IDH2/R140Q mutation is replaced with the glioma cell U87MG overexpressing the IDH1/R132H mutation.
  • test results are shown in Table 3. Among them, “+” in Table 4 refers to the inhibitory activity against IDH2/R140Q IC50 ⁇ 20 ⁇ M; “-” refers to the inhibitory activity against IDH2/R140Q IC50>20 ⁇ M.

Abstract

本发明提供了一种二聚或多聚体形式的突变型IDH抑制剂。具体地，本发明提供了一种式I化合物、或其药学上可接受的盐，D a-W a-L-W b-D b(I)。本发明的化合物具有优异的突变型IDH1抑制活性。

Description

二聚或多聚体形式的突变型IDH抑制剂 技术领域
本发明属于药物化学技术领域，具体涉及一种突变型IDH抑制剂。
背景技术
异柠檬酸脱氢酶(IDH)是参与细胞能量代谢的三羧酸循环中的关键限速酶，催化异柠檬酸氧化脱羧生成α-酮戊二酸(α-KG)及CO2。IDH酶家族有两类不同的亚型，其中一类亚型利用NAD(+)作为电子受体，另一类亚型利用NADP(+)作为电子受体。已经报道的IDH家族有五种同工酶，其中3种为NAD(+)依赖型异柠檬酸脱氢酶，它们位于线粒体基质中；还有两种为NADP(+)依赖型异柠檬酸脱氢酶，异柠檬酸脱氢酶1(IDH1)位于胞质中，异柠檬酸脱氢酶2(IDH2)位于线粒体中。
异柠檬酸脱氢酶的突变发生于很多种类型的癌症，比如脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、***癌、甲状腺癌、结肠癌、软骨肉瘤、胆管上皮癌、外周T细胞白血病、黑色素瘤等。其中，多种肿瘤中均发现了IDH1的突变。IDH1突变(IDH1m)会导致其正常功能缺失，并将α-KG转化为致癌代谢物2-羟基戊二酸(2-HG)，使2-HG在突变的肿瘤细胞中累积。研究表明，α-KG与2-HG结构相似，2-HG与α-KG竞争，由此降低了α-KG依赖性酶的活性，导致一些基因组关键区域的核小体和/或DNA高度甲基化，这种表观遗传改变被认为干扰了正常的细胞分化，导致未成熟细胞过度增殖，从而引发癌症。2009年，Bleeker等对672例不同来源的肿瘤和84个不同的肿瘤细胞系进行了IDH1突变的检测，发现这种突变特异性集中发生在脑胶质瘤中。但后续的文献报道显示，急性髓细胞白血病、***癌、副神经节瘤等也存在IDH1的突变。Bleeker等发现在IDH1突变的病例中，R132H占了86.9％。其它类型如R132C、R132G、R132L、R132V、R132S所占比例较小。
在含IDH1突变的肿瘤细胞中，突变型IDH1抑制剂可特异结合于突变酶蛋白催化结构域，通过变构抑制等方式，有效抑制突变蛋白酶活，使体内致癌代谢物2-HG减少，从而诱导组蛋白和/或DNA的去甲基化，达到促进肿瘤细胞分化，抑制肿瘤发展的效果。目前，抑制突变型IDH1活性的唯一上市药物Ivosidenib(AG-120)是Agios公司开发的用于治疗携带IDH1基因突变的成人复发或难治性急性髓系白血病的新药。Ivosidenib的用药指南说明为500mg每天，用药剂量大，且在此剂量下进行的针对复发或进展中携带IDH1突变型的胶质瘤病人临床实验中并没有取得理想的效果。携带IDH1突变型的病人基本为杂合体突变，因此，持续急需新型的、高效低毒的突变型IDH1的抑制剂。
综上所述，本领域迫切需要开发一种新的、高效低毒的突变型IDH1的抑制 剂。
发明内容
本发明的目的就是一种新的、高效低毒的突变型IDH1的抑制剂。
在本发明的第一方面，提供了一种式I化合物、或其药学上可接受的盐，
D a-W a-L-W b-D b   (I)
其中，
Wa和Wb各自独立地选自下组：无、O、S、NR a、CO、COO、SO、SO 2、CO-NR a、NR a-CO、SO-N(R a)、N(R a)-SO、NR a-COO、COO-NR a、NR a-SO 2、SO 2-NR a、CS-NR a、NR a-CS、或N(R a)-CO-NR a；
其中，R a各自独立地选自下组：H、氘、CN、卤素、C1-C6烷基、C1-C6卤代烷基，或取代或未取代的C3-C6环烷基(较佳地所述取代为被C1-C6烷基取代和/或卤素取代)；较佳地，R a各自独立地选自下组：H、氘、-CH 3、-C 2H 5、-CH(CH 3) 2、-CH 2CH 2CH 3、环丙基；
L为如式II所示的连接基团
-(X) n-   (II)
其中，
n为1～50的整数(较佳地为3～40的整数)；
各个X是相同或者不同的，且各个X独立地选自下组：O、S、取代或未取代的C1-C6亚烷基、取代或未取代的C2-C6亚烯基、取代或未取代的C2-C6亚炔基、CO、SO 2、NR b、C(R c) 2、取代或未取代的4到10元碳环(较佳地4到7元碳环)、取代或未取代的4到10元杂环(较佳地4到7元杂环)、取代或未取代的6到12元芳环(较佳地6元芳环)、取代或未取代的5到12元杂芳环(较佳地5～7元杂芳环)；或-Wc(T) k-，其中，Wc为三价基团、四价基团、或五价基团(优选N、CH、C、树枝状基团)，而k为1、2或3；T为-R d-Wa-L'-Wb-D c，其中，Wa和Wb如上所述；
各个R d独立地为无，或选自下组的二价基团：取代或未取代的C1-C6亚烷基、取代或未取代的C2-C6亚烯基、取代或未取代的C1-C6卤代亚烷基、取代或未取代的C3-C6环烷基；
L'为无或如式II-A所示的连接基团
-(Y) m-   (II-A)
式中，
m为1～50的整数(较佳地为3～40的整数)；
各个Y是相同或者不同的，且各个Y独立地选自下组：O、S、取代或未取 代的C1-C6亚烷基、取代或未取代的C2-C6亚烯基、取代或未取代的C2-C6亚炔基、CO、SO 2、NR b、C(R c) 2、取代或未取代的4到10元碳环(较佳地4到7元碳环)、取代或未取代的4到10元杂环(较佳地4到7元杂环)、取代或未取代的6到12元芳环(较佳地6元芳环)、取代或未取代的或5到12元杂芳环(较佳地5～7元杂芳环)；
各个R b独立地选自下组：H、氘、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基；
各个R c独立地选自下组：H、氘、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、OH、CN；(较佳地H、氘、C1-C4烷基、或卤素；更佳地H、氘、甲基、乙基、丙基或异丙基)；
其中，所述杂环或杂芳环含有1、2或3个选自O、S或N的杂原子；
附加条件是，当所述的X为取代的碳环、取代的杂环、取代的芳环、或取代的杂芳基时，所述碳环、杂环、芳环或杂芳基上的取代基可任选地含有1、2或3个T，其中T如上定义；
除非特别说明，所述的“取代”是指所述基团中的1～5个氢(较佳地，1～3个)各自独立地被选自下组的取代基所取代：氘、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、取代或未取代的苯基、取代或未取代的苄基、-N(R b) 2、-C(R c) 3、-CN、-OH、-COOR f、-SO 2R f、-NHC(O)R f；其中，R f各自独立地选自下组：氢、氘、C1-C6烷基，R b和R c如上定义；
D a、D b和D c各自独立地为抑制突变型IDH蛋白的活性基团。
在另一优选例中，D a、D b和D c各自独立地为特异性抑制突变型IDH1蛋白的活性基团。
在另一优选例中，所述突变型IDH蛋白为突变型IDH1蛋白。
在另一优选例中，所述的“特异性抑制”指对IDH2(如突变型IDH2)无或基本上无抑制效果。
在另一优选例中，所述的突变型IDH1选自下组：IDH1/R132H、IDH1/R132C。
在另一优选例中，D a、D b和D c都是相同的。
在另一优选例中，D a和D b是相同的。
在另一优选例中，D a和D c是相同的。
在另一优选例中，D b和D c是相同的。
在另一优选例中，各个Dc是相同的。
在另一优选例中，式I中所述活性基团的数量为2、3、4或5个(即D c的数量为0、1、2或3个)。
在另一优选例中，所述活性基团为衍生自活性化合物的一价或二价基团。
在另一优选例中，D a、D b和各个D c是一价基团。
在另一优选例中，所述的活性化合物选自：WO2013046136A1中公开的抑制突变型IDH蛋白的化合物(即WO2013046136A1中公开的式(I)化合物)。
在另一优选例中，所述的活性化合物为
Figure PCTCN2020084041-appb-000001
或者，
所述的活性化合物选自：WO2013046136A1中公开的化合物1-169、170-212、213-312、313-442、443a和443b、444-455、456a和456b、457a和457b、458a和458b、459-485、486-507、508、509-513、514、515、516-546、547-550、552-559、560-562、563、564-565、566-579、580-582、583-586、587-589、590-604。
