WO2022063128A1 - 一类芳环或芳基杂环并吡啶酮类化合物、药物组合物及其应用 - Google Patents

一类芳环或芳基杂环并吡啶酮类化合物、药物组合物及其应用 Download PDF

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WO2022063128A1
WO2022063128A1 PCT/CN2021/119638 CN2021119638W WO2022063128A1 WO 2022063128 A1 WO2022063128 A1 WO 2022063128A1 CN 2021119638 W CN2021119638 W CN 2021119638W WO 2022063128 A1 WO2022063128 A1 WO 2022063128A1
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heteroatoms
membered monocyclic
alkyl
bridged
heterocycloalkyl
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PCT/CN2021/119638
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English (en)
French (fr)
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万惠新
王亚周
查传涛
马金贵
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上海凌达生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a class of aromatic ring or aryl heterocyclic pyridone compounds, which have the activity of inhibiting methionine adenosyltransferase (MAT2a) and can be used to prepare compounds with MAT2a or MTAP.
  • MAT2a methionine adenosyltransferase
  • Methionine adenosyltransferase (also known as S-adenosylmethionine synthase) catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP cellular enzyme and is considered the rate-limiting step of the methionine cycle.
  • SAM is the propylamino donor in polyamine biosynthesis and the major methyl donor for DNA methylation, and it is involved in gene transcription and cell proliferation and the production of secondary metabolites.
  • Methylthioadenosine phosphorylase is involved in the salvage pathway of methionine, metabolizing methylthioadenosine (MTA) to adenine and methionine.
  • MTA methylthioadenosine
  • MTAP is located on chromosome 9p21 and is similar to the tumor suppressor gene CDKN2A.
  • MTAP deficiency exists in various tumors such as leukemia, glioma, melanoma, lung and ovarian cancer, endometrial cancer, and breast cancer. Among them, the deletion rate was 41% in glioma, 31% in mesothelioma, and 26% in pancreatic cancer.
  • SAM S-adenosyl-L-methionine
  • MAT methionine adenosine Enzyme family
  • MAT2a is a key enzyme in the adenosylmethionine (SAM) synthesis pathway. Studies have shown that the expression of MAT2a is up-regulated in a variety of cancer cells, and knocking out the MAT2a gene can lead to cancer cell death. MTAP-deficient tumors are the most sensitive. Therefore, MAT2a is a potential therapeutic target for MTAP-deficient tumors. The discovery and search of MAT2a inhibitors with novel structures and excellent druggability has become a hot spot in the development of MTAP-deficient tumor therapy drugs.
  • SAM adenosylmethionine
  • One of the technical problems to be solved by the present invention is to provide a novel MAT2a inhibitor for the preparation of tumor therapeutic drugs.
  • the inventor After long-term and in-depth research, the inventor has prepared a class of aromatic ring or aryl heterocyclic pyridone compounds with a novel structure shown in formula I, and found that it has better inhibition of MAT2a enzyme activity, and the described The compound has a specific inhibitory effect on MAT2a protein at very low concentration (as low as less than 100 nM), and has excellent inhibitory activity on cell proliferation related to MTAP deletion. Based on the above findings, the inventors have completed the present invention.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides an aromatic ring or aryl heterocyclic pyridone compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof , tautomer, torsion isomer, solvate, polymorph or prodrug,
  • Ar is selected from 5-12-membered monocyclic or cycloaryl, monocyclic or cycloaryl substituted by 1-3 Rn, "heteroatom is selected from one or more of N, O, P and S” , 5-12-membered monocyclic or heterocyclic heteroaryl with 1-3 heteroatoms" and "heteroatoms substituted by 1-3 Rn" selected from one or more of N, O, P and S Species, 5-12-membered monocyclic or heterocyclic heteroaryl with 1-3 heteroatoms";
  • the Rn is independently selected from deuterium, halogen, cyano, amide, sulfonamide, hydroxyl, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C 1 -C 12 alkyl, C 1 - C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy, -NRz 1 Rz 2 , alkenyl, alkynyl, 3-12 membered monocyclic, spirocyclic or bridged cycloalkanes base, "heteroatoms selected from one or more of N, O, P and S, and 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl groups with 1-3 heteroatoms", C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl-SO-, C 1 -C 12 alkyl-SO 2 -, 3-12-membered cycloalky
  • R 1 is selected from halogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy, C 1 -C 12 monoalkylamino, C 1 -C 12 dialkylamino, C 1 -C 12 haloalkylamino, 3-12-membered monocyclic, spiro or bridged cycloalkyl, "heteroatom selected from N, O, P and S One or more of 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms, C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl-SO-, C 1 -C 12 alkyl-SO 2 -, 3-12-membered cycloalkyl ether, 3-12-membered heterocycloalkyl ether, 5-10-membered monocyclic or cyclic
  • R 2 is selected from halogen, cyano, amide, sulfonamide, phosphoryl, alkylphosphooxy, alkylsilyl, C 1 -C 12 haloalkyl and C 1 -C 12 haloalkoxy;
  • R 3a is selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 monoalkylaminoalkyl, C 1 -C 12 dialkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 membered monocyclic, spirocyclic or bridged ring Cycloalkyl, 3-12-membered monocyclic, spirocyclic or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm 3 selected from N, O, P and S
  • R 3b is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12Monoalkylaminoalkyl, C1 - C12dialkylaminoalkyl , cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 -membered monocyclic, spirocyclic or bridged cycloalkane base, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one or more of N, O, P and S, heteroatom A 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1 to 3 "heterocycloalkyl groups" and "heteroatoms substituted by one or more R
  • R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl", "heteroatoms substituted by one or more Rm 4 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3.
  • heteroatoms are selected from one or more of N, O, P and S, and 3-heteroatoms with 1-3 heteroatoms 12-membered monocyclic or heterocyclic heteroaryl" or “heteroatoms substituted by one or more Rm 5 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3.
  • 3-12-membered monocyclic or heterocyclic heteroaryl ;
  • Rx is selected from C 1 -C 12 alkyl and C 1 -C 12 alkoxy
  • Ry 2 is independently selected from C 1 -C 12 alkyl and hydroxy-substituted C 1 -C 12 alkyl;
  • Ry 3 is independently selected from C 1 -C 12 alkyl and C 1 -C 12 haloalkyl;
  • W, Z, Y are independently selected from O, S, CR 4 and N; wherein R 4 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amido, sulfonamido, C 1 -C 12 Alkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl -SO-, C 1 -C 12 alkyl -SO 2 -, C 1 -C 12 Alkyl-O-, C 1 -C 12 haloalkyl-O-, -NRz 1 Rz 2 , 3-12-membered cycloalkylamino, 3-12-membered heterocycloalkylamino, 3-12-membered monocyclic, spiro Ring or bridged cycloalkyl, "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic
  • R 5 is selected from hydrogen, C 1 -C 12 alkyl, 3-12 membered monocyclic, spiro Ring or bridged cycloalkyl and "hetero atoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spiro or bridged rings with 1-3 heteroatoms.
  • Heterocycloalkyl ;
  • aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) does not include the following compounds:
  • Ar is independently selected from a 5-12-membered monocyclic or bicyclic aromatic ring or heteroaromatic ring, which may be substituted by 1-3 different substituents Rn, and the Rn Selected from hydrogen, deuterium, halogen, cyano, amide, sulfonamide, hydroxyl, amino, ureido, phosphoryl, alkylphosphooxy, alkylsilyl, C1 - C10 alkyl, C1 - C10 Alkoxy, haloalkyl, haloalkoxy, C 1 -C 10 monoalkylamino, C 1 -C 10 dialkylamino, alkenyl, alkynyl, 3-10 membered cycloalkyl or heterocycloalkyl, C 1 -C 10 alkyl-S-, C 1 -C 10 alkyl-SO-, C 1 -C 10 alkyl-SO 2 -, 3-10 membered cycloalkyl ether or heterocycloal
  • R 1 is independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 haloalkoxy, C 1 -C 10 monoalkylamino , C 1 -C 10 dialkylamino, C 1 -C 10 haloalkylamino, 3-10 membered cycloalkyl or heterocycloalkyl, C 1 -C 10 alkyl-S-, C 1 -C 10 Alkyl-SO-, C 1 -C 10 alkyl-SO 2 -, 3-10 membered cycloalkyl ether or heterocycloalkyl ether, 5-10 membered aryl or heteroaryl;
  • R 2 is independently selected from halogen, cyano, amide, sulfonamide, phosphoryl, alkylphosphooxy, alkylsilyl, haloalkyl, haloalkoxy;
  • R 3a is selected from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 monoalkylaminoalkyl, C 1 -C 10 dioxane alkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 membered cycloalkyl or heterocycloalkyl;
  • R 3b is independently selected from C 1 -C 10 alkyl, C 1 - C 10 alkoxy, C 1 -C 10 haloalkyl, C 1 -C 10 monoalkylaminoalkyl, C 1 -C 10 dialkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylamino Alkyl, 3-12-membered cycloalkyl or heterocycloalkyl; the above R 3a and R 3b can form a 3-12-member
  • W, Z, Y are independently selected from CR 4 or N; wherein R 4 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonamido, C 1 -C 12 alkyl , C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-S-, C 1 -C 6 alkyl -SO-, C 1 -C 6 alkyl -SO 2 -, C 1 -C 6 alkyl -O-, C 1 -C 6 haloalkyl-O-, C 1 -C 6 monoalkylamino, C 1 -C 6 dialkylamino, 3-12 membered cycloalkylamino or heterocycloalkylamino, 3-12-membered cycloalkyl or heterocycloalkyl, 3-12-membered halocycloalkyl or haloheterocycloalkyl, 3-12-membered
  • R 5 is selected from hydrogen, C 1 -C 12 alkyl, 3-12-membered cycloalkyl, 3-12-membered heteroalkyl cycloalkyl;
  • One or more hydrogen atoms on any of the above-mentioned groups can be substituted by a substituent selected from the following group: including but not limited to deuterium, halogen, C 1 -C 8 alkyl; wherein, the heteroaryl group includes 1-3 heteroatoms selected from the group consisting of N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, the The ring system includes spiro rings, bridged rings, fused rings, and rings and other saturated or partially unsaturated ring systems.
