WO2022268180A1 - 嘧啶并含氮六元芳香杂环类化合物及其用途 - Google Patents

嘧啶并含氮六元芳香杂环类化合物及其用途 Download PDF

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WO2022268180A1
WO2022268180A1 PCT/CN2022/100895 CN2022100895W WO2022268180A1 WO 2022268180 A1 WO2022268180 A1 WO 2022268180A1 CN 2022100895 W CN2022100895 W CN 2022100895W WO 2022268180 A1 WO2022268180 A1 WO 2022268180A1
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alkyl
independently selected
membered
alkoxy
aryl
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PCT/CN2022/100895
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English (en)
French (fr)
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王矿磊
褚文浩
郭见桥
赵传武
张晓琳
秦亚楠
宁帅
郭书龙
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石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2022268180A1 publication Critical patent/WO2022268180A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medical technology, in particular, to a class of novel compounds as MAT2A inhibitors and their use in the treatment and prevention of MAT2A-mediated diseases, disorders and conditions, such as tumors.
  • Methionine adenosyltransferase 2A also known as S-Adenosylmethionine Synthase Isoform Type.
  • MAT2A is expressed in all tissues including erythrocytes, brain, fetal liver, kidney, and pancreas, but less in adult liver tissues. Increased expression of MAT2A and MAT2B has been reported in human liver and colon cancers, and increased MAT2A expression has also been reported in human gastric cancer and tamoxifen-resistant breast cancer cells. Higher MAT2A and MAT2B expression leads to cancer cell growth, migration and invasion. Overall, lower MAT2A and MAT2B expression resulted in increased apoptosis and decreased cell growth, migration, and metastasis.
  • MTAP is a methionine transferase that catalyzes the transfer of adenylate and plays an important role in the salvage synthesis of ATP.
  • MTAP deletions account for approximately 15% of all solid tumors. MTAP is missing to varying degrees in various types of tumors. Loss of MTAP leads to accumulation of the enzyme substrate methylthioadenosine (MTA). Increased MTA concentration partially inhibited the activity of PRMT5, while other methyltransferases were relatively unaffected. Inhibition of MAT2A will reduce the methyl donor S-adenosylmethionine (SAM), which is the substrate of PRMT5, thereby further inhibiting PRMT5, affecting tumor cell mRNA splicing and causing DNA damage. Therefore, MAT2A inhibitors can benefit MTAP-deficient tumors.
  • SAM methyl donor S-adenosylmethionine
  • MAT2A inhibitors for example, WO2018039972, WO2019191470, WO2020139991, WO2020139992, WO2020243376, WO2020123395.
  • UGTs are one of the important ways to clear exogenous drugs and endogenous substances in the body.
  • UGT1A1 is an enzyme that catalyzes the glucuronidation of the toxic endogenous substance bilirubin. The glucuronidation reaction mediated by it is a necessary step for bilirubin to be excreted from the body, and is most closely related to human health.
  • a large number of studies at home and abroad have confirmed that the gene mutation of UGT1A1 makes the ability of glucuronidation of bilirubin all or partly lost, which affects the metabolism of bilirubin, resulting in severe hyperbilirubinemia.
  • UGT1A1 some clinical drugs can inhibit UGT1A1, thereby reducing the body's ability to metabolize and remove bilirubin, causing an increase in bilirubin in the blood, leading to hyperbilirubinemia or exacerbating the patient's condition. Therefore, avoiding excessive UGT1A1 inhibitory ability is of great significance for safe drug use.
  • the present invention provides a class of novel structure MAT2A inhibitor compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts, as well as the compounds or their Use of prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts to treat and prevent MAT2A mediated diseases, disorders and conditions.
  • the present invention provides a compound represented by formula (I) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt:
  • L 1 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R a1 )C(O )-, -C(O)N(R a1 )- or -N(R a1 )-; each occurrence of R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alky
  • R a is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-14 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more
  • the position is independently substituted by R a2 , wherein each occurrence of R a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R a3 , -OR a3 , -SR a3 , -S(O)R a3 , -SO 2 (R a3 ), -C(O)R a3 , -C(O)OR a3 , -OC(O)R a3 ,
  • L 2 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R b1 )C(O )-, -C(O)N(R b1 )- or -N(R b1 )-; each occurrence of R b1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alky
  • R b is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more
  • the position is independently replaced by R b2 , wherein each occurrence of R b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 , -OR b3 , -SR b3 , -S(O)R b3 , -SO 2 (R b3 ), -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 ,
  • L 3 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R c1 )C(O )-, -C(O)N(R c1 )- or -N(R c1 )-; each occurrence of R c1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, Mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy
  • R c is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more
  • the position is independently substituted by Rc2 , wherein each occurrence of Rc2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -Rc3 , -ORc3 , -SR c3 , -S(O)R c3 , -SO 2 (R c3 ), -C(O)R c3 , -C(O)OR c3 , -OC(O)R c3 , -NH(
  • X 1 is selected from N or CR d ;
  • R d is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl;
  • Optionally substituted means that the mentioned group is unsubstituted or independently substituted at one or more substitutable positions by Rd1 , wherein Rd1 is independently selected from each occurrence of deuterium, halogen, hydroxyl, amino, Nitro, mercapto, cyano, oxo, -R d2 , -OR d2 , -SR d2 , -S(O)R d2 , -SO 2 (R d2 ), -C(O)R d2 ,
  • heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.
  • L 1 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -N(R a1 )C(O)-, -C (O)N(R a1 )- or -N(R a1 )-.
  • L is selected from a bond, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH-.
  • L is selected from a bond, -O-, -S-, -C(O)-.
  • L is a bond
  • R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are independently substituted by deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, and oxo.
  • R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or in one or Multiple substitutable positions are independently substituted by deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo.
  • R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or substitutable at one or more The positions are independently substituted by deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano.
  • R a1 is selected from hydrogen.
  • R a is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-10 cycloalkyl, 3 -12-membered heterocyclic group, C 6-14 aryl group, 5-14 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or independently at one or more substitutable positions Replaced by R a2 .
  • R is selected from optionally substituted C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; Substitution means that the referenced group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R is selected from optionally substituted 3-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl;
  • the atoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the optional substitution means that the mentioned group is unsubstituted or in one or Multiple substitutable positions are independently substituted by R a2 .
  • R is selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-10 membered bicyclic heterocyclyl, C 6-8 aryl, 5-12 membered heteroaryl;
  • the heteroatoms in the heterocycloalkyl, heterocyclyl and heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution is means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted 5-10 membered heteroaryl; the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2 One, three or four; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted 5-10 membered bicyclic heteroaryls; the heteroatoms in the heteroaryls are selected from N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution means that the mentioned group is not substituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted 9-10 membered bicyclic heteroaryl; the heteroatoms in the heteroaryl are selected from N, and the number of heteroatoms is 2; the optional substitution is means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R a3 , -OR a3 , -SR a3 , -S( O)R a3 , -SO 2 (R a3 ), -C(O)R a3 , -C(O)OR a3 , -OC(O)R a3 , -NH(R a3 ), -N(R a3 ) (R a4 ), -C(O)NH(R a3 ), -C(O)N(R a3 )(R a4 ), -NHC(O)(R a3 ), -N(R a3 )C(O )(R a4 ), -NHC(O)(R a3 ), -N(R a3 )C(O )(R a4
  • R a2 is independently selected from halogen, hydroxy, amino, cyano, -R a3 .
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C 6-14 aryl group, 5-12 membered heteroaryl group; or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 are connected with their Nitrogen atoms together are optionally replaced by one
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C 6-14 aryl, 5-12 membered heteroaryl; or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 are formed together with the nitrogen atom to which they are connected, optionally by one or A plurality of 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl substituted by substituents independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy.
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy Substituent C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 heterocycloalkyl, C 6-8 aryl, 5-6 heteroaryl base.
  • R a3 , R a4 are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino.
  • R a3 , R a4 are independently selected from hydrogen or C 1-4 alkyl optionally substituted with one or more hydroxy substituents.
  • R a3 and R a4 are independently selected from hydrogen, C 1-4 alkyl.
  • R is selected from 5-10 membered bicyclic heteroaryls optionally substituted by C 1-4 alkyls; the heteroatoms in the heteroaryls are selected from N, and the number of heteroatoms 1, 2, 3 or 4.
  • R a is selected from
  • L 2 is selected from a bond, -CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -N(R b1 )C (O)-, -C(O)N(R b1 )-.
  • L2 is selected from a bond, -CH2- , -C (O)-, -C(O)O-, -OC(O)-.
  • L2 is selected from a bond.
  • R b1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl base replaced.
  • R b1 is independently selected from hydrogen or C 1-6 alkyl, C 3-6 cycloalkane optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino Base, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R b1 is independently selected from hydrogen or C 1-4 alkyl.
  • R b is selected from optionally substituted C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or independently substituted by R b2 at one or more substitutable positions.
  • R b is selected from optionally substituted C 3-10 cycloalkyl, 3-6 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R b2 at one or more substitutable positions.
  • R b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; said optionally substituted means the mentioned The group is unsubstituted or independently substituted by R at one or more substitutable positions.
  • R b is selected from optionally substituted C 6-8 aryl, 5-6 membered heteroaryl; said optional substitution means that the mentioned groups are unsubstituted or in one or Multiple substitutable positions are independently substituted by R b2 .
  • R b is selected from optionally substituted phenyl; said optionally substituted means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable positions replace.
  • R b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 , -OR b3 , -SR b3 , -S( O)R b3 , -SO 2 (R b3 ), -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH(R b3 ), -N(R b3 ) (R b4 ), -C(O)NH(R b3 ), -C(O)N(R b3 )(R b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O )(R b4 ), -S(O)NH(R b4 ), -S(O)N(R b4 ), -S(O)
  • R b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 , -OR b3 , -SR b3 , -S(O)R b3 , -SO 2 (R b3 ), -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH(R b3 ), -N(R b3 )(R b4 ), -C(O)NH(R b3 ), -C(O)N(R b3 )(R b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ), -SO 2 NH(R b3 ), -SO 2 NH(R
  • R b2 is independently selected from halogen, hydroxyl, amino, -R b3 , -OR b3 , -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH(R b3 ), -C(O)NH(R b3 ), -NHC(O)(R b3 ).
  • R b2 is independently selected from halogen, hydroxy, amino, -R b3 , -OR b3 .
  • R b2 is independently selected from halogen, or -O(C 1-6 alkyl), C 1-6 alkyl optionally substituted by one or more halogens.
  • R b2 is independently selected from halogen, or -O(C 1-4 alkyl) optionally substituted with one or more halogens.
  • R b2 is independently selected from chlorine, -OCH 3 , -OCH 2 CH 3 , -O(CH 2 F), -O(CHF 2 ), -O(CF 3 ), -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CHFCH 3 , -CH 2 CHF 2 .
  • R b3 and R b4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C 6-14 aryl group, 5-12 membered heteroaryl group; or when R b3 and R b4 are connected to the same nitrogen atom, R b3 and R b4 are connected with their Nitrogen atoms together are optionally replaced by one
  • R b3 and R b4 are independently selected from hydrogen or C 1-6 alkyl, C 1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl .
  • R b3 and R b4 are independently selected from hydrogen or C 1-6 alkyl, C 1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino 6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R b3 and R b4 are independently selected from hydrogen or C 1-6 alkyl, C 1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino 6 alkoxy, C 6-8 aryl, 5-6 membered heteroaryl.
  • R b3 , R b4 are independently selected from C 1-6 alkyl optionally substituted by one or more halogens.
  • L 3 is selected from -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, - N(R c1 )C(O)-, -C(O)N(R c1 )- or -N(R c1 )-.
  • L 3 is selected from -O-, -C(O)-, -N(R c1 )C(O)-, -C(O)N(R c1 )- or -N(R c1 )-.
  • L 3 is selected from -O-, -N(R c1 )-, -C(O)-.
  • L 3 is selected from -CH 2 -, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH- or - NH-.
  • L3 is selected from -O-, -NH-, -C(O)-.
  • L3 is selected from -O-, -NH-.
  • R c1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkene Base, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • the groups mentioned are unsubstituted or are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1 at one or more substitutable positions -6 alkoxy, C 1-6 alkylamino, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aromatic Base, 5-6 membered heteroaryl substituted.
  • R c1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl group, 3-10 membered heterocycloalkyl group, C 6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution refers to the mentioned group
  • the group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkane at one or more substitutable positions Oxygen, C 1-6 alkylamino is substituted.
  • R c1 is independently selected from hydrogen or optionally replaced by one or more independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy Substituent substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R c1 is independently selected from hydrogen or optionally replaced by one or more independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy Substituent substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino.
  • R c1 is independently selected from hydrogen.
  • R c is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional replacement refers to the mentioned groups Unsubstituted or independently substituted by R c2 at one or more substitutable positions.
  • R is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted Or independently substituted by R c2 at one or more substitutable positions.
  • R c is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 member Heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable positions replaced by c2 .
  • Rc is selected from optionally substituted C 1-6 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions Replaced by R c2 .
  • Rc is selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl group, cyclobutyl, cyclopentyl, cyclohexyl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R c2 at one or more substitutable positions.
  • R c2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 , -OR c3 , -C(O)R c3 , -C(O)OR c3 , -OC(O)R c3 , -NH(R c3 ), -N(R c3 )(R c4 ), -C(O)NH(R c3 ), -C(O )N(R c3 )(R c4 ), -NHC(O)(R c3 ), -N(R c3 )C(O)(R c4 ).
  • R c2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 .
  • R c2 is independently selected from halogen, hydroxy, amino.
  • R c2 is independently selected from halogen.
  • R c2 is F.
  • R c3 , R c4 are independently selected from hydrogen or are optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkane Base, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5- C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 Membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl.
  • Rc3 , Rc4 are independently selected from hydrogen or C1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5 -12 membered heteroaryl.
  • R c3 and R c4 are independently selected from hydrogen or C 3-10 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R c is selected from optionally substituted C 1-6 alkyl; said optional substitution means that the mentioned group is unsubstituted or at one or more substitutable positions Dots are independently replaced by halogen.
  • X is selected from N.
  • X 1 is selected from CR d .
  • R d is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R d1 at one or more substitutable positions.
  • R is independently selected from hydrogen, deuterium , halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 Member heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R d1 at one or more substitutable positions.
  • R is independently selected from hydrogen, deuterium , halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C 1-6 alkyl, C 1-6 alkoxy , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or independently substituted by Rd1 at one or more substitutable positions.
  • Rd is selected from hydrogen
  • R d1 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R d2 , -OR d2 , -N(R d2 )( R d3 ), -C(O)N(R d2 )(R d3 ), -N(R d2 )C(O)(R d3 ).
  • R d1 is independently selected from halogen, hydroxy, amino, cyano, -R d2 .
  • Rd2 , Rd3 are independently selected from hydrogen or C 1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano Alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5 -12 membered heteroaryl.
  • Rd2 , Rd3 are independently selected from hydrogen or C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • the present invention provides a compound represented by formula (II) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt, which has the following structure:
  • L 1 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R a1 )C(O )-, -C(O)N(R a1 )- or -N(R a1 )-; each occurrence of R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alky
  • R a is selected from optionally substituted 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; said optional substitution means that the mentioned group is unsubstituted or in a or a plurality of substitutable positions are independently substituted by R a2 , wherein each occurrence of R a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -C 1-6 Alkylene-N(R a3 )(R a4 ), -R a3 , -OR a3 , -SR a3 , -S(O)R a3 , -SO 2 (R a3 ), -C(O)R a3 , -C(O)OR a3 , -OC(O)R a3 , -NH(R a3 ), -N(R a3 )(R a4 ),
  • L 2 is selected from bond, -C(R b1 ) 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R b1 )C(O)-, -C(O)N(R b1 )- or -N(R b1 )-; each occurrence of R b1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered Heteroaryl; said optionally substituted means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano at one or more substitutable positions , oxo, C 1-6 alky
  • R b is selected from optionally substituted 3-12 membered heterocyclic group, C 6-14 aryl group, 5-12 membered heteroaryl group; said optional substitution means that the mentioned group is unsubstituted or in a or multiple substitutable positions are independently substituted by R b2 , wherein each occurrence of R b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 , - OR b3 , -SR b3 , -S(O)R b3 , -SO 2 (R b3 ), -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH( R b3 ), -N(R b3 )(R b4 ), -C(O)NH(R b3 ), -C(O)N(R b3
  • L 3 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R c1 )C(O )-, -C(O)N(R c1 )- or -N(R c1 )-;
  • R c1 is selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl
  • the optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxygen at one or more substitutable positions Substitute, C 1-6 alky
  • R c is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 ring Alkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more
  • the position is independently substituted by Rc2 , wherein each occurrence of Rc2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -Rc3 , -ORc3 , -SR c3 , -S(O)R c3 , -SO 2 (R c3 ), -C(O)R c3 , -C(O)OR c3 , -OC(O)R c3 , -NH(
  • heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.
  • L 1 is selected from a bond, -CH 2 -, -O-, -S-, -C(O)-, -N(R a1 )C(O)-, -C (O)N(R a1 )- or -N(R a1 )-.
  • L 1 is selected from a bond, -CH 2 -, -O-, -S- or -N(R a1 )-, wherein R a1 is selected from hydrogen or C 1-6 alkyl.
  • L is selected from a bond, -O-, -S-, -C(O)-, -NH-, -NHC(O)-, -C(O)NH-.
  • L is selected from a bond, -O-, -S-, -C(O)-, -NH-.
  • L is selected from a bond, -NH-, -O- or -S-.
  • L is a bond
  • R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are independently substituted by substituents selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, and oxo.
  • R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or in one or Multiple substitutable positions are independently substituted with substituents selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo.
  • R a1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or substitutable at one or more The sites are independently substituted with substituents selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano.
  • R a1 is selected from hydrogen.
  • R a is selected from optionally substituted 3-12 membered heterocyclic groups, C 6-14 aryl groups, 5-14 membered heteroaryl groups, said heterocyclic group, heteroaryl group
  • the heteroatoms in are independently selected from O, N or S, the number of heteroatoms is 1, 2, 3 or 4, and the optional substitution means that the mentioned groups are unsubstituted or in one or Multiple substitutable positions are independently substituted by R a2 .
  • R a is selected from optionally substituted 3-10 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group; said optional substitution means that the mentioned group is unsubstituted or in a or multiple substitutable positions are independently substituted by R a2 .
  • R is selected from optionally substituted 3-10 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl;
  • the atoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the optional substitution means that the mentioned group is unsubstituted or in one or Multiple substitutable positions are independently substituted by R a2 .
  • R is selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-10 membered bicyclic heterocyclyl, C 6-8 aryl, 5-12 membered heteroaryl;
  • the heteroatoms in the heterocycloalkyl, heterocyclyl and heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution is means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted 5-10 membered bicyclic heterocyclic groups, 5-10 membered heteroaryl groups; the heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O , N or S, the number of heteroatoms is 1, 2, 3 or 4; the optional substitution means that the mentioned group is unsubstituted or independently replaced at one or more substitutable positions R a2 replaced.
  • R a is selected from optionally substituted 5-10 membered bicyclic heterocyclyl, 5-10 membered bicyclic heteroaryl, and the heteroatoms in the heterocyclic group and heteroaryl are independently selected from O or N, the number of heteroatoms is 1, 2 or 3, the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions .
  • R a is selected from optionally substituted 5-10 membered heteroaryl; the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2 One, three or four; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from an optionally substituted 5-10 membered bicyclic heterocyclic group; the heteroatoms in the heterocyclic group are independently selected from O or N, and the number of heteroatoms is 1 or 2 , 3 or 4; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted 5-10 membered bicyclic heteroaryls; the heteroatoms in the heteroaryls are selected from N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution means that the mentioned group is not substituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted
  • the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted
  • the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a is selected from optionally substituted
  • the optional substitution means that the mentioned group is unsubstituted or independently substituted by R a2 at one or more substitutable positions.
  • R a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -C 1-6 alkylene-N(R a3 )( R a4 ), -R a3 , -OR a3 , -SR a3 , -S(O)R a3 , -SO 2 (R a3 ), -C(O)R a3 , -C(O)OR a3 , -OC (O)R a3 , -NH(R a3 ), -N(R a3 )(R a4 ), -C(O)NH(R a3 ), -C(O)N(R a3 )(R a4 ), -NHC(O)(R a3 ), -N(R a3 )C(O)(R a4 ), -NHC(O)(R a
  • R a2 is independently selected from halogen, hydroxyl, amino, cyano, -C 1-6 alkylene-N(R a3 )(R a4 ), -R a3 , -OR a3 , - N(R a3 )(R a4 ), -C(O)N(R a3 )(R a4 ), -N(R a3 )C(O)(R a4 ).
  • R a2 is independently selected from halogen, hydroxyl, amino, cyano, -C 1-6 alkylene-N(R a3 )(R a4 ), -R a3 .
  • R a2 is independently selected from halogen, hydroxyl, amino, cyano, -C 1-6 alkylene-N(R a3 )(R a4 ), C 1-4 alkyl , -C 1-4 alkyl-C 1-4 alkoxy or -C 1-4 alkylhydroxy.
  • R a2 is independently selected from halogen, -C(O)R a3 , hydroxyl, amino, -C 1-6 alkylene-N(R a3 )(R a4 ), any C 1-6 alkyl optionally substituted by one or more independently selected from halogen, hydroxy, amino, C 1-6 alkoxy.
  • R a2 is independently selected from -C 1-6 alkylene-N(R a3 )(R a4 ), optionally selected from one or more independently selected from hydroxyl and C C 1-6 alkyl substituted by 1-6 alkoxy.