在另一优选例中，D a、D b和D c各自独立地为式III所示的基团：
Figure PCTCN2020084041-appb-000002
其中，
R 1为二价连接基团；
R 21、R 22各自独立地选自下组：氢、氘、卤素、氨基、氰基、取代或未取代的C1-C6烷基，或者R 21、R 22和与其相连的碳原子共同形成取代或未取代的C3-C5环烷基；其中，所述取代是指基团上一个或多个(较佳地1-3个)H被选自下组的取代基取代：氘、卤素、C1-C6烷基；
R 23选自下组：NR 62(较佳地，R 23为NH)；
R 31、R 32、R 33、和R 34各自独立地选自下组：N、CR 61(较佳地CH)；
R 8选自下组：N、CR 61(较佳地，R 8为N)；
R 9为C；
R 10选自下组：O、S(较佳地，R 10为O)；
R 41和R 42各自独立地选自下组：O、S、C(R 53) 2；
R 51各自独立地选自下组：H、氘、取代或未取代的C1-C6烷基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5～7元杂芳基、取代或未取代的二苯基甲基(即-CH(C 6H 5) 2)；R 52选自下组：H、氘、C1-C6烷基；
或者，R 51和R 52和与其相连的碳原子共同形成取代或未取代的C1-C6(较佳地，C1-C4)环烷基、取代或未取代的5到7元杂环基；
R 53各自独立地选自下组：H、氘、取代或未取代的C1-C6烷基、苯基、苄基；或者两个R 53和与其相连的碳原子共同形成取代或未取代的3-7元环烷基或取代或未取代的4-7元杂环；R 53基团中，所述的取代是指基团中的1～3个氢各自独立地被选自下组的取代基所取代：氘、卤素、羟基、C1-6烷基、C1-C6卤代烷基、 氨基；
R 61各自独立地选自下组：氢、氘、卤素(较佳地，F、Cl、Br)、C1-C6烷基、C1-C6卤代烷基；和
R 62各自独立地选自下组：氢、氘、C1-C6烷基、C1-C6卤代烷基。
在另一优选例中，R 21、R 22各自独立地选自下组：氢、氘、C1-C6烷基、C1-C6卤代烷基(较佳地，R 21和R 22之一为氢或氘；且另一个为C1-C6烷基)；或者，R 21、R 22和与其相连的碳原子共同形成C3-C5环烷基。
在另一优选例中，R 31选自下组：CH、N。
在另一优选例中，R 32选自下组：CH、N。
在另一优选例中，R 33为CR 61；较佳地，R 33为CH或CF。
在另一优选例中，R 34为N。
在另一优选例中，R 41为C(R 53) 2；较佳地，R 41为CH 2。
在另一优选例中，R 42选自下组：O、S；较佳地，R 42为O。
在另一优选例中，R 51选自下组：C1-C6烷基、C1-C6卤代烷基。
在另一优选例中，R 52选自下组：氢、氘。
在另一优选例中，R 1为-Ar 1-L 1-Ar 2-L 2-Ar 3-，其中，
Ar 1、Ar 2和Ar 3各自独立地选自下组：无、取代或未取代的C6-C20芳环、取代或未取代的C3-C18芳杂环；
L 1和L 2各自独立为无、-O-、C1-C3亚烷基、或C3-C6亚环烷基；
并且Ar 1、Ar 2和Ar 3中至少一个不为无；
R 1基团中，所述的取代指环上一个或多个(较佳地1-3个)H被选自下组的取代基取代：卤素(较佳地，F、Cl、Br)、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基。
在另一优选例中，R 1为取代或未取代的C6-C20芳基(较佳地，为取代或未取代的苯基或萘基)、取代或未取代的C3-C18杂芳基(较佳地为取代或未取代的吡啶基)、取代或未取代的C6-C20芳基-L 1-取代或未取代的C6-C20芳基(较佳地，为取代或未取代的联苯)、取代或未取代的C6-C20芳基-L 1-取代或未取代的C3-C18杂芳基、或取代或未取代的C3-C18杂芳基-L 1-取代或未取代的C3-C18杂芳基。
在另一优选例中，R 1为吡啶基。
在另一优选例中，R 1为如式VI-A或式VI-B所示的基团，
Figure PCTCN2020084041-appb-000003
其中，R 11、R 12、R 13、R 14和R 15各自独立地选自：N、CR 61；R 16各自独立地选自：N、CR 63；
其中，R 63选自下组：氘、卤素(较佳地，F、Cl)、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基(较佳地，氟代烷基)。
在另一优选例中，R 11选自下组：N、CR 61(较佳地CH)；且R 12、R 13、R 14和R 15为CR 61(较佳地CH)。
在另一优选例中，R 11、R 12、R 13、R 14、和R 15各自独立地选自：N、CH、CF、CCl。
在另一优选例中，R 11为N，且R 12、R 13、R 14和R 15各自独立地选自下组：N、CH、CF、CCl。
在另一优选例中，R 1为取代或未取代的选自下组的二价基团：
Figure PCTCN2020084041-appb-000004
在另一优选例中，D a、D b和D c各自独立地为式III-A或III-B所示的基团：
Figure PCTCN2020084041-appb-000005
其中，R 21、R 22、R 23、R 31、R 32、R 33、R 34、R 8、R 9、R 10、R 41、R 42、R 51、R 52、R 11、R 12、R 13、R 14、R 15和R 16如前定义。
在另一优选例中，D a、D b和D c各自独立地为式III-C所示的基团：
Figure PCTCN2020084041-appb-000006
其中，R 1、R 21、R 22、R 31、R 32、R 33和R 51如前定义。
在另一优选例中，D a、D b和D c各自独立地为式III-D或III-E所示的基团：
Figure PCTCN2020084041-appb-000007
其中，R 21、R 22、R 51、R 31、R 32、R 33、R 11、R 12、R 13、R 14、R 15和R 16如前定义。
在另一优选例中，D a、D b和各个D c各自独立地为选自下组的一价基团：
Figure PCTCN2020084041-appb-000008
在另一优选例中，D a、D b和D c是相同的一价基团。
在另一优选例中，D a、D b和D c为
Figure PCTCN2020084041-appb-000009
在另一优选例中，D a和D b为相同的一价基团。
在另一优选例中，D a和D b为
Figure PCTCN2020084041-appb-000010
在另一优选例中，所述的取代的苯基具有1-5个选自(a)组的取代基：
(a)卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷氨基、C2-C6 链烯基、C2-C6链炔基、C3-C8环烷基、OH、CN。
在另一优选例中，所述的取代的苄基具有1-5个选自(a)组的取代基。
在另一优选例中，各个X为二价基团。
在另一优选例中，X的定义与Y的定义相同。
在另一优选例中，各个X独立地选自下组：O、S、C1-C6亚烷基、NR b、C(R c) 2、取代或未取代的4到7元碳环或杂环失去任意位置上的二个氢形成的二价基团。
在另一优选例中，各个X各自独立地选自下组：O、S、NH、C1-C6亚烷基(较佳地CH 2、CH(CH 3)、(CH 2) 2、CH 2CH(CH 3)、(CH 2) 3)。
在另一优选例中，各个X独立地选自下组：O、NH、或C1-C6亚烷基。
在另一优选例中，各个X独立地选自下组：O或CH 2。
在另一优选例中，L为如式II-C所示的连接基团
-(Y 1-Y 2-Y 3) S-   (II-C)
s为1～15的整数(较佳地为2～12的整数；更佳地为3～9的整数)；
Y 1、Y 2和Y 3各自独立地选自下组：O、S、C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基、CO、SO 2、NR b、或C(R b) 2、或者，取代或未取代的4到10元碳环(较佳地4到7元碳环)、4到10元杂环(较佳地4到7元杂环)、6到12元芳环(较佳地6元芳环)、或5到12元杂芳环(较佳地5～7元杂芳环)失去任意位置上的二个氢(包括同一原子上的氢或不同原子上的氢)形成的二价基团。
在另一优选例中，s为2～10的整数；较佳地为3～7的整数。
在另一优选例中，Y 1、Y 2和Y 3各自独立地选自下组：O、S、C1-C6亚烷基、NR b、或C(R c) 2，或者取代或未取代的4到7元碳环或杂环失去任意位置上的二个氢形成的二价基团；较佳地，各自独立地选自下组无、O、或C1-C6亚烷基。
在另一优选例中，Y 1、Y 2和Y 3各自独立地选自下组：O或CH 2(相邻不同时为O)。
在另一优选例中，L为-(CH 2-CH 2-O) s-；其中，s为2～10的整数(更佳地s为3、4、5、6或7)。
在另一优选例中，至少一个X为三价基团、四价基团、或五价基团。
在另一优选例中，至少一个X为三价基团。
在另一优选例中，L为如式II-D所示的基团
-(Y) p-Z-(Y) q-   (II-D)
其中，
Z为-Wc(T) k-；