  • the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) is a compound represented by any of the following general formulas:
  • the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) is a compound represented by any of the following general formulas:
  • M 6 is selected from C or N; M 1 , M 2 , M 3 , M 4 , M 5 are independently selected from CR 6 or N; R 6 is preferably selected from hydrogen, deuterium, halogen, cyano, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 3-8 membered cycloalkyl or heterocycloalkyl; other groups such as any of the rest.
  • said Rn is independently selected from halogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3- to 10-membered monocyclic cycloalkyl groups.
  • R 1 is selected from halogen, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10 membered monocyclic cycloalkyl.
  • R 2 is cyano
  • R 3a is selected from hydrogen and C 1 -C 12 alkyl
  • R 3b is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 dialkylaminoalkyl, 3-12 membered monocyclic ring, spirocyclic ring or bridged cycloalkyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one of N, O, P and S or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm 3 are selected from N, O, One or more of P and S, a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";
  • R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl" or "heteroatoms substituted by one or more Rm 4 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12 membered monocyclic, spirocyclic or bridged heterocycloalkyl".
  • Rz 1 and Rz 2 are independently selected from C 1 -C 12 alkyl groups.
  • Y is CH or N.
  • Z is CH.
  • W is CH or N.
  • Ar is selected from 5-12-membered monocyclic or non-cyclic aryl, monocyclic or non-cyclic aryl substituted by 13 Rn, "heteroatom is selected from N, O, P and S One or more of 5-12-membered monocyclic or heterocyclic heteroaryl groups with 1-3 heteroatoms” and “heteroatoms substituted by 1-3 Rn are selected from N, O, P and S One or more of the 5-12-membered monocyclic or heterocyclic heteroaryl groups with 1-3 heteroatoms";
  • Rn is independently selected from halogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10 membered monocyclic ring cycloalkyl;
  • R 1 is selected from halogen, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10-membered monocyclic cycloalkyl;
  • R 2 is cyano
  • R 3a is selected from hydrogen and C 1 -C 12 alkyl
  • R 3b is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 dialkylaminoalkyl, 3-12 membered monocyclic ring, spirocyclic ring or bridged cycloalkyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one of N, O, P and S or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm 3 are selected from N, O, One or more of P and S, a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";
  • R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl" or "heteroatoms substituted by one or more Rm 4 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl";
  • Rx is C 1 -C 12 alkyl or C 1 -C 12 alkoxy
  • Ry 2 is independently C 1 -C 12 alkyl or hydroxy-substituted C 1 -C 12 alkyl
  • Ry 3 is independently C 1 -C 12 alkyl or C 1 -C 12 haloalkyl
  • Rz 1 and Rz 2 are independently selected from C 1 -C 12 alkyl.
  • R 1 is selected from Cl, CF 3 , OCF 3 and cyclopropyl.
  • Ar is selected from phenyl
  • the aryl group is independently a 6-10-membered monocyclic or bicyclic aryl group, such as phenyl or naphthyl.
  • the heteroaryl group is independently "the heteroatom is selected from one or more of N, O and S. , a 5-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms".
  • the "heteroatom is selected from one or more of N, O, P and S, and a 5-12-membered monocyclic ring with 1-3 heteroatoms or a Cyclic heteroaryl" and “heteroatoms substituted by 1-3 Rn" are selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 5-12-membered monocyclic or "Heteroatoms are selected from one or more of N, O, P and S, and a 5-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms" in "heteroaryl group” independently pyridyl (e.g. ) or imidazo[1,2-a]pyridine (e.g. ).
  • the halogen is independently F, Cl , Br or I, such as F or Cl.
  • the alkyl group is independently a C 1 -C 10 alkyl group, for example, the alkyl group is independently a C 1 -C 6 alkyl group, such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl.
  • the alkoxy group is independently C 1 -C 10 alkoxy, for example, the alkoxy is independently a C 1 -C 6 alkoxy, another example is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, eg methoxy.
  • the haloalkyl groups are independently is a C 1 -C 10 haloalkyl, eg, the haloalkyl is independently a C 1 -C 6 haloalkyl, another example is CF 3 or CH 2 CF 3 .
  • the haloalkoxy is independently a C 1 -C 10 haloalkoxy,
  • the haloalkoxy is independently a C1 - C6 haloalkoxy, another example is OCF3.
  • the cycloalkyl group is 3-10
  • a membered cycloalkyl group for example, the cycloalkyl group is a 3-6 membered monocyclic, spirocyclic or bridged cycloalkyl group, and another example is a 3-6 membered monocyclic cycloalkyl group, and also such as cyclopropyl or cyclobutyl base.
  • the heterocycloalkyl group is "heterocycloalkyl"
  • Atoms are selected from one or more of N, O and S, 3-10-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms", for example "heteroatoms are selected from One or more of N and O, a 4-10-membered monocyclic or spirocyclic heterocycloalkyl group with 1-2 heteroatoms, also for example azetidinyl (for example ), oxetanyl (e.g. ), pyrrolidinyl (e.g. ), piperidinyl (such as )or
  • R 3a and R 3b when R 3b is "one or more heteroatoms selected from N, O, P and S, the number of heteroatoms is 1-3 3- 12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", the "heteroatom is selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. -12-membered monocyclic, spirocyclic or bridged heterocycloalkyl" is
  • R 3b When R 3b is substituted by one or more Rm 3 "heteroatoms are selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 3-12-membered monocyclic, spiro ring or bridged ring heterocycloalkyl", the "heteroatoms substituted by one or more Rm 3 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3.
  • a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl is
  • R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic rings with 1-3 heteroatoms or bridged ring heterocycloalkyl"
  • the “heteroatom is selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 3-12-membered monocyclic, spiro cyclic or bridged heterocycloalkyl” is
  • R 3a and R 3b together with the atoms to which they are attached, form a "heteroatom selected from one or more of N, O, P and S, which is substituted by one or more Rm 4 , and the number of heteroatoms is 1-3.
  • 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl the "heteroatom substituted by one or more Rm 4 is selected from one or more of N, O, P and S , a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" is
  • the "heteroatom is selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3.
  • a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl is The "heteroatom substituted by one or more Ry 3 is selected from one or more of N, O, P and S, and the 3-12-membered monocyclic, spirocyclic or Bridged ring heterocycloalkyl" is
  • Ar is selected from phenyl
  • Rn is independently selected from halogen (eg Cl, F), C 1 -C 6 haloalkyl (eg CF 3 ), C 1 -C 6 haloalkoxy (eg OCF 3 ) and 3-6 membered cycloalkyl (eg cyclo propyl).
  • R 1 is Cl or CF 3 ;
  • R 3a is hydrogen
  • R 3b is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 Rm 1 , C 1 -C 6 dialkylaminoalkyl, 3-6 membered monocyclic Cycloalkyl, 3-6-membered monocyclic cycloalkyl substituted by 1-3 Rm 2 , "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2
  • the 3-6-membered monocyclic or spirocyclic heterocycloalkyl" and the "heteroatoms substituted by 1-3 Rm 3 are selected from one or more of N, O and S, and the number of heteroatoms is 1- 2 3-6 membered monocyclic or spirocyclic heterocycloalkyl";
  • the above R 3a and R 3b together with the atoms to which they are attached form "the heteroatom is selected from N, a 3-5-membered monocyclic heterocycloalkyl with 1-3 heteroatoms” or is surrounded by 1-3 Rm 4
  • Substituted “heteroatoms are selected from N, 3-5-membered monocyclic heterocycloalkyl with 1-2 heteroatoms" wherein, when the above R 3a and R 3b together with the atoms to which they are attached, form “hetero atoms selected from From N, a 5-membered monocyclic heterocycloalkyl with 1-3 heteroatoms "or a 5-membered heteroatom substituted with 1-3 Rm 4 " from N, with 1-2 heteroatoms "monocyclic heterocycloalkyl", Ar is phenyl or
  • aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) is selected from any of the following compounds:
  • the present invention also provides a method for preparing an aromatic ring or an aryl heterocyclic pyridone compound shown in formula (I), which mainly includes the following preparation methods one and two:
  • the first method for preparing an aromatic ring or an aryl heterocyclic pyridone compound shown in formula (I) is mainly characterized in that the method mainly comprises the following steps a-d:
  • the compound of general formula (C) is generated by dehydration and ring closure reaction under alkali catalysis to generate the compound of general formula (D);
  • the second method for preparing the aromatic ring or aryl heterocyclic pyridone compound shown in formula (I) is mainly characterized in that the method mainly comprises the following steps e-f:
  • the compound of general formula (F) is generated by dehydration and ring closure reaction under alkali catalysis to generate the compound of general formula (G);
  • Rc is an ester group or a cyano group;
  • the step is performed in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, diethyl ether Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or its composition.
  • a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, diethyl ether Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile,
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
  • the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof;
  • the halogenating agent is selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride or a combination thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition comprises:
  • the present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof.
  • the present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof.
  • the disease related to the activity or expression of MAT2a or MTAP protein is especially a preventive or therapeutic drug for tumor or autoimmune disease.
  • the present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof
  • a compound of formula I represented by formula (I) or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof
  • the present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof Use of a form, solvate, polymorph or prodrug, or a pharmaceutical composition as previously described, for the manufacture of a medicament.
  • the medicament can be a medicament for the treatment and/or prevention of diseases related to the activity or expression of MAT2a or MTAP protein; especially a medicament for the prevention or treatment of tumors or autoimmune diseases.
  • the present invention also provides the aryl ring or aryl heterocyclic pyridone compound represented by the formula (I) according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, A diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug, or a pharmaceutical composition as described in any preceding item in the manufacture of a therapeutic and/or prophylactic treatment with MAT2a or Use in medicines for diseases related to MTAP protein activity or expression; especially medicines for the treatment and/or prevention of tumors or autoimmune diseases.
  • the present invention also provides a method for treating and/or preventing a disease associated with MAT2a or MTAP protein activity or expression, comprising: administering to an individual in need thereof a therapeutically effective amount of said formula (I) A compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or said drug combination.
  • the disease related to the activity or expression of MAT2a or MTAP protein is especially a preventive or therapeutic drug for tumor or autoimmune disease.