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C 6-14 aryl group, 5-12 membered heteroaryl group; or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 are connected with their Nitrogen atoms together are optionally replaced by one
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C 6-14 aryl, 5-12 membered heteroaryl; or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 are formed together with the nitrogen atom to which they are connected, optionally by one or A plurality of 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl substituted by substituents independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy.
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy Substituent C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 heterocycloalkyl, C 6-8 aryl, 5-6 heteroaryl group; when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from halogen, hydroxyl, C 1-6 alkane A 3-10-membered heterocycloalkyl group substituted by a substituent of a C 1-6 alkoxy group, the heteroatoms in the heterocycloalkyl group are selected from N, S, O, and the number of heteroatoms is 1 or 2 or 3.
  • R a3 and R a4 are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino; when R a3 When R a4 is connected to the same nitrogen atom, R a3 and R a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from F, Cl, Br, hydroxyl, methyl, methoxy A 3-10-membered heterocycloalkyl group substituted by a substituent, wherein the heteroatoms in the heterocycloalkyl group are selected from N and O, and the number of heteroatoms is 1 or 2.
  • R a3 and R a4 are independently selected from hydrogen, C 1-4 alkyl, -C 1-4 alkyl hydroxyl; when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R together with the nitrogen atom to which they are attached form tetrahydropyrrolyl, piperidinyl or morpholinyl optionally substituted by one or more substituents independently selected from F, hydroxyl, methyl, methoxy .
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl Substituent substituted C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; or when R a3 and R a4 When connected to the same nitrogen atom, R a3 and R a4 together with the nitrogen atom they are connected to form are optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 3-6 member heterocycl
  • R a3 and R a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 C 1-6 alkyl substituted by substituents of alkoxy group; or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 together with the nitrogen atom to which they are connected are optionally formed by one or more 3-10 membered heterocycloalkyl groups independently selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy substituents, the heteroatoms in the heterocycloalkyl are selected from N , S, O, and the number of heteroatoms is 1, 2 or 3.
  • R a3 and R a4 are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino; Or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from halogen, hydroxyl, C 1-4 alkyl , a 3-10 membered heterocycloalkyl group substituted by a C 1-4 alkoxy substituent, the heteroatoms in the heterocycloalkyl group are selected from N and O, and the number of heteroatoms is 1 or 2.
  • R a3 and R a4 are independently selected from C 1-4 alkyl; or when R a3 and R a4 are connected to the same nitrogen atom, R a3 and R a4 are connected with the The nitrogen atoms together form tetrahydropyrrolyl, piperidinyl or morpholinyl optionally substituted with one or more substituents independently selected from F, hydroxy, methyl, methoxy.
  • R a2 is independently selected from methyl, Br,
  • R a2 is independently selected from
  • R a is selected from
  • R a is selected from
  • L 2 is selected from a bond, -CH 2 -, -C(O)-, -C(O)O-, -OC(O)-, -N(R b1 )C (O)-, -C(O)N(R b1 )-.
  • L2 is selected from a bond, -CH2- , -C (O)-, -C(O)O-, -OC(O)-.
  • L2 is selected from a bond, -CH2- , -C (O)-.
  • L2 is selected from a bond, -CH2- .
  • L is a bond
  • R b1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl base replaced.
  • R b1 is independently selected from hydrogen or C 1-6 alkyl, C 3-6 cycloalkane optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino Base, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R b1 is independently selected from hydrogen or C 1-4 alkyl.
  • R b is selected from optionally substituted 3-12 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; The groups mentioned are unsubstituted or independently substituted by R b2 at one or more substitutable positions.
  • R b is selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;
  • the optional substitution means that the mentioned group is unsubstituted or independently substituted by R b2 at one or more substitutable positions.
  • R b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl; said optionally substituted means the mentioned The group is unsubstituted or independently substituted by R at one or more substitutable positions.
  • R b is selected from optionally substituted 5-10 membered bicyclic heterocyclyl, C 6-8 aryl, 5-6 membered heteroaryl; The group is unsubstituted or independently substituted by R at one or more substitutable positions.
  • R b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, the optional substitution refers to the mentioned The group is unsubstituted or independently substituted by R at one or more substitutable positions.
  • R b is selected from optionally substituted phenyl, pyridyl or benzotetrahydrofuranyl; said optionally substituted means that the mentioned groups are unsubstituted or may be substituted in one or more The positions are independently replaced by R b2 .
  • R b is selected from optionally substituted phenyl or pyridyl; said optionally substituted means that the mentioned groups are unsubstituted or independently replaced at one or more substitutable positions R b2 replaced.
  • R b is selected from optionally substituted phenyl; said optionally substituted means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable positions replace.
  • R b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 , -OR b3 , -SR b3 , -S( O)R b3 , -SO 2 (R b3 ), -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH(R b3 ), -N(R b3 ) (R b4 ), -C(O)NH(R b3 ), -C(O)N(R b3 )(R b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O )(R b4 ), -S(O)NH(R b4 ), -S(O)N(R b4 ), -S(O)
  • R b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 , -OR b3 , -SR b3 , -S(O)R b3 , -SO 2 (R b3 ), -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH(R b3 ), -N(R b3 )(R b4 ), -C(O)NH(R b3 ), -C(O)N(R b3 )(R b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ), -SO 2 NH(R b3 ), -SO 2 NH(R
  • R b2 is independently selected from halogen, hydroxyl, amino, -R b3 , -OR b3 , -C(O)R b3 , -C(O)OR b3 , -OC(O)R b3 , -NH(R b3 ), -C(O)NH(R b3 ), -NHC(O)(R b3 ).
  • R b2 is independently selected from halogen, hydroxy, amino, -R b3 , -OR b3 .
  • R b2 is independently selected from halogen, hydroxyl, or -O(C 1-6 alkyl) optionally substituted by one or more halogen, -O(C 1-6 Alkyl) phenyl, C 1-6 alkyl.
  • R b2 is independently selected from halogen, hydroxyl, or -O(C 1-4 alkyl), -O(C 1-4 alkyl) optionally substituted by one or more halogen Phenyl or C 1-4 alkyl.
  • R b2 is independently selected from chlorine, -OCH 3 , -OH, -O-benzyl, -OCH 2 CH 3 , -O(CH 2 F), -O(CHF 2 ), - O(CF 3 ), -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CHFCH 3 , -CH 2 CHF 2 or
  • R b2 is independently selected from halogen, hydroxyl, amino, C 3-6 cycloalkyl, -OR b3 , wherein R b3 is selected from optionally selected from one or more independently C 1-6 alkyl substituted by substituents from halogen or C 6-10 aryl.
  • R b2 is independently selected from halogen, hydroxyl, C 3-6 cycloalkyl, -OR b3 , wherein R b3 is selected from optionally selected from one or more independently selected from halogen or phenyl C 1-4 alkyl substituted by substituents.
  • R b2 is independently selected from fluorine, chlorine, -OH, C 3-6 cycloalkyl, -OR b3 , wherein R b3 is selected from optionally selected from one or more independently selected from chlorine Or C 1-4 alkyl substituted by a substituent of phenyl.
  • R b2 is independently selected from chloro, cyclopropyl or -O(C 1-4 alkyl) optionally substituted with one or more halogen.
  • R b2 is independently selected from chloro or -O(C 1-4 alkyl) optionally substituted with one or more fluoro.
  • R b2 is independently selected from chlorine, -OCH 3 , -O(CHF 2 ) or -O(CF 3 ).
  • R b2 is independently selected from -O(CHF 2 ).
  • R b3 and R b4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C 6-14 aryl group, 5-12 membered heteroaryl group; or when R b3 and R b4 are connected to the same nitrogen atom, R b3 and R b4 are connected with their Nitrogen atoms together are optionally replaced by one
  • R b3 , R b4 are independently selected from hydrogen or C 1- optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C 6-8 aryl 6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl.
  • R b3 and R b4 are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, phenyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R b3 and R b4 are independently selected from hydrogen or C 1-4 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, phenyl, C 1-4 alkoxy, C 3-4 cycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R b3 and R b4 are independently selected from hydrogen or C 1-4 alkyl, C 1-4 optionally substituted by one or more substituents independently selected from halogen and phenyl Alkoxy or cyclopropyl.
  • R b3 , R b4 are independently selected from hydrogen or C 1-4 alkoxy optionally substituted by one or more substituents independently selected from halogen, phenyl.
  • R b3 , R b4 are independently selected from methoxy optionally substituted by one or more substituents independently selected from F, Cl.
  • R b is selected from
  • R b is selected from
  • L 3 is selected from -CH 2 -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, - N(R c1 )C(O)-, -C(O)N(R c1 )- or -N(R c1 )-.
  • L 3 is selected from -CH 2 -, -O-, -S- or -N(R c1 )-, wherein R c1 is selected from hydrogen or C 1-6 alkyl.
  • L 3 is selected from -O-, -S-, -C(O)-, -N(R c1 )C(O)-, -C(O)N(R c1 )- or -N(R c1 )-.
  • L 3 is selected from -O-, -N(R c1 )-, -C(O)-.
  • L 3 is selected from -O-, -N(R c1 )-, wherein R c1 is selected from hydrogen or C 1-6 alkyl.
  • L 3 is selected from -CH 2 -, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH- or - NH-.
  • L3 is selected from -O-, -NH-, -C(O)-.
  • L3 is selected from -O-, -NH-.
  • L3 is selected from -O-.
  • R c1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkene Base, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • the groups mentioned are unsubstituted or are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1 at one or more substitutable positions -6 alkoxy, C 1-6 alkylamino, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aromatic Substituents of radicals, 5-6 membered heteroaryl groups.
  • R c1 is independently selected from hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl group, 3-10 membered heterocycloalkyl group, C 6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution refers to the mentioned group
  • the group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 alkane at one or more substitutable positions Oxygen, C 1-6 alkylamino is substituted.
  • R c1 is independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R c1 is independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino substituted by substituents.
  • R c1 is independently selected from hydrogen.
  • R c is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl; the optional replacement refers to the mentioned group Unsubstituted or independently substituted by R c2 at one or more substitutable positions.
  • R is selected from optionally substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkyne group, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted Or independently substituted by R c2 at one or more substitutable positions.
  • R c is selected from optionally substituted C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 member Heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable positions replaced by c2 .
  • R c is selected from optionally substituted C 1-4 alkyl or C 3-6 cycloalkyl; said optional substitution means that the mentioned groups are unsubstituted or in one or Multiple substitutable positions are independently substituted by R c2 .
  • R c is selected from optionally substituted C 1-3 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions Replaced by R c2 .
  • Rc is selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl group, cyclobutyl, cyclopentyl, cyclohexyl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R c2 at one or more substitutable positions.
  • R c2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 , -OR c3 , -C(O)R c3 , -C(O)OR c3 , -OC(O)R c3 , -NH(R c3 ), -N(R c3 )(R c4 ), -C(O)NH(R c3 ), -C(O )N(R c3 )(R c4 ), -NHC(O)(R c3 ), -N(R c3 )C(O)(R c4 ).
  • R c2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 .
  • R c2 is independently selected from halogen, hydroxy, amino or -R c3 .
  • R c2 is independently selected from halogen or -R c3 .
  • R c3 , R c4 are independently selected from hydrogen or are optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkane Base, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl, 5- C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 Membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl.
  • Rc3 , Rc4 are independently selected from hydrogen or C1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5 -12 membered heteroaryl.
  • Rc3 , Rc4 are independently selected from hydrogen or C1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-8 aryl, 5-6 membered heteroaryl.
  • R c3 , R c4 are independently selected from hydrogen or CF 3 .
  • R is selected from C 1-6 alkyl optionally substituted by one or more halogens or C 3-6 cycloalkane optionally substituted by one or more R A group, wherein R c3 is selected from hydrogen or C 1-6 alkyl optionally substituted by one or more substituents independently selected from halogen.
  • R c is selected from optionally substituted C 1-6 alkyl; said optional substitution means that the mentioned group is unsubstituted or at one or more substitutable positions Dots are independently replaced by halogen.
  • R c is selected from C 1-4 alkyl optionally substituted by one or more halogens or C 3-6 cycloalkyl optionally substituted by CF 3 .
  • R c is selected from methyl, ethyl,
  • R c is selected from ethyl
  • Rc is selected from ethyl.
  • the object of the present invention also includes providing a method for preparing the compound represented by the general formula (I) in which X is N, the general formula (II), or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.
  • the method can be prepared, for example, using the methods shown in the following schemes.
  • intermediate 1.6 can be prepared by the following steps:
  • the compound or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof can be prepared by the following steps:
  • Another aspect of the present invention also provides the following intermediate compounds:
  • L 2 , L 3 , R b and R c are as described in the compound of formula (I) or formula (II);
  • L is a bond
  • R is optionally substituted phenyl or pyridyl; said optionally substituted means that the mentioned groups are unsubstituted or at one or more substitutable positions dots are independently replaced by R b2
  • Another aspect of the present invention also provides a pharmaceutical composition, which comprises the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable Salt.
  • composition of the present invention also includes pharmaceutically acceptable excipients.
  • the compounds of the present invention or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts can be administered in pure form or in a suitable pharmaceutical composition by providing a similar Any acceptable mode of administration of the drug for use.
  • the pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations.
  • the above-mentioned pharmaceutical composition can be prepared by conventional preparation methods using conventional excipients in the formulation field.
  • Another aspect of the present invention also provides the compounds of the present invention or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present invention for the prevention and/or treatment of Use in medicine for diseases, disorders and conditions mediated by MAT2A.
  • the diseases, disorders and conditions are MTAP-deficient tumors.
  • the tumor includes solid tumor and hematological tumor; preferably, the solid tumor includes colorectal cancer.
  • the cancer may also be referred to as a malignancy.
  • the present application provides methods for preventing and/or treating diseases, disorders and conditions mediated by MAT2A, comprising administering the compounds of the present invention or their prodrugs, tautovariants to individuals in need thereof conformation, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention; preferably, said disease, disorder and condition are MTAP-deficient cancer; more preferably, said Tumors include solid tumors and hematological tumors.
  • the present application provides the compounds described in the present invention or their prodrugs, tautomers, stereoisomers, solvates for preventing and/or treating diseases, disorders and conditions mediated by MAT2A , isotope derivatives or pharmaceutically acceptable salts or the pharmaceutical composition of the present invention; preferably, the diseases, disorders and conditions are MTAP-deficient cancers; more preferably, the tumors include solid tumors and hematological tumors.
  • the compound described in the present invention or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt or the present invention is used in combination with another, two or more drugs having tumor suppressing activity.
  • the present invention also provides a pharmaceutical composition, comprising the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt and another, two One or more drugs with tumor suppressive activity.
  • the "optionally substituted” or “optionally substituted” means that the mentioned groups are unsubstituted or replaced by one or more independently selected from hydroxyl, halogen, hydroxyl, amino, nitro, Mercapto, cyano, azido, oxo, carboxyl, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)-C 1-6 alkyl , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 alkyl, -NHC(O) -C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 ring Substituents of alkylsulfonyl, 3-10 membered heterocycloalkyl,
  • oxo means that two hydrogen atoms at the same substituent position are replaced by the same oxygen atom to form a double bond.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, straight-chain or branched, containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e. C 1-10 Alkyl), further preferably containing 1-8 carbon atoms (C 1-8 alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 alkyl), for example "C 1-6 alkyl” It means that the group is an alkyl group, and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , N-octyl, etc.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • Alkenyl can contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e. C 2-10 alkenyl), more preferably 2-8 carbon atoms (C 2-8 alkenyl), more preferably 2-6 carbon atoms (ie C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 carbon atoms (ie C 2-4 alkenyl), 2- 3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e.
  • C 2 alkenyl for example "C 2-6 alkenyl” means that the group is alkenyl, and the carbon chain The number of carbon atoms is between 2-6 (specifically 2, 3, 4, 5 or 6).
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • the alkynyl group can contain 2-20 carbon atoms, preferably contains 2-10 carbon atoms (i.e. C 2-10 alkynyl), further preferably contains 2-8 carbon atoms (C 2-8 alkynyl), more preferably contains 2-6 carbon atoms (ie C 2-6 alkynyl), 2-5 carbon atoms (ie C 2-5 alkynyl), 2-4 carbon atoms (ie C 2-4 alkynyl), 2- 3 carbon atoms (i.e.
  • C 2-3 alkynyl 2 carbon atoms (i.e. C 2 alkynyl), for example "C 2-6 alkynyl” means that the group is alkynyl, and the carbon chain The number of carbon atoms is between 2-6 (specifically 2, 3, 4, 5 or 6).
  • alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, preferably containing 3-12 carbon atoms (i.e. C 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl), more preferably 3-7 carbon atoms (C 3-7 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5-6 carbon atoms (C 5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
  • alkoxy refers to an -O-alkyl group as defined above, that is, containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, Oxygen, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • alkylamino refers to -NR'R", R' and R" are the same or different, and can be H or an alkyl group as defined above, and the alkyl group is as defined above, that is, includes 1 - 20 carbon atoms, preferably comprising 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4 , 5 or 6).
  • Representative examples include, but are not limited to, -NH(CH 3 ), -N(CH 3 )(CH 3 ), -N(CH 2 CH 3 )(CH 3 ), -N(CH 2 CH 3 )[CH(CH 3 ) 2 ] and so on.
  • halogen refers to F, Cl, Br, I unless otherwise specified.
  • haloalkyl refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkyl include CCl3 , CF3 , CHCl2 , CH2Cl , CH2Br , CH2I , CH2CF3 , CF2CF3 , and the like.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring non-aromatic substituent having ring carbon atoms and 1 or more ring heteroatoms, Contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. It preferably contains 3 to 12 ring atoms (3-12 membered heterocyclic group), further preferably contains 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group).
  • heterocyclyl a compound having 3-6 membered heterocyclyl, or 4 to 6 ring atoms (4-6 membered heterocyclyl), or 5 to 6 ring atoms (5-6 membered heterocyclyl) heterocyclyl).
  • the number of heteroatoms is preferably 1-4, more preferably 1-3 (ie 1, 2 or 3).
  • monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Heterocyclyl can be monocyclic (“monocyclic heterocyclyl") or a fused (“fused heterocyclyl” or “heterofused cycloyl”), bridged (“heterobridged cycloyl” or “bridged heterocyclyl”) or spiro-fused (“heterospirocyclyl” or “spiroheterocyclyl") ring system, such as a bicyclic ring system (“bicyclic heterocyclyl”), and can be saturated or may be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "Heterocyclyl” also includes ring systems wherein the heterocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, or a cycloalkyl ring as defined above is fused by one or more A ring system fused to a heteroaryl group, wherein the point of attachment is on the heterocyclyl ring or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the post-fused ring system atomic number.
  • each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents ( a "substituted heterocyclyl").
  • exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2,5-diketones.
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and Oxazolidin-2-ones.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazidinyl, thiadiazinyl, oxathiazinyl, and dioxo Dioxazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacanyl, oxocanyl, and thiecanyl.
  • Exemplary 5-membered heterocyclyl groups (also referred to herein as a 5,6-bicyclic heterocycle) fused to a C6 aryl ring include, but are not limited to, indolinyl, isodihydro Indolyl, Dihydrobenzofuranyl, Dihydrobenzothienyl, Benzo oxazolinone, etc.
  • Exemplary 6-membered heterocyclyl groups (also referred to herein as a 6,6-bicyclic heterocycle) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl Base etc.
  • heterocycloalkyl means a monocyclic, saturated “heterocyclyl” or “heterocycle” as defined above, with ring atoms as defined above, i.e. containing 3 to 20 ring atoms ("3 -20-membered heterocycloalkyl”), the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein The atoms are each independently selected from N, O or S.
  • ring atoms Preferably comprising 3 to 12 ring atoms (“3-12 membered heterocycloalkyl”), more preferably comprising 3 to 10 ring atoms (“3-10 membered heterocycloalkyl”), still more preferably comprising 3 to 8 ring atoms ("3-8 membered heterocycloalkyl”), more preferably contain 4 to 7 ring atoms ("4-7 membered heterocycloalkyl”), still more preferably contain 5-10 ring atoms ("5-10 membered heterocycloalkyl”), more preferably comprising 5-6 ring atoms ("5-6 membered heterocycloalkyl”).
  • each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an “unsubstituted heterocycloalkyl”) or substituted by one or more Substituted (a "substituted heterocycloalkyl").
  • heterocyclyl or “heterocycle” part has given some exemplary “heterocycloalkyl”, including, but not limited to, aziridine, oxirane, thiiridine Azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , Oxathianyl, Azolidinyl, two Alkyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.
  • aryl or “aromatic ring group” means a group containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms Monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems, preferably 6-10 carbon atoms, the term “aryl” may be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, and the like.
  • heteroaryl or “heteroaryl ring group” means a group containing 5-14 membered structure, or preferably 5-10 membered structure, or preferably 5-8 membered structure, more preferably 5-6 membered structure
  • An aromatic monocyclic or polycyclic ring system wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms Preferably it is 1, 2 or 3.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, Azolyl, thiazolyl, iso Azolyl, Diazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl , Phthalazinyl, quinolinyl, isoquinolyl, pteridyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzopyridyl, benzene Pyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo
  • the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to any salt suitable for use within the scope of sound medical judgment without undue toxicity, irritation, allergic reaction, or in contact with the tissues of mammals, especially humans. Salts commensurate with a reasonable benefit/risk ratio, such as the pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or alone by reacting the free base or acid with a suitable reagent.
  • the compounds of the present invention also include "isotopic derivatives" thereof.
  • isotopically derivative means that the compounds of the present invention may exist in isotopically labeled or enriched forms containing one or more atoms having an atomic mass or mass number different from that found in nature The atomic mass or mass number of the most abundant atom. Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes commonly used for isotope labeling are: Hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I ; Nitrogen isotopes: 13 N and 15 N; Oxygen isotopes: 15 O, 17 O, and 18 O; and Sulfur isotopes: 35 S.