p为0～50的整数，q为0～50的整数，且1≤p+q＜50；
Y、Wc、T、k的定义如前所述。
在另一优选例中，p为1～30的整数，q为1～30的整数，且2≤p+q＜50。
在另一优选例中，p为3～30的整数，q为3～30的整数，且6≤p+q＜30。
在另一优选例中，主链(即L)的链长为3-50个链原子(不含H原子)；较佳地6～40个链原子；更佳地9～30个链原子，最佳地9～21个链原子。
在另一优选例中，Wa和Wb各自独立的选自下组：无、O、S、CO、COO、NH、CO-NH、或NH-CO。
在另一优选例中，Wa和Wb各自独立的选自下组：无、或O。
在另一优选例中，所述化合物为如式IV所示的化合物，
Figure PCTCN2020084041-appb-000011
其中，
R 1、R 21、R 22、R 31、R 32、R 33、R 51、Wa、Wb、L如前定义。
在另一优选例中，所述化合物如式V所示
Figure PCTCN2020084041-appb-000012
其中，s为3、4、5、6或7；
R 1、R 21、R 22、R 31、R 32、R 51如前定义。
在另一优选例中，所述化合物为选自下组的化合物：
Figure PCTCN2020084041-appb-000013
在本发明的第二方面提供了一种药物组合物，其中，所述组合物包括；(i)如 第一方面所述的化合物，和(ii)药学上可接受的载体。
在本发明的第三方面提供了一种如第一方面所述化合物的制备方法，包括步骤：
Figure PCTCN2020084041-appb-000014
(i)使式V-A化合物与式V-B反应，从而得到式V-C化合物；
Figure PCTCN2020084041-appb-000015
(ii)使式V-C化合物脱去保护基，从而得到式V-D化合物；和
Figure PCTCN2020084041-appb-000016
(iii)使式V-D化合物与V-E化合物反应，从而得到式V化合物；
各式中，R 7选自：F、Cl、Br、I(较佳地，R 7为Br或Cl)；R 1、R 21、R 22、R 31、R 32、R 33、R 51和s的定义如前。
在本发明的第五方面提供了一种如第一方面所述化合物的用途，用于制备(i)用于抑制突变型IDH的活性；和/或(ii)用于治疗和/或预防突变型IDH介导的疾病的药物。
在本发明的第六方面提供了一种治疗和/或预防突变型IDH介导的疾病的方法，所述方法包括步骤：向需要的对象施用第一方面所述的化合物或其药学上可 接受的盐，或者如第二方面所述的药物组合物。
在另一优选例中，所述的对象为人或非人哺乳动物；较佳地人。
在另一优选例中，所述的IDH为IDH1。
在另一优选例中，所述突变型IDH介导的疾病包括：癌症。
在另一优选例中，所述癌症选自：脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、***癌、甲状腺癌、结肠癌、软骨肉瘤、胆管上皮癌、外周T细胞白血病、黑色素瘤，或其组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现将小分子化合物通过连接基团连接形成多聚体化合物(如式I所示的化合物)后，其抑制活性相比未形成多聚体的小分子化合物有大幅改善。实验表明，在细胞水平上，本发明的化合物对两种主要突变体的抑制效果增加了百倍以上。在此基础上完成了本发明。
术语
除非另有表述，术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即，C1-8表示1-8个碳)。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。
除非另有表述，术语“烯基”指具有一个或多个双键的不饱和烷基。类似地，术语“炔基”指具有一个或多个三键的不饱和烷基。此类不饱和烷基的例子包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基和更高级的同系物和异构体。
除非另有表述，术语“环烷基”是指具有指定环原子数(例如，C 3-6环烷基)并且完全饱和的或在环顶之间具有不超过一个双键的烃环。“环烷基”也指双环和多环烃环，例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。
除非另有表述，术语“杂环烷基”是指含有一至五个选自N、O和S的杂原子的环烷基，其中氮和硫原子任选被氧化，且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。杂环烷基的非限制性例子包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、 哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以经环碳或杂原子连接于分子的其余部分。对于诸如环烷基烷基和杂环烷基烷基的术语，是指环烷基或杂环烷基通过烷基或亚烷基连接体连接到分子的其余部分。例如，环丁基甲基-是连接到分子其余部分的亚甲基连接基上的环丁基环。
除非另有表述，术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团，例如-CH 2CH 2CH 2CH 2-。烷基(或亚烷基)通常具有1-24个碳原子，其中本发明优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短链烷基或亚烷基，通常具有4个或更少的碳原子。类似地，“亚烯基”或“亚炔基”分别指具有双键或三键的不饱和形式的“亚烷基”。
除非另有说明，术语“杂烷基”本身或与其它术语组合是指的稳定的直链或支链或环状烃基或其组合，由指定数目的碳原子和和1至3个选自O，N，Si和S的杂原子组成，且其中氮和硫原子可选地被氧化，氮杂原子可任选地被季铵化。杂原子O，N和S可以位于杂烷基的任何内部位置。杂原子Si可以位于杂烷基的任何位置，包括烷基连接到分子其余部分的位置。实施例包括-CH 2-CH 2-O-CH 3,-CH 2-CH 2-NH-CH 3,-CH 2-CH 2-N(CH 3)-CH 3,-CH 2-S-CH 2-CH 3,-CH 2-CH 2,-S(O)-CH 3,-CH 2-CH 2-S(O) 2-CH 3,-CH＝CH-O-CH 3,-Si(CH 3) 3,-CH 2-CH＝N-OCH 3,和-CH＝CH-N(CH 3)-CH 3。最多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3和-CH 2-O-Si(CH 3) 3。
类似地，除非另有说明，术语“杂烯基”和“杂炔基”其本身或与另一个术语的组合分别指烯基或炔基，其分别含有指定数目的碳和1至3个选自O，N，Si和S的杂原子，且其中氮和硫原子可选地被氧化，氮杂原子可任选地被季铵化。杂原子O，N和S可以位于杂烷基的任何内部位置。
除非另有表述，术语“杂亚烷基”本身或作为另一取代基的一部分是指由杂烷基衍生的饱和或不饱和或多不饱和的二价基团，例如-CH 2-CH 2-S-CH 2CH 2-和-CH 2-S-CH 2-CH 2-NH-CH 2-,-O-CH 2-CH＝CH-,-CH 2-CH＝C(H)CH 2-O-CH 2-和-S-CH 2-C≡C-。对于杂亚烷基，杂原子也可以占据链末端中的任一个或两个(例如，亚烷基氧基，亚烷基二氧基，亚烷基氨基，亚烷基二氨基等)。
除非另有表述，术语"烷氧基"、"烷氨基"和"烷硫基"(或硫代烷氧基)以其常规意义使用，指代分别经氧原子、氨基或硫原子连接于分子的其余部分的那些烷基。此外，对于二烷基氨基，烷基部分可以相同或不同，也可和与各烷基相连的氮原子组合形成3-7元环。因此，-NR aR b所示基团表示包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基(azetidinyl)等。
除非另有表述，术语“卤代”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴、或碘原子。此外，诸如“卤代烷基”等术语表示包括单卤代烷基或多卤代 烷基。例如，术语“C 1-4卤代烷基”表示包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有表述，术语“芳基”表示多不饱和的(通常芳香性)的烃基，其可以是单环或稠合在一起或共价连接的多环(最多三环)。术语"杂芳基"是指含有1至5个选自N、O、和S的杂原子的芳基(或环)，其中氮和硫原子任选被氧化，氮原子任选被季铵化。杂芳基可通过杂原子连接于分子的其余部分。芳基的非限制性例子包括苯基、萘基和联苯基，而杂芳基的非限制性例子包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基(benzotriazinyl)、嘌呤基、苯并咪唑基、苯并吡唑基、苯并***基、苯并异噁唑基、异苯并呋喃基(isobenzofuryl)、异吲哚基、中氮茚基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等等。以上芳基和杂芳基环***各自的取代基选自下述可接受的取代基的组。