  • the present invention also provides a method of treating and/or preventing a disease associated with MAT2a or MTAP protein activity or expression, comprising: administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) as described in any preceding item ) represented by the aromatic ring or aryl heterocyclic pyridone compound, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, torsion isomer body, solvate, polymorph or prodrug, or a pharmaceutical composition as described in any of the preceding items; in particular for the treatment and/or prevention of neoplastic or autoimmune diseases.
  • a compound of formula (I) as described in any preceding item represented by the aromatic ring or aryl heterocyclic pyridone compound, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, torsion isomer body, solvate, polymorph or prodrug,
  • the tumor is independently selected from the group consisting of lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, gallbladder cancer, brain cancer, gastric cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal cancer, glioma, bladder cancer carcinoma, astrocytoma, basal cell carcinoma, osteosarcoma, head and neck cancer, chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma and mesothelioma, etc.; the autoimmune disease is independently selected from Thyroiditis, inflammatory bowel disease, erythematosus, fibrosis, muscle weakness, vasculitis, psoriasis, arthritis, scleroderma, dermatitis, etc.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention relates to a compound with structural features of general formula (I), which can inhibit the enzymatic activity of MAT2a, significantly inhibit the growth of various tumor cells, especially the tumor cells related to MTAP deletion, and is a therapeutic drug with a new mechanism of action.
  • reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • polymorph refers to the different solid crystalline phases of certain compounds of the invention in the solid state due to the presence of two or more different molecular arrangements.
  • Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention may form true solvates, but in some cases, only indefinite water or mixtures of water plus some indefinite solvent may remain.
  • the present invention also includes prodrugs of the above compounds.
  • the term “prodrug” refers to a compound that can be converted to the biologically active compound of the present invention under physiological conditions or by solvolysis.
  • the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention.
  • a prodrug may be inactive when administered to an individual in need thereof, but be converted in vivo to an active compound of the present invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compounds of the invention, eg, by hydrolysis in blood.
  • Prodrug compounds generally provide the advantages of solubility, histocompatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino and carboxyl protecting groups.
  • plurality means 2, 3, 4 or 5, preferably 2 or 3.
  • variable such as Rn
  • the definition that appears at each position of the variable has nothing to do with the definitions that appear at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 Rn groups, that is, the group may be substituted with up to 3 Rn groups, the definition of Rn at this position is independent of the definition of Rn at the remaining positions of. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It resembles an alkyl group.
  • alkoxy refers to the group -OR M , wherein R M is an alkyl group as defined above.
  • alkenyl refers to a straight-chain or branched alkene of the specified number of carbon atoms containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds, which one or more carbon-carbon double bonds may be internal Also terminal, examples of olefins include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2propenyl, hexenyl, and the like.
  • alkynyl refers to a straight or branched chain hydrocarbon group having one or more triple bonds of the specified number of carbon atoms (eg, C2 - C8 alkynyl, eg, C2 - C4 alkynyl).
  • the one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl where the triple bond is internal or propynyl with triple bond at the end Wait.
  • cycloalkyl refers to a monocyclic, spirocyclic or bridged saturated cyclic alkyl group, preferably a monocyclic, spirocyclic or bridged monocyclic, spirocyclic or bridged group having 3-12 ring carbon atoms, more preferably 3-6 carbon atoms Saturated cyclic alkyl of the ring, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocycloalkyl refers to a monocyclic, spirocyclic or bridged saturated cyclic group having a heteroatom, preferably containing 1, 2 or 3 cyclic heterocyclic groups independently selected from N, O and S.
  • heterocycloalkyl examples include: tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomo olinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like.
  • Preferred heterocyclyl groups are Morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl.
  • aryl refers to a C6 - C10 aryl group, such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur,
  • at least one ring is aromatic, such as furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrole base, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, Wait.
  • pharmaceutical composition refers to the formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of a compound of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing an adverse biological response or Interacts in an undesired manner with any components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authority as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the "tumor”, “diseases related to abnormal cell proliferation” and the like in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • prophylactic As used herein, the terms “prophylactic”, “preventing” and “preventing” include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
  • An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • intermediate compound functional groups may need to be protected by suitable protecting groups.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the first step under nitrogen protection, sodium hydride (NaH) (890 mg, 22.22 mmol) was added to 2-cyanoacetanilide (0.89 g, 5.56 mmol) in tetrahydrofuran (THF) (30 mL), and after stirring at room temperature for 10 minutes, Then a solution of 2-chloro-6-trifluoromethylnicotinyl chloride (1.63 g, 6.67 mmol) in tetrahydrofuran (5 mL) was added slowly. The temperature of the reaction mixture was raised to 70 degrees, and the reaction was continued for 4 hours.
  • NaH sodium hydride
  • the second step N,N-diisopropylethylamine (DIPEA) (0.74 g, 5.738 mmol) was added to a solution of phosphorus oxychloride (POCl 3 ) (15 mL) of the intermediate product of the previous step at room temperature. Under nitrogen protection, the reaction mixture was reacted at 100 degrees for 16 hours. LC-MS detected that the reaction of the starting materials was complete. Decompression-rotary evaporation-removal of excess phosphorus oxychloride, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate volume ratio 4/1) to obtain the intermediate product (700mg, light yellow solid) .
  • DIPEA N,N-diisopropylethylamine
  • the third step at room temperature, tetrahydropyrrole (356mg, 5.01mmol) was added to the previous step intermediate (350mg, 1.0mmol) and N,N-diisopropylethylamine (389mg, 3.01mmol) in tetrahydrofuran (10mL) , the reaction mixture was reacted at room temperature for 2 hours under nitrogen protection. LC-MS detection of raw materials basically disappeared. The excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with sodium chloride solution.
  • the first step under nitrogen protection, tris(dibenzylideneacetone)dipalladium (Pd2(dba) 3 ) (3.26g, 3.559mmol), 4,5-bis(diphenylphosphine)-9,9 - Dimethyl xanthene (Xantphos) (2.06g, 3.56mmol) was added to methyl 2-amino-4-trifluoromethylbenzoate (7.8g, 35.59mmol), iodobenzene (7.26g, 35.59 mmol) and cesium carbonate (34.79 g, 106.77 mmol) in 1,4-dioxane (150 mL).
  • reaction mixture was heated to 100°C and reacted at this temperature for 16 hours.
  • the reaction solution was diluted with ethyl acetate (500 mL), filtered through celite, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio 20:1) to obtain the intermediate product (8.6 g, pale yellow solid) ).
  • Step 2 Under nitrogen protection, sodium hydride (610 mg, 15.24 mmol) was added to the above intermediate (1.5 g, 5.079 mmol) in N,N-dimethylformamide DMF (30 mL). After half an hour of reaction, cyanoacetyl chloride (5.26 g, 50.8 mmol) was added slowly, and the reaction was stirred at room temperature overnight. The reaction was basically complete by LC-MS. Ethyl acetate (200 mL) was added to dilute the reaction solution, and the organic phase was washed with sodium chloride solution.
  • the third step N,N-diisopropylethylamine (1.02 g, 7.878 mmol) was added to a solution of the above intermediate (650 mg, 1.970 mmol) in phosphorus oxychloride (15 mL) at room temperature. Under nitrogen protection, the reaction mixture was reacted at 100 degrees for 2 hours. LC-MS detection of raw materials basically disappeared. After the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 4/1) to obtain the intermediate product (310 mg, pale yellow solid).
  • the fourth step at room temperature, tetrahydropyrrole (311mg, 4.382mmol) was added to the above intermediate (305mg, 0.876mmol) and N,N-diisopropylethylamine (340mg, 2.628mmol) in tetrahydrofuran (5mL) , the reaction mixture was reacted at room temperature for 2 hours. LC-MS detected that the reaction was basically complete. After the excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with sodium chloride solution.
  • the first step under argon, methyl 2-amino-4 chlorobenzoate (5g, 26.9mmol), iodobenzene (6.5g, 31.9mmol), 4,5-bis(diphenylphosphine)-
  • Xantphos 9,9-dimethylxanthene
  • cesium carbonate 1,4-dioxane
  • the fifth step at room temperature, tetrahydropyrrole (98 mg, 1.36 mmol) was added to the dichloromethane (8 mL) solution containing the above intermediate (200 mg, 0.63 mmol) and diisopropylethylamine (178 mg, 1.36 mmol). 1.36 mmol). The mixture was reacted at room temperature for 2 hours. After the reaction was detected by LC-MS, water (20 mL) was added to the reaction solution, followed by extraction with dichloromethane (20 mL) three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. .
  • the first step at room temperature, add 4-chloro-2-oxo-1-phenyl-7 trifluoromethyl-1,2-dihydroquinoline-3-methylcyanide (246 mg, 1.43 mmol) To a solution of diisopropylethylamine (178 mg, 1.36 mmol) in tetrahydrofuran (10 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (300 mg, 0.86 mmol). The mixture was reacted at room temperature for 2 hours. After the reaction was detected by LC-MS, water (20 mL) was added to the reaction solution, followed by extraction with dichloromethane (20 mL) three times.
  • Second step Trifluoroacetic acid (2 ml) was added to a solution of the above compound (200 mg, 0.286 mmol) in dichloromethane (10 mL) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (100 mL), and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol in a volume ratio of 10:1) to obtain the compound of Example 37 (100 mg).
  • the third step 1 drop of acetic acid was added to the methanol (10 mL) solution of the above compound (50 mg, 0.13 mmol) and aqueous formaldehyde solution (208 mg, 0.286 mmol) at room temperature.
  • the reaction mixture was reacted at room temperature for 1 hour, sodium cyanoborohydride (53 mg, 0.832 mmol) was added to the reaction solution, the reaction at room temperature was continued for 1 hour, the solvent was spin-dried, ethyl acetate (100 mL) was dissolved, saturated sodium bicarbonate solution (100 mL) ), dried, filtered, the organic phase was spin-dried, and the crude product was prepared by HPLC to obtain the compound of Example 38 (12.8 mg).