  • These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 2 H and 13 C are more widely used because of their easy labeling and convenient detection.
  • Isotopically labeled compounds are generally synthesized starting from labeled starting materials and carried out in the same way as non-isotopically labeled compounds using known synthetic techniques.
  • the compounds of the present invention also include “solvates” and “solvates” thereof.
  • solvate mean a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding.
  • solvent molecules in solvates may exist in regular and/or disordered arrangements.
  • Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.
  • Solvate encompasses both solution-phase and isolatable solvates.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • stereoisomer refers to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.
  • tautomer refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Bonded tautomers include interconversions by recombination of some of the bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.
  • the compounds of the present invention also include "prodrugs" thereof.
  • the term “prodrug” refers to a drug that is converted into the parent drug in vivo.
  • Prodrugs are often useful to ameliorate some identified, undesirable physical or biological property. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they are bioavailable orally, whereas the parent is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug.
  • a prodrug may be any compound of the invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility, but once in Intracellular water solubility is beneficial, which is then metabolically hydrolyzed to carboxylic acids, the active entities.
  • prodrug could be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.
  • DIPEA N,N-Diisopropylethylamine
  • This application designs a class of compounds with novel structures, which provides a new direction for the treatment of diseases such as tumors.
  • Tests show that the compound of the present invention has strong inhibitory effect on MAT2A, shows strong cell proliferation activity on HCT116MTAP knockout cells, shows weak cell proliferation activity on MTAP wild-type HCT116 cells, and shows better selectivity. Has good in vivo efficacy.
  • the enzyme activity test of human UGT1A1 shows that the risk of the compound of the present invention inhibiting UGT1A1 is small.
  • the present invention studies a specific synthesis method, which has simple process, convenient operation, and is beneficial to large-scale industrial production and application.
  • Step 3 Synthesis of N 4 -(4-chlorophenyl)-2-ethoxypyrimidine-4,5-diamine
  • Step 6 8-(4-Chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one
  • Step 3 4-(2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-di Borolane-2-yl)-1H-benzo[d]imidazol-2-yl)ethyl)morpholine
  • Step 4 8-(4-Methoxyphenyl)-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2- ((2,2,2-Trifluoroethyl)amino)pterin-7(8H)-one
  • 6-(2-(2-hydroxyethyl)-1-methyl-1H was synthesized using 3-phenylethylaniline and 2,2,2-trifluoroethylamine as starting materials -Benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(3-(phenylethoxy)phenyl)pterin-7( 8H)-ketone (13 mg, yield 58%), ESI-MS (m/z): 572.2 [M+H] + .
  • Step 2 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Borane-2-yl)-1H-indole
  • Step 3 6-(2-((tert-Butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2 -Ethoxypteridin-7(8H)-one
  • Step 4 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1H-indol-5-yl)pteridine- 7(8H)-keto
  • Step 1 6-(2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-(4-( Difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one
  • Oxypteridine-7(8H)-one (30mg, 0.049mmol) and DMF (5mL) were added in a 100mL round bottom flask, 60% sodium hydride (4mg, 0.1mmol) was added under ice-cooling, stirred at room temperature for 10 Minutes, iodomethane (14.2 mg, 0.1 mmol) was added, and the reaction was stirred at room temperature.
  • Step 2 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-indole-5- Base) pteridin-7-(8H)-one
  • 6-(2-(tert-butyl)) was synthesized with 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, pivalic acid, etc.
  • Test Example 1 MAT2A enzymatic activity test
  • MAT2A Inhibitor Enzyme Screening Kit (BPS Bioscience, Catalog: 71402) was used to determine the inhibitory effect of test compounds on MAT2A enzymatic activity.
  • the specific operation procedure is as follows:
  • test compound 1) Dissolve the test compound in DMSO and mix thoroughly until the test compound is completely dissolved. All compounds were diluted with DMSO to an initial concentration of 2 mM, and three-fold serially diluted to a total of 10 concentration gradients, repeated wells, and added to the reaction system at a ratio of 1:100 during detection (the maximum final concentration was 20 ⁇ M). Prepare 100 ⁇ positive control (1 mM AGI-24512) and 100 ⁇ negative control (100% DMSO).
  • A represents IC 50 ⁇ 50nM
  • B represents 50nM ⁇ IC 50 ⁇ 100nM.
  • HCT116-MTAP -/- and wild-type control HCT116-WT cells were seeded in a 384-well culture plate at a density of 600/well, and treated with different concentrations of test compounds (starting at 20 ⁇ M, 10 concentration gradients). Cells were incubated at 37°C, 5% CO 2 , saturated humidity for 5 days.
  • Cell proliferation was detected using an ATP-based cell proliferation assay kit (Cell Titer Glo, Promega Corporation). Cells were treated with Cell Titer Glo reagent after equilibrating at room temperature for 30 minutes. The dish was then covered with aluminum foil and shaken for 15 minutes to allow for thorough mixing and lysis. Chemiluminescent detection was performed using a multi-functional microplate reader (Envision 2105, PerkinElmer). Set blank wells (blank, no cells) and DMSO control wells.
  • IR (%) [1-(RLU compound-RLU blank control)/(RLU vehicle control-RLU blank control)] ⁇ 100%
  • test compound showed strong cell proliferation activity on HCT116 MTAP knockout cells, and showed weak cell proliferation activity on MTAP wild-type HCT116 cells, that is, showed better selectivity.
  • CD-1 mice male, 22-25 g were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Test procedure CD-1 mice (male, 22-25g) were intravenously injected with the test compound (2mg/kg), orally administered with the test compound (5mg/kg), after administration for 5min, 15min, 0.5h, 1h , 2h, 4h, 8h, and 24h to collect mouse plasma, LC-MS/MS to detect the concentration of the compound, and investigate its plasma clearance Cl, elimination half-life T 1/2 , peak time T max , peak concentration C max , and drug-time curve Pharmacokinetic parameters such as area AUC, apparent volume of distribution Vss, absolute bioavailability F, etc.
  • Determination method Dilute the stock solution of the analyte with 50% acetonitrile to obtain the required concentration of the working solution series. Add 10 ⁇ L of working solution (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng/mL) to 10 ⁇ L of blank CD1 mouse plasma to achieve a total volume of 20 ⁇ L of 1-10000 ng/mL (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng/mL) calibration standards. Five quality control (QC) samples (2 ng/mL, 5 ng/mL, 10 ng/mL, 800 ng/mL, 8000 ng/ml) were prepared in the same manner as the calibration standards on the day of analysis.
  • QC quality control
  • IV intravenous injection
  • PO oral administration
  • Cl apparent clearance rate
  • T 1/2 half-life
  • AUC last the area under the drug-time curve from the beginning of administration to the last point (24 hours)
  • AUC inf from The area under the drug-time curve from the beginning of administration to the theoretically extrapolated infinity time
  • MRT Inf the average residence time from zero time to infinity time
  • Vss apparent volume of distribution
  • T max peak time
  • Peak concentration F: relative bioavailability.
  • mice Female BALB/c nude mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., with a body weight of 18-22 g, and were kept in an SPF-level laminar flow clean room with constant temperature and humidity, using IVC cages with independent ventilation. One cage per 5 mice.
  • HCT116-MTAP -/- cells were cultured in McCoy's 5a medium (GIBCO) containing 10% FBS.
  • the cells were inoculated subcutaneously on the back of 42 BALB/c nude mice at a quantity of 5 ⁇ 10 6 /mouse.
  • 30 mice with a tumor volume of about 150 mm 3 were selected and grouped evenly according to the tumor volume.
  • Oral administration once a day for 14 consecutive days. The difference in tumor growth rate between the administration group and the solvent group was compared, and the tumor growth inhibition rate TGI (%) and the tumor weight inhibition rate TWI (%) were used as evaluation indexes.
  • TV X1 Average tumor volume of the administration group on day 1
  • TV M1 the average tumor volume of the model group on day 1
  • Tumor weight inhibition rate (1-Tumor weight of administration group/Tumor weight of solvent group) ⁇ 100%
  • Test example 6 In vivo serum total bilirubin detection
  • mice Female Nu/Nu mice, 18-22 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • the test compound was orally administered once a day for 14 consecutive days.
  • Whole blood was collected from the heart of the animal after anesthesia, and after standing at room temperature for 0.5 hour, it was centrifuged at 3500 rpm for 10 minutes to separate the serum, and the blood total bilirubin level was detected by an automatic biochemical analyzer. The results are shown in the table below, the test compound did not cause a significant increase in total blood bilirubin.

Abstract

提供一类式(I)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，所述化合物具有较强的MAT2A抑制作用，能够用于治疗和/或预防MAT2A介导的疾病、病症和病况，例如肿瘤等。

Description

嘧啶并含氮六元芳香杂环类化合物及其用途 技术领域
本申请涉及医药技术领域，具体而言，涉及一类作为MAT2A抑制剂的新颖化合物及其用于治疗和预防MAT2A介导的疾病、病症和病况，例如肿瘤的用途。
背景技术
MAT2A全称Methionine adenosyltransferase 2A，又叫S-Adenosylmethionine Synthase Isoform Type。
MAT2A在包括红细胞、脑、胎儿肝脏、肾、胰腺组织在内的所有组织中均存在表达，但在成人肝脏组织中含量较少。人肝癌和结肠癌中MAT2A和MAT2B表达增加，人胃癌和他莫昔芬耐药性乳腺癌细胞中也报道了MAT2A表达增加。较高的MAT2A和MAT2B表达导致癌细胞生长、迁移和侵袭。总的来说，较低的MAT2A和MAT2B表达会导致细胞凋亡增加，细胞生长、迁移和转移减少。
MTAP是甲硫氨酸转移酶，能够催化腺苷酸的转移，在ATP的补救合成过程中发挥重要功能。MTAP缺失在所有实体瘤中的占比约15％。MTAP在多种类型肿瘤中有不同程度的缺失。MTAP缺失会导致酶底物甲硫基腺苷(MTA)积累。MTA浓度增加会部分抑制PRMT5的活性，而其他甲基转移酶相对不受影响。抑制MAT2A会使甲基供体S-腺苷甲硫氨酸(SAM)减少，而SAM为PRMT5的底物，从而进一步抑制PRMT5，影响肿瘤细胞mRNA剪接并引起DNA损伤。因此，MAT2A抑制剂能够使MTAP缺失的肿瘤获益。
已有若干篇专利申请公开了MAT2A抑制剂，比如，WO2018039972、WO2019191470、WO2020139991、WO2020139992、WO2020243376、WO2020123395。
UGTs作为体内最重要的Ⅱ相代谢酶，是外源性药物、内源性物质在体内清除的重要途径之一。UGT1A1是催化毒性内源性物质胆红素葡萄糖醛酸化的酶，它介导的葡萄糖醛酸化反应是胆红素排除体外的必须步骤，和人体健康的关系最为密切。国内外已有大量研究证实UGT1A1的基因突变使得胆红素葡萄糖醛酸化的能力全部或部分的缺失进而影响胆红素的代谢，从而导致严重的高胆红素血症。此外，部分临床药物会抑制UGT1A1，从而减少机体对胆红素的代谢清除能力，引起血液中胆红素的上升，进而导致高胆红素血症或加剧患者的病情。因此，避免过高的UGT1A1抑制能力对于安全用药有着重要意义。
发明内容
本发明提供了一类新型结构的MAT2A抑制剂化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，同时提供该类化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐治疗和预防MAT2A介导的疾病、病症和病况的用途。
具体来说，本发明提供一种式(I)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐：
Figure PCTCN2022100895-appb-000001
其中：
L 1选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R a1)C(O)-、-C(O)N(R a1)-或-N(R a1)-；R a1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
R a选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代，其中R a2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R a3、-OR a3、-SR a3、-S(O)R a3、-SO 2(R a3)、-C(O)R a3、-C(O)OR a3、-OC(O)R a3、-NH(R a3)、-N(R a3)(R a4)、-C(O)NH(R a3)、-C(O)N(R a3)(R a4)、-NHC(O)(R a3)、-N(R a3)C(O)(R a4)、-S(O)NH(R a4)、-S(O)N(R a3)(R a4)、-SO 2NH(R a3)、-SO 2N(R a3)(R a4)、-NHS(O)(R a3)、-N(R a3)S(O)(R a4)、-NHSO 2(R a4)、-N(R a3)SO 2(R a4)；其中R a3、R a4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
L 2选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R b1)C(O)-、-C(O)N(R b1)-或-N(R b1)-；R b1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
R b选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代，其中R b2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-S(O)N(R b3)(R b4)、-SO 2NH(R b3)、-SO 2N(R b3)(R b4)、-NHS(O)(R b3)、-N(R b3)S(O)(R b4)、-NHSO 2(R b4)、-N(R b3)SO 2(R b4)；其中R b3、R b4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R b3和R b4连接至同一氮原子时，R b3和R b4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
L 3选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-；R c1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、 C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代，其中R c2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3、-OR c3、-SR c3、-S(O)R c3、-SO 2(R c3)、-C(O)R c3、-C(O)OR c3、-OC(O)R c3、-NH(R c3)、-N(R c3)(R c4)、-C(O)NH(R c3)、-C(O)N(R c3)(R c4)、-NHC(O)(R c3)、-N(R c3)C(O)(R c4)、-S(O)NH(R c4)、-S(O)N(R c3)(R c4)、-SO 2NH(R c3)、-SO 2N(R c3)(R c4)、-NHS(O)(R c3)、-N(R c3)S(O)(R c4)、-NHSO 2(R c4)、-N(R c3)SO 2(R c4)；其中R c3、R c4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R c3和R c4连接至同一氮原子时，R c3和R c4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
X 1选自N或CR d；
R d独立地选自氢、氘、卤素、羟基、氨基、硝基、巯基、氰基，或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R d1所取代，其中R d1每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R d2、-OR d2、-SR d2、-S(O)R d2、-SO 2(R d2)、-C(O)R d2、-C(O)OR d2、-OC(O)R d2、-N(R d2)(R d3)、-C(O)N(R d2)(R d3)、-N(R d2)C(O)(R d3)；其中R d2、R d3每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；
除非另有说明，上述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个。
在本发明的一个优选实施方案中，L 1选自键、-CH 2-、-O-、-S-、-C(O)-、-N(R a1)C(O)-、-C(O)N(R a1)-或-N(R a1)-。
在进一步优选实施方案中，L 1选自键、-O-、-S-、-C(O)-、-NHC(O)-、-C(O)NH-。
在进一步优选实施方案中，L 1选自键、-O-、-S-、-C(O)-。
在进一步优选实施方案中，L 1是键。
在本发明的一个优选实施方案中，R a1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代所取代。
在进一步优选实施方案中，R a1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代所取代。
在进一步优选实施方案中，R a1独立地选自氢或任选取代的C 1-6烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基所取代。
在进一步优选实施方案中，R a1选自氢。
在本发明的一个优选实施方案中，R a选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基 氨基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的3-10元杂环基、C 6-12芳基、5-12元杂芳基；所述杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个、4个或5个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的3-6元单环杂环烷基、5-10元双环杂环基、C 6-8芳基、5-12元杂芳基；所述杂环烷基、杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元杂芳基；所述杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元双环杂芳基；所述杂芳基中的杂原子选自N，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的9-10元双环杂芳基；所述杂芳基中的杂原子选自N，杂原子数目为2个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在本发明的一个优选实施方案中，R a2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R a3、-OR a3、-SR a3、-S(O)R a3、-SO 2(R a3)、-C(O)R a3、-C(O)OR a3、-OC(O)R a3、-NH(R a3)、-N(R a3)(R a4)、-C(O)NH(R a3)、-C(O)N(R a3)(R a4)、-NHC(O)(R a3)、-N(R a3)C(O)(R a4)。
在进一步优选实施方案中，R a2独立地选自卤素、羟基、氨基、氰基、-R a3。
在本发明的一个优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的3-10元杂环烷基或5-12元杂芳基。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个羟基取代基取代的C 1-4烷基。
在进一步优选实施方案中，R a3、R a4独立地选自氢、C 1-4烷基。
在本发明的一个优选实施方案中，R a选自任选自C 1-4烷基取代的5-10元双环杂芳基；所述杂芳基中的杂原子选自N，杂原子数目为1个、2个、3个或4个。
在进一步优选实施方案中，R a选自
Figure PCTCN2022100895-appb-000002
在本发明的一个优选实施方案中，L 2选自键、-CH 2-、-C(O)-、-C(O)O-、-OC(O)-、-N(R b1)C(O)-、-C(O)N(R b1)-。
在进一步优选实施方案中，L 2选自键、-CH 2-、-C(O)-、-C(O)O-、-OC(O)-。
在进一步优选实施方案中，L 2选自键。
在本发明的一个优选实施方案中，R b1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基所取代。
在进一步优选实施方案中，R b1独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R b1独立地选自氢或C 1-4烷基。
在本发明的一个优选实施方案中，R b选自任选取代的C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的C 3-10环烷基、3-6元单环杂环烷基、5-12元双环杂环基、C 6-10芳基、5-10元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的5-12元双环杂环基、C 6-10芳基、5-10元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的苯基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在本发明的一个优选实施方案中，R b2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-S(O)N(R b3)(R b4)、-SO 2NH(R b3)、-SO 2N(R b3)(R b4)、-NHS(O)(R b3)、-N(R b3)S(O)(R b4)、-NHSO 2(R b4)、-N(R b3)SO 2(R b4)。