为简洁起见，当术语“芳基”与其它术语(例如芳氧基，芳硫基，芳烷基)组合使用时，包括如上所定义的芳基和杂芳基环。因此，术语“芳烷基”是指包括其中芳基连接到与分子的其余部分连接的烷基的那些基团(例如苄基，苯乙基，吡啶基甲基等)。
在一些实施例中，上述术语(如“烷基”，“芳基”和“杂芳基”)将包括指定基团的取代和未取代形式。下面提供了每种类型基团的优选取代基。为简洁起见，术语芳基和杂芳基将指代如下文所提供的取代或未取代的形式，而术语“烷基”和相关的脂肪族基团是指未取代的形式，除非指明被取代。
烷基(包括通常称为亚烷基，烯基，炔基和环烷基的那些基团)的取代基可以是选自下组的各种基团：-卤素、-OR'、-NR'R”、-SR'、-SiR'R”R”'、-OC(O)R'、-C(O)R'、-CO 2R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O) 2R'、-NH-C(NH 2)＝NH、-NR'C(NH 2)＝NH、-NH-C(NH 2)＝NR'、-S(O)R'、-S(O) 2R'、-S(O) 2NR'R”、-NR'S(O) 2R”、-CN和-NO 2，数量从零到(2m'+1)，其中m'是这种基团中的碳原子总数。R'、R”和R”'各自独立地表示氢，未取代的C 1-8烷基，未取代的杂烷基，未取代的芳基，被1-3个卤素取代的芳基，未取代的C 1-8烷基，C 1-8烷氧基或C 1-8硫代烷氧基，或未取代的芳基-C 1-4烷基。当R'和R”连接到相同的氮原子时，它们可以与氮原子结合形成3-，4-，5-，6-或7-元环。例如，-NR'R”是指包括1-吡咯烷基和4-吗啉基。术语“酰基”，单独或作为另一基团的一部分使用，是指其中在最接近该基团的连接点的碳上两个取代基的被取代基＝O取代(例如-C(O)CH 3,-C(O)CH 2CH 2OR'等)。
如本文所用，术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)。
对于本文提供的化合物，从取代基(通常为R基团)到芳香环(例如苯，吡啶等)的中心的键将被理解为是指在芳香环的任何可用顶点提供连接的键。在一些实施例中，该描述也包括稠合在芳环上的环上的连接。例如，绘制到吲哚苯部分的中心的键将表示与吲哚的六元或五元环部分的任何可用顶点连接的键。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键；消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如，分离的对映体)均应包括在本发明范围内。当本文提供的化合物具有确定的立体化学(表示为R或S，或具有虚线或楔形键指明)时，被本领域技术人员将理解那些化合物为基本上不含其他异构体(例如至少80％，90％，95％，98％，99％和至多100％不含其他异构体)。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-OH、未取代或卤代的、-CN。
如本文所用，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
如本文所用，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和***反应)，即有合理的效益/风险比的物质。
如本文所用，术语“治疗有效剂量”是指药物的任何如下所述的量，当单独使用或与另一种治疗剂组合使用该量的药物时，可促进疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。本发明药物的“治疗有效剂量”也包括“预防有效剂量”，“预防有效剂量”是药物的任何如下所述的量，当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。
本发明化合物
本发明提供了用于抑制突变型IDH的化合物。本发明化合物为二聚或多聚体形式抑制剂。
如本文所用，术语“本发明化合物”指具有式I结构的化合物、药学上可接受的盐、前药、光学异构体、外消旋体、溶剂化物，
D a-W a-L-W b-D b   (I)
式中，各基团定义如第一方面中所述。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
除盐形式外，本发明还提供了前药形式的化合物。本文所述的化合物的前药是在生理条件下很容易经历化学变化以提供本发明化合物的那些化合物。另外，前药可以在离体环境中通过化学或生物化学方法转变为本发明化合物。例如，当置于含合适的酶或化学试剂的经皮贴片贮器中时，前药可缓慢转变为本发明的化合物。一类优选的前药为酯形式。
本发明化合物可以是无定形的、晶型或其混合物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在，包括水化形式。溶剂化形式通常与非溶剂化形式等价，应包括在本发明范围内。本发明的某些化合物可以多晶型或无定形形式存在。通常，就本发明所考虑的应用而言，所有物理形式是等价的，应包括在本发明范围内。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100％该原子的量。例如，化合物可以掺入放射性同位素，例如氚( 3H)、碘-125( 125I)或碳-14( 14C)，或非放射性同位素，例如氘( 2H)或碳-13( 13C)。除了本申请所述的那些用途，此类同位素变体可提供额外的用途。例如，本发明化合物的同位素变体可以有额外的用途，包括但不限于作为诊断的和/或成像试剂，或作为细胞毒性/放射毒性治疗剂。另外，本发明化合物的同位素变体可具有改变的药代动力学和药效学特征，从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性，本发明化合物的所有同位素变体均应包括在本发明范围内。
制备方法
在本发明中，对于D a、D b和D c等用于抑制突变型IDH蛋白的活性基团(或相应的活性化合物)，可参考现有技术进行制备或购买获得。
一种典型的制备本发明化合物的方法采用以下流程：
Figure PCTCN2020084041-appb-000017
(i)使式V-A化合物与式V-B反应，从而得到式V-C化合物；
Figure PCTCN2020084041-appb-000018
(ii)使式V-C化合物脱去保护基，从而得到式V-D化合物；和
Figure PCTCN2020084041-appb-000019
(iii)使式V-D化合物与V-E化合物反应，从而得到式V化合物；
各式中，R 7选自：F、Cl、Br、I(较佳地，R 7为Br或Cl)；R 1、R 21、R 22、R 31、R 32、R 33、R 51和s的定义如前。
典型地，在步骤(i)中，通常可在溶剂(如乙腈)中，碱性条件下，于室温或加热下，反应4小时或以上(如4-20小时)，从而获得式V－C化合物。式V-C化合物可以分离，也可直接用于后一步骤。
在步骤(ii)中，通常可在溶剂(如甲醇)中，酸性条件下，于室温或加热下，反应2小时或以上(如2-10小时)，从而获得式V化合物。
在步骤(iii)中，通常可在溶剂(如DMSO)中，碱性条件下，于室温或加热下，反应2小时或以上，从而获得式V化合物。
药物组合物和施用方法
由于本发明化合物具有优异的对突变型IDH1(例如，IDH1/R132H和IDH1/R132C)的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由突变型IDH1介导的疾病。
优选地，本发明化合物可用于治疗癌症。代表性的癌症包括(但并不限于)：脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、***癌、甲状腺癌、结肠癌、软骨肉瘤、胆管上皮癌、外周T细胞白血病、黑色素瘤，或其组合。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020084041-appb-000020
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或 酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括
(a)本发明的化合物高效无毒、抑制活性高。
(b)本发明的多聚体化合物的活性，相比未进行连接的小分子化合物的活性显著提升，甚至成百倍地提升。
(c)本发明的化合物的特异性好。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
本申请涉及的化合物说明
(1)本实施例的对照化合物为AG-120，CAS：1448347-49-6，商业购得，结构 式如下：
Figure PCTCN2020084041-appb-000021
AG-120(Ivosidenib)是一种具有口服活性的IDH1抑制剂，具有潜在的抗肿瘤活性。
(2)本发明使用的部分化合物可从商用和/或公开的化合物库获得，例如本发明部分化合物购自上海毕得医药科技有限公司或北京伊诺凯科技有限公司或上海超岚化工科技中心或上海阿拉丁生化科技股份有限公司或梯希爱(上海)化成工业发展有限公司或韶远化学科技(上海)有限公司或上海昀冠机电设备有限公司。
(3)本发明的其它化合物可由普通技术人员使用化学合成领域中众所周知的方法例如取代反应合成得到。例如，可根据下列通用方案制备本发明的化合物。