  • Example 39 4-((1-Isopropylazetidin-3-yl)amino)-2-oxo-1-phenyl-7-trifluoromethyl-1,2-dihydroquinoline Lino-3-methyl cyanide
  • Example 40 4-((1-Acetylazetidin-3-yl)amino)-2-oxo-1-phenyl-7-trifluoromethyl-1,2-dihydroquinoline -3-Methyl cyanide
  • Example 37 At room temperature, the compound of Example 37 (50 mg, 0.13 mmol), 1-ethyl-3(3-dimethylpropylamine) carbodiimide EDCI (50 mg, 0.26 mmol), 1-hydroxybenzotriazole HOBT (To a solution of 26 mg, 0.195 mmol) in dichloromethane (10 mL) was added acetic acid (32 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was complete by LCMS. The reaction solution was diluted with dichloromethane (100 mL), and the mixture solution was washed with saturated brine (100 mL).
  • the first step at room temperature, oxalyl chloride (7.24g, 57.02mmol) was added to cyanoacetic acid (2.4g, 28.51mmol) in dichloromethane (30mL), and five drops of N,N-dimethylformamide were added, The reaction mixture was reacted at this temperature for 2 hours.
  • sodium hydride 342.1 mg, 8.553 mmol was added to the N,N- In dimethylformamide (30 mL), after the reaction for half an hour, the concentrated solution of cyanoacetyl chloride prepared above was added, and the reaction was carried out at room temperature overnight.
  • the main reaction product was detected by LCMS, the reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated aqueous sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio of 10:1) to obtain a light red solid intermediate compound (520 mg). LCMS (ESI) m/z: 364.9 [M+H] + .
  • the second step at room temperature, N,N-diisopropylethylamine (99.39mg, 5.699mmol) was added to the phosphorus oxychloride (8mL) of the above-mentioned intermediate compound (520mg, 1.426mmol), and the reaction was carried out under nitrogen protection The mixture was reacted at 100°C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product.
  • the third step at room temperature, 3-aminocyclobutan-1-one (190mg, 1.570mmol) was added to the above-mentioned intermediate compound (120mg, 0.314mmol), N,N,-diisopropylethylamine (122mg, 0.942 mmol) in tetrahydrofuran (5 mL), the reaction mixture was reacted at 20°C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated aqueous sodium chloride solution.
  • Examples 45a and 45b 1-(4-Chlorobenzene)-4-((trans-3-fluorocyclobutyl)amino)-2-oxo-7-trifluoromethyl-1,2-dihydro Quinoline-3-methylcyanide and 1-(4-chlorobenzene)-4-((cis-3-fluorocyclobutyl)amino)-2-oxo-7-trifluoromethyl-1,2- Dihydroquinoline-3-methylcyanide
  • the first step at room temperature, sodium borohydride (31 mg, 0.810 mmol) was added to the compound of Example 44 (70 mg, 0.16 mmol) in ethanol (5 mL), and the reaction mixture was reacted at 20 degrees for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The excess ethanol was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by HPLC to obtain the compound of Example 31 (55 mg) as a white solid.
  • the second step at room temperature, diethylaminosulfur trifluoride (1 mL) was added to the above compound (35 mg, 0.081 mmol) in dichloromethane (5 mL), and the reaction mixture was reacted at 20 degrees for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product.
  • the reaction was quenched with sodium bicarbonate, the reaction solution was diluted with dichloromethane (100 mL), the organic phase was washed with saturated sodium chloride solution, the separated organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of Example 45 as a white solid (28 mg) .
  • the first step at room temperature, oxalyl chloride (4.97g, 37.0mmol) was added to 2-chloro-6-trifluoromethylnicotinic acid (4.17g, 18.5mmol) in dichloromethane (150mL), and 3 drops of N were added. , N-dimethylformamide, the reaction mixture was reacted at this temperature for 2 hours.
  • sodium hydride (3.7 g, 61.66 mmol) was added to N-(4-chlorobenzene)-2-cyanoacetamide (3 g, 15.42 mmol) in N,N-dimethylformamide (80 mL).
  • the second step at room temperature, N,N-diisopropylethylamine (5.8g, 44.84mmol) was added to the phosphorus oxychloride (20mL) of the above-mentioned intermediate compound (4.1g, 11.21mmol), under nitrogen protection
  • the reaction mixture was reacted at 100°C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product.
  • the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate in a volume ratio of 4:1) to obtain a pale yellow solid intermediate compound (1.68 g).
  • the third step at room temperature, 3-amino-cyclobutyl-1 ketone (152mg, 1.25mmol) was added to the above intermediate compound (50mg, 0.13mmol), N,N-diisopropylethylamine (162mg, 1.25 mmol) in tetrahydrofuran (5 mL), the reaction mixture was reacted at 20 °C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. After the excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution.
  • Example 77a (white solid, 9.7 mg).
  • the fourth step under ice cooling, methylmagnesium bromide (50 mg, 0.3 mmol) was added dropwise to a solution of the above intermediate compound (100 mg, 0.23 mmol) in tetrahydrofuran (10 mL).
  • the reaction was carried out under ice cooling for 1 hour.
  • Water (70 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL) twice.
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio of 10:1) to obtain the compound of Example 77b ( white solid, 70 mg).
  • Examples 86 and 87 1-(4-Chlorobenzene)-4-(((cis)-3-fluoro-(3-methylcyclobutyl)amino)-2-oxo-7-(trifluoro Methyl)-1,2-dihydro-1,8-naphthyridine-3-methylcyanide and 1-(4-chlorobenzene)-4-(((trans)-3-fluoro-(3-methyl) Cyclobutyl)amino)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-methylcyanide
  • test compound concentration gradients the test compound test concentration is 10uM starting, 3-fold dilution, 10 concentrations, single-well test. 10 different concentration solutions were serially diluted to 100-fold final concentration in 384-well plates. Then use Echo 550 to transfer 250nL to 384 reaction plate for use. 250nL of 100% DMSO was added to negative control wells and positive control wells, respectively.
  • %Inhibition (OD 620 _max-OD 620 _sample)/(OD 620 _max-OD 620 _min) x 100; wherein: OD 620 _sample is the absorbance value of the sample hole; OD 620 _min: negative control Well absorbance value, representing the reading of the well without enzymatic activity; OD620_max : absorbance value of the positive control well, representing the reading of the well without compound inhibition.
  • Test Example 2 Proliferation-inhibitory effects of Example compounds on HCT-116 wt and HCT-116 MTAP -cells.
  • Test method 1) Take HCT-116 wt /HCT116 MTAP -cells (Horizon) in logarithmic growth phase and inoculate them into a 96-well culture plate at an appropriate density, 80 ⁇ L per well, and after culturing overnight, add compounds of different concentrations Act for 4hr, and set solvent control group (negative control). 2) After the compound acts on the cells for 120 hr, the effect of the compound on the cell proliferation was detected by CTG cell counting kit. 40 ⁇ L of CTG reagent was added to each well, and placed in a 37°C incubator for 60 min, and then used a Multilabel Reader microplate reader of PerkinElmer Company. reading.
  • inhibition rate (%) (OD negative control well-OD administration well)/OD negative control well ⁇ 100%.
  • IC 50 values were obtained by four-parameter regression using the software GraphPad Prism5 that came with the microplate reader.
  • the IC 50 of most of the example compounds of the present invention is less than 1 uM for HCT-116 MTAP -cell proliferation inhibition, such as Examples 25, 26, 34, 45b, 72, 77a, 81, 82, 83, 85, 86, 88, etc.
  • the inhibitory activity IC 50 of HCT-116 wt cells was less than 200nM, which was significantly better than that of the comparative compound 4; and the proliferation inhibitory activity IC 50 of some example compounds of the present invention on HCT-116 wt cells was greater than 5uM, showing high cell selectivity.
  • Metabolic stability test 150 ⁇ L of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation, and the system contained NADPH (final concentration 1 mM), 1 ⁇ M test compound and positive control midazole The reaction was terminated with acetonitrile containing tinidazole at 0min, 5min, 10min, 20min and 30min, respectively, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 ⁇ L of supernatant was injected into a 96-well plate. Compound metabolic stability was calculated by determining the relative reduction of the parent drug.
  • the compounds of the examples of the present invention have high stability to liver microsomes of various genera (such as rat, mouse, dog, monkey, human), and the half-life is more than 30min, such as compounds 25, 43, 83, 85, 86 of the examples. , 88, etc.
  • mice Six male SPF Balb c mice (Shanghai Sipple-Bike laboratory animals) were divided into two groups, and the test compounds were formulated into appropriate solutions or suspensions; one group was administered intravenously, and the other group was administered orally. Blood was collected by jugular vein puncture, each sample was collected about 0.2 mL/time point, and heparin sodium was anticoagulated. 24h; blood samples were placed on ice after collection, centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C), and the collected plasma was stored at -80°C before analysis. Plasma samples were analyzed by LC-MS/MS.
  • the pharmacokinetic parameters AUC 0-t , AUC 0- ⁇ , MRT 0- ⁇ , C max of the test substance were calculated using the non-compartmental model of the pharmacokinetic calculation software WinNonlin5.2 , T max , T 1/2 and V d parameters and their mean and standard deviation.
  • the bioavailability (F) will be calculated by the following formula.
  • the samples taken before reaching Cmax should be calculated as zero value, and the samples at the sampling point after reaching Cmax should be calculated as non-quantitative (BLQ).
  • Example 25 The mouse PK data results of Example 25 are as follows:
  • Example 43 The mouse PK data results of Example 43 are as follows:
  • Example 72 The mouse PK data results of Example 72 are as follows:
  • Example 83 The mouse PK data results of Example 83 are as follows:
  • Example 85 The mouse PK data results of Example 85 are as follows:
  • Example 86 The mouse PK data results of Example 86 are as follows:
  • Example 88 The mouse PK data results of Example 88 are as follows:
  • Test Example 5 Inhibitory effect of example compounds on the growth of human colon cancer HCT116 MTAP -/- nude mice subcutaneous xenograft tumor in vivo
  • BALB/c nude mice (6-8 weeks old, Shanghai Lingchang Biotechnology Co., Ltd.) were raised in SPF environment, temperature 20-25°C, relative humidity 30-70%, 12:12h light and dark lighting; free Drinking water and eating food. Animals were adaptively reared before experimental treatment; (2) HCT116 MTAP -/- cells (Horizon) were cultured and expanded in vitro, and the cells in logarithmic growth phase were collected and resuspended in serum-free RPMI1640 medium, and the cell concentration was adjusted to 1.33 ⁇ 10 7 /mL; (3) Inject the cell suspension subcutaneously into the axilla of the front right limb of BALB/c nude mice with a 1 mL syringe, and inject 150 ⁇ L into each animal; observe the growth of the animals and the transplanted tumor regularly; (4) When the average tumor volume grows to At about 100-150 mm 3 , animals with too large, too small or irregular tumor shape were eliminated and grouped by random block method; the solvent
  • the tumor volume inhibition rate (GI): the calculation formula is GI [1–(TV t –TV initial )/(CV t –CV initial )] ⁇ 100%; where, TV t represents each treatment group The tumor volume at the time of measurement; TV initial represents the tumor volume of the treatment group during group administration; CV t represents the tumor volume of the solvent control group at each measurement; CV initial represents the tumor volume of the solvent control group during group administration.