在进一步优选实施方案中，R b2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-SO 2NH(R b3)、-NHS(O)(R b3)、-NHSO 2(R b4)。
在进一步优选实施方案中，R b2独立地选自卤素、羟基、氨基、-R b3、-OR b3、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-C(O)NH(R b3)、-NHC(O)(R b3)。
在进一步优选实施方案中，R b2独立地选自卤素、羟基、氨基、-R b3、-OR b3。
在本发明的一个优选实施方案中，R b2独立地选自卤素，或任选地被一个或多个卤素取代的-O(C 1-6烷基)、C 1-6烷基。
在进一步优选实施方案中，R b2独立地选自卤素，或被任选地被一个或多个卤素取代的-O(C 1-4烷基)。
在进一步优选实施方案中，R b2独立地选自氯、-OCH 3、-OCH 2CH 3、-O(CH 2F)、-O(CHF 2)、-O(CF 3)、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、-CHFCH 3、-CH 2CHF 2。
在本发明的一个优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R b3和R b4连接至同一氮原子时，R b3和R b4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自任选地被一个或多个卤素取代的C 1-6烷基。
在本发明的一个优选实施方案中，L 3选自-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-。
在进一步优选实施方案中，L 3选自-O-、-C(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-。
在进一步优选实施方案中，L 3选自-O-、-N(R c1)-、-C(O)-。
在本发明的一个优选实施方案中，L 3选自-CH 2-、-O-、-S-、-C(O)-、-NHC(O)-、-C(O)NH-或-NH-。
在进一步优选实施方案中，L 3选自-O-、-NH-、-C(O)-。
在进一步优选实施方案中，L 3选自-O-、-NH-。
在本发明的一个优选实施方案中，R c1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基所取代。
在进一步优选实施方案中，R c1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基所取代。
在进一步优选实施方案中，R c1独立地选自氢或任选被一个或多个独立地选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基 氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R c1独立地选自氢或任选被一个或多个独立地选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基。
在进一步优选实施方案中，R c1独立地选自氢。
在本发明的一个优选实施方案中，R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-6烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在本发明的一个优选实施方案中，R c选自任选取代的甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在本发明的一个优选实施方案中，R c2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3、-OR c3、-C(O)R c3、-C(O)OR c3、-OC(O)R c3、-NH(R c3)、-N(R c3)(R c4)、-C(O)NH(R c3)、-C(O)N(R c3)(R c4)、-NHC(O)(R c3)、-N(R c3)C(O)(R c4)。
在进一步优选实施方案中，R c2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3。
在进一步优选实施方案中，R c2独立地选自卤素、羟基、氨基。
在进一步优选实施方案中，R c2独立地选自卤素。
在进一步优选实施方案中，R c2是F。
在本发明的一个优选实施方案中，R c3、R c4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R c3、R c4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、氧代的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R c3、R c4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、氧代的取代基取代的C 3-10环烷基、3-10元杂环烷基、C 6-8芳基、5-6元杂芳基。
在本发明的一个优选实施方案中，R c选自任选取代的C 1-6烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被卤素所取代。
在本发明的一个优选实施方案中，X 1选自N。
在本发明的一个优选实施方案中，X 1选自CR d。
在本发明的一个优选实施方案中，R d独立地选自氢、氘、卤素、羟基、氨基、硝基、巯基、氰基，或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R d1所取代。
在进一步优选实施方案中，R d独立地选自氢、氘、卤素、羟基、氨基、硝基、巯基、氰基，或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R d1所取代。
在进一步优选实施方案中，R d独立地选自氢、氘、卤素、羟基、氨基、硝基、巯基、氰基，或任选取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R d1所取代。
在进一步优选实施方案中，R d选自氢。
在本发明的一个优选实施方案中，R d1独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R d2、-OR d2、-N(R d2)(R d3)、-C(O)N(R d2)(R d3)、-N(R d2)C(O)(R d3)。
在进一步优选实施方案中，R d1独立地选自卤素、羟基、氨基、氰基、-R d2。
在本发明的一个优选实施方案中，R d2、R d3独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R d2、R d3独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
本发明提供一种式(II)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其具有如下结构：
Figure PCTCN2022100895-appb-000003
其中：
L 1选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R a1)C(O)-、-C(O)N(R a1)-或-N(R a1)-；R a1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
R a选自任选取代的3-12元杂环基、C 6-14芳基、5-14元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代，其中R a2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-C 1-6亚烷基-N(R a3)(R a4)、-R a3、-OR a3、-SR a3、-S(O)R a3、-SO 2(R a3)、-C(O)R a3、-C(O)OR a3、-OC(O)R a3、-NH(R a3)、-N(R a3)(R a4)、-C(O)NH(R a3)、-C(O)N(R a3)(R a4)、-NHC(O)(R a3)、-N(R a3)C(O)(R a4)、-S(O)NH(R a4)、-S(O)N(R a3)(R a4)、-SO 2NH(R a3)、-SO 2N(R a3)(R a4)、-NHS(O)(R a3)、-N(R a3)S(O)(R a4)、-NHSO 2(R a4)、-N(R a3)SO 2(R a4)；其中R a3、R a4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代 的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
L 2选自键、-C(R b1) 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R b1)C(O)-、-C(O)N(R b1)-或-N(R b1)-；R b1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
R b选自任选取代的3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代，其中R b2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-S(O)N(R b3)(R b4)、-SO 2NH(R b3)、-SO 2N(R b3)(R b4)、-NHS(O)(R b3)、-N(R b3)S(O)(R b4)、-NHSO 2(R b4)、-N(R b3)SO 2(R b4)；其中R b3、R b4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R b3和R b4连接至同一氮原子时，R b3和R b4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
L 3选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-；R c1选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代，其中R c2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3、-OR c3、-SR c3、-S(O)R c3、-SO 2(R c3)、-C(O)R c3、-C(O)OR c3、-OC(O)R c3、-NH(R c3)、-N(R c3)(R c4)、-C(O)NH(R c3)、-C(O)N(R c3)(R c4)、-NHC(O)(R c3)、-N(R c3)C(O)(R c4)、-S(O)NH(R c4)、-S(O)N(R c3)(R c4)、-SO 2NH(R c3)、-SO 2N(R c3)(R c4)、-NHS(O)(R c3)、-N(R c3)S(O)(R c4)、-NHSO 2(R c4)、-N(R c3)SO 2(R c4)；其中R c3、R c4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R c3和R c4连接至同一氮原子时，R c3和R c4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
除非另有说明，上述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个。
在本发明的一个优选实施方案中，L 1选自键、-CH 2-、-O-、-S-、-C(O)-、-N(R a1)C(O)-、-C(O)N(R a1)-或-N(R a1)-。
在进一步优选实施方案中，L 1选自键、-CH 2-、-O-、-S-或-N(R a1)-，其中R a1选自氢或C 1-6烷基。
在进一步优选实施方案中，L 1选自键、-O-、-S-、-C(O)-、-NH-、-NHC(O)-、-C(O)NH-。
在进一步优选实施方案中，L 1选自键、-O-、-S-、-C(O)-、-NH-。
在进一步优选实施方案中，L 1选自键、-NH-、-O-或-S-。
在进一步优选实施方案中，L 1是键。
在本发明的一个优选实施方案中，R a1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代的取代基所取代。
在进一步优选实施方案中，R a1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代的取代基所取代。
在进一步优选实施方案中，R a1独立地选自氢或任选取代的C 1-6烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基的取代基所取代。
在进一步优选实施方案中，R a1选自氢。
在本发明的一个优选实施方案中，R a选自任选取代的3-12元杂环基、C 6-14芳基、5-14元杂芳基，所述杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个，所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
R a选自任选取代的3-10元杂环基、C 6-12芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的3-10元杂环基、C 6-12芳基、5-12元杂芳基；所述杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个、4个或5个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的3-6元单环杂环烷基、5-10元双环杂环基、C 6-8芳基、5-12元杂芳基；所述杂环烷基、杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元双环杂环基、5-10元杂芳基；所述杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元双环杂环基、5-10元双环杂芳基，所述杂环基、杂芳基中的杂原子独立地选自O或N，杂原子数目为1个、2个或3个，所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元杂芳基；所述杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及 的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元双环杂环基；所述杂环基中的杂原子独立地选自O或N，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的5-10元双环杂芳基；所述杂芳基中的杂原子选自N，杂原子数目为1个、2个、3个或4个；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的
Figure PCTCN2022100895-appb-000004
Figure PCTCN2022100895-appb-000005
所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的
Figure PCTCN2022100895-appb-000006
Figure PCTCN2022100895-appb-000007
所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在进一步优选实施方案中，R a选自任选取代的
Figure PCTCN2022100895-appb-000008
所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
在本发明的一个优选实施方案中，R a2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-C 1-6亚烷基-N(R a3)(R a4)、-R a3、-OR a3、-SR a3、-S(O)R a3、-SO 2(R a3)、-C(O)R a3、-C(O)OR a3、-OC(O)R a3、-NH(R a3)、-N(R a3)(R a4)、-C(O)NH(R a3)、-C(O)N(R a3)(R a4)、-NHC(O)(R a3)、-N(R a3)C(O)(R a4)。
在进一步优选实施方案中，R a2独立地选自卤素、羟基、氨基、氰基、-C 1-6亚烷基-N(R a3)(R a4)、-R a3、-OR a3、-N(R a3)(R a4)、-C(O)N(R a3)(R a4)、-N(R a3)C(O)(R a4)。
在本发明的一个优选实施方案中，R a2独立地选自卤素、羟基、氨基、氰基、-C 1-6亚烷基-N(R a3)(R a4)、-R a3。
在本发明的一个优选实施方案中，R a2独立地选自卤素、羟基、氨基、氰基、-C 1-6亚烷基-N(R a3)(R a4)、C 1-4烷基、-C 1-4烷基-C 1-4烷氧基或-C 1-4烷基羟基。
在本发明的一个优选实施方案中，R a2独立地选自卤素、-C(O)R a3、羟基、氨基、-C 1-6亚烷基-N(R a3)(R a4)、任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷氧基取代的C 1-6烷基。
在本发明的一个优选实施方案中，R a2独立地选自-C 1-6亚烷基-N(R a3)(R a4)、任选地被一个或多个独立地选自羟基和C 1-6烷氧基取代的C 1-6烷基。
在本发明的一个优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地 被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的3-10元杂环烷基或5-12元杂芳基。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、C 1-6烷基、C 1-6烷氧基的取代基取代的3-10元杂环烷基，所述杂环烷基中的杂原子选自N、S、O，杂原子数目为1个、2个或3个。
在进一步优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基；当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自F、Cl、Br、羟基、甲基、甲氧基的取代基取代的3-10元杂环烷基，所述杂环烷基中的杂原子选自N、O，杂原子数目为1个或2个。
在进一步优选实施方案中，R a3、R a4独立地选自氢、C 1-4烷基、-C 1-4烷基羟基；当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自F、羟基、甲基、甲氧基的取代基取代的四氢吡咯基、哌啶基或吗啉基。
在本发明的一个优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基，所述杂环烷基或杂芳基中的杂原子选自N、S、O，杂原子数目为1个、2个或3个。
在本发明的一个优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、C 1-6烷基、C 1-6烷氧基的取代基取代的3-10元杂环烷基，所述杂环烷基中的杂原子选自N、S、O，杂原子数目为1个、2个或3个。
在本发明的一个优选实施方案中，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、C 1-4烷基、C 1-4烷氧基的取代基取代的3-10元杂环烷基，所述杂环烷基中的杂原子选自N、O，杂原子数目为1个或2个。
在本发明的一个优选实施方案中，R a3、R a4独立地选自C 1-4烷基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自F、羟基、甲基、甲氧基的取代基取代的四氢吡咯基、哌啶基或吗啉基。
在进一步优选实施方案中，R a2独立地选自甲基、Br、
Figure PCTCN2022100895-appb-000009
Figure PCTCN2022100895-appb-000010
在进一步优选实施方案中，R a2独立地选自
Figure PCTCN2022100895-appb-000011
在进一步优选实施方案中，R a选自
Figure PCTCN2022100895-appb-000012
Figure PCTCN2022100895-appb-000013
在进一步优选实施方案中，R a选自
Figure PCTCN2022100895-appb-000014
在本发明的一个优选实施方案中，L 2选自键、-CH 2-、-C(O)-、-C(O)O-、-OC(O)-、-N(R b1)C(O)-、-C(O)N(R b1)-。
在进一步优选实施方案中，L 2选自键、-CH 2-、-C(O)-、-C(O)O-、-OC(O)-。
在进一步优选实施方案中，L 2选自键、-CH 2-、-C(O)-。
在进一步优选实施方案中，L 2选自键、-CH 2-。
在进一步优选实施方案中，L 2是键。
在本发明的一个优选实施方案中，R b1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所 述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基所取代。
在进一步优选实施方案中，R b1独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R b1独立地选自氢或C 1-4烷基。
在本发明的一个优选实施方案中，R b选自任选取代的3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的3-6元单环杂环烷基、5-12元双环杂环基、C 6-10芳基、5-10元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的5-12元双环杂环基、C 6-10芳基、5-10元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的5-10元双环杂环基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的5-12元双环杂环基、C 6-10芳基、5-10元杂芳基，所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的苯基、吡啶基或苯并四氢呋喃基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的苯基或吡啶基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在进一步优选实施方案中，R b选自任选取代的苯基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
在本发明的一个优选实施方案中，R b2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-S(O)N(R b3)(R b4)、-SO 2NH(R b3)、-SO 2N(R b3)(R b4)、-NHS(O)(R b3)、-N(R b3)S(O)(R b4)、-NHSO 2(R b4)、-N(R b3)SO 2(R b4)。
在进一步优选实施方案中，R b2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-SO 2NH(R b3)、-NHS(O)(R b3)、-NHSO 2(R b4)。
在进一步优选实施方案中，R b2独立地选自卤素、羟基、氨基、-R b3、-OR b3、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-C(O)NH(R b3)、-NHC(O)(R b3)。
在进一步优选实施方案中，R b2独立地选自卤素、羟基、氨基、-R b3、-OR b3。
在本发明的一个优选实施方案中，R b2独立地选自卤素、羟基，或任选地被一个或多个卤素取代的-O(C 1-6烷基)、-O(C 1-6烷基)苯基、C 1-6烷基。
在进一步优选实施方案中，R b2独立地选自卤素、羟基，或任选地被一个或多个卤素取代的-O(C 1-4烷基)、-O(C 1-4烷基)苯基或C 1-4烷基。
在进一步优选实施方案中，R b2独立地选自氯、-OCH 3、-OH、-O-苄基、-OCH 2CH 3、 -O(CH 2F)、-O(CHF 2)、-O(CF 3)、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、-CHFCH 3、-CH 2CHF 2或
Figure PCTCN2022100895-appb-000015
在本发明的一个优选实施方案中，R b2独立地选自卤素、羟基、氨基、C 3-6环烷基、-OR b3，其中R b3选自任选地被一个或多个独立地选自卤素或C 6-10芳基的取代基取代的C 1-6烷基。
在进一步优选实施方案中，R b2独立地选自卤素、羟基、C 3-6环烷基、-OR b3，其中R b3选自任选地被一个或多个独立地选自卤素或苯基的取代基取代的C 1-4烷基。
在进一步优选实施方案中，R b2独立地选自氟、氯、-OH、C 3-6环烷基、-OR b3，其中R b3选自任选地被一个或多个独立地选自氯或苯基的取代基取代的C 1-4烷基。
在进一步优选实施方案中，R b2独立地选自氯、环丙基或任选地被一个或多个卤素取代的-O(C 1-4烷基)。
在进一步优选实施方案中，R b2独立地选自氯或任选地被一个或多个氟取代的-O(C 1-4烷基)。
在进一步优选实施方案中，R b2独立地选自氯、-OCH 3、-O(CHF 2)或-O(CF 3)。
在进一步优选实施方案中，R b2独立地选自-O(CHF 2)。
在本发明的一个优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R b3和R b4连接至同一氮原子时，R b3和R b4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 6-8芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、苯基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、苯基的取代基取代的C 1-4烷基、C 1-4烷氧基、C 3-4环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、苯基的取代基取代的C 1-4烷基、C 1-4烷氧基或环丙基。
在进一步优选实施方案中，R b3、R b4独立地选自氢或任选地被一个或多个独立地选自卤素、苯基的取代基取代的C 1-4烷氧基。
在进一步优选实施方案中，R b3、R b4独立地选自任选地被一个或多个独立地选自F、Cl的取代基取代的甲氧基。
在进一步优选实施方案中，R b选自
Figure PCTCN2022100895-appb-000016
Figure PCTCN2022100895-appb-000017
在进一步优选实施方案中，R b选自
Figure PCTCN2022100895-appb-000018
在本发明的一个优选实施方案中，L 3选自-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-。
在进一步优选实施方案中，L 3选自-CH 2-、-O-、-S-或-N(R c1)-，其中R c1选自氢或C 1-6烷基。
在进一步优选实施方案中，L 3选自-O-、-S-、-C(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-。
在进一步优选实施方案中，L 3选自-O-、-N(R c1)-、-C(O)-。
在进一步优选实施方案中，L 3选自-O-、-N(R c1)-，其中R c1选自氢或C 1-6烷基。
在本发明的一个优选实施方案中，L 3选自-CH 2-、-O-、-S-、-C(O)-、-NHC(O)-、-C(O)NH-或-NH-。
在进一步优选实施方案中，L 3选自-O-、-NH-、-C(O)-。
在进一步优选实施方案中，L 3选自-O-、-NH-。
在进一步优选实施方案中，L 3选自-O-。
在本发明的一个优选实施方案中，R c1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基所取代。
在进一步优选实施方案中，R c1独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基所取代。
在进一步优选实施方案中，R c1独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R c1独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基。
在进一步优选实施方案中，R c1独立地选自氢。
在本发明的一个优选实施方案中，R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取 代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-4烷基或C 3-6环烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在进一步优选实施方案中，R c选自任选取代的C 1-3烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在本发明的一个优选实施方案中，R c选自任选取代的甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代。
在本发明的一个优选实施方案中，R c2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3、-OR c3、-C(O)R c3、-C(O)OR c3、-OC(O)R c3、-NH(R c3)、-N(R c3)(R c4)、-C(O)NH(R c3)、-C(O)N(R c3)(R c4)、-NHC(O)(R c3)、-N(R c3)C(O)(R c4)。
在进一步优选实施方案中，R c2独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3。
在进一步优选实施方案中，R c2独立地选自卤素、羟基、氨基或-R c3。
在进一步优选实施方案中，R c2独立地选自卤素或-R c3。
在本发明的一个优选实施方案中，R c3、R c4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R c3、R c4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、氧代的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基。
在进一步优选实施方案中，R c3、R c4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、氧代的取代基取代的C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-8芳基、5-6元杂芳基。
在进一步优选实施方案中，R c3、R c4独立地选自氢或CF 3。
在本发明的一个优选实施方案中，R c选自任选地被一个或多个卤素取代的C 1-6烷基或任选地被一个或多个R c3取代的C 3-6环烷基，其中R c3选自氢或任选地被一个或多个独立地选自卤素的取代基取代的C 1-6烷基。
在本发明的一个优选实施方案中，R c选自任选取代的C 1-6烷基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被卤素所取代。
在进一步优选实施方案中，R c选自任选地被一个或多个卤素取代的C 1-4烷基或任选地被CF 3取代的C 3-6环烷基。
在进一步优选实施方案中，R c选自甲基、乙基、
Figure PCTCN2022100895-appb-000019
在进一步优选实施方案中，R c选自乙基、
Figure PCTCN2022100895-appb-000020
在进一步优选实施方案中，R c选自乙基。
本发明的代表性化合物的结构式与编号如下表所示：
Figure PCTCN2022100895-appb-000021
Figure PCTCN2022100895-appb-000022
Figure PCTCN2022100895-appb-000023
Figure PCTCN2022100895-appb-000024
Figure PCTCN2022100895-appb-000025
Figure PCTCN2022100895-appb-000026
本发明的目的还包括提供制备通式(I)中X为N、通式(II)所示化合物或其互变异构体、立体异构体、或其药学上可接受的盐的方法。
所述方法例如可以使用下述方案中示出的方法来制备。
Figure PCTCN2022100895-appb-000027
中间体1.6在钯催化剂的存在下与硼酸或硼酸酯得到最终产物1.7。
在一个实施方案中，中间体1.6可通过下述步骤制备：
Figure PCTCN2022100895-appb-000028
在进一步优选实施方案中，所述化合物或其互变异构体、立体异构体、或其药学上可接受的盐可通过下述步骤制备：
Figure PCTCN2022100895-appb-000029
以2,4-二氯-5-硝基嘧啶(1.1)为起始原料，与不同种类的伯胺反应得到中间体1.2，中间体1.2与相应的R c-L 3H作用得到中间体1.3，采用还原剂将1.3的硝基还原为氨基得到中间体1.4，中间体1.4与草酰氯单甲酯作用得到并环化合物1.5，中间体1.5在氯化亚砜的作用下得到中间体1.6，最后在钯催化剂的存在下与硼酸或硼酸酯得到最终产物1.7。所示化合物中各取代基定义如前所述。
备注：本步骤中涉及到的保护与脱保护的反应步骤已省略。
本发明另一方面还提供了下述中间体化合物：
Figure PCTCN2022100895-appb-000030
其中L 2、L 3、R b和R c如式(I)或式(II)化合物所述；
在进一步优选实施方案中，L 2为键，R b为任选取代的苯基或吡啶基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代
本发明另一方面还提供了一种药物组合物，其包含本发明所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐。
进一步地，本发明所述的药物组合物还包含药学上可接受的辅料。
本发明化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐的给药可以以纯的形式或适宜的药物组合物的形式通过提供类似用途的药物的任何可接受的给药方式来进行。本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的辅料相组合而制备。本发明的药物组合物可配制成固态、半固态、液态或气态制剂。一般地，上述药物组合物可以采用制剂领域中常规的赋形剂通过常规的制备方法制备。