实施例1化合物1的合成
(1)(S)-3-(2-氯嘧啶-4-基)-4-异丙基噁唑烷-2-酮的合成
(S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one的合成
Figure PCTCN2020084041-appb-000022
在冰浴中，向(S)-4-(S)-4-异丙基噁唑烷-2-酮(1.50g,11.6mmol)和2,4-二氯嘧啶(1.90g,12.8mmol)于DMF中的溶液中，分批加入NaH(60％于矿物油中,520mg,13.0mmol)。在室温下，将得到的黄色悬浮液搅拌过夜。然后将混合物倒进水(150mL)中并用EtOAc(70mL×3)萃取。合并的有机层用盐水(70ml)洗涤，用MgSO 4干燥并浓缩。粗产品用柱层析(石油醚:EtOAc＝5:1)提纯，得到标题化合物(2.05g,收率73％)，为白色固体。
1H NMR(400MHz,CDCl 3)δ8.47(d,J＝6.0Hz,1H),8.18(d,J＝6.0Hz,1H),4.81-4.77(m,1H),4.43-4.34(m,2H),2.64-2.56(m,1H),0.99(d,J＝7.2Hz,3H),0.88(d,J＝7.2Hz,3H)
(2)(乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基)双(4-甲基苯磺酸酯)的合成
(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate)的合成
Figure PCTCN2020084041-appb-000023
在冰浴中，向TsCl(9.50g,49.8mmol)和TEA(7.27g,72.0mmol)于DCM(70mL)的悬浮液中逐滴加入2,2'-(乙烷-1,2-二基双(氧基))二乙醇(3.60g,23.9mmol)于DCM的溶液。在室温下，将混合物搅拌过夜。然后反应混合物用水(80mL)和盐水(80mL)洗涤，用MgSO 4干燥并浓缩。粗产品用硅胶柱色谱(石油醚:EtOAc＝5:1)提纯，得到期望产品(8.1g，收率74％)，为白色固体。
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.4Hz,4H),7.34(d,J＝8.0Hz,4H),4.15-4.13(m,4H),3.67-3.64(m,4H),3.53(s,4H),2.44(s,6H).
(3)(S,E)-N-((5-溴吡啶-2-基)甲基丙烷-2-亚磺酰胺的合成
(S,E)-N-((5-bromopyridin-2-yl)))-2-methylpropane-2-sulfinamide的合成
Figure PCTCN2020084041-appb-000024
向5-溴吡啶甲基醛(27.9g,150mmol)于二氯甲烷(200mL)中的溶液中加入(S)-2-甲基丙烷-2-亚磺酰胺(19.5g,165mmol)和Cs2CO3(73.5g,225mmol)。在室温下，将得到的混合物搅拌5小时。然后过滤混合物，并浓缩滤液。用柱层析(二氯甲烷)纯化残余物，得到期望的产物(40.0g，产率92％)，为白色固体。
1H NMR(400MHz,CDCl 3)δ8.80(dd,J＝2.0,0.8Hz,1H),8.66(s,1H),7.97-7.91(m,2H),1.29(s,9H).
(4)(S)-N-((S)-1-(5-溴吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺的合成
(S)-N-((S)-1-(5-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide的合成
Figure PCTCN2020084041-appb-000025
在-65℃下，在N 2氛围下，向(S,E)-N-((5-溴吡啶-2-基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(30.0g,104mmol)于THF(200mL)中的溶液逐滴加入CH 3MgCl(2.5M于甲苯中,75mL,187mmol)。加入完成后，在-65℃下，将得到的混合物搅拌2小时。然后向反应混合物中加入NH 4Cl(饱和,200mL)并在-65℃下搅拌混合物10min。过滤混合物，滤液用EtOAc(200mL×3)萃取。合并的有机层用盐水(200mL)洗涤，用Na 2SO 4干燥，过滤并浓缩至得到期望产物(31.1g,收率100％)，为黄色固体。
1H NMR(400MHz,CDCl 3)δ8.60(d,J＝2.4Hz,1H),7.78(dd,J＝8.4,2.4Hz,1H),7.21(d,J＝8.4Hz,1H),4.57-4.53(m,2H),1.50(d,J＝6.4Hz,3H),1.25(s, 9H).
(5)(S)-1-(5-溴吡啶-2-基)乙胺的合成
(S)-1-(5-bromopyridin-2-yl)ethanamine的合成
Figure PCTCN2020084041-appb-000026
在室温下，搅拌(S)-N-((S)-1-(5-溴吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(30.0g,98.6mmol)于HCl(6M水溶液，200mL)中的混合物2小时。然后加入NaOH(2M水溶液)调节pH＝7-8，并用EtOAc(500mL×3)萃取水层。合并的有机层用盐水(500mL)洗涤，用Na 2SO 4干燥并浓缩，得到期望产物(19.7g粗产物)，为黄色固体，其直接用于下一步骤。
1H NMR(400MHz,CDCl 3)δ8.60(d,J＝2.0Hz,1H),7.76(dd,J＝8.4,2.4Hz,1H),7.24(d,J＝8.4Hz,1H),4.13(q,J＝6.8Hz,1H),1.71(s,2H),1.41(d,J＝6.4Hz,3H).
(6)(S)-叔丁基(1-(5-溴吡啶-2-基)乙基)氨基甲酸酯的合成
(S)-tert-butyl(1-(5-bromopyridin-2-yl)ethyl)carbamate的合成
Figure PCTCN2020084041-appb-000027
向(S)-1-(5-溴吡啶-2-基)乙胺(19.7g,98.6mmol)于二氯甲烷(300mL)中的溶液中加入TEA(29.8g,296mmol)和Boc 2O(32.2g,148mmol)。在室温下，搅拌得到的混合物2小时。然后浓缩反应混合物，粗产物用硅胶柱色谱(石油醚:EtOAc＝5:1)提纯，以获得黄色固体状的期望产物(28.9g，产率96％)，为。通过手性制备进一步分离35.2g产物。HPLC[chiralpakIG5μm，20×250mm；相:Hex(十六烷):EtOH＝85:15；UV＝214nm；F＝18mL/min]，得到光学异构的(S)-叔丁基(1-(5-溴吡啶-2-基)乙基)氨基甲酸酯(27.4g)，为白色固体。
1H NMR(400MHz,CDCl 3)δ8.59(d,J＝2.0Hz,1H),7.77-7.76(m,1H),7.16(d,J＝8.4Hz,1H),5.50(br s,1H),4.89-4.74(m,1H),1.43(s,12H).
手性色谱：:(条件:chiralpak IB 5μm,4.6×250mm；相:Hex:EtOH＝50:50；UV＝230nm；F＝1mL/min；T＝30℃),Rt＝12.930min,100％ee.
(7)(S)-叔丁基(1-(5-羟基吡啶-2-基)乙基)氨基甲酸酯
(S)-tert-butyl(1-(5-hydroxypyridin-2-yl)ethyl)carbamate的合成
Figure PCTCN2020084041-appb-000028
用N 2对(S)-叔丁基(1-(5-溴吡啶-2-基)乙基)氨基甲酸酯(5.00g,16.6mmol) B 2Pin 2(5.00g,19.9mmol),KOAc(4.9g,49.8mmol)和Pd(dppf)Cl 2(364mg,0.498mmol)于二恶烷中的悬浮液进行脱气。在90℃下，将所得混合物搅拌过夜。浓缩反应混合物，使残余物在水(150mL)和EtOAc(100mL)之间分配。用EtOAc(100mL×2)萃取水层。合并的有机层用盐水(100mL)洗涤，用MgSO 4干燥并浓缩。将粗产物溶于THF(100mL)中。加入NaOH(1M,41.5mL,41.5mmol)并将混合物搅拌5分钟。然后在冰浴下逐滴加入H 2O 2(30％,3.76g,33.2mmol)。将得到的混合物在室温下搅拌2小时。将反应混合物倒入Na 2S 2O 3(5％,200mL)水溶液中。搅拌5分钟后，用EtOAc(80mL×3)萃取水层。合并的有机层用盐水(80mL×3)洗涤，经MgSO 4干燥并浓缩。通过硅胶柱(石油醚:EtOAc＝2:1)提纯粗产物，得到期望产物(5.77g粗品)，为棕色油状物。
1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.10(s,2H),5.65-5.55(m,1H),4.83-4.70(m,1H),1.43-1.40(m,12H).