  • Statistical analysis method The test data were calculated and related statistical processing with Microsoft Office Excel 2010 software. Unless otherwise specified, data are expressed as mean ⁇ standard error (Mean ⁇ SE), and t-test was used for comparison between two groups.
  • intragastric administration once a day for 35 consecutive days inhibited the growth of subcutaneous xenograft tumors in HCT116 MTAP -/- nude mice in a dose-dependent manner (tumor inhibition rate was 30% to 93%), and the body weight of the animals was similar to that of the mice. There was no significant difference compared to the solvent control group.

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Abstract

一类芳环或芳基杂环并吡啶酮类化合物、药物组合物及其应用，具体为一种如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其制备方法及在药学上的应用。以上化合物具有较好的抑制MAT2a酶活性，显著抑制多种肿瘤细胞的生长，特别是MTAP缺失相关的肿瘤细胞。

Description

一类芳环或芳基杂环并吡啶酮类化合物、药物组合物及其应用
本申请要求申请日为2020/9/24的中国专利申请2020110183911的优先权，要求申请日为2020/12/19的中国专利申请2020115111271的优先权，要求申请日为2021/1/10的中国专利申请2021100275150的优先权，要求申请日为2021/2/10的中国专利申请2021101855079的优先权，要求申请日为2021/4/2的中国专利申请2021103638917的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，具体地，涉及一类芳环或芳基杂环并吡啶酮类化合物，具有抑制甲硫氨酸腺苷转移酶(MAT2a)活性，可以用于制备与MAT2a或MTAP的活性或表达相关的疾病的治疗和预防药物。
背景技术
甲硫氨酸腺苷转移酶(MAT)(也称为S-腺苷甲硫氨酸合成酶)是催化由甲硫氨酸和ATP合成S-腺苷甲硫氨酸(SAM或AdoMet)的细胞酶，并被认为是甲硫氨酸循环的限速步骤。SAM是多胺生物合成中的丙氨基供体，并且是用于DNA甲基化的主要甲基供体，并且其参与基因转录和细胞增殖以及次级代谢产物的生成。通过药理学方法发现，肿瘤细胞的增殖和转移对甲硫氨酸异常依赖，抑制甲硫氨酸循环能显著抑制肿瘤干细胞的增殖与转移(Nature Medicine(2019),25,825-837)。
甲基硫腺苷磷酸化酶(MTAP)参与甲硫氨酸补救合成途径，将甲硫腺苷(MTA)代谢生成腺嘌呤和甲硫氨酸。MTAP位于染色体9p21上，与抑癌基因CDKN2A相近，MTAP缺陷存在于白血病、胶质瘤、黑色素瘤、肺癌卵巢癌、子宫内膜癌、乳腺癌等各种肿瘤中。其中，在脑胶质瘤的缺失率为41％，间皮质瘤中缺失率为31％，胰腺癌中达到26％。S-腺苷-L-甲硫氨酸(SAM)是一种可参与甲基转移反应和多胺生物合成的酶辅因子，可由ATP和L-甲硫氨酸在甲硫氨酸腺苷转移酶家族(MAT)蛋白催化下反应生成。在哺乳动物组织中，MAT基因主要存在两种不同的同工酶，分别由MAT1a和MAT2a编码。MAT1a仅在成人的肝组织中表达，具有肝脏特异性，其主要功能是促进SAM合成。MAT2a在所有非肝组织中均存在表达，其主要功能是抑制SAM合成。MAT2a是腺苷甲硫氨酸(SAM)合成通路中的关键酶，研究表明MAT2a的表达上调在多种癌细胞中存在且敲出MAT2a基因能导致癌细胞的死亡，MTAP缺失的肿瘤最为敏感。因此，MAT2a是MTAP 缺失肿瘤的潜在的治疗靶点。发现和寻找结构新颖、成药性优异的MAT2a抑制剂，成为研发MTAP缺失肿瘤治疗药物的一大热点。
发明内容
本发明需要解决的技术问题之一是提供一种新型的MAT2a抑制剂，用于制备肿瘤治疗药物。发明人经过长期而深入的研究，制备了一类具有式I所示结构新颖的芳环或芳基杂环并吡啶酮类化合物，并发现其具有较好的抑制MAT2a酶活性，且所述的化合物在极低浓度(可低至小于100nM)下，即对MAT2a蛋白产生特异性抑制作用，并且对MTAP缺失相关的细胞增殖抑制活性相当优异。基于上述发现，发明人完成了本发明。
本发明通过以下技术方案解决上述技术问题。
本发明提供了一种如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2021119638-appb-000001
式中：
Ar选自5-12元单环或并环芳基、被1-3个Rn取代的单环或并环芳基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”和被1-3个Rn取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”；
所述的Rn独立地选自氘、卤素、氰基、酰胺、磺酰胺、羟基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基、-NRz 1Rz 2、烯基、炔基、3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、3-12元环烷基醚、3-12元杂环烷基醚、5-10元单环或并环芳基和“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”；或者上述任意两个Rn可以通过碳链或者杂原子构成3-12元 的饱和或部分不饱和或芳香的环系；Rz 1和Rz 2独立地选自H和C 1-C 12烷基；
R 1选自卤素、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基、C 1-C 12单烷基氨基、C 1-C 12双烷基氨基、C 1-C 12的卤代烷基氨基、3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、3-12元环烷基醚、3-12元杂环烷基醚、5-10元单环或并环芳基和“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”；
R 2选自卤素、氰基、酰胺、磺酰胺、磷酰基、烷基磷氧基、烷基硅基、C 1-C 12卤代烷基和C 1-C 12卤代烷氧基；
R 3a选自氢、C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12单烷基氨基烷基、C 1-C 12双烷基氨基烷基、环烷基氨基烷基、杂环烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
R 3b选自C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12单烷基氨基烷基、C 1-C 12双烷基氨基烷基、环烷基氨基烷基、杂环烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”或被一个或多个Rm 5取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”；
所述的Rm 1、Rm 2、Rm 3、Rm 4和Rm 5独立地选自氘、氧代(＝O)、卤素、氰基、酰胺、磺酰胺、羟基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 12烷基、被一个或多个Ry 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基、烯基、炔基、3-12元单环、螺环或桥环的环烷基、被一个或多个Ry 2取代的3-12元单环、螺环或 桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、-NRz 1Rz 2和
Figure PCTCN2021119638-appb-000002
或者上述两个Rm 1、两个Rm 2、两个Rm 3、两个Rm 4或两个Rm 5可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和或芳香的环系；
Rx选自C 1-C 12烷基和C 1-C 12烷氧基；
Ry 1独立地为羟基；
Ry 2独立地选自C 1-C 12烷基和羟基取代C 1-C 12烷基；
Ry 3独立地选自C 1-C 12烷基和C 1-C 12卤代烷基；
W、Z、Y分别独立地选自O、S、CR 4和N；其中R 4分别独立地选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C 1-C 12烷基、C 1-C 12卤代烷基、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、C 1-C 12烷基-O-、C 1-C 12卤代烷基-O-、-NRz 1Rz 2、3-12元环烷基氨基、3-12元杂环烷基氨基、3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、3-12元卤代环烷基或卤代杂环烷基、3-12元环烷基-O-、3-12元卤代环烷基-O-、3-12元杂环烷基-O-、5-12元的单环或并环芳基和5-12元单环或并环杂芳基；
或者-Y＝Z-可以形成＝CH-、＝N-、-O-、-S-或-NR 5；R 5选自氢、C 1-C 12烷基、3-12元单环、螺环或桥环的环烷基和“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
上述如式(I)所示的芳环或芳基杂环并吡啶酮类化合物不包含以下化合物：
Figure PCTCN2021119638-appb-000003
在本发明某些优选实施方案中，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异 构体、溶剂化物、多晶型物或前药中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”)，
Ar独立地选自5-12元的单环或者双并环芳环或杂芳环，所述的芳环或杂芳环可以被1-3个不同的取代基Rn所取代，所述的Rn选自氢、氘、卤素、氰基、酰胺、磺酰胺、羟基、氨基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 10烷基、C 1-C 10烷氧基、卤代烷基、卤代烷氧基、C 1-C 10单烷基氨基、C 1-C 10双烷基氨基、烯基、炔基、3-10元环烷基或杂环烷基、C 1-C 10烷基-S-、C 1-C 10烷基-SO-、C 1-C 10烷基-SO 2-、3-10元环烷基醚或杂环烷基醚、5-10元芳基或杂芳基等；或者上述任意两个Rn可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和或芳香的环系；
R 1独立地选自C 1-C 10烷基、C 1-C 10烷氧基、C 1-C 10的卤代烷基、C 1-C 10卤代烷氧基、C 1-C 10单烷基氨基、C 1-C 10双烷基氨基、C 1-C 10的卤代烷基氨基、3-10元环烷基或杂环烷基、C 1-C 10烷基-S-、C 1-C 10烷基-SO-、C 1-C 10烷基-SO 2-、3-10元环烷基醚或杂环烷基醚、5-10元芳基或杂芳基；
R 2独立地选卤素、氰基、酰胺、磺酰胺、磷酰基、烷基磷氧基、烷基硅基、卤代烷基、卤代烷氧基；
R 3a选自氢、C 1-C 10烷基、C 1-C 10烷氧基、C 1-C 10卤代烷基、C 1-C 10单烷基氨基烷基、C 1-C 10双烷基氨基烷基、环烷基氨基烷基、杂环烷基氨基烷基、3-12元环烷基或杂环烷基；R 3b独立地选自C 1-C 10烷基、C 1-C 10烷氧基、C 1-C 10卤代烷基、C 1-C 10单烷基氨基烷基、C 1-C 10双烷基氨基烷基、环烷基氨基烷基、杂环烷基氨基烷基、3-12元环烷基或杂环烷基；上述R 3a和R 3b可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和或芳香的环系；所述的烷基(单烷基，双烷基，卤代烷基)、环烷基或杂环烷基可以被1-2个不同的取代基Rm所取代，所述的Rm选自氢、氘、卤素、氰基、酰胺、磺酰胺、羟基、氨基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 6烷基、C 1-C 6烷氧基、卤代烷基、卤代烷氧基、C 1-C 6单烷基氨基、C 1-C 6双烷基氨基、烯基、炔基、3-8元环烷基或杂环烷基、C 1-C 6烷基-S-、C 1-C 6烷基-SO-、C 1-C 6烷基-SO 2-等；或者上述两个Rm可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和或芳香的环系；