本发明另一方面还提供了本发明所述的化合物或其互变异构体、立体异构体、或其药学上可接受的盐或本发明药物组合物在制备用于预防和/或治疗通过MAT2A介导的疾病、病症和病况的药物中的用途。
进一步地，在本发明提供的用途中，所述的疾病、病症和病况为MTAP缺失的肿瘤。
进一步地，在本发明提供的用途中，所述肿瘤包括实体瘤和血液瘤；优选地，所述实体瘤包含结直肠癌。
在本领域某些语境下，所述癌症也可称为恶性肿瘤。
还一方面，本申请提供了用于预防和/或治疗通过MAT2A介导的疾病、病症和病况的方法，其包括向有需要的个体施用本发明所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐或本发明药物组合物；优选地，所述疾病、病症和病况为MTAP缺失的癌症；更优选地，所述肿瘤包括实体瘤和血液瘤。
还一方面，本申请提供了用于预防和/或治疗通过MAT2A介导的疾病、病症和病况的本发明所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐或本发明药物组合物；优选地，所述疾病、病症和病况为MTAP缺失的癌症；更优选地，所述肿瘤包括实体瘤和血液瘤。
进一步地，在本发明提供的用途或方法中，本发明所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐或本发明药物组合物与另一种、两种或更多种具有抑制肿瘤活性的药物组合使用。
本发明还提供了一种药物组合物，包括本发明化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐以及另一种、两种或更多种具有抑制肿瘤活性的药物。
定义
术语“任选”、“任意”、“任选地”或“任意地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
除另有规定外，所述“任选取代”或“任意取代”是指所提及的基团未被取代或者被一个或多个独立地选自羟基、卤素、羟基、氨基、硝基、巯基、氰基、叠氮基、氧代、羧基、 -C(O)C 1-6烷基、-C(O)O-C 1-6烷基、-OC(O)-C 1-6烷基、-NH(C 1-6烷基)、-N(C 1-6烷基)(C 1-6烷基)、-C(O)NH-C 1-6烷基、-NHC(O)-C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、C 3-10环烷基磺酰基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代；其中所述C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、C 3-10环烷基磺酰基、3-10元杂环烷基、C 6-14芳基或5-12元杂芳基任选地被一个或多个独立地选自卤素、羟基、氨基、氰基、C 1-6烷基或C 1-6烷氧基的取代基所取代。
术语“氧代”是指相同取代位的两个氢原子被同一个氧原子替代形成双键。
除另有规定外，术语“烷基”指一价饱和脂肪族烃基团，包含1-20个碳原子的直链或支链基团，优选包含1-10个碳原子(即C 1-10烷基)，进一步优选包含1-8个碳原子(C 1-8烷基)，更优选包含1-6个碳原子(即C 1-6烷基)，例如“C 1-6烷基”指的是该基团为烷基，且碳链上的碳原子数目在1-6之间(具体地为1个、2个、3个、4个、5个或6个)。实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、新戊基、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、正庚基、正辛基等。
除另有规定外，术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基可以包含2-20个碳原子，优选包含2-10个碳原子(即C 2-10烯基)，进一步优选包含2-8个碳原子(C 2-8烯基)，更优选包含2-6个碳原子(即C 2-6烯基)、2-5个碳原子(即C 2-5烯基)、2-4个碳原子(即C 2-4烯基)、2-3个碳原子(即C 2-3烯基)、2个碳原子(即C 2烯基)，例如“C 2-6烯基”指的是该基团为烯基，且碳链上的碳原子数目在2-6之间(具体地为2个、3个、4个、5个或6个)。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基和1,3-丁二烯基等。
除另有规定外，术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个叁键的不饱和脂肪族烃基。炔基可以包含2-20个碳原子，优选包含2-10个碳原子(即C 2-10炔基)，进一步优选包含2-8个碳原子(C 2-8炔基)，更优选包含2-6个碳原子(即C 2-6炔基)、2-5个碳原子(即C 2-5炔基)、2-4个碳原子(即C 2-4炔基)、2-3个碳原子(即C 2-3炔基)、2个碳原子(即C 2炔基)，例如“C 2-6炔基”指的是该基团为炔基，且碳链上的碳原子数目在2-6之间(具体地为2个、3个、4个、5个或6个)。炔基的非限制性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基和1-丁炔基等。
除另有规定外，术语“环烷基”指的是具有特定碳原子数的单环饱和脂烃基，优选地包含3-12个碳原子(即C 3-12环烷基)，更优选包含3-10个碳原子(C 3-10环烷基)，进一步优选3-7个碳原子(C 3-7环烷基)、4-6个碳原子(C 4-6环烷基)、5-6个碳原子(C 5-6环烷基)。实例包括但不限于环丙基、环丁基、环戊基、环己基、甲基环丙基、2-乙基-环戊基、二甲基环丁基等。
除另有规定外，术语“烷氧基”指-O-烷基，所述烷基的定义同上，即包含1-20个碳原子，优选地，包含1-10个碳原子，较佳地1-8个碳原子，更佳地1至6个碳原子(具体地为1个、2个、3个、4个、5个或6个)。代表的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、叔丁氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基等。
除另有规定外，术语“烷基氨基”指-NR′R″，R′和R″相同或不同，可为H或如上所定义的烷基，所述烷基的定义同上，即包含1-20个碳原子，优选地，包含1-10个碳原子，较佳地1-8个碳原子，更佳地1至6个碳原子(具体地为1个、2个、3个、4个、5个或6个)。代表的例子包括但不限于-NH(CH 3)、-N(CH 3)(CH 3)、-N(CH 2CH 3)(CH 3)、-N(CH 2CH 3)[CH(CH 3) 2]等。
除另有规定外，术语“卤素”或“卤代”是指F、Cl、Br、I。术语“卤代烷基”是指如上所定义的烷基中一个、两个或多个氢原子或全部氢原子被卤素取代。卤代烷基的代表性例子 包括CCl 3、CF 3、CHCl 2、CH 2Cl、CH 2Br、CH 2I、CH 2CF 3、CF 2CF 3等。
除另有规定外，术语“杂环基”或“杂环”指具有环碳原子和1个或多个环杂原子的饱和或部分不饱和单环或多环环状非芳香族取代基，包含3-20个环原子，其中1个、2个、3个或更多个环原子选自N、O或S，其余环原子为C。优选包含3至12个环原子(3-12元杂环基)，进一步优选包含3-10个环原子(3-10元杂环基)，或3至8个环原子(3-8元杂环基)，或3至6个环原子(3-6元杂环基)，或4至6个环原子(4-6元杂环基)，或5至6个环原子(5-6元杂环基)。杂原子优选1-4个，更优选1至3个(即1个、2个或3个)。单环杂环基的实例包括吡咯烷基、咪唑烷基、四氢呋喃基、二氢吡咯基、哌啶基、哌嗪基、吡喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。“杂环基”可以是单环的(“单环杂环基”)或一种稠合的(“稠杂环基”或“杂稠环基”)、桥接的(“杂桥环基”或“桥环杂环基”)或螺接-稠合(“杂螺环基”或“螺环杂环基”)的环系统，如一个双环系统(“双环杂环基”)，并且可以是饱和的或可以是部分不饱和的。杂环基双环系统可以在一个或两个环中包括一个或多个杂原子。“杂环基”还包括其中如上所定义的该杂环基环被一个或多个碳环基基团稠合的环系统，其中附接点是在该碳环基或杂环基环上，或者“杂环基”还包括其中如上所定义的该杂环基环被一个或多个芳基或杂芳基基团稠合的环系统，或如上所定义的环烷基环被一个或多个杂芳基基团稠合的环系统，其中附接点是在该杂环基环或环烷基环上，并且在此类情况下，该杂环基环系统的元数为稠合后环系统原子数。在某些实施例中，杂环基的每个例子独立地是任选取代的，例如，未取代的(一种“未取代的杂环基”)或被一个或多个取代基取代的(一种“取代的杂环基”)。含有1个杂原子的示例性3元杂环基基团包括，但不限于氮杂环丙烷基、氧杂环丙烷基(oxiranyl)和硫杂环丙烷基(thiorenyl)。含有1个杂原子的示例性4元杂环基基团包括，但不限于氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。含有1个杂原子的示例性5元杂环基基团包括，但不限于四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基以及吡咯基-2,5-二酮。含有2个杂原子的示例性5元杂环基基团包括，但不限于二氧戊环基、氧杂硫杂环戊烷基、二硫杂环戊烷基以及
Figure PCTCN2022100895-appb-000031
唑烷-2-酮。含有3个杂原子的示例性5元杂环基基团包括，但不限于三唑啉基、
Figure PCTCN2022100895-appb-000032
二唑啉基和噻二唑啉基。含有1个杂原子的示例性6元杂环基基团包括，但不限于哌啶基、四氢吡喃基、二氢吡啶基以及硫杂环己烷基(thianyl)。含有2个杂原子的示例性6元杂环基基团包括，但不限于哌嗪基、吗啉基、二硫杂环己烷基以及二氧杂环己烷基。含有3个杂原子的示例性6元杂环基基团包括，但不限于三氮杂环己烷基、氧杂二嗪烷基、噻二嗪烷基、氧杂噻嗪烷基以及二氧杂氮杂环己烷基(dioxazinanyl)。含有1个杂原子的示例性7元杂环基基团包括，但不限于氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。含有1个杂原子的示例性8元杂环基基团包括，但不限于氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。稠合到一个C 6芳基环上的示例性5元杂环基基团(在此又称为一种5,6-双环杂环)包括，但不限于二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并
Figure PCTCN2022100895-appb-000033
唑啉酮基等。稠合到一个芳基环上的示例性6元杂环基基团(在此又称为一种6,6-双环杂环)包括，但不限于四氢喹啉基、四氢异喹啉基等。
除另有规定外，“杂环烷基”是指单环、饱和的如上文定义的“杂环基”或“杂环”，环原子定义同上，即包含3至20个环原子(“3-20元杂环烷基”)，杂原子数目为1至4个(1个、2个、3个或4个)，优选1至3个(1个、2个或3个)，其中杂原子各自独立地选自N、O或S。优选包含3至12个环原子(“3-12元杂环烷基”)，进一步优选包含3至10个环原子(“3-10元杂环烷基”)，更进一步优选包含3至8个环原子(“3-8元杂环烷基”)，更进一步优选包含4至7个环原子(“4-7元杂环烷基”)，更进一步优选地包含5-10个环原子(“5-10元杂环烷基”)，更进一步优选包含5-6个环原子(“5-6元杂环烷基”)。在某些实施例中，杂环烷基的每个例子独立地是可任选取代的，例如，未取代的(一种“未取代的杂环烷基”)或被一个或多个取代基取代的(一种“取代的杂环烷基”)。上文“杂环基”或“杂环”部分已给出了部分示例性的“杂 环烷基”，还包括，但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、氧杂环己烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氧杂硫杂环己基、
Figure PCTCN2022100895-appb-000034
唑烷基、二
Figure PCTCN2022100895-appb-000035
烷基、二硫杂环己基、噻唑烷基、吡咯烷基、吡唑烷基、咪唑啉啶等。
除另有规定外，术语“芳基”或“芳环基”表示含有6-16个碳原子，或6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环、双环和三环的芳香碳环体系，优选6-10个碳原子，术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括但不限于苯基、萘基、蒽基、菲基或芘基等。
除另有规定外，术语“杂芳基”或“杂芳环基”表示含有5-14元结构，或优选5-10元结构，或优选5-8元结构，更优选5-6元结构的芳香单环或者多环环状系统，其中1个、2个、3个或更多个环原子为杂原子且其余原子为碳，杂原子独立地选自O、N或S，杂原子数目优选为1个、2个或3个。杂芳基的实例包括但不限于呋喃基、噻吩基、
Figure PCTCN2022100895-appb-000036
唑基、噻唑基、异
Figure PCTCN2022100895-appb-000037
唑基、
Figure PCTCN2022100895-appb-000038
二唑基、噻二唑基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、硫代二唑基、三嗪基、酞嗪基、喹啉基、异喹啉基、喋啶基、嘌呤基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基、苯并酞嗪基、吡咯并[2,3-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基等。
除另有规定外，术语“药物上可接受的盐”或“可药用盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其他类型化合物的医学上可接受的盐在所属领域中是被熟知的。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐。
本发明化合物还包括其“同位素衍生物”。除另有规定外，术语“同位素衍生物”是指本发明的化合物可以以同位素示踪的或富集形式存在，含有一个或多个原子，这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。通常用作同位素标记的同位素是：氢同位素， 2H和 3H；碳同位素： 13C和 14C；氯同位素： 35Cl和 37Cl；氟同位素： 18F；碘同位素： 123I和 125I；氮同位素： 13N和 15N；氧同位素： 15O、 17O和 18O；和硫同位素： 35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是 2H和 13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢( 2H)的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目的而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
本发明化合物还包括其“溶剂合物”、“溶剂化物”。除另有规定外，术语“溶剂合物”、“溶剂化物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
除另有规定外，术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体等。所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
除另有规定外，术语“互变异构体”是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的互相转化。
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明化合物还包括其“前药”，除另有规定外，术语“前药”是指在体内转化为母体药物的药物。前药通常是有用的，其可以改善一些确定的、不合需要的物理或生物学性质。物理性能通常是相关的溶解度(过高或不足的脂质或水溶性)或稳定性，而有问题的生物学特性包括代谢太快或生物利用率差，这本身可能与物理化学性质相关。例如，它们可以通过口服而被生物利用，而母体则不能。与母体药物相比，前药在药物组合物中的溶解度也有所提高。前药的一个例子，但不限于此，可以是任何本发明的化合物，其作为酯(“前药”)给药，以促进穿过细胞膜的传递，其中水溶性对迁移性有害，但一旦进入细胞内水溶性是有益的，其随后被代谢水解成羧酸，即活性实体。前药的另一个例子可以是与酸基团结合的短肽(聚氨基酸)，其中肽被代谢以显示活性部分。
制备实施例、实施例及本文其他地方使用的缩写词是：
DMF：N,N-二甲基甲酰胺
DIPEA：N,N-二异丙基乙胺
本发明的有益效果：
本申请设计了一类结构新颖的化合物，为治疗肿瘤等疾病提供一个新的方向。试验表明，本发明化合物对MAT2A具有较强的抑制作用，对HCT116MTAP敲除的细胞表现了较强的细胞增殖活性，对MTAP野生型的HCT116细胞表现了较弱的细胞增殖活性，表现了较好的选择性。具有良好的体内药效。并且，人UGT1A1酶活性测试表明，本发明化合物抑制UGT1A1的风险较小。结合体内血清总胆红素检测，说明本发明化合物未引起胆红素病理性升高，毒性小，安全性好。此外，本发明研究了特定的合成方法，该合成方法工艺简单，操作便捷，利于规模化工业生产和应用。
具体实施方式
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者按照制造厂商所建议的条件。除非另行定义，文中所使用的所有专业与科学用语与本领域专业人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法之中。文中所示的较佳实施方法与材料仅做示范之用。
以下为本申请示例性化合物的制备实施例。
制备例1：8-(4-氯苯基)-2-乙氧基-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A1)
Figure PCTCN2022100895-appb-000039
步骤1：2-氯-N-(4-氯苯基)-5-硝基嘧啶-4-胺
往250mL圆底烧瓶中加入2,4-二氯-5-硝基嘧啶(7.55g，38.92mmol)、对氯苯胺(4.965g，38.92mmol)、DIPEA(5.03g，38.92mmol)和DMF(85mL)，室温搅拌反应。反应结束后，将反应液倒入500mL水中，析出沉淀，过滤，干燥得2-氯-N-(4-氯苯基)-5-硝基嘧啶-4-胺(8.80g，收率79.3％)。ESI-MS(m/z)：285.0[M+H] +。
步骤2：N-(4-氯苯基)-2-乙氧基-5-硝基嘧啶-4-胺的合成
将上一步产物2-氯-N-(4-氯苯基)-5-硝基嘧啶-4-胺(1.50g，5.2817mmol)、碳酸钾(1.0955g，7.922mmol)和乙醇(50mL)加入到100mL圆底烧瓶中，过夜搅拌。反应结束后，浓缩反应液，直接经柱层析纯化得产物N-(4-氯苯基)-2-乙氧基-5-硝基嘧啶-4-胺(750mg，收率48.4％)。ESI-MS(m/z)：295.1[M+H] +。
步骤3：N 4-(4-氯苯基)-2-乙氧基嘧啶-4,5-二胺的合成
将上一步产物N-(4-氯苯基)-2-乙氧基-5-硝基嘧啶-4-胺(730mg，2.477mmol)、锌粉(1296mg，19.817mmol)、氯化铵(2114mg，39.6mmol)和甲醇(20mL)加入到50mL圆底烧瓶中，室温搅拌，两小时后反应结束，过滤，滤液浓缩直接经柱层析纯化得N 4-(4-氯苯基)-2-乙氧基嘧啶-4,5-二胺(560mg，收率85.4％)。ESI-MS(m/z)：265.1[M+H] +。
步骤4：8-(4-氯苯基)-2-乙氧基-5,8-二氢蝶啶-6,7-二酮的合成
取上一步产物N 4-(4-氯苯基)-2-乙氧基嘧啶-4,5-二胺(350mg，1.30mmol)、DIPEA(503mg，3.90mmol)、甲苯(15mL)和二氯甲烷(3mL)加入到50mL圆底烧瓶中，冰浴，滴加含有草酰氯单甲酯(159mg，1.30mmol)的二氯甲烷溶液，升至室温，搅拌反应2小时后，加入碳酸铯(1059mg，3.25mmol)，升温至50℃反应。反应结束后，加入20mL乙酸乙酯和15mL水，分层，水相用20mL乙酸乙酯洗两次，合并有机相，有机相依次用水，饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标产物8-(4-氯苯基)-2-乙氧基-5,8-二氢蝶啶-6,7-二酮(203mg，收率55.3％)。ESI-MS(m/z)：319.1[M+H] +。
步骤5：6-氯-8-(4-氯苯基)-2-乙氧基蝶啶-7(8H)-酮
将上一步产物8-(4-氯苯基)-2-乙氧基-5,8-二氢蝶啶-6,7-二酮(150mg，1.30mmol)、DMF(0.2mL)和甲苯(5mL)加入到25mL圆底烧瓶中，然后加入氯化亚砜(350mg，1.30mmol)，接着加热到50℃搅拌反应。反应结束后，减压浓缩得目标化合物6-氯-8-(4-氯苯基)-2-乙氧基蝶啶-7(8H)-酮(103mg，收率64.9％)。ESI-MS(m/z)：337.1[M+H] +。
步骤6：8-(4-氯苯基)-2-乙氧基-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮
取上一步产物6-氯-8-(4-氯苯基)-2-乙氧基蝶啶-7(8H)-酮(30mg，0.089mmol)、2-甲基-2H-吲唑-5-硼酸(26mg，0.1486mmol)、四(三苯基膦)钯(3mg，0.01335mmol)、碳酸钾(25mg，0.178mmol)、二氧六环(10mL)和水(1mL)加入到25mL圆底烧瓶中，用氮气置换三次后，加热到100℃。反应结束后，往反应液中加入100mL乙酸乙酯和5mL水，水相用乙酸乙 酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物8-(4-氯苯基)-2-乙氧基-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(18mg，收率46.8％)，ESI-MS(m/z)：433.1[M+H] +； 1H NMR(600MHz,CDCl 3)δ9.043(s,1H),9.036(s,1H),8.28(d,J＝9.2Hz,1H),8.01(s,1H),7.78(d,J＝9.2Hz,1H),7.57(d,J＝8.5Hz,2H),7.28(d,J＝8.5Hz,2H),4.30–4.25(m,4H),1.34(t,J＝7.1Hz,3H)。
制备例2至14：
参照制备例1的合成路线及操作，采用对应的中间体作为起始物，制备化合物A2-A14。
Figure PCTCN2022100895-appb-000040
Figure PCTCN2022100895-appb-000041
Figure PCTCN2022100895-appb-000042
Figure PCTCN2022100895-appb-000043
制备例15：8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A15)
Figure PCTCN2022100895-appb-000044
按照合成A1的方法，以对甲氧基苯胺和2,2,2-三氟乙胺等为起始原料合成8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(50mg，收率57％)，ESI-MS(m/z)：482.1[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.89(d,J＝16.8Hz,1H),8.83(s,1H),8.50(s,1H),8.09(d,J＝9.0Hz,1H),7.67(d,J＝9.0Hz,1H),7.33(br,2H),7.11(d,J＝6.0Hz,2H),6.82-6.81(m,1H),4.19(s,3H),4.15(br,1H),3.84(s,3H),3.80(br,1H)。
制备例16：8-(3-甲氧基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A16)
Figure PCTCN2022100895-appb-000045
按照合成A1的方法，以间甲氧基苯胺和2,2,2-三氟乙胺等为起始原料合成8-(3-甲氧基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(135mg，收率42％)，ESI-MS(m/z)：482.1[M+H] +。
制备例17：8-(3-羟基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A17)
Figure PCTCN2022100895-appb-000046
取化合物A16(100mg，0.208mmol)、20mL无水二氯甲烷加入到50mL圆底烧瓶中，放入乙醇浴，冷却至-20℃，滴加三溴化硼(1.0M的二氯甲烷溶液)(1.4mL，1.4mmol)。反应结束后，缓慢加入水淬灭反应，依次用水和饱和氯化钠溶液洗涤有机相，浓缩，经柱层析纯化得目标化合物(45mg，收率46％)，ESI-MS(m/z)：468.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.79–9.63(m,1H),8.92–8.77(m,2H),8.49(s,1H),8.40–8.13(m,1H),8.08(d,J＝9.2Hz,1H),7.65(d,J＝9.2Hz,1H),7.33(s,1H),6.89(d,J＝8.0Hz,1H),6.81(s,2H),4.18(s,3H),4.15(s,1H),3.80(s,1H)。
制备例18：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A18)
Figure PCTCN2022100895-appb-000047
按照制备例1的方法合成6-氯-8-(6-甲氧基吡啶-3-基)-2-乙氧基蝶啶-7(8H)-酮，取该中间体(50mg，0.150mmol)、2-甲基-5-氨基-2H-吲唑(33mg，0.225mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯(20mg，0.030mmol)、碳酸钾(63mg，0.450mmol)和二氧六环(2mL)加入到25mL圆底烧瓶内，用氮气置换三次后，加热到100℃反应3h。反应结束后，往反应液中加入100mL乙酸乙酯和50mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(30mg，收率45％)，ESI-MS(m/z)：433.1[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.62(s,1H),8.72(d,J＝8.6Hz,2H),8.32(s,1H),8.27(d,J＝2.3Hz,1H),7.84(dd,J＝8.7,2.5Hz,1H),7.71(dd,J＝9.2,1.6Hz,1H),7.58(d,J＝9.2Hz,1H),7.06(d,J＝8.7Hz,1H),4.20(d,J＝7.0Hz,2H),4.13(s,3H),3.96(s,3H),1.24(t,J＝7.0Hz,3H)。
制备例19：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-((2-甲基-2H-吲唑-5-基)氧基)蝶啶-7(8H)-酮(A19)
Figure PCTCN2022100895-appb-000048
步骤1：2-甲基-2H-吲唑-5-醇
取2-甲基-2H-吲唑-5-硼酸(600mg，3.409mmol)、碳酸氢铵(270mg，3.409mmo1)、双氧水(660μL)和乙腈(8mL)加入到50mL圆底烧瓶内，室温反应2h。反应结束后，往反应液中加入100mL乙酸乙酯和50mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物2-甲基-2H-吲唑-5醇(350mg，收率69％)，ESI-MS(m/z)：149.1[M+H] +；
步骤2：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-((2-甲基-2H-吲唑-5-基)氧基)蝶啶-7(8H)-酮
取6-氯-8-(6-甲氧基吡啶-3-基)-2-乙氧基蝶啶-7(8H)-酮(55mg，0.165mmol)、2-甲基-2H-吲唑-5醇(24mg，0.164mmo1),碳酸钾(63mg，0.450mmol)和N,N-二甲基甲酰胺(1mL)加入到5mL圆底烧瓶内，加热到100℃反应3h。反应结束后，往反应液中加入25mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-((2-甲基-2H-吲唑-5-基)氧基)蝶啶-7(8H)-酮(40mg，收率54％)，ESI-MS(m/z)：446.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.59(s,1H),8.39(s,1H),8.25(d,J＝2.5Hz,1H),7.81(dd,J＝8.7,2.6Hz,1H),7.72(d,J＝9.2Hz,1H),7.59(d,J＝2.0Hz,1H),7.20(dd,J＝9.2,2.2Hz,1H),7.08(d,J＝8.7Hz,1H),4.21(s,3H),4.19(q,J＝7.0Hz,2H),3.96(s,3H),1.23(t,J＝7.0Hz,3H)。
制备例20：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-(2,3,3a,7a-四氢苯呋喃-6-基)蝶啶-7(8H)-酮(A20)
Figure PCTCN2022100895-appb-000049
按照合成A1的方法，以6-甲氧基吡啶-3-胺、(2,3,3a,7a-四氢苯呋喃-6-基)硼酸和乙醇等为起始原料合成2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-(2,3,3a,7a-四氢苯呋喃-6-基)蝶啶-7(8H)-酮(16mg，收率25％)，ESI-MS(m/z)：420.2[M+H] +； 1H NMR(600MHz,CDCl 3)δ9.03(s,1H),8.17(s,1H),7.89(d,J＝7.1Hz,1H),7.73(s,1H),7.56(d,J＝7.7Hz,1H),7.31(d,J＝8.6Hz,1H),6.96(d,J＝8.3Hz,1H),4.65(t,J＝8.1Hz,2H),4.32(q,J＝6.5Hz,2H),4.05(s,3H),3.29(t,J＝7.9Hz,2H),1.38(t,J＝5.9Hz,3H)。
制备例21：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-(7-溴-3,4-二氢异喹啉-2(1H)基)蝶啶-7(8H)-酮(A21)
Figure PCTCN2022100895-appb-000050
按照合成A18的方法，以6-甲氧基3-氨基吡啶和6-溴-1,2,3,4-四氢异喹啉等为起始原料合成2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-(7-溴-3,4-二氢异喹啉-2(1H)基)蝶啶-7(8H)-酮(8mg，收率35％)，ESI-MS(m/z)：509.2[M+H] +。
制备例22：8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氧基)-6-([1,2,4]三唑[4,3a]吡啶-6-基)蝶啶-7(8H)-酮(A22)
Figure PCTCN2022100895-appb-000051
按照合成A1的方法，以对甲氧基苯胺，2,2,2-三氟乙醇和[1,2,4]三唑[4,3a]吡啶-6-基硼酸等为起始原料合成8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氧基)-6-([1,2,4]三唑[4,3a]吡啶-6-基)蝶啶-7(8H)-酮(5mg，收率7％)，ESI-MS(m/z)：470.1[M+H] +。
制备例23：8-(4-氯苯基)-2-乙氧基-6-(2,3-二氢苯并呋喃-5-基)蝶啶-7(8H)-酮(A23)
Figure PCTCN2022100895-appb-000052
按照合成A1的方法，以2,3-二氢苯并呋喃-5-基硼酸等为起始原料合成8-(4-氯苯基)-2-乙氧基-6-(2,3-二氢苯并呋喃-5-基)蝶啶-7(8H)-酮(1.2mg，收率5％)，ESI-MS(m/z)：421.1[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.04(s,1H),8.17(s,1H),8.13(d,J＝8.4Hz,1H),7.67(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,2H),6.90(d,J＝8.4Hz,1H),4.64(t,J＝9.0Hz,2H),4.25-4.21(m,2H),3.27-3.26(m,2H),1.24(t,J＝7.2Hz,3H)。
制备例24：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-((2-甲基-2H-吲唑-5-基)硫代)蝶啶-7(8H)-酮(A24)
Figure PCTCN2022100895-appb-000053
步骤1：3-((2-甲基-2H-吲唑-5-基)硫代)丙酸甲酯
取5-溴-2-甲基-2H-吲唑(1000mg，4.730mmol)、3-巯基丙酸甲酯(850mg，7.110mmo1)、三[二亚苄基丙酮]二钯(260mg，0.280mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(274mg，0.473mmol)、N,N-二异丙基乙胺(2.34mL，1.420mmol)和二氧六环(40mL)加入到100mL圆底烧瓶内，用氮气置换三次后，加热到100℃反应4h。反应结束后，往反应液中加入25mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物3-((2-甲基-2H-吲唑-5-基)硫代)丙酸甲酯(500mg，收率42％)，ESI-MS(m/z)：251.1[M+H] +；
步骤2：2-甲基-2H-吲唑-5-硫醇
取3-((2-甲基-2H-吲唑-5-基)硫代)丙酸甲酯(500mg，1.997mmol)、氢氧化钠(80mg，2.000mmo1)和甲醇(5mL)加入到25mL圆底烧瓶内，用氮气置换三次后，加热到50℃反应3h。反应结束后，往反应液中加入25mL乙酸乙酯和10mL水，用乙酸调pH＝4，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物2-甲基-2H-吲唑-5-硫醇(98mg，收率30％)，ESI-MS(m/z)：165.1[M+H] +；
步骤3：2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-((2-甲基-2H-吲唑-5-基)硫代)蝶啶-7(8H)-酮