(8)二-叔丁基((1S,1'S)-(5,5'-(((乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))双(乙烷-1,1-二基))二氨基甲酸酯的合成
di-tert-butyl((1S,1'S)-(5,5'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(ethane-1,1-diyl))dicarbamate的合成
Figure PCTCN2020084041-appb-000029
在85℃下，将(乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基)双(4-甲基苯磺酸酯)(1.05g,2.30mmol)，(S)-叔丁基(1-(5-羟基吡啶-2-基)乙基)氨基甲酸酯(1.30g粗品,5.00mmol)，K 2CO 3(954mg,6.90mmol)和KI(4mg,0.023mmol)的CH 3CN(20mL)溶液的悬浮液搅拌过夜。将反应混合物倒入水(100mL)中并用EtOAc(100mL)萃取。将合并的有机层用盐水(50mL)洗涤，经MgSO4干燥并浓缩。粗产物通过硅胶柱(石油醚:EtOAc从1：1至0：1)提纯，得到期望产物(920mg,产率68％)，为黄色油状物。
LC-MS[流动相:自95％水和5％CH 3CN至5％水和95％CH 3CN,2.5min内],Rt＝1.56min；纯度>90％(254nm)；MS计算值:590.3；MS实测值:591.5[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.24(d,J＝2.4Hz,2H),7.20-7.14(m,4H),5.65-5.54(m,2H),4.85-4.73(m,2H),4.16(t,J＝4.8Hz,4H),3.87(t,J＝4.8Hz,4H),3.75(s,4H),1.43-1.41(m,24H).
(9)(1S,1'S)-1,1'-(5,5'-(((乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基)双(氧基))双(吡啶-5,2-二基))二乙胺四盐酸盐的合成
(1S,1'S)-1,1'-(5,5'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))diethanamine tetrahydrochloride的合成
Figure PCTCN2020084041-appb-000030
在室温下，向二-叔丁基((1S,1'S)-(5,5'-(((乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))双(乙烷-1,1-二基))二氨基甲酸酯(620mg,0105mmol)于甲醇(10mL)中的溶液中逐滴加入浓盐酸(2mL)。将所得混合物搅拌过夜。然后浓缩反应混合物，得到期望化合物(640mg粗产物，收率100％)，为无色油状物。
LC-MS[流动相:自95％水和5％CH 3CN至5％水和95％CH 3CN，2.5min内],Rt＝0.29min；MS计算值:390.2；MS实测值:591.3[M+H] +.
(10)(4S,4'S)-3,3'-(2,2'-(((1S,1'S)-(5,5'-(((乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))双(乙烷-1,1-二基))双(氮烷二基)双(嘧啶-4,2-二基)双(4-异丙基噁唑烷-2-酮)
(4S,4'S)-3,3'-(2,2'-(((1S,1'S)-(5,5'-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(ethane-1,1-diyl))bis(azanediyl))bis(pyrimidine-4,2-diyl))bis(4-isopropyloxazolidin-2-one)的合成
Figure PCTCN2020084041-appb-000031
在130℃下，搅拌(1S,1'S)-1,1'-(5,5'-(((乙烷-1,2-二基双(氧基))双(乙烷-2,1-二基)双(氧基))双(吡啶-5,2-二基))二乙胺四盐酸盐(540mg crude,0.89mmol)，(S)-3-(2-氯嘧啶-4-基)-4-异丙基噁唑烷-2-酮(538mg,2.23mmol)和DIEA(1.15g,8.9mmol)于DMSO(8mL)中的溶液过夜。冷却至室温后，将反应混合物倒入水(100mL)中并用EtOAc(50mL×3)萃取。将合并的有机层用水(50mL)，盐水(50mL)洗涤，经MgSO4干燥并浓缩。通过硅胶柱(EtOAc：MeOH＝20：1)纯化粗产物，并通过C18(5-60％CH3CN/水)进一步纯化，得到所需产物1(110mg，收率15％)，为浅黄色固体。
LC-MS[流动相:自80％水(0.02％NH 4OAc)和20％CH 3CN至20％水(0.02％NH 4OAc)和80％CH 3CN，6.5min内],Rt＝4.019min；纯度:95.91％(214nm),94.56％(254nm)；MS计算值:800.4；MS实测值:801.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.25(d,J＝2.4Hz,2H),8.19(d,J＝6.0Hz,2H),7.43(d,J＝6.0Hz,2H),7.19-7.14(m,4H),6.03-5.89(m,2H),5.16-4.98(m,2H), 4.70-4.60(m,2H),4.28(t,J＝8.4Hz,2H),4.22(dd,J＝9.2,3.2Hz,2H),4.15(t,J＝4.4Hz,4H),3.86(t,J＝4.8Hz,4H),3.74(s,4H),2.44-1.85(m,2H),1.53(d,J＝6.8Hz,6H),0.78-0.73(m,12H).
实施例2化合物2的合成
(1)((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基)双(4-甲基苯磺酸酯)的合成
((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate)的合成
Figure PCTCN2020084041-appb-000032
冰浴条件下，向TsCl(6.20g,32.3mmol)和TEA(4.70g,46.2mmol)于DCM(50mL)中的悬浮液中逐滴加入2,2'-((氧基双(乙烷-2,1-二基)双(氧基))二乙醇(3.00g,15.4mmol)的二氯甲烷(10mL)溶液。在室温下，搅拌得到的混合物过夜。将反应混合物用水(60mL)、盐水(60mL)洗涤，经MgSO4干燥并浓缩。粗产物用硅胶柱色谱(石油醚:EtOAc自2:1至0:1)提纯，得到期望产物(5.6g，收率72％)，为棕色油状物。
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.4Hz,4H),7.34(d,J＝8.0Hz,4H),4.15(t,J＝4.8Hz,4H),3.68(t,J＝4.8Hz,4H),3.60-3.53(m,8H),2.44(s,6H).
(2)二-叔丁基((1S,1'S)-(5,5'-((((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))双(乙烷-1,1-二基))二氨基甲酸酯的合成
di-tert-butyl((1S,1'S)-(5,5'-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(ethane-1,1-diyl))dicarbamate的合成
Figure PCTCN2020084041-appb-000033
向((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基)双(4-甲基苯磺酸酯)(400mg,0.796mmol)和(S)-叔丁基(1-(5-羟基吡啶-2-基)乙基)氨基甲酸酯(379mg,1.59mmol)于CH 3CN(7mL)中的溶液中加入K 2CO 3(330mg,2.39mmol)and KI(4mg,0.024mmol)。在85℃下，将得到的混合物搅拌过夜。反应混合物(第一批次)与另一批一起操作。
向((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基)双(4-甲基苯磺酸酯) (800mg,1.59mmol)和(S)-叔丁基(1-(5-羟基吡啶-2-基)乙基)氨基甲酸酯(796mg,3.34mmol)于CH 3CN(16mL)中的溶液中加入K 2CO 3(659mg,4.77mmol)和KI(8mg,0.05mmol)。在85℃下，将得到的混合物搅拌过夜。将与(第一批次)合并的反应混合物倒进水(100mL)中并用EtOAc(50mL×3)萃取。合并的有机层用盐水(50mL)洗涤，经MgSO 4干燥并浓缩。粗产物通过硅胶柱(石油醚:EtOAc从1:1至0:1)提纯，得到期望产物(578mg,收率38％)，为淡黄色油状物。
1H NMR(400MHz,CDCl 3)δ8.24(d,J＝2.4Hz,2H),7.20-7.14(m,4H),5.59(br s,2H),4.85-4.71(m,2H),4.16-4.14(m,4H),3.87-3.84(m,4H),3.74-3.67(m,8H),1.43-1.41(m,24H).