W、Z、Y分别独立地选自CR 4或N；其中R 4分别独立地选自氢、氘、卤素、氰基、羟基、氨基、酰胺基、磺酰胺基、C 1-C 12烷基、C 1-C 6卤代烷基、C 1-C 6烷基-S-、C 1-C 6烷基-SO-、C 1-C 6烷基-SO 2-、C 1-C 6烷基-O-、C 1-C 6卤代烷基-O-、C 1-C 6单烷基氨基、C 1-C 6双烷基氨基、3-12元环烷基氨基或杂环烷基氨基、3-12元环烷基或杂环烷基、3-12元卤代环烷基或卤代杂环烷基、3-12元环烷基-O-、3-12元卤代环烷基-O-、3-12元杂环烷基- O-、5-12元的芳基或5-12元杂芳基；
或者-Z＝Y-可以独立地选自-O-或-S-或-NR 5；R 5选自氢、C 1-C 12烷基、3-12元环烷基、3-12元杂环烷基；
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代：包括但不限于氘、卤素、C 1-C 8烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
在本发明某一方案中，如式(I)所示的芳环或芳基杂环并吡啶酮类化合物为如下任一通式所示的化合物：
Figure PCTCN2021119638-appb-000004
其中R 1、R 2、R 3a、R 3b、R 4、R 5、Ar的范围如上文所定义。
在本发明某一方案中，如式(I)所示的芳环或芳基杂环并吡啶酮类化合物为如下任一通式所示的化合物：
Figure PCTCN2021119638-appb-000005
其中：M 6选自C或N；M 1、M 2、M 3、M 4、M 5分别独立地选自CR 6或N；R 6优选自氢、氘、卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、3-8元环烷基或杂环烷基；其它基团的范围如其余任一项所示。
在本发明某一方案中，所述的Rn独立地选自卤素、C 1-C 12烷基、C 1-C 12烷氧基、C 1- C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基。
在本发明某一方案中，R 1选自卤素、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基。
在本发明某一方案中，R 2为氰基。
在本发明某一方案中，R 3a选自氢和C 1-C 12烷基；
R 3b选自C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12双烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”或被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”。
在本发明某一方案中，所述的Rm 1、Rm 2、Rm 3和Rm 4独立地选自氧代(＝O)、卤素、氰基、羟基、C 1-C 12烷基、被一个或多个Ry 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、3-8元单环、螺环或桥环的环烷基、被一个或多个Ry 2取代的3-8元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、-NRz 1Rz 2和
Figure PCTCN2021119638-appb-000006
在本发明某一方案中，Rz 1和Rz 2独立地选自C 1-C 12烷基。
在本发明某一方案中，Y为CH或N。
在本发明某一方案中，Z为CH。
在本发明某一方案中，W为CH或N。
在本发明某一方案中，Ar选自5-12元单环或并环芳基、被13个Rn取代的单环或并环芳基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”和被1-3个Rn取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”；
所述的Rn独立地选自卤素、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤 代烷氧基和3-10元单环的环烷基；
Figure PCTCN2021119638-appb-000007
为
Figure PCTCN2021119638-appb-000008
Figure PCTCN2021119638-appb-000009
R 1选自卤素、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基；
R 2为氰基；
R 3a选自氢和C 1-C 12烷基；
R 3b选自C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12双烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”或被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
所述的Rm 1、Rm 2、Rm 3和Rm 4独立地选自氧代(＝O)、卤素、氰基、羟基、C 1-C 12烷基、被一个或多个Ry 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、3-8元单环、螺环或桥环的环烷基、被一个或多个Ry 2取代的3-8元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、-NRz 1Rz 2和
Figure PCTCN2021119638-appb-000010
Rx为C 1-C 12烷基或C 1-C 12烷氧基；
Ry 1独立地为羟基；
Ry 2独立地为C 1-C 12烷基或羟基取代C 1-C 12烷基；
Ry 3独立地为C 1-C 12烷基或C 1-C 12卤代烷基；
Rz 1和Rz 2独立地选自C 1-C 12烷基。
在本发明某一方案中，
Figure PCTCN2021119638-appb-000011
为
Figure PCTCN2021119638-appb-000012
Figure PCTCN2021119638-appb-000013
在本发明某一方案中，R 1选自Cl、CF 3、OCF 3和环丙基。
在本发明某一方案中，Ar选自苯基、
Figure PCTCN2021119638-appb-000014
Figure PCTCN2021119638-appb-000015
在本发明某一方案中，
Figure PCTCN2021119638-appb-000016
选自
Figure PCTCN2021119638-appb-000017
Figure PCTCN2021119638-appb-000018
Figure PCTCN2021119638-appb-000019
在本发明某一方案中，Ar、Rn、R 1和R 4中，所述芳基独立地为6-10元单环或并环芳基，例如苯基或萘基。
在本发明某一方案中，Ar、Rn、R 1、R 3a、R 3b和R 4中，所述杂芳基独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”。
在本发明某一方案中，Ar中，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”和被1-3个Rn取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”中的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”独立地为吡啶基(例如
Figure PCTCN2021119638-appb-000020
)或咪唑并[1,2-a]吡啶(例如
Figure PCTCN2021119638-appb-000021
)。
在本发明某一方案中，Rn、R 1、R 2、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5和R 4中，所述卤素独立地为F、Cl、Br或I，例如F或Cl。
在本发明某一方案中，Rn、Rz 1、Rz 2、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、Rx、Ry 2、Ry 3、R 4和R 5中，所述烷基独立地为C 1-C 10的烷基，例如，所述烷基独立地为C 1-C 6的烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在本发明某一方案中，Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5和Rx中，所述烷氧基独立地为C 1-C 10的烷氧基，例如，所述烷氧基独立地为C 1-C 6的烷氧基，又例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，例如甲氧基。
在本发明某一方案中，Rn、R 1、R 2、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、Ry 3和R 4中，所述卤代烷基独立地为C 1-C 10的卤代烷基，例如，所述卤代烷基独立地为C 1-C 6的卤代烷基，又例如CF 3或CH 2CF 3。
在本发明某一方案中，Rn、R 1、R 2、Rm 1、Rm 2、Rm 3、Rm 4和Rm 5中，所述卤代烷氧基独立地为C 1-C 10的卤代烷氧基，例如所述卤代烷氧基独立地为C 1-C 6的卤代烷氧基，又例如OCF 3。
在本发明某一方案中，Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、R 4和R 5中，所述环烷基为3-10元环烷基，例如所述环烷基为3-6元单环、螺环或桥环的环烷基，又例如3-6元单环的环烷基，还例如环丙基或环丁基。
在本发明某一方案中，Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、R 4和R 5中，所述杂环烷基为“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的3-10元单环、螺环或桥环的杂环烷基”，例如“杂原子选自N和O中的一种或多种，杂原子数为1-2个的4-10元单环或螺环的杂环烷基”，又例如氮杂环丁基(例如
Figure PCTCN2021119638-appb-000022
)、氧杂环丁基(例如
Figure PCTCN2021119638-appb-000023
)、吡咯烷基(例如
Figure PCTCN2021119638-appb-000024
)、哌啶基(例如
Figure PCTCN2021119638-appb-000025
)或
Figure PCTCN2021119638-appb-000026
在本发明某一方案中，R 3a、R 3b中，当R 3b为“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷 基”为
Figure PCTCN2021119638-appb-000027
当R 3b为被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
Figure PCTCN2021119638-appb-000028
Figure PCTCN2021119638-appb-000029
当R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
Figure PCTCN2021119638-appb-000030
当R 3a和R 3b与其相连的原子一起形成被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
Figure PCTCN2021119638-appb-000031
Figure PCTCN2021119638-appb-000032
在本发明某一方案中，Rm 1、Rm 2、Rm 3和Rm 4中，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
Figure PCTCN2021119638-appb-000033