取6-氯-8-(6-甲氧基吡啶-3-基)-2-乙氧基蝶啶-7(8H)-酮(100mg，0.300mmol)、2-甲基-2H-吲唑-5硫醇(98mg，0.599mmo1)、三[二亚苄基丙酮]二钯(33mg，0.036mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(35mg，0.060mmol)、碳酸钾(208mg，1.498mmol)和二氧六环(5mL)加入到25mL圆底烧瓶内，用氮气置换三次后，加热到100℃反应3h。反应结束后，往反应液中加入25mL乙酸乙酯和10mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物2-乙氧基-8-(6-甲氧基吡啶-3-基)-6-((2-甲基-2H-吲唑-5-基)硫代)蝶啶-7(8H)-酮(18mg，收率13％)，ESI-MS(m/z)：462.1[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.58(s,1H),8.47(s,1H),8.25(d,J＝2.2Hz,1H),8.06(s,1H),7.81(dd,J＝8.7,1.9Hz,1H),7.74(d,J＝8.9Hz,1H),7.35(d,J＝8.9Hz,1H),7.06(d,J＝8.7Hz,1H),4.23(s,3H),4.19(q,J＝7.0Hz,2H),3.95(s,3H),1.22(t,J＝7.0Hz,3H)。
制备例25：8-(2-羟基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A25)
Figure PCTCN2022100895-appb-000054
按照合成A17的方法，以邻甲氧基苯胺和2,2,2-三氟乙胺等为起始原料合成8-(2-羟基苯基)-2-((2,2,2-三氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(50mg，收率57％)，ESI-MS(m/z)：468.1[M+H] +。
制备例26：8-(4-甲氧基苯基)-6-(1-甲基-2-(2-吗啉乙基)-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(A26)
Figure PCTCN2022100895-appb-000055
步骤1：2-(6-溴-1-甲基-1H-苯并[d]咪唑-2-基)乙烷-1-醇
取4-溴-2-甲基氨基苯胺(15g，0.181mmol)、3-羟基丙酸(28％水溶液)(33.6mL，111.90mmol)、盐酸(150mL)和水(120mL)加入到500mL圆底烧瓶内，加热到105℃反应48h。反应结束后，用氢氧化钠调pH 8至9，水相用乙酸乙酯萃取3次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物2-(6-溴-1-甲基-1H-苯并[d]咪唑-2-基)乙烷-1-醇(3.5g，收率18％)，ESI-MS(m/z)：255.1[M+H] +；
步骤2：4-(2-(6-溴-1-甲基-1H-苯并[d]咪唑-2-基)乙基)吗啉
取25mL圆底烧瓶2-(6-溴-1-甲基-1H-苯并[d]咪唑-2-基)乙烷-1-醇(200mg，0.789mmol)溶解于二氯甲烷(5mL)，加入三乙胺(238mg，2.352mmol)、甲基磺酰氯(135mg，1.176mmol)，室温反应1h后。加入吗啉(341mg，3.920mmol)，室温反应48h。反应结束后，往反应液中加入100mL乙酸乙酯和50mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物4-(2-(6-溴-1-甲基-1H-苯并[d]咪唑-2-基)乙基)吗啉(179mg，收率70％)，ESI-MS(m/z)：324.1[M+H] +；
步骤3：4-(2-(1-甲基-6-(4,4,5,5-四甲基-1,3,2-二
Figure PCTCN2022100895-appb-000056
硼戊环-2-基)-1H-苯并[d]咪唑-2-基)乙基)吗啉
取4-(2-(6-溴-1-甲基-1H-苯并[d]咪唑-2-基)乙基)吗啉(67mg，0.207mmol)、双联频哪醇硼酸酯(79mg，0.310mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯(23mg，0.031mmol)、醋酸钾(61mg，0.621mmol)和二氧六环(2mL)加入到10mL圆底烧瓶内，用氮气置换三次后，加热到110℃反应3h，反应结束后，降温至室温直接用于下一步，ESI-MS(m/z)：372.2[M+H] +。
步骤4：8-(4-甲氧基苯基)-6-(1-甲基-2-(2-吗啉乙基)-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮
按照合成A1的方法合成化合物8-(4-甲氧基苯基)-6-(1-甲基-2-(2-吗啉乙基)-1H-苯并[d] 咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(20mg，收率16％)，ESI-MS(m/z)：595.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.91(s,1H),8.43(s,1H),8.17(s,1H),8.08(d,J＝7.5Hz,1H),7.62(d,J＝8.5Hz,1H),7.34(s,2H),7.11(d,J＝6.1Hz,2H),4.21-4.14(m,1H),3.85(s,3H),3.84-3.83(m,1H),3.80(s,3H),3.61-3.59(m,4H),3.1(t,J＝7.2Hz,2H),2.86-2.81(m,2H),2.50–2.46(m,4H)。
制备例27：6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(A27)
Figure PCTCN2022100895-appb-000057
按照合成A26的方法，以4-甲氧基苯胺和2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸等为起始原料合成6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(20mg，收率21％)，ESI-MS(m/z)：526.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.90(d,J＝15.7Hz,1H),8.44(s,1H),8.17(s,1H),8.09(d,J＝8.5Hz,1H),7.63(d,J＝8.5Hz,1H),7.35(s,2H),7.11(d,J＝6.9Hz,2H),4.89(t,J＝5.3Hz,1H),4.21-4.13(m,1H),3.90-3.87(m,2H),3.85(s,3H),3.84-3.82(m,1H),3.80(s,3H),3.08(t,J＝6.7Hz,2H)。
制备例28：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A28)
Figure PCTCN2022100895-appb-000058
按照合成8-(4-甲氧基苯基)-6-(1-甲基-2-(2-吗啉乙基)-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(A26)的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基丙酸烷等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(240mg，收率38％)，ESI-MS(m/z)：509.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.10(s,1H),8.47(s,1H),8.12(d,J＝8.4Hz,1H),7.66(d,J＝8.5Hz,1H),7.54(d,J＝8.7Hz,2H),7.41(d,J＝8.6Hz,2H),7.39(t,J＝73.9Hz,1H),4.91(t,J＝5.3Hz,1H),4.26(q,J＝6.9Hz,2H),3.90-3.87(m,2H),3.81(s,3H),3.08(t,J＝6.6Hz,2H),1.26(t,J＝7.0Hz,3H)。
制备例29：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(甲氧基甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A29)
Figure PCTCN2022100895-appb-000059
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、2-甲氧基乙酸等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(甲氧基甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(48mg，收率35％)，ESI-MS(m/z)：509.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.12(s,1H),8.53(s,1H),8.16(d,J＝8.5Hz,1H),7.74(d,J＝8.6Hz,1H),7.54(t,J＝8.8Hz,2H),7.41(d,J＝8.7Hz,2H),7.39(t,J＝73.9Hz,1H),4.75(s,2H),4.27(q,J＝7.0Hz,2H),3.86(s,3H),3.37(s,3H),1.26(t,J＝7.0Hz,3H)。
制备例30：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(3-甲氧基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A30)
Figure PCTCN2022100895-appb-000060
取8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A26)(40mg，0.079mmol)溶于25mL圆底烧瓶内的二氯甲烷(5ml)，加入三乙胺(109μL，0.786mmol)、甲基磺酰氯(50μL，0.629mmol)，室温反应1h，加入3-甲氧基吡咯烷盐酸盐(162mg，1.179mmol)、三乙胺(220μL，1.572mmol)，室温反应48h。反应结束后，往反应液中加入100mL乙酸乙酯和50mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(3-甲氧基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(18mg，收率39％)，ESI-MS(m/z)：592.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.10(s,1H),8.47(s,1H),8.13(d,J＝8.4Hz,1H),7.66(d,J＝8.5Hz,1H),7.54(d,J＝8.8Hz,2H),7.41(d,J＝8.7Hz,2H),7.40(t,J＝74Hz,1H),4.26(q,J＝7.0Hz,2H),3.90(s,1H),3.81(s,3H),3.19(s,3H),3.10(s,2H),2.94(s,2H),2.78(s,1H),2.70(s,1H),2.00(s,1H),1.68(s,1H),1.26(t,J＝7.0Hz,3H)。
制备例31：8-(2,3-二氢苯并呋喃-4-基)-2-乙氧基-6-(2-甲基-2H-吲唑-5-基)蝶呤-7(8H)-酮(A31)
Figure PCTCN2022100895-appb-000061
按照合成A1的方法，由2,3-二氢-4-氨基苯并呋喃等为起始原料合成8-(2,3-二氢苯并 呋喃-4-基)-2-乙氧基-6-(2-甲基-2H-吲唑-5-基)蝶呤-7(8H)-酮(15mg，收率53％)，ESI-MS(m/z)：441.2[M+H] +。
制备例32：6-(2-(2-(3-羟基吡咯烷-1-基)乙基)-1-甲基-1H-苯并咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)胺基)蝶呤-7(8H)-酮(A32)
Figure PCTCN2022100895-appb-000062
按照合成A26的方法，以4-甲氧基苯胺和2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸、吡咯烷醇等为起始原料合成6-(2-(2-(3-羟基吡咯烷-1-基)乙基)-1-甲基-1H-苯并咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)胺基)蝶呤-7(8H)-酮(15mg，收率17％)，ESI-MS(m/z)：595.2[M+H] +； 1H NMR(600MHz,CDCl 3)δ8.90(s,1H),8.60(s,1H),8.28(d,J＝8.6Hz,1H),7.78(d,J＝8.6Hz,1H),7.28–7.22(m,3H),7.12(d,J＝8.7Hz,2H),5.91(brs,1H),3.92(s,3H),3.86(s,1H),3.80(s,3H),2.89(t,J＝10.2Hz,2H),2.67-2.64(m,2H),2.50–2.40(m,1H),2.28-2.22(m,2H),1.87–1.78(m,2H)。
制备例33：6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(3-(苄氧基)苯基)蝶呤-7(8H)-酮(A33)
Figure PCTCN2022100895-appb-000063
按照合成A1的方法，以3-苄氧基苯胺和2,2,2-三氟乙胺等为起始原料合成6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(3-(苄氧基)苯基)蝶呤-7(8H)-酮(9mg，收率42％)，ESI-MS(m/z)：558.2[M+H] +。
制备例34：6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(3-(苯基乙氧基)苯基)蝶呤-7(8H)-酮(A34)
Figure PCTCN2022100895-appb-000064
按照合成A1的方法，以3-苯基乙基苯胺和2,2,2-三氟乙胺等为起始原料合成6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(3-(苯基乙氧基)苯基)蝶呤-7(8H)-酮(13mg，收率58％)，ESI-MS(m/z)：572.2[M+H] +。
制备例35：6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(4-(三 氟甲氧基)苯基)蝶呤-7(8H)-酮(A35)
Figure PCTCN2022100895-appb-000065
按照合成A26的方法，以4-(三氟甲氧基)苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸等为起始原料合成6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(33mg，收率15％)，ESI-MS(m/z)：580.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.93-8.89(m,1H),8.44(s,1H),8.16(s,1H),8.08(s,1H),7.65–7.55(m,5H),4.87(t,J＝5.4Hz,1H),4.19-4.12(m,1H),3.89-3.86(m,2H),3.79(s,3H),3.77–3.70(m,1H),3.06(t,J＝6.7Hz,2H)。
制备例36：6-(2-(2-(3-羟基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(A36)
Figure PCTCN2022100895-appb-000066
按照合成A26的方法，以4-(三氟甲氧基)苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸和吡咯烷醇等为起始原料合成6-(2-(2-(3-羟基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(20mg，收率9％)，ESI-MS(m/z)：649.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.94-8.91(m,1H),8.45(s,1H),8.18(s,1H),8.09(s,1H),7.68–7.56(m,5H),4.71(brs,1H),4.23-4.16(m,2H),3.80(s,3H),3.78-3.73(m,1H),3.07(t,J＝7.5Hz,2H),2.94-2.86(m,2H),2.79(dd,J＝9.2,6.3Hz,1H),2.71–2.63(m,1H),2.54-2.52(m,1H),2.41(d,J＝6.3Hz,1H),2.02-1.96(m,1H),1.59–1.52(m,1H)。
制备例37：6-(2-(2,4-二氟哌啶-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(A37)
Figure PCTCN2022100895-appb-000067
按照合成A26的方法，以4-(三氟甲氧基)苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸和4,4-二氟哌啶等为起始原料合成6-(2-(2,4-二氟哌啶-1-基)乙基)-1-甲基-1H-苯 并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(25mg，收率11％)，ESI-MS(m/z)：683.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.94-8.90(m,1H),8.45(s,1H),8.18(s,1H),8.09(s,1H),7.67–7.56(m,5H),4.22-4.14(m,1H),3.80(s,3H),3.78-3.74(m,1H),3.11(t,J＝7.0Hz,2H),2.98-2.90(m,2H),2.70-2.62(m,4H),2.02-1.94(d,J＝12.4Hz,4H)。
制备例38：8-(4-(三氟甲氧基)苯基)-2-((1-(三氟甲基)环丙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A38)
Figure PCTCN2022100895-appb-000068
按照合成A1的方法，以(1-(三氟甲基)环丙基)胺和4-(三氟甲氧基)苯胺等为起始原料合成8-(4-(三氟甲氧基)苯基)-2-((1-(三氟甲基)环丙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(30mg，收率20％)，ESI-MS(m/z)：562.1[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.94(br,1H),8.86(s,1H),8.63(s,1H),8.51(s,1H),8.10(d,J＝9.0Hz,1H),7.67-7.60(m,5H),4.20(s,3H),1.33-1.12(m,2H),0.90(br,2H)。
制备例39：6-(2-(2-(3-甲氧基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(A39)
Figure PCTCN2022100895-appb-000069
按照合成A26的方法，以4-(三氟甲氧基)苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸和3-甲氧基吡咯烷等为起始原料合成6-(2-(2-(3-甲氧基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-(2,2,2-三氟乙基)氨基)-8-(4-(三氟甲氧基)苯基)蝶呤-7(8H)-酮(9mg，收率6％)，ESI-MS(m/z)：663.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.94-8.92(m,1H),8.45(s,1H),8.18(s,1H),8.09(d,J＝4.5Hz,1H),7.66–7.57(m,5H),4.21-4.14(m,1H),3.92-3.88(m,2H),3.80(s,3H),3.76(s,3H),3.10(t,J＝6.9Hz,2H),3.05(t,J＝7.0Hz,2H),2.78(s,1H),2.69(s,1H),2.63(s,1H),2.53(s,1H),2.01–1.98(m,1H),1.68(s,1H)。
制备例40：8-(4-(二氟甲氧基)苯基)-6-(2-(2-(3-甲氧基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(A40)
Figure PCTCN2022100895-appb-000070
按照合成A26的方法，以4-(二氟甲氧基)苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、3-羟基丙酸和3-甲氧基吡咯烷等为起始原料合成8-(4-(二氟甲氧基)苯基)-6-(2-(2-(3-甲氧基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶呤-7(8H)-酮(13mg，收率9％)，ESI-MS(m/z)：645.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ8.93-8.90(m,1H),8.43(s,1H),8.18(s,1H),8.08(d,J＝8.5Hz,1H),7.63(d,J＝8.5Hz,1H),7.56–7.48(m,2H),7.39(d,J＝7.1Hz,2H),7.23(d,J＝8.5Hz,1H),4.20-4.16(m,1H),3.90-3.87(s,2H),3.79(s,3H),3.18(s,3H),3.10-3.03(m,2H),2.95-2.86(s,2H),2.76(s,1H),2.68(s,1H),2.63-2.60(m,1H),2.01-1.98(m,1H),1.69-1.64(m,1H),1.50-1.45(m,1H)。
制备例41：8-(4-(二氟甲氧基)苯基)-6-(2-(2-(2,6-二甲基吗啉基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-乙氧基蝶呤-7(8H)-酮(A41)
Figure PCTCN2022100895-appb-000071
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基丙酸和2,6-二甲基吗啉等为起始原料合成8-(4-(二氟甲氧基)苯基)-6-(2-(2-(2,6-二甲基吗啉基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-乙氧基蝶呤-7(8H)-酮(51mg，收率27％)，ESI-MS(m/z)：606.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.10(d,J＝6.8Hz,1H),8.46(s,1H),8.11(dd,J＝8.6,1.4Hz,1H),7.65(d,J＝8.5Hz,1H),7.54(d,J＝8.8Hz,2H),7.41(d,J＝8.7Hz,2H),7.39(t,J＝73.8Hz,1H),4.26(q,J＝7.0Hz,2H),3.80(s,3H),3.60–3.54(m,2H),3.10(t,J＝7.5Hz,2H),2.88(d,J＝10.6Hz,2H),2.80(t,J＝7.6Hz,2H),1.73(t,J＝10.6Hz,2H),1.26(t,J＝7.0Hz,3H),1.08(s,3H),1.07(s,3H)。
制备例42：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-(3-羟基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A42)
Figure PCTCN2022100895-appb-000072
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基 丙酸和吡咯烷醇等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-(3-羟基吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(32mg，收率16％)(25mg，收率11％)，ESI-MS(m/z)：578.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.10(s,1H),8.49(s,1H),8.13(d,J＝8.5Hz,1H),7.67(d,J＝8.5Hz,1H),7.54(d,J＝8.7Hz,2H),7.41(d,J＝8.7Hz,2H),7.39(t,J＝74Hz,1H),5.10(brs,1H),4.35-4.31(m,1H),4.26(q,J＝7.0Hz,2H),3.82(s,3H),3.25-3.21(m,3H),3.14-3.0(m,3H),2.99–2.84(m,2H),2.12-2.06(m,1H),1.75-1.69(m,1H),1.26(t,J＝7.0Hz,3H)。
制备例43：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(1-甲基-2-(2-(哌啶-1-基)乙基)-1H苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A43)
Figure PCTCN2022100895-appb-000073
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基丙酸和哌啶等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(1-甲基-2-(2-(哌啶-1-基)乙基)-1H苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(32mg，收率16％)，ESI-MS(m/z)：576.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.10(s,1H),8.47(s,1H),8.12(d,J＝8.3Hz,1H),7.66(d,J＝8.1Hz,1H),7.54(d,J＝8.7Hz,2H),7.41(d,J＝8.6Hz,2H),7.39(t,J＝73.9Hz,1H),4.26(q,J＝7.0Hz,2H),3.81(s,3H),3.16-3.09(m,2H),2.95-2.82(m,2H),2.63-2.5(s,4H),1.59-1.52(m,4H),1.46-1.40(m,2H),1.26(t,J＝7.0Hz,3H)。
制备例44：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(1-甲基-2-(2-(吡咯烷-1-基)乙基)-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A44)
Figure PCTCN2022100895-appb-000074
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基丙酸和四氢吡咯烷等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(1-甲基-2-(2-(吡咯烷-1-基)乙基)-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(17mg，收率9％)，ESI-MS(m/z)：562.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.11(s,1H),8.49(s,1H),8.14(s,1H),7.69(s,1H),7.54(d,J＝8.1Hz,2H),7.41(d,J＝8.3Hz,2H),7.39(t,J＝74.1Hz,1H),4.27(q,J＝6.8Hz,2H),3.83(s,3H),3.27–3.20(m,4H),3.02-2.88(m,4H),1.89-1.81(m,4H),1.26(t,J＝6.7Hz,3H)。
制备例45：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-(3-氟吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A45)
Figure PCTCN2022100895-appb-000075
取8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A28)(40mg，0.079mmol)溶于25mL圆底烧瓶内的二氯甲烷(5ml)，加入三乙胺(109μL，0.786mmol)、甲基磺酰氯(50μL，0.629mmol)，室温反应1h，加入3-氟四氢吡咯盐酸盐(99mg，0.786mmol)、三乙胺(164μL，1.179mmol)，室温反应48h。反应结束后，往反应液中加入100mL乙酸乙酯和50mL水，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-(3-氟吡咯烷-1-基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(21mg，收率47％)，ESI-MS(m/z)：580.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.10(s,1H),8.47(s,1H),8.12(d,J＝7.8Hz,1H),7.66(d,J＝8.1Hz,1H),7.54(d,J＝7.4Hz,2H),7.52-7.27(m,3H),5.22(d,J＝55.7Hz,1H),4.26(q,J＝6.5Hz,2H),3.81(s,3H),3.12(t,J＝6.0Hz,2H),2.97(t,J＝6.0Hz,2H),2.92(s,2H),2.72-2.67(m,1H),2.42(s,1H),2.16(s,1H),1.92-1.87(m,J＝24.9Hz,1H),1.26(t,J＝6.5Hz,3H)。
制备例46：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A46)
Figure PCTCN2022100895-appb-000076
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、羟基乙酸和等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(150mg，收率21％)，ESI-MS(m/z)：495.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.11(s,1H),8.52(s,1H),8.15(d,J＝8.5Hz,1H),7.71(d,J＝8.6Hz,1H),7.54(d,J＝8.8Hz,2H),7.41(d,J＝8.7Hz,2H),7.39(t,J＝73.9Hz,1H),5.67(t,J＝6.0Hz,1H),4.78(d,J＝6.0Hz,2H),4.27(q,J＝7.0Hz,2H),3.88(s,3H),1.26(t,J＝7.1Hz,3H)。
制备例47：8-(4-(二氟甲氧基)苯基)-6-(2-(2-(二甲基氨基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-乙氧基蝶啶-7(8H)-酮(A47)
Figure PCTCN2022100895-appb-000077
按照合成A45的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基 丙酸和二甲胺盐酸盐等为起始原料合成8-(4-(二氟甲氧基)苯基)-6-(2-(2-(二甲基氨基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-乙氧基蝶啶-7(8H)-酮(16mg，收率38％)，ESI-MS(m/z)：536.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.09(s,1H),8.46(s,1H),8.11(d,J＝8.4Hz,1H),7.65(d,J＝8.4Hz,1H),7.53(d,J＝8.4Hz,2H),7.51–7.25(m,3H),4.25(q,J＝,6.8Hz,2H),3.80(s,3H),3.10(t,J＝6.7Hz,2H),2.89(s,2H),2.34(s,6H),1.25(t,J＝6.9Hz,3H)。
制备例48：6-(2-(2-(二乙基氨基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(A48)
Figure PCTCN2022100895-appb-000078
按照合成A45的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、3-羟基丙酸和二乙胺胺盐酸盐等为起始原料合成6-(2-(2-(二乙基氨基)乙基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(15mg，收率37％)，ESI-MS(m/z)：564.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.09(s,1H),8.46(s,1H),8.11(d,J＝8.5Hz,1H),7.65(d,J＝8.4Hz,1H),7.53(d,J＝8.7Hz,2H),7.40(d,J＝8.7Hz,2H),7.38(t,J＝73.7Hz,1H),4.25(q,J＝7.0Hz,2H),3.80(s,3H),3.10–2.90(m,4H),2.70–2.55(s,4H),1.25(t,J＝7.0Hz,3H),1.01(s,6H)。
制备例49：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(A49)
Figure PCTCN2022100895-appb-000079
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、2-甲基-2-羟基丙酸和二乙胺胺盐酸盐等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(35mg，收率35％)，ESI-MS(m/z)：523.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.10(s,1H),8.47(s,1H),8.12(d,J＝8.5Hz,1H),7.69(d,J＝8.5Hz,1H),7.53(d,J＝8.7Hz,2H),7.40(d,J＝8.7Hz,2H),7.38(t,J＝73.7Hz,1H),5.69(s,1H),4.25(q,J＝7.0Hz,2H),4.05(s,3H),1.65(s,6H),1.25(t,J＝7.0Hz,3H).