(3)(1S,1'S)-1,1'-(5,5'-((((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基))双(氧基)双(吡啶-5,2-二基))二乙胺四盐酸盐的合成
(1S,1'S)-1,1'-(5,5'-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))diethanamine tetrahydrochloride的合成
Figure PCTCN2020084041-appb-000034
在室温下，向二-叔丁基((1S,1'S)-(5,5'-((((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))双(乙烷-1,1-二基))二氨基甲酸酯(578mg,0.911mmol)于MeOH(10mL)中的溶液逐滴加入浓HCl(2mL)。将得到的混合物搅拌过夜。然后浓缩反应混合物，得到期望化合物(715mg粗产物，收率100％)，为棕色油状物。
LC-MS[流动相:自95％水和5％CH 3CN至5％水和95％CH 3CN，2.5min内],Rt＝1.07min；MS计算值:434.3；MS实测值:435.4[M+H] +.
(4)(4S,4'S)-3,3'-(2,2'-(((1S,1'S)-(5,5'-((((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))双(乙烷-1,1-二基))双(氮烷二基))双(嘧啶-4,2-二基))双(4-异丙基噁唑烷-2-酮)的合成
(4S,4'S)-3,3'-(2,2'-(((1S,1'S)-(5,5'-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(ethane-1,1-diyl))bis(azanediyl))bis(pyrimidine-4,2-diyl))bis(4-isopropyloxazolidin-2-one)的合成
Figure PCTCN2020084041-appb-000035
在130℃下，将1S,1'S)-1,1'-(5,5'-((((氧基双(乙烷-2,1-二基))双(氧基))双(乙烷-2,1-二基))双(氧基))双(吡啶-5,2-二基))二乙胺四盐酸盐(715mg粗产物,0.911mmol)、(S)-3-(2-氯嘧啶-4-基)-4-异丙基噁唑烷-2-酮(660mg,2.73mmol)和DIEA(1.18g,9.11mmol)于DMSO(8mL)中的溶液搅拌过夜。冷却至室温后，将反应混合物倒入水(50mL)中并用EtOAc(30mL×3)萃取。将合并的有机层用水(30mL)，盐水(30mL)洗涤，经MgSO4干燥并浓缩。粗产物通过硅胶柱(EtOAc:MeOH＝25:1)提纯，并进一步通过C18(5-60％CH 3CN水溶液)提纯，得到期望的产物2(155mg,收率20％)，为淡黄色固体。
LC-MS[流动相:自70％水(0.02％NH 4OAc)和30％CH 3CN至30％水(0.02％NH 4OAc)和70％CH 3CN，6.5min内],Rt＝3.619min；纯度:96.91％(214nm),96.73％(254nm)；MS计算值:844.4；MS实测值:845.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.25(d,J＝2.4Hz,2H),8.19(d,J＝5.6Hz,2H),7.43(d,J＝6.0Hz,2H),7.20-7.14(m,4H),6.12-5.90(m,2H),5.16-4.98(m,2H),4.69-4.60(m,2H),4.30-4.21(m,4H),4.15(t,J＝4.8Hz,4H),3.85(t,J＝4.8Hz,4H),3.73-3.66(m,8H),2.35-1.82(m,2H),1.53(d,J＝6.8Hz,6H),0.78-0.73(m,12H).
实施例3化合物在细胞水平对突变型IDH1/R132H的抑制活性
2-羟基戊二酸脱氢酶(2HGDH)在2-HG存在的情况下，能够将NAD+还原成NADH。后者可以通过心肌黄酶及其底物Resazurin(刃天青)进行定量测定。
过表达IDH1/R132H突变的胶质瘤细胞U87MG，培养在1％丙酮酸钠的高糖MEM，10％FBS中，置于CO 2培养箱(37℃，5％CO 2,95％空气)培养。
细胞通过胰酶消化并以1×10 4的密度接种于96孔板中，培养基为200μL，37℃培养箱培养过夜。第二天加入待测化合物，DMSO终浓度均为0.1％，在培养24小时后，吸取100μL培养基，使用10KD
Figure PCTCN2020084041-appb-000036
超滤管(购自PALL公司)14000g离心10分钟，过滤培养基中存在的可能干扰结果的蛋白等成分，使用后续方法检测2-HG的含量。
细胞外2-HG测定体系：
(1)50μL反应体系：反应缓冲液(50mM Tris pH7.5，100mM NaCl，20mM MgCl 2，0.05％BSA)，其中NAD+终浓度为40μM，2HGDH终浓度为20nM，待 测样品加入5μL培养液；反应液混匀离心，避光25℃反应1小时；
(2)25μL显色体系：显色缓冲液(50mM Tris pH7.5，100mM NaCl，20mM MgCl 2，0.05％BSA)，其中心肌黄酶的终浓度为36μg/mL，刃天青钠的终浓度为3μM；将上述25μL显色液加入(1)中的50μL反应体系中，混匀并离心，立即在Ex544/Em590下进行荧光值测定。
2-HG标准曲线制备：将2-HG储液使用反应缓冲液稀释至20μM，之后进行2倍梯度稀释，共计6个点。之后将上述2-HG按照细胞外2-HG测定体系测定，计算并绘制标准曲线。
细胞外2-HG含量计算：
细胞外2-HG测定体系中获得的荧光值使用2-HG标准曲线计算培养基中2-HG的含量，以DMSO作为阴性对照，计算化合物对IDH1/R132H突变产生2-HG活性的抑制。
测试结果见表1。其中，“-”指对IDH1/R132H的抑制活性范围为IC 50≥10μM；“+”指对IDH1/R132H的抑制活性范围为500nM≤IC 50≤10μM；“++”“-”指对IDH1/R132H的抑制活性范围为5nM<IC 50<500nM；“+++”指对IDH1/R132H的抑制活性范围为IC 50≤5nM。
表1本发明的化合物以及对IDH1/R132H抑制活性
Figure PCTCN2020084041-appb-000037
Figure PCTCN2020084041-appb-000038
结果显示，化合物1和2具有优异的IDH1/R132H抑制活性(IC 50≤5nM)。
实施例4化合物在细胞水平对突变型IDH1/R132C的抑制活性
实验步骤与实施例3相同，不同点在于，用含IDH1/R132C突变的纤维肉瘤细胞HT-1080，替换过表达IDH1/R132H突变的胶质瘤细胞U87MG。
测试结果见表2。“-”指对IDH1/R132H的抑制活性范围为IC 50≥10μM；“+”指对IDH1/R132H的抑制活性范围为500nM≤IC 50≤10μM；“++”“-”指对IDH1/R132H的抑制活性范围为5nM<IC 50<500nM；“+++”指对IDH1/R132H的抑制活性范围为IC 50≤5nM。
表2优选化合物对IDH1/R132C抑制活性
化合物编号 IC 50(nM)
1 +++
2 +++
Ref1 +
IDH125 +
AG-120 ++
结果显示，化合物1和2具有优异的IDH1/R132C抑制活性(IC 50≤5nM)。
实施例5化合物在细胞水平对突变型IDH2/R140Q的抑制活性
实验操作与实施例7同，不同点在于，用过表达IDH2/R140Q突变的胶质瘤细胞U87MG，替换过表达IDH1/R132H突变的胶质瘤细胞U87MG。
测试结果见表3。其中，表4的“+”指对IDH2/R140Q的IC50≤20μM的抑制活性；“-”指对IDH2/R140Q的IC50>20μM的抑制活性。
表3优选化合物的IDH2/R140Q抑制活性
化合物编号 IC 50(μM)
1 -
2 -
Ref1 -
IDH125 -
AG-120 -
结果显示，本发明化合物1和2均不抑制IDH2/R140Q，显示了化合物优异的特异性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种式I化合物、或其药学上可接受的盐，其特征在于，
    D a-W a-L-W b-D b  (I)
    其中，
    Wa和Wb各自独立地选自下组：无、O、S、NR a、CO、COO、SO、SO 2、CO-NR a、NR a-CO、SO-N(R a)、N(R a)-SO、NR a-COO、COO-NR a、NR a-SO 2、SO 2-NR a、CS-NR a、NR a-CS、或N(R a)-CO-NR a；