所述被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为 1-3个的3-12元单环、螺环或桥环的杂环烷基”为
Figure PCTCN2021119638-appb-000034
在本发明某一方案中，
Figure PCTCN2021119638-appb-000035
为
Figure PCTCN2021119638-appb-000036
Figure PCTCN2021119638-appb-000037
例如
Figure PCTCN2021119638-appb-000038
在本发明某一方案中，Ar选自苯基、
Figure PCTCN2021119638-appb-000039
Rn独立地选自卤素(例如Cl、F)、C 1-C 6卤代烷基(例如CF 3)、C 1-C 6卤代烷氧基(例如OCF 3)和3-6元环烷基(例如环丙基)。
在本发明某一方案中，R 1为Cl或CF 3；
R 3a为氢；
R 3b独立地选自C 1-C 6烷基、被1-3个Rm 1取代的C 1-C 6烷基、C 1-C 6双烷基氨基烷基、3-6元单环的环烷基、被1-3个Rm 2取代的3-6元单环的环烷基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-2个的3-6元单环或螺环的杂环烷基”和被1-3个Rm 3取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-2个的3-6元单环或螺环的杂环烷基”；
或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N，杂原子数为1-3个的3-5元单环的杂环烷基”或被1-3个Rm 4取代的“杂原子选自N，杂原子数为1-2个的3-5元单环的杂环烷基”，其中，当上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N，杂原子数为1-3个的5元单环的杂环烷基”或被1-3个Rm 4取代的“杂原子选自N，杂原子数为1-2个的5元单环的杂环烷基”时，Ar为苯基或
Figure PCTCN2021119638-appb-000040
在本发明某一方案中，所述如式(I)所示的芳环或芳基杂环并吡啶酮类化合物选自如下任一化合物：
Figure PCTCN2021119638-appb-000041
Figure PCTCN2021119638-appb-000042
本发明还提供了一种制备如式(I)所示的芳环或芳基杂环并吡啶酮类化合物的方法，主要包括如下制备方法一和二：
制备如式(I)所示的芳环或芳基杂环并吡啶酮类化合物的方法一，主要特征在于，所述方法主要包括如下步骤a-d：
Figure PCTCN2021119638-appb-000043
a、将通式(A)化合物与R2取代的乙酰基芳胺(B)通过碱催化的取代反应生成 通式(C)化合物，其中Ra为甲酰卤或甲酸酯基；
b、将通式(C)化合物在碱催化下通过脱水关环反应生成通式(D)化合物；
c、将通式(D)化合物与卤化试剂，或者磷酰卤或酸酐，或磺酸酰卤或者酸酐等反应，生成通式(E)化合物，其中LG为卤素、磺酸酯等离去基团；
d、将通式(E)与R 3aR 3bNH在碱催化下发生取代反应生成如式(I)所示的芳环或芳基杂环并吡啶酮类化合物。
制备如式(I)所示的芳环或芳基杂环并吡啶酮类化合物的方法二，主要特征在于，所述方法主要包括如下步骤e-f：
Figure PCTCN2021119638-appb-000044
e、将通式(F)化合物在碱催化下通过脱水关环反应生成通式(G)化合物；Rc为酯基或者氰基；
f、当通式化合物G为羟基化合物时，采用与上述方法1的步骤c、d相同的方法制备得到如式(I)所示的芳环或芳基杂环并吡啶酮类化合物；当通式化合物G为氨基化合物时，通过各种氨基官能团转化的方法得到如式(I)所示的芳环或芳基杂环并吡啶酮类化合物。
优选地，所述步骤在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
优选地，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠，或其组合物；所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
优选地，所述酸选自下组：盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸，三氟甲磺酸或其组合物；
优选地，所述卤化试剂选自下组：三氯氧磷、五氯化磷、氯化亚砜或其组合物。
本发明还提供了一种药物组合物，所述药物组合物包括：
(1)如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、 或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药；以及
(2)药学上可接受的载体。
在本发明某一方案中，所述药物组合物包括：
(i)有效量的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药；和
(ii)药学上可接受的载体。
本发明还提供了一种包含所述的如式(I)所示的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药的药物(或药物组合物)。
本发明还提供了一种包含所述的如式(I)所示的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药的与MAT2a或MTAP蛋白活性或表达相关的疾病的治疗药物(或药物组合物)。
所述的与MAT2a或MTAP蛋白活性或表达相关的疾病特别是肿瘤或自身免疫性疾病的预防或治疗药物。
本发明还提供了一种所述的如式(I)所示的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或所述的药物组合物在用于制备MAT2a酶抑制剂中的应用。
本发明还提供了一种所述的如式(I)所示的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、或如前所述的药物组合物在用于制备药物中的应用。所述的药物可为治疗和/或预防与MAT2a或MTAP蛋白活性或表达相关的疾病的药物；特别的用于***或自身免疫性疾病的预防或治疗药物。
本发明还提供了如前任一项所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药、或如前任一项所述的药物组合物在制备治疗和/或预防与MAT2a或MTAP蛋白活性或表达相关的疾病的药物中的应用；特别是治疗和/或预防肿瘤或自身免疫性疾病的药物。
本发明还提供了一种治疗和/或预防与MAT2a或MTAP蛋白活性或表达相关的疾病的方法，其包括：向有需要的个体施用治疗有效量的所述的如式(I)所示的式I化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶 型物或前药、或所述的药物组合物。所述的与MAT2a或MTAP蛋白活性或表达相关的疾病特别是肿瘤或自身免疫性疾病的预防或治疗药物。
本发明还提供了一种治疗和/或预防与MAT2a或MTAP蛋白活性或表达相关的疾病的方法，其包括：向有需要的个体施用治疗有效量的如前任一项所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药、或如前任一项所述的药物组合物；特别是治疗和/或预防肿瘤或自身免疫性疾病。
所述的肿瘤独立地选自肺癌、胰腺癌、肝癌、结直肠癌、胆管癌、胆囊癌、脑癌、胃癌、白血病、淋巴癌、黑色素瘤、甲状腺癌、鼻咽癌、胶质瘤、膀胱癌、星形细胞瘤、基底细胞癌、骨肉瘤、头颈癌、软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤和间皮瘤等；所述的自身免疫性疾病独立地选自甲状腺炎、炎性肠炎、红斑狼仓、纤维化、肌无力、血管炎、银屑病、关节炎、硬皮病、皮炎等。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明涉及具有通式(I)结构特征的化合物，可以抑制MAT2a的酶活，显著抑制多种肿瘤细胞的生长，特别是MTAP缺失相关的肿瘤细胞，是一类全新作用机制的治疗药物。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
如无特别说明，本发明所用术语具有如下含义：
本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中 所使用的
Figure PCTCN2021119638-appb-000045
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
术语“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
术语“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本发明中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
术语“多个”是指2个、3个、4个或5个，优选为2个或3个。
当任意变量(例如Rn)在化合物的定义中多次出现时，该变量每一位置出现的定义与其余位置出现的定义无关，它们的含义互相独立、互不影响。因此，若某基团被1个、2个或3个Rn基团取代，也就是说，该基团可能会被最多3个Rn取代，该位置Rn的定义与其余位置Rn的定义是互相独立的。另外，取代基及/或变量的组合只有在该组合 产生稳定的化合物时才被允许。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。
术语“烷氧基”是指基团-O-R M，其中，R M为如上文所定义的烷基。
术语“烯基”是指具有特定碳原子数的含一个或多个碳碳双键并且没有碳碳三键的直链或支链的烯烃，该一个或多个碳碳双键可以是内部的也可以是末端的，烯烃的实例包括乙烯基、烯丙基、甲基乙烯基、丙烯基、丁烯基、戊烯基、1,1-二甲基-2丙烯基、己烯基等。
术语“炔基”是指具有特定碳原子数的一个或多个叁键的直链或支链的烃基(例如C 2-C 8炔基，又例如C 2-C 4炔基)。该一个或多个碳碳叁键可以是内部的也可以是末端的，例如叁键在内部的丙炔基
Figure PCTCN2021119638-appb-000046
或叁键在末端的丙炔基
Figure PCTCN2021119638-appb-000047
等。
术语“环烷基”是指单环、螺环或桥环的饱和的环状烷基，优选具有3-12个环碳原子、更优选3-6个碳原子的单环、螺环或桥环的饱和的环状烷基，例如环丙基、环丁基、环戊基或环己基。
术语“杂环烷基”是指具有杂原子的单环、螺环或桥环的饱和的环状基团，优选含有1个、2个或3个独立选自N、O和S的环杂原子的3-10元饱和的单环、螺环或桥环。杂环烷基的示例为：
Figure PCTCN2021119638-appb-000048
四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。优选的杂环基为
Figure PCTCN2021119638-appb-000049
吗啉-4-基、哌啶-1-基、吡咯烷-1-基、硫代吗啉-4-基和1,1-二氧代-硫代吗啉-4-基。
术语“芳基”是指C 6-C 10芳基，例如苯基或萘基。
术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族5-6元单环或9-10元双环，当为双环时，至少有一个环具有芳香性，例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、***基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、 吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基、
Figure PCTCN2021119638-appb-000050
等。
术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本发明中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物 作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organic Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：2-氧代-1-苯基-4-(4-吡咯啉-1-基)-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲氰
Figure PCTCN2021119638-appb-000051
第一步：氮气保护下，氢化钠(NaH)(890mg,22.22mmol)加入到2-氰基乙酰苯胺(0.89g,5.56mmol)的四氢呋喃(THF)(30mL)中，室温搅拌10分钟后，然后慢慢加入2-氯-6-三氟甲基烟酰氯(1.63g，6.67mmol)的四氢呋喃溶液(5mL)。反应混合液升温到70度，再继续反应4小时。LC-MS检测反应完成后，用乙酸乙酯(EA)(200mL)稀释反应液，氯化钠(NaCl)溶液洗涤有机相。有机相用无水硫酸钠干燥， 过滤，滤液浓缩后，粗产品经硅胶柱层析(洗脱剂：二氯甲烷/甲醇体积比9/1)纯化得到中间体产物(950mg，淡黄色固体)。LC-MS(ESI)m/z:353.9[M+Na] +。 1H-NMR(400MHz,DMSO-d 6)δ8.47(dd,J＝7.8,0.7Hz,1H),7.52(d,J＝7.8Hz,1H),7.48-7.43(m,2H),7.41-7.38(m,1H),7.20-7.18(m,2H)。
第二步：室温下，N,N-二异丙基乙胺(DIPEA)(0.74g,5.738mmol)加入到上一步中间体产物的三氯氧磷(POCl 3)(15mL)溶液中。在氮气保护下，反应混合液在100度下反应16小时。LC-MS检测原料反应完全。减压-旋蒸-除去过量的三氯氧磷，剩余物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯体积比4/1)纯化得到中间体产物(700mg,浅黄色固体)。LC-MS(ESI)m/z:349.9[M+H] +。 1H-NMR(400MHz,DMSO-d 6)δ8.80(d,J＝7.9Hz,1H),7.95(d,J＝8.2Hz,1H),7.64-7.54(m,2H),7.54-7.46(m,1H),7.34(dt,J＝8.7,2.6Hz,2H)。
第三步：室温下，四氢吡咯(356mg,5.01mmol)加入到上一步中间体(350mg,1.0mmol)和N,N-二异丙基乙胺(389mg,3.01mmol)的四氢呋喃(10mL)中,氮气保护下反应混合液在室温下反应2小时。LC-MS检测原料基本消失。减压旋蒸除去多余的四氢呋喃，用乙酸乙酯(100mL)稀释反应液，氯化钠溶液洗有机相。分离的有机相用无水硫酸钠干燥后过滤，滤液浓缩。粗产品经HPLC制备后得到实施例1化合物(224.7mg，白色固体)。LC-MS(ESI)m/z:385.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.78(d,J＝8.3Hz,1H),7.64(d,J＝8.4Hz,1H),7.55-7.47(m,2H),7.44(dt,J＝9.6,4.3Hz,1H),7.24(dd,J＝5.2,3.2Hz,2H),4.05(t,J＝6.4Hz,4H),1.99(t,J＝6.4Hz,4H)。
实施例2：2-氧代-1-苯基-4-(4-吡咯啉-1-基)-7-(三氟甲基)-1,2-二氢-1,8-喹啉-3-甲氰
Figure PCTCN2021119638-appb-000052
第一步：在氮气保护下，三(二亚苄基丙酮)二钯(Pd 2(dba) 3)(3.26g,3.559mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)(2.06g,3.56mmol)依次加入到2-胺基-4-三氟甲基苯甲酸甲酯(7.8g,35.59mmol)，碘苯(7.26g,35.59mmol)和碳酸铯(34.79g,106.77mmol)的1,4-二氧六环(150mL)溶液中。反应混合液加热到100℃并在此温度下反应16小时。乙酸乙酯(500mL)稀释反应液，硅藻土过滤，滤液减压浓缩后经硅胶柱层析(石油醚:乙酸乙酯体积比20:1)纯化得到中间体产物(8.6g,淡黄色固体)。LC-MS(ESI)m/z:296.0[M+H] +。 1H-NMR(400MHz,CDCl 3)δ9.59(s,1H),8.06(d, J＝8.3Hz,1H),7.45-7.35(m,3H),7.21-7.24(m,2H),7.17-7.18(m,1H),6.92(dd,J＝8.3,1.3Hz,1H),3.94(s,3H)。
第二步：氮气保护下，氢化钠(610mg,15.24mmol)加入到上述中间体(1.5g,5.079mmol)的N,N-二甲基甲酰胺DMF(30mL)中。反应半小时后，慢慢加入氰乙酰氯(5.26g，50.8mmol)，反应在室温下搅拌过夜。LC-MS检测基本反应完全。加入乙酸乙酯(200mL)稀释反应液，用氯化钠溶液洗有机相。分离的有机相经无水硫酸钠干燥，滤液浓缩后经硅胶柱层析(二氯甲烷/甲醇体积比9/1)纯化得到中间体产物(670mg,浅红色固体)。LC-MS(ESI)m/z:330.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝8.0Hz,1H),7.57-7.58(m,2H),7.50-7.52(m,1H),7.34(dd,J＝8.1,1.1Hz,1H),7.27(m,2H),6.51(s,1H)。
第三步：室温下，N,N-二异丙基乙胺(1.02g,7.878mmol)加入到上述中间体(650mg,1.970mmol)的三氯氧磷(15mL)溶液中。在氮气保护下，反应混合液在100度下反应2小时。LC-MS检测原料基本消失。减压旋蒸除去多余的三氯氧磷后，粗产物经硅胶柱层析(石油醚/乙酸乙酯体积比4/1)纯化得到中间体产物(310mg,浅黄色固体)。LC-MS(ESI)m/z:348.9[M+H] +。 1H-NMR(400MHz,DMSO-d 6)δ8.37(d,J＝8.5Hz,1H),7.81(dd,J＝8.5,1.3Hz,1H),7.74-7.61(m,3H),7.49-7.41(m,2H),6.76(s,1H)。
第四步：室温下，四氢吡咯(311mg,4.382mmol)加入到上述中间体(305mg,0.876mmol)和N,N-二异丙基乙胺(340mg,2.628mmol)的四氢呋喃(5mL)中,反应混合液在室温下反应2小时。LC-MS检测反应基本完全。减压旋蒸除去多余的四氢呋喃后，用乙酸乙酯(100mL)稀释反应液，氯化钠溶液洗有机相。分离的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品经HPLC制备后得到实施例2化合物(114.21mg,白色固体)。LC-MS(ESI)m/z:384.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.34(d,J＝8.6Hz,1H),7.64(dd,J＝8.1,6.7Hz,2H),7.60-7.54(m,1H),7.50(dd,J＝8.6,1.4Hz,1H),7.39-7.31(m,2H)，6.62(s,1H),4.04(t,J＝6.4Hz,4H),1.98(t,J＝6.4Hz,4H)。
实施例3：7-氯-2-氧代-1-苯基-4-(4-吡咯啉-1-基)-1,2-二氢喹啉-3-甲氰
Figure PCTCN2021119638-appb-000053
第一步：在氩气保护下，向2-氨基-4氯苯甲酸甲酯(5g，26.9mmol)，碘苯(6.5g，31.9mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos)(1.56g，2.7mmol)和碳酸铯(17.5g，53.8mmol)的1，4-二氧六环(100mL)溶液中加入Pd 2(dba) 3(1.23g，2.7 mmol)。该反应混合物在100℃反应16小时。LC-MS检测反应结束后，混合物溶液用乙酸乙酯(200mL)稀释，氯化钠溶液洗有机相。分离的有机相用无水硫酸钠干燥，过滤后浓缩。粗产品经硅胶层析柱(石油醚：乙酸乙酯体积比50:1到20:1)纯化得到中间体产物(5.2g，淡黄色固体)。LC-MS:(ESI)m/z＝262.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ9.53(s,1H),7.87(d,J＝8.6Hz,1H),7.37(m,2H),7.24(t,J＝5.4Hz,2H),7.18-7.11(m,2H),6.67(dd,J＝8.6,2.0Hz,1H),3.88(d,J＝10.5Hz,3H)。
第二步：在冰水冷却下，将2-氰基乙酰氯(400mg,3.88mmol)滴加入化合物上述中间体(1g，3.8mmol)和三乙胺(TEA)(405mg，4.0mmol)的无水二氯甲烷(5mL)溶液中，然后于室温下反应过夜。LC-MS检测反应完全后，加入水(20mL)。反应混合物用乙酸乙酯(20mL)萃取三次。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩。粗产品经硅胶层析柱(石油醚：乙酸乙酯体积比3:1到1:1)纯化得到中间体化合物(300mg，淡黄色固体)。LC-MS:(ESI)m/z＝329.0[M+H] +。
第三步：在室温下，向上述中间体(250mg，0.8mmol)和DMF(8mL)的100mL溶液中加入碳酸钾(526mg，3.8mmol)。将该混合物于80℃下反应1小时。LC-MS检测应结束后，用(1N)盐酸水溶液调节溶液pH调至4，有淡黄色固体析出，过滤并干燥后得到中间体产物(200mg，淡黄色固体)。LC-MS:(ESI)m/z＝297.0[M+H] +。
第四步：在室温下，向上述中间体(200mg,0.67mmol)的三氯氧磷(8mL)溶液中加入二异丙基乙基胺(474mg,5.0mmol)。在氩气保护下，该反应混合物在120℃反应2小时。减压浓缩除去过量的三氯氧磷，得到棕色油状粗产物(200mg)。该粗品无需纯化，直接用于下一步反应。LC-MS:(ESI)m/z＝350.0[M+H] +。
第五步：在室温下，向装有上述中间体(200mg,0.63mmol)和二异丙基乙基胺(178mg,1.36mmol)的二氯甲烷(8mL)溶液中加入四氢吡咯(98mg,1.36mmol)。该混合物于室温下反应2小时。LC-MS检测反应结束后，向反应液中加入水(20mL)，然后用二氯甲烷(20mL)萃取三次，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。粗产品经硅胶层析柱(二氯甲烷：甲醇体积比40:1到20:1)纯化得到实施例3化合物(125.9mg,浅白色固体)。LC-MS:(ESI)m/z＝350.0[M+H] +。 1H-NMR(400MHz,DMSO-d 6)δ8.14(d,J＝8.9Hz,1H),7.65-7.59(m,2H),7.59-7.52(m,1H),7.34-7.28(m,2H),7.24(dd,J＝8.9,2.2Hz,1H),6.36(d,J＝2.2Hz,1H),4.02(t,J＝6.4Hz,4H),1.97(t,J＝6.4Hz,4H)。
以不同的苯胺、脂肪胺为原料，参照实施例1-3的方法合成，得到实施例4-35；
Figure PCTCN2021119638-appb-000054
Figure PCTCN2021119638-appb-000055
Figure PCTCN2021119638-appb-000056
Figure PCTCN2021119638-appb-000057
Figure PCTCN2021119638-appb-000058
实施例36-38的制备
Figure PCTCN2021119638-appb-000059
第一步：在室温下，向装有4-氯-2-氧代-1-苯基-7三氟甲基-1，2-二氢喹啉-3-甲氰(246mg,1.43mmol)和二异丙基乙基胺(178mg,1.36mmol)的四氢呋喃(10mL)溶液中加入3-氨基氮杂环丁烷-1-甲酸叔丁酯(300mg,0.86mmol)。该混合物于室温下反应2小时。LC-MS检测反应结束后，向反应液中加入水(20mL)，然后用二氯甲烷(20mL)萃取三次，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩。粗产品经硅胶层析柱(洗脱剂：二氯甲烷/甲醇体积比从40:1到20:1)纯化得到实施例36化合物(125.9mg,浅白色固体)。LCMS(ESI)m/z:485.2[M+H] +. 1H NMR(400MHz,DMSO)δ8.60(d,J＝8.4Hz, 1H),7.68-7.56(m,4H),7.36(d,J＝7.6Hz,2H),6.63(s,1H),4.97(m,1H),4.27-4.25(m,2H),4.18-4.15(m,2H),1.42(s,9H)。
第二步：室温下，三氟乙酸(2ml)加入到上述化合物(200mg,0.286mmol)的二氯甲烷(10mL)溶液中。反应混合液室温下反应2小时。二氯甲烷(100mL)稀释反应液，饱和碳酸氢钠溶液(100mL)洗涤，分离有机相并用无水硫酸钠干燥。过滤后，有机相减压浓缩,粗产物经硅胶柱层析(洗脱剂：二氯甲烷/甲