制备例50：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1H-吲哚-5-基)蝶啶-7(8H)-酮(A50)
Figure PCTCN2022100895-appb-000080
步骤1：5-溴-2-(2-((叔丁基二甲基硅基)氧基)乙基)-1H-吲哚
往100mL烧瓶内加入5-溴吲哚(1.96g，10mmol)、(2-溴乙氧基)-叔丁基二甲基硅烷(4.78g，20mmol)、降冰片烯(1.88g，20mmol)、双(乙腈)二氯化钯(260mg，1mmol)、碳酸钾(2.76g，20mmol)和DMF(20mL)，氮气置换后，70℃搅拌反应。反应结束后，降温并加水150mL，用乙酸乙酯200mL萃取两次，合并有机相并用无水硫酸钠干燥，过滤后浓缩。经柱层析纯化得5-溴-2-(2-((叔丁基二甲基硅基)氧基)乙基)-1H-吲哚(1.0g，收率为28％)，ESI-MS(m/z)：354.1,356.1[M+H] +；
步骤2：2-(2-((叔丁基二甲基硅基)氧基)乙基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吲哚
取上一步产物5-溴-2-(2-((叔丁基二甲基硅基)氧基)乙基)-1H-吲哚(200mg，0.56mmol)、双(频哪醇合)二硼(0.28g，1.14mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(82mg，0.11mmol)、醋酸钾(165mg，1.6mmol)和二氧六环(5mL)加入到100mL圆底烧瓶内，氮气置换后，105℃搅拌反应。反应结束后，未进一步处理直接降温进行下一步反应，ESI-MS(m/z)：402.3[M+H] +；
步骤3：6-(2-((叔丁基二甲基硅基)氧基)-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮
向上述反应液内加入水(1mL)、6-氯-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(100mg，0.28mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(82mg，0.11mmol)和醋酸钾(165mg，1.6mmol)，氮气置换后，100℃搅拌反应。反应结束后降温，加水100mL，乙酸乙酯200mL萃取两次，合并有机相并用无水硫酸钠干燥，过滤后浓缩，经柱层析纯化得到6-(2-((叔丁基二甲基硅基)氧基)-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(50mg，收率为29％)，ESI-MS(m/z)：608.2[M+H] +；
步骤4：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1H-吲哚-5-基)蝶啶-7(8H)-酮
取上一步产物6-(2-((叔丁基二甲基硅基)氧基)-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(20mg，0.033mmol)、四氢呋喃(5mL)和四丁基氟化铵(1M，0.1ml)加入到100mL圆底烧瓶内，室温搅拌反应。反应结束后，将反应液浓缩，经薄板层析纯化得到8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1H-吲哚-5-基)蝶啶-7(8H)-酮(4mg，25％)，ESI-MS(m/z)：494.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ11.14(s,1H),9.04(s,1H),8.50(s,1H),7.98(dd,J＝8.4,1.2Hz,1H),7.52(d,J＝9.0Hz,2H),7.39-7.36(m,3H),7.38(t,J＝73.8Hz,1H),6.29(s,1H),4.25-4.22(m,2H),3.74(t,J＝7.2Hz,2H),2.44(br,1H)2.88(t,J＝6.6Hz,2H),1.24(t,J＝6.6Hz,3H)。
制备例51：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-吲哚-5-基)蝶啶-7-(8H)-酮(A51)
Figure PCTCN2022100895-appb-000081
步骤1：6-(2-(2-((叔丁基二甲基硅基)氧基)乙基)-1-甲基-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮
取6-(2-((叔丁基二甲基硅基)氧基)-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(30mg，0.049mmol)和DMF(5mL)加入到100mL圆底烧瓶内，冰浴下加入60％的氢化钠(4mg，0.1mmol)，室温下搅拌10分钟，加入碘甲烷(14.2mg，0.1mmol)，室温下搅拌反应。反应结束后，加入水100mL，乙酸乙酯200mL萃取两次，合并有机相，无水硫酸钠干燥，过滤后浓缩。经薄板层析纯化得到6-(2-(2-((叔丁基二甲基硅基)氧基)乙基)-1-甲基-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(20mg，65％)，ESI-MS(m/z)：622.3[M+H] +
步骤2：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-吲哚-5-基)蝶啶-7-(8H)-酮
取上一步产物6-(2-(2-((叔丁基二甲基硅基)氧基)乙基)-1-甲基-1H-吲哚-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(20mg，0.032mmol)，四氢呋喃(5mL)和四丁基氟化铵(1M，0.1mL)加入到100mL圆底烧瓶内，室温搅拌反应。反应结束后，将反应液浓缩，经薄板层析纯化得到8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(2-羟乙基)-1-甲基-1H-吲哚-5-基)蝶啶-7-(8H)-酮(5mg，收率为31％)，ESI-MS(m/z)：508.2[M+H] +； 1H NMR(600MHz,DMSO-d 6)δ9.04(s,1H),8.52(s,1H),7.52-7.50(m,4H),7.39-7.37(m,3H),6.38(s,1H),4.25-4.22(m,2H),3.77-3.73(m,5H),2.95-2.92(m,2H),1.25-1.23(m,3H)。
制备例52：2-乙氧基-8-(4-氟苯基)-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(A52)
Figure PCTCN2022100895-appb-000082
按照合成A26的方法，以对氟苯胺、乙醇、4-溴-2-甲基氨基苯胺、羟基乙酸等为起始原料合成2-乙氧基-8-(4-氟苯基)-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(19mg，收率15％)，ESI-MS(m/z)：447.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.10(s,1H),8.51(s,1H),8.14(dd,J＝8.6,1.5Hz,1H),7.70(d,J＝8.6Hz,1H),7.53(dd,J＝8.8,5.1Hz,2H),7.44(t,J＝8.8Hz,2H),5.64(t,J＝5.8Hz,1H),4.76(d,J＝5.8Hz,2H),4.23(q,J＝7.0Hz,2H),3.87(s,3H),1.24(t,J＝7.0Hz,3H)。
制备例53：8-(4-氯苯基)-2-乙氧基-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(A53)
Figure PCTCN2022100895-appb-000083
按照合成A26的方法，以对氯苯胺、乙醇、4-溴-2-甲基氨基苯胺、羟基乙酸等为起始原料合成8-(4-氯苯基)-2-乙氧基-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(12mg，收率13％)，ESI-MS(m/z)：463.1[M+H] +； 1H NMR(600MHz,DMSO)δ9.10(s,1H),8.50(s,1H),8.14(d,J＝8.5Hz,1H),7.71(d,J＝8.5Hz,1H),7.67(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),5.64(t,J＝5.8Hz,1H),4.76(d,J＝5.8Hz,2H),4.24(q,J＝7.0Hz,2H),3.87(s,3H),1.25(t,J＝7.1Hz,3H)。
制备例54：8-(6-环丙基吡啶-3-基)-2-乙氧基-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(A54)
Figure PCTCN2022100895-appb-000084
按照合成A26的方法，以对6-环丙基吡啶-3-胺、乙醇、4-溴-2-甲基氨基苯胺、羟基乙酸等为起始原料合成8-(6-环丙基吡啶-3-基)-2-乙氧基-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶呤-7(8H)-酮(10mg，收率11％)，ESI-MS(m/z)：470.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.11(s,1H),8.49(s,1H),8.46(d,J＝2.3Hz,1H),8.13(dd,J＝8.6,1.6Hz,1H),7.77(dd,J＝8.3,2.5Hz,1H),7.70(d,J＝8.5Hz,1H),7.48(d,J＝8.5Hz,1H),5.64(t,J＝5.8Hz,1H),4.76(d,J＝5.8Hz,2H),4.26(q,J＝7.0Hz,2H),3.76(s,3H),2.26–2.21(m,2H),1.26(t,J＝7.1Hz,3H),1.24–1.22(m,2H),1.03-1.00(m,2H)。
制备例55：6-(2-(叔丁基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(A55)
Figure PCTCN2022100895-appb-000085
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、特戊酸等为起始原料合成6-(2-(叔丁基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(50mg，收率35％)，ESI-MS(m/z)：521.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.09(s,1H),8.45(s,1H),8.10(d,J＝8.5Hz,1H),7.66(d,J＝8.5Hz,1H),7.53(d,J ＝8.7Hz,2H),7.39(d,J＝8.7Hz,2H),7.38(t,J＝73.7Hz,1H),4.25(q,J＝7.0Hz,2H),3.95(s,3H),1.51(s,9H),1.25(t,J＝7.0Hz,3H)。
制备例56：6-(2-乙酰基-2H-吲唑-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(A56)
Figure PCTCN2022100895-appb-000086
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、1-(5-溴-2H-吲唑-2-基)乙烷-1-酮等为起始原料合成6-(2-乙酰基-2H-吲唑-5-基)-8-(4-(二氟甲氧基)苯基)-2-乙氧基蝶啶-7(8H)-酮(35mg，收率18％)，ESI-MS(m/z)：493.1[M+H] +； 1H NMR(600MHz,DMSO)δ9.11(s,1H),8.84(d,J＝0.7Hz,1H),8.62(s,1H),8.45(dd,J＝8.8,1.6Hz,1H),8.41(d,J＝8.8Hz,1H),7.52(d,J＝8.8Hz,2H),7.40(d,J＝8.8Hz,2H),7.39(t,J＝73.7Hz,1H),4.25(q,J＝7.0Hz,2H),2.75(s,3H),1.25(t,J＝7.0Hz,3H)。
制备例57：8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(1-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(A57)
Figure PCTCN2022100895-appb-000087
按照合成A26的方法，以4-(二氟甲氧基)苯胺、乙醇、4-溴-2-甲基氨基苯胺、乳酸等为起始原料合成8-(4-(二氟甲氧基)苯基)-2-乙氧基-6-(2-(1-羟乙基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(25mg，收率18％)，ESI-MS(m/z)：509.2[M+H] +； 1H NMR(600MHz,DMSO)δ9.10(s,1H),8.49(s,1H),8.13(d,J＝8.5Hz,1H),7.70(d,J＝8.5Hz,1H),7.53(d,J＝8.6Hz,2H),7.40(d,J＝8.6Hz,2H),7.38(t,J＝73.7Hz,1H),5.66(d,J＝6.1Hz,1H),5.11–5.06(m,1H),4.25(q,J＝6.9Hz,2H),3.90(s,3H),1.60(d,J＝6.5Hz,3H),1.25(t,J＝7.0Hz,3H)。
制备例58：6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(A58)
Figure PCTCN2022100895-appb-000088
按照合成A26的方法，以4-甲氧基苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、2-甲基-2-羟基丙酸等为起始原料合成6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4- 甲氧基苯基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(20mg，收率14％)，ESI-MS(m/z)：540.2[M+H] +； 1H NMR(600MHz,DMSO)δ8.89(d,J＝15.8Hz,1H),8.44(s,1H),8.40-8.16(m,1H),8.08(d,J＝8.3Hz,1H),7.65(d,J＝8.5Hz,1H),7.34(s,2H),7.10(d,J＝6.1Hz,2H),5.67(s,1H),4.20–4.12(m,1H),4.04(s,3H),3.84(s,3H),3.82–3.77(m,1H),1.65(s,6H)。
制备例59：6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(A59)
Figure PCTCN2022100895-appb-000089
按照合成A26的方法，以4-甲氧基苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、羟基乙酸等为起始原料合成6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-(4-甲氧基苯基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(25mg，收率19％)，ESI-MS(m/z)：512.2[M+H] +； 1H NMR(600MHz,DMSO)δ8.90(d,J＝15.9Hz,1H),8.47(s,1H),8.40-8.17(m,1H),8.10(d,J＝8.6Hz,1H),7.67(d,J＝8.6Hz,1H),7.34(s,2H),7.10(d,J＝6.8Hz,2H),5.64(t,J＝5.4Hz,1H),4.75(d,J＝5.4Hz,2H),4.19–4.12(m,1H),3.86(s,3H),3.84(s,3H),3.81–3.76(m,1H)。
制备例60：8-((1H-咪唑-2-基)甲基)-2-乙氧基-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(A60)
Figure PCTCN2022100895-appb-000090
按照合成A26的方法，以(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)甲胺、乙醇、4-溴-2-甲基氨基苯胺、2-甲基-2-羟基丙酸等为起始原料合成2-乙氧基-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-((1-((2-(三甲基甲硅烷基))乙氧基)甲基)-1H-咪唑-2-基)甲基)蝶啶-7(8H)-酮。
取2-乙氧基-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)-8-((1-((2-(三甲基甲硅烷基))乙氧基)甲基)-1H-咪唑-2-基)甲基)蝶啶-7(8H)-酮(50mg，0.084mmol)溶于25mL圆底烧瓶内的二氯甲烷(5ml)，加入2.5mL三氟乙酸，室温反应3h。反应结束后，减压除去溶剂，加入50mL水，碳酸氢钠调节pH至7左右，水相用乙酸乙酯萃取2次，合并有机相，有机相依次用水和饱和氯化钠溶液洗涤，浓缩，经柱层析纯化得目标化合物8-((1H-咪唑-2-基)甲基)-2-乙氧基-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)蝶啶-7(8H)-酮(12mg，收率31％)，ESI-MS(m/z)：461.2[M+H] +； 1H NMR(600MHz,DMSO)δ12.03(brs,1H),9.06(s,1H),8.48(s,1H),8.11(d,J＝8.5Hz,1H),7.67(d,J＝8.5Hz,1H),7.55(s,1H),7.04(s,1H),5.70(s,1H),5.45(s,2H),4.48(q,J＝7.0Hz,2H),4.07(s,3H),1.65(s,6H),1.37(t,J＝7.0Hz,3H)。
制备例61：8-(4-氯苯基)-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(A61)
Figure PCTCN2022100895-appb-000091
按照合成A26的方法，以4-氯苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、羟基乙酸等为起始原料合成8-(4-氯苯基)-6-(2-(羟甲基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(15mg，收率11％)，ESI-MS(m/z)：516.1[M+H] +； 1H NMR(600MHz,DMSO)δ8.91(d,J＝16.5Hz,1H),8.46(s,1H),8.45-8.20(m,1H),8.10(d,J＝8.4Hz,1H),7.70–7.60(m,3H),7.50(s,2H),5.63(t,J＝5.8Hz,1H),4.75(d,J＝5.8Hz,2H),4.16(s,1H),3.86(s,3H),3.78(s,1H)。
制备例62：8-(4-氯苯基)-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(A62)
Figure PCTCN2022100895-appb-000092
按照合成A26的方法，以4-氯苯胺、2,2,2-三氟乙胺、4-溴-2-甲基氨基苯胺、2-甲基-2-羟基丙酸等为起始原料合成8-(4-氯苯基)-6-(2-(2-羟基丙-2-基)-1-甲基-1H-苯并[d]咪唑-6-基)-2-((2,2,2-三氟乙基)氨基)蝶啶-7(8H)-酮(20mg，收率14％)，ESI-MS(m/z)：544.2[M+H] +； 1H NMR(600MHz,DMSO)δ8.91(d,J＝16.8Hz,1H),8.44(s,2H),8.20(s,1H),8.09(d,J＝8.5Hz,1H),7.66(m,J＝8.5Hz,3H),7.50(s,2H),5.67(s,1H),4.16(s,1H),4.04(s,3H),3.78(s,1H),1.65(s,6H)。
制备例63：8-(4-甲氧基苯基)-2-((2,2-二氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(A63)
Figure PCTCN2022100895-appb-000093
按照合成A1的方法，以对甲氧基苯胺和2,2,2-二氟乙胺等为起始原料合成8-(4-甲氧基苯基)-2-((2,2-二氟乙基)胺基)-6-(2-甲基-2H-吲唑-5-基)蝶啶-7(8H)-酮(30mg，收率43％)，ESI-MS(m/z)：464.1[M+H] +； 1H NMR(600MHz,DMSO)δ8.89-8.79(m,2H),8.49(s,1H),8.08(d,J＝9.1Hz,1H),8.05(d,J＝169Hz,1H),7.91(s,1H),7.65(d,J＝9.2Hz,1H),7.38–7.25(d,J＝7.5Hz,2H),7.10(d,J＝8.9Hz,2H),5.94(td,J＝168,56Hz,2H),4.18(s,3H),3.83(s,3H),3.77–3.62(s,1H)。
以下是本发明化合物的效果试验及数据。
试验例1：MAT2A酶学活性测试
使用MAT2A抑制剂酶学筛选试剂盒(BPS Bioscience，Catalog:71402)，测定待测化合物对MAT2A酶学活性的抑制作用。具体操作程序如下：
1)用DMSO溶解待测化合物，充分混匀直至待测化合物完全溶解。所有化合物用DMSO稀释至起始浓度2mM，并3倍倍比稀释为共10个浓度梯度，复孔，检测时1：100加入到反应体系中(终浓度最大为20μM)。准备100×阳性对照(1mM AGI-24512)和100×阴性对照(100％DMSO)。
2)用Echo 550移液系统向反应板(784075,Greiner)每孔转移200nL稀释好的化合物，用封板膜封住反应板，1000g离心1分钟。DMSO终浓度为1％。
3)制备1×MAT2A酶反应缓冲液：1倍体积的5×MAT2A酶反应缓冲液加4倍体积的水充分混匀。
4)用1×的酶反应缓冲液配制2×MAT2A酶液。
5)向384-反应板(Corning3702)中每孔加入10μL 2×MAT2A酶液，用封板膜封住板子。
6)1000g离心60秒，室温孵育30分钟。
7)用1×MAT2A酶反应缓冲液配制2×L-蛋氨酸和ATP混合液。
8)向384-反应板(Corning3702)中每孔加入10μL 2×L-蛋氨酸和ATP混合液，用封板膜封住板。总反应体系为20μL。
9)1000g离心60秒，室温孵育60分钟。
10)准备检测缓冲液比色检测试剂(Colorimetric Detection Reagent)。
11)每孔加入20μL检测缓冲液，1000g离心30秒，室温反应15分钟。
12)用多功能酶标仪(PerkinElmer，Nivo)测定630nm的荧光信号。
本发明代表性化合物的酶活性见下表。
Figure PCTCN2022100895-appb-000094
Figure PCTCN2022100895-appb-000095
A代表IC 50≤50nM，B代表50nM<IC 50≤100nM。
以上数据表明，本发明化合物具有较强的MAT2A抑制作用。
试验例2.抑制细胞增殖的测试
具体操作程序如下：用化合物处理肿瘤细胞5天，评估待测化合物对肿瘤细胞增殖的影响。将HCT116-MTAP -/-及野生型对照HCT116-WT细胞以600/孔的密度接种于384孔培养板，同时加入不同浓度待测化合物处理(20μM起始，10个浓度梯度)。将细胞在37℃、5％CO 2、饱和湿度条件下孵育5天。
使用基于ATP的细胞增殖检测试剂盒(Cell Titer Glo，Promega Corporation)检测细胞增殖情况。细胞在室温平衡30分钟后用Cell Titer Glo试剂处理。然后将培养皿用铝箔覆盖并振荡15分钟，使其充分混合和裂解。使用多功能酶标仪(Envision 2105，PerkinElmer)进行化学发光检测。设定空白孔(blank，无细胞)及DMSO对照孔。
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：
IR(％)＝[1-(RLU化合物-RLU空白对照)/(RLU溶媒对照-RLU空白对照)]×100％
采用GraphPad Prism进行作图、数据分析及IC 50计算。
在上述测定中测试本发明化合物，并确定它们抑制细胞增殖的IC 50，如下表所示。
Figure PCTCN2022100895-appb-000096
结果表明，待测化合物对HCT116 MTAP敲除的细胞表现了较强的细胞增殖活性，对MTAP野生型的HCT116细胞表现了较弱的细胞增殖活性，即，表现了较好的选择性。
试验例3.人UGT1A1酶活性测试
测定化合物对UGT1A1的酶抑制活性，具体操作程序如下：
1)将1μL 2mM对照化合物(阿塔扎那韦)、1μL 440μM试验化合物或1μL二甲基亚砜(溶剂对照)加入至培养板，加入含终浓度0.01mg/mL UGT1A1(Corning，456411)、0.5μM底物胆红素(Bilirubin)以及Tris缓冲液的主反应溶液，在37℃水浴中预孵育10min，对照化合物的终浓度为10μM，试验化合物的终浓度为2.2μM。
2)通过添加20μL终浓度为2mM的UDPGA溶液开始反应，在37℃反应5min，加入400μL含内标物的冷乙腈停止反应。