    其中，R a各自独立地选自下组：H、氘、CN、卤素、C1-C6烷基、C1-C6卤代烷基，或取代或未取代的C3-C6环烷基(较佳地所述取代为被C1-C6烷基取代和/或卤素取代)；较佳地，R a各自独立地选自下组：H、氘、-CH 3、-C 2H 5、-CH(CH 3) 2、-CH 2CH 2CH 3、环丙基；
    L为如式II所示的连接基团
    -(X) n-  (II)
    其中，
    n为1～50的整数(较佳地为3～40的整数)；
    各个X是相同或者不同的，且各个X独立地选自下组：O、S、取代或未取代的C1-C6亚烷基、取代或未取代的C2-C6亚烯基、取代或未取代的C2-C6亚炔基、CO、SO 2、NR b、C(R c) 2、取代或未取代的4到10元碳环、取代或未取代的4到10元杂环、取代或未取代的6到12元芳环、取代或未取代的5到12元杂芳环；或-Wc(T) k-，其中，Wc为三价基团、四价基团、或五价基团，而k为1、2或3；T为-R d-Wa-L'-Wb-D c，其中，Wa和Wb如上所述；
    各个R d独立地为无，或选自下组的二价基团：取代或未取代的C1-C6亚烷基、取代或未取代的C2-C6亚烯基、取代或未取代的C1-C6卤代亚烷基、取代或未取代的C3-C6环烷基；
    L'为无或如式II-A所示的连接基团
    -(Y) m-   (II-A)
    式中，
    m为1～50的整数；
    各个Y是相同或者不同的，且各个Y独立地选自下组：O、S、取代或未取代的C1-C6亚烷基、取代或未取代的C2-C6亚烯基、取代或未取代的C2-C6亚炔基、CO、SO 2、NR b、C(R c) 2、取代或未取代的4到10元碳环、取代或未取代的4到10元杂环、取代或未取代的6到12元芳环、取代或未取代的或5到12元杂芳环；
    各个R b独立地选自下组：H、氘、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧 基；
    各个R c独立地选自下组：H、氘、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、OH、CN；；
    其中，所述杂环或杂芳环含有1、2或3个选自O、S或N的杂原子；
    附加条件是，当所述的X为取代的碳环、取代的杂环、取代的芳环、或取代的杂芳基时，所述碳环、杂环、芳环或杂芳基上的取代基可任选地含有1、2或3个T，其中T如上定义；
    除非特别说明，所述的“取代”是指所述基团中的1～5个氢各自独立地被选自下组的取代基所取代：氘、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、取代或未取代的苯基、取代或未取代的苄基、-N(R b) 2、-C(R c) 3、-CN、-OH、-COOR f、-SO 2R f、-NHC(O)R f；其中，R f各自独立地选自下组：氢、氘、C1-C6烷基，R b和R c如上定义；以及
    D a、D b和D c各自独立地为抑制突变型IDH蛋白的活性基团。
  2. 如权利要求1所述的化合物，其特征在于，D a、D b和D c各自独立地为如式III所示的基团：
    Figure PCTCN2020084041-appb-100001
    其中，
    R 1为二价连接基团；
    R 21、R 22各自独立地选自下组：氢、氘、卤素、氨基、氰基、取代或未取代的C1-C6烷基，或者R 21、R 22和与其相连的碳原子共同形成取代或未取代的C3-C5环烷基；其中，所述取代是指基团上一个或多个(较佳地1-3个)H被选自下组的取代基取代：氘、卤素、C1-C6烷基；
    R 23选自下组：NR 62；
    R 31、R 32、R 33、和R 34各自独立地选自下组：N、CR 61；
    R 8选自下组：N、CR 61；
    R 9为C；
    R 10选自下组：O、S；
    R 41和R 42各自独立地选自下组：O、S、C(R 53) 2；
    R 51各自独立地选自下组：H、氘、取代或未取代的C1-C6烷基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5～7元杂芳基、取代或未取代的二苯基甲基；
    R 52选自下组：H、氘、C1-C6烷基；
    或者，R 51和R 52和与其相连的碳原子共同形成取代或未取代的C1-C6(较佳地，C1-C4)环烷基、取代或未取代的5到7元杂环基；
    R 53各自独立地选自下组：H、氘、取代或未取代的C1-C6烷基、苯基、苄基；或者两个R 53和与其相连的碳原子共同形成取代或未取代的3-7元环烷基或取代或未取代的4-7元杂环；R 53基团中，所述的取代是指基团中的1～3个氢各自独立地被选自下组的取代基所取代：氘、卤素、羟基、C1-6烷基、C1-C6卤代烷基、氨基；
    R 61各自独立地选自下组：氢、氘、卤素(较佳地，F、Cl、Br)、C1-C6烷基、C1-C6卤代烷基；和
    R 62各自独立地选自下组：氢、氘、C1-C6烷基、C1-C6卤代烷基。
  3. 如权利要求1所述的化合物，其特征在于，D a、D b和各个D c各自独立地为选自下组的一价基团：
    Figure PCTCN2020084041-appb-100002
  4. 如权利要求1所述的化合物，其特征在于，L为如式II-C所示的连接基团
    -(Y 1-Y 2-Y 3) S-  (II-C)
    s为1～15的整数；
    Y 1、Y 2和Y 3各自独立地选自下组：O、S、C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基、CO、SO 2、NR b、或C(R b) 2；或者，取代或未取代的4到10元碳环、4到10元杂环、6到12元芳环、或5到12元杂芳环失去任意位置上的二个氢形成的二价基团。
  5. 如权利要求1所述的化合物，其特征在于，所述化合物为如式IV所示的化合物，
    Figure PCTCN2020084041-appb-100003
    其中，
    R 1为二价连接基团；
    R 21、R 22各自独立地选自下组：氢、氘、卤素、氨基、氰基、取代或未取代的C1-C6烷基，或者R 21、R 22和与其相连的碳原子共同形成取代或未取代的C3-C5环烷基；其中，所述取代是指基团上一个或多个H被选自下组的取代基取代：氘、卤素、C1-C6烷基；
    R 31、R 32、和R 33各自独立地选自下组：N、CR 61；
    R 51各自独立地选自下组：H、氘、取代或未取代的C1-C6烷基、取代或未取代的苯基、取代或未取代的苄基、取代或未取代的5～7元杂芳基、取代或未取代的二苯基甲基；
    R 61各自独立地选自下组：氢、氘、卤素(较佳地，F、Cl、Br)、C1-C6烷基、C1-C6卤代烷基；和
    Wa、Wb、L的定义同权利要求1中所述。
  6. 如权利要求5所述的化合物，其特征在于，所述化合物如式V所示
    Figure PCTCN2020084041-appb-100004
    其中，s为3、4、5、6或7；
    R 1、R 21、R 22、R 31、R 32、R 51定义如权利要求5中所述。
  7. 如权利要求1所述的化合物，其特征在于，所述化合物为选自下组：
    Figure PCTCN2020084041-appb-100005
  8. 一种药物组合物，其特征在于，所述组合物包括；(i)如权利要求1所述的化合物，和(ii)药学上可接受的载体。
  9. 一种如权利要求6所述化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2020084041-appb-100006
    (i)使式V-A化合物与式V-B反应，从而得到式V-C化合物；
    Figure PCTCN2020084041-appb-100007
    (ii)使式V-C化合物脱去保护基，从而得到式V-D化合物；和
    Figure PCTCN2020084041-appb-100008
    (iii)使式V-D化合物与V-E化合物反应，从而得到式V化合物；
    各式中，R 7选自：F、Cl、Br、I(较佳地，R 7为Br或Cl)；R 1、R 21、R 22、R 31、R 32、R 33、R 51和s的定义同权利要求6中定义。
  10. 一种如权利要求1所述化合物的用途，其特征在于，用于制备(i)用于抑制突变型IDH的活性；和/或(ii)用于治疗和/或预防突变型IDH介导的疾病的药物。
  11. 如权利要求10所述的用途，其特征在于，所述突变型IDH介导的疾病包 括：癌症。
  12. 如权利要求11所述的用途，其特征在于，所述癌症选自：脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、***癌、甲状腺癌、结肠癌、软骨肉瘤、胆管上皮癌、外周T细胞白血病、黑色素瘤，或其组合。
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