3)将样品涡旋5分钟，4℃，3220g，离心40min。然后将100μL上清液转移到新的96孔板上，进行LC-MS/MS分析代谢物的形成。通过比较测试药与对照组代谢物形成的减少量(峰面积定量)来计算％抑制率。
％剩余活性＝(测试化合物或抑制剂的平均比率)/(载体对照的平均比率)*100％抑制＝100-％剩余活性
Figure PCTCN2022100895-appb-000097
以上结果表明，化合物A49抑制UGT1A1的风险较小，而WO2021139775化合物45和91对UGT1A1存在较高的抑制率，存在体内胆红素升高的风险。
试验例4.小鼠体内药代动力学研究
实验动物：CD-1小鼠(雄性，22～25g)购自北京维通利华实验动物技术有限公司。
试验步骤：对CD-1小鼠(雄性，22-25g)静脉注射受试化合物(2mg/kg)，灌胃给予受试化合物(5mg/kg)，在给药5min、15min、0.5h、1h、2h、4h、8h、24h采集小鼠血浆，LC-MS/MS检测化合物浓度，考察其血浆清除率Cl、消除半衰期T 1/2、峰时间T max、峰浓度C max、药时曲线下面积AUC、表观分布容积Vss、绝对生物利用度F等药代参数。
测定方法：用50％乙腈稀释分析物的储备溶液，获得所需的工作溶液系列浓度。向10μL空白CD1小鼠血浆中添加10μL工作溶液(1、2、5、10、50、100、500、1000、5000、10000ng/mL)以达到总体积为20μL的1-10000ng/mL(1、2、5、10、50、100、500、1000、5000、10000ng/mL)校准标准。5个质控(QC)样品(2ng/mL、5ng/mL、10ng/mL，800ng/mL，8000ng/ml)在分析当天以与校准标准相同的方式制备。将20μL标准品、20μL QC样品20μL未知样品(10μL未知样品血浆和10μL空白溶液)分别添加到200μL含乙腈的IS混合物中以沉淀蛋白质。然后将样品震荡涡旋3min。在4℃、4700rpm下离心15min后，用超纯水以1:2(V/V)的比例稀释上清液，然后将10μL稀释上清液注入LC/MS/MS系统进行定量分析。
化合物A49的药代动力学参数如下表：
Figure PCTCN2022100895-appb-000098
Figure PCTCN2022100895-appb-000099
I.V.：静脉注射；P.O.：口服；Cl：表观清除率；T 1/2：半衰期；AUC last：从给药开始到最后一个点(24小时的)的药时曲线下面积；AUC inf：从给药开始到理论外推无穷远的时间的药时曲线下面积；MRT Inf：零时间到无限大时间的平均滞留时间；Vss：表观分布容积；T max：达峰时间；C max：达峰浓度；F：相对生物利用度。
试验例5.化合物体内抗肿瘤药效考察
测试了本发明的化合物A49对HCT116-MTAP -/-细胞小鼠移植瘤生长的抑制作用。
实验动物：雌性BALB/c nude小鼠购买于江苏集萃药康生物科技股份有限公司，体重范围在18～22g，饲养在SPF级恒温恒湿的层流清洁房间内，使用独立通风笼具IVC，每5只鼠一笼。
将HCT116-MTAP -/-细胞培养于含10％FBS的McCoy's 5a培养基(GIBCO)。细胞以5×10 6/只数量接种于42只BALB/c裸小鼠背部皮下，接种后第6天，挑选30只肿瘤体积约150mm 3大小的小鼠，按照肿瘤体积均匀分组。每天口服给药一次，连续给药14天。比较给药组与溶剂组肿瘤生长速度差异，以肿瘤生长抑制率TGI(％)、瘤重抑制率TWI(％)作为评价指标。
Figure PCTCN2022100895-appb-000100
注：TV Xn：给药组第n天平均肿瘤体积
TV X1：给药组第1天平均肿瘤体积
TV Mn：模型组第n天平均肿瘤体积
TV M1：模型组第1天平均肿瘤体积
瘤重抑制率＝(1－给药组瘤重/溶剂组瘤重)×100％
Figure PCTCN2022100895-appb-000101
以上结果表明本发明化合物表现了较好的体内药效的同时，未引起胆红素的升高。
试验例6.体内血清总胆红素检测
雌性Nu/Nu小鼠，18-22g，购自北京维通利华实验动物技术有限公司。每天口服给予受试化合物一次，连续给药受试化合物共14天。动物麻醉后心脏采全血，室温静置0.5小时后，3500rpm离心10min，分离血清，采用全自动生化仪检测血总胆红素水平。结果如下表所示，受试化合物未引起血总胆红素显著升高。
Figure PCTCN2022100895-appb-000102
上述结果说明本发明化合物不引起胆红素病理性升高，毒性小，安全性好。

Claims (15)

  1. 一种如式(I)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐：
    Figure PCTCN2022100895-appb-100001
    其中：
    L 1选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R a1)C(O)-、-C(O)N(R a1)-或-N(R a1)-；R a1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
    R a选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代，其中R a2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R a3、-OR a3、-SR a3、-S(O)R a3、-SO 2(R a3)、-C(O)R a3、-C(O)OR a3、-OC(O)R a3、-NH(R a3)、-N(R a3)(R a4)、-C(O)NH(R a3)、-C(O)N(R a3)(R a4)、-NHC(O)(R a3)、-N(R a3)C(O)(R a4)、-S(O)NH(R a4)、-S(O)N(R a3)(R a4)、-SO 2NH(R a3)、-SO 2N(R a3)(R a4)、-NHS(O)(R a3)、-N(R a3)S(O)(R a4)、-NHSO 2(R a4)、-N(R a3)SO 2(R a4)；其中R a3、R a4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
    L 2选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R b1)C(O)-、-C(O)N(R b1)-或-N(R b1)-；R b1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
    R b选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代，其中R b2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-S(O)N(R b3)(R b4)、-SO 2NH(R b3)、-SO 2N(R b3)(R b4)、-NHS(O)(R b3)、-N(R b3)S(O)(R b4)、-NHSO 2(R b4)、-N(R b3)SO 2(R b4)；其中 R b3、R b4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R b3和R b4连接至同一氮原子时，R b3和R b4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
    L 3选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-；R c1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
    R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代，其中R c2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3、-OR c3、-SR c3、-S(O)R c3、-SO 2(R c3)、-C(O)R c3、-C(O)OR c3、-OC(O)R c3、-NH(R c3)、-N(R c3)(R c4)、-C(O)NH(R c3)、-C(O)N(R c3)(R c4)、-NHC(O)(R c3)、-N(R c3)C(O)(R c4)、-S(O)NH(R c4)、-S(O)N(R c3)(R c4)、-SO 2NH(R c3)、-SO 2N(R c3)(R c4)、-NHS(O)(R c3)、-N(R c3)S(O)(R c4)、-NHSO 2(R c4)、-N(R c3)SO 2(R c4)；其中R c3、R c4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R c3和R c4连接至同一氮原子时，R c3和R c4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
    X 1选自N或CR d；
    R d独立地选自氢、氘、卤素、羟基、氨基、硝基、巯基、氰基，或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R d1所取代，其中R d1每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R d2、-OR d2、-SR d2、-S(O)R d2、-SO 2(R d2)、-C(O)R d2、-C(O)OR d2、-OC(O)R d2、-N(R d2)(R d3)、-C(O)N(R d2)(R d3)、-N(R d2)C(O)(R d3)；其中R d2、R d3每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；
    除非另有说明，上述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个。
  2. 一种如式(II)所示的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐：
    Figure PCTCN2022100895-appb-100002
    其中：
    L 1选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R a1)C(O)-、-C(O)N(R a1)-或-N(R a1)-；R a1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷胺基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
    R a选自任选取代的3-12元杂环基、C 6-14芳基、5-14元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代，其中R a2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-C 1-6亚烷基-N(R a3)(R a4)、-R a3、-OR a3、-SR a3、-S(O)R a3、-SO 2(R a3)、-C(O)R a3、-C(O)OR a3、-OC(O)R a3、-NH(R a3)、-N(R a3)(R a4)、-C(O)NH(R a3)、-C(O)N(R a3)(R a4)、-NHC(O)(R a3)、-N(R a3)C(O)(R a4)、-S(O)NH(R a4)、-S(O)N(R a3)(R a4)、-SO 2NH(R a3)、-SO 2N(R a3)(R a4)、-NHS(O)(R a3)、-N(R a3)S(O)(R a4)、-NHSO 2(R a4)、-N(R a3)SO 2(R a4)；其中R a3、R a4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
    L 2选自键、-C(R b1) 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R b1)C(O)-、-C(O)N(R b1)-或-N(R b1)-；R b1每次出现时独立地选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
    R b选自任选取代的3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代，其中R b2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R b3、-OR b3、-SR b3、-S(O)R b3、-SO 2(R b3)、-C(O)R b3、-C(O)OR b3、-OC(O)R b3、-NH(R b3)、-N(R b3)(R b4)、-C(O)NH(R b3)、-C(O)N(R b3)(R b4)、-NHC(O)(R b3)、-N(R b3)C(O)(R b4)、-S(O)NH(R b4)、-S(O)N(R b3)(R b4)、-SO 2NH(R b3)、-SO 2N(R b3)(R b4)、-NHS(O)(R b3)、-N(R b3)S(O)(R b4)、-NHSO 2(R b4)、-N(R b3)SO 2(R b4)；其中R b3、R b4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6 炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R b3和R b4连接至同一氮原子时，R b3和R b4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
    L 3选自键、-CH 2-、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R c1)C(O)-、-C(O)N(R c1)-或-N(R c1)-；R c1选自氢或任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基所取代；
    R c选自任选取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-12元杂环基、C 6-14芳基、5-12元杂芳基；所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R c2所取代，其中R c2每次出现时独立地选自氘、卤素、羟基、氨基、硝基、巯基、氰基、氧代、-R c3、-OR c3、-SR c3、-S(O)R c3、-SO 2(R c3)、-C(O)R c3、-C(O)OR c3、-OC(O)R c3、-NH(R c3)、-N(R c3)(R c4)、-C(O)NH(R c3)、-C(O)N(R c3)(R c4)、-NHC(O)(R c3)、-N(R c3)C(O)(R c4)、-S(O)NH(R c4)、-S(O)N(R c3)(R c4)、-SO 2NH(R c3)、-SO 2N(R c3)(R c4)、-NHS(O)(R c3)、-N(R c3)S(O)(R c4)、-NHSO 2(R c4)、-N(R c3)SO 2(R c4)；其中R c3、R c4每次出现时独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R c3和R c4连接至同一氮原子时，R c3和R c4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、硝基、巯基、氰基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基；
    除非另有说明，上述杂环烷基、杂芳基、杂环基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个。
  3. 根据权利要求1或2所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    L 1选自键、-CH 2-、-O-、-S-或-N(R a1)-，其中R a1选自氢或C 1-6烷基；
    优选的，L 1选自键、-O-、-S-、-NH-；
    优选的，L 1是键。
  4. 根据权利要求1至3中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    R a选自任选取代的3-12元杂环基、C 6-14芳基、5-14元杂芳基，所述杂环基、杂芳基中的杂原子独立地选自O、N或S，杂原子数目为1个、2个、3个或4个；
    优选的，R a选自任选取代的5-10元双环杂环基、5-10元双环杂芳基，所述杂环基、杂芳基中的杂原子独立地选自O或N，杂原子数目为1个、2个或3个；
    优选的，R a选自任选取代的
    Figure PCTCN2022100895-appb-100003
    Figure PCTCN2022100895-appb-100004
    优选的，R a选自任选取代的
    Figure PCTCN2022100895-appb-100005
    优选的，R a选自任选取代的
    Figure PCTCN2022100895-appb-100006
    所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R a2所取代。
  5. 根据权利要求1至4中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    R a2独立地选自卤素、-C(O)R a3、羟基、氨基、-C 1-6亚烷基-N(R a3)(R a4)、任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷氧基取代的C 1-6烷基；
    优选的，R a2独立地选自-C 1-6亚烷基-N(R a3)(R a4)、任选地被一个或多个独立地选自羟基和C 1-6烷氧基取代的C 1-6烷基。
  6. 根据权利要求1至5中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-14芳基、5-12元杂芳基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、3-6元杂环烷基、C 6-8芳基、5-6元杂芳基的取代基取代的3-10元杂环烷基或5-12元杂芳基，所述杂环烷基或杂芳基中的杂原子选自N、S、O，杂原子数目为1个、2个或3个；
    优选的，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基的取代基取代的C 1-6烷基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、C 1-6烷基、C 1-6烷氧基的取代基取代的3-10元杂环烷基，所述杂环烷基中的杂原子选自N、S、O，杂原子数目为1个、2个或3个；
    优选的，R a3、R a4独立地选自氢或任选地被一个或多个独立地选自卤素、羟基、氨基的取代基取代的C 1-6烷基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自卤素、羟基、C 1-4烷基、C 1-4烷氧基的取代基取代的3-10元杂环烷基，所述杂环烷基中的杂原子选自N、O，杂原子数目为1个或2个；
    优选的，R a3、R a4独立地选自C 1-4烷基；或当R a3和R a4连接至同一氮原子时，R a3和R a4与它们所连接的氮原子一起形成任选地被一个或多个独立地选自F、羟基、甲基、甲氧基的取代基取代的四氢吡咯基、哌啶基或吗啉基。
  7. 根据权利要求1至6中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    L 2选自键、-CH 2-；
    优选的，L 2是键。
  8. 根据权利要求1至7中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    R b选自任选取代的5-12元双环杂环基、C 6-10芳基、5-10元杂芳基；
    优选的，R b选自任选取代的5-10元双环杂环基、C 6-10芳基、5-6元杂芳基；
    优选的，R b选自任选取代的苯基、吡啶基或苯并四氢呋喃基；
    优选的，R b选自任选取代的苯基或吡啶基；
    优选的，R b选自任选取代的苯基，
    所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R b2所取代。
  9. 根据权利要求1至8中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    R b2独立地选自卤素、羟基、氨基、C 3-6环烷基、-OR b3，其中R b3选自任选地被一个或多个独立地选自卤素或C 6-10芳基的取代基取代的C 1-6烷基；
    优选的，R b2独立地选自卤素、羟基、C 3-6环烷基、-OR b3，其中R b3选自任选地被一个或多个独立地选自卤素或苯基的取代基取代的C 1-4烷基；
    优选的，R b2独立地选自氟、氯、-OH、C 3-6环烷基、-OR b3，其中R b3选自任选地被一个或多个独立地选自氯或苯基的取代基取代的C 1-4烷基；
    优选的，R b2独立地选自氯、环丙基或任选地被一个或多个卤素取代的-O(C 1-4烷基)；
    优选的，R b2独立地选自氯或任选地被一个或多个氟取代的-O(C 1-4烷基)；
    优选的，R b2独立地选自氯、-OCH 3、-O(CHF 2)或-O(CF 3)。
  10. 根据权利要求1至9中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    L 3选自-CH 2-、-O-、-S-或-N(R c1)-，其中R c1选自氢或C 1-6烷基；
    优选的，L 3选自-O-、-N(R c1)-；
    优选的，L 3选自-O-、-NH-。
  11. 根据权利要求1至10中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或药学上可接受的盐，其特征在于：
    R c选自任选地被一个或多个卤素取代的C 1-6烷基或任选地被一个或多个R c3取代的C 3-6环烷基，其中R c3选自氢或任选地被一个或多个独立地选自卤素的取代基取代的C 1-6烷基；
    优选的，R c选自任选地被一个或多个卤素取代的C 1-4烷基或任选地被CF 3取代的C 3-6环烷基；
    优选的，R c选自甲基、乙基、
    Figure PCTCN2022100895-appb-100007
    优选的，R c选自乙基、
    Figure PCTCN2022100895-appb-100008
  12. 根据权利要求1至11中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐，其特征在于：所述化合物选自：
    Figure PCTCN2022100895-appb-100009
    Figure PCTCN2022100895-appb-100010
    Figure PCTCN2022100895-appb-100011
    Figure PCTCN2022100895-appb-100012
    Figure PCTCN2022100895-appb-100013
    Figure PCTCN2022100895-appb-100014
  13. 一种药物组合物，其特征在于：包含权利要求1至12中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐。
  14. 根据权利要求1至12中任一项所述的化合物或其前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或权利要求13所述的药物组合物在制备用于治疗预防和/或治疗通过MAT2A介导的疾病、病症和病况的药物中的用途；优选的，所述的疾病、病症和病况为MTAP缺失的肿瘤；优选的，所述肿瘤包括实体瘤和血液瘤。
  15. 一种药物组合物，其特征在于：包括权利要求1至12中任一项所述的化合物或其 前药、互变异构体、立体异构体、溶剂化物、同位素衍生物或其药学上可接受的盐或权利要求13所述的药物组合物以及另一种、两种或更多种具有抑制肿瘤活性的药物。
PCT/CN2022/100895 2021-06-23 2022-06-23 嘧啶并含氮六元芳香杂环类化合物及其用途 WO2022268180A1 (zh)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN106279173A (zh) * 2015-05-29 2017-01-04 华东理工大学 蝶啶酮衍生物作为egfr抑制剂的应用
CN107151249A (zh) * 2016-03-04 2017-09-12 华东理工大学 作为flt3抑制剂的蝶啶酮衍生物及应用
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279173A (zh) * 2015-05-29 2017-01-04 华东理工大学 蝶啶酮衍生物作为egfr抑制剂的应用
CN107151249A (zh) * 2016-03-04 2017-09-12 华东理工大学 作为flt3抑制剂的蝶啶酮衍生物及应用
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用

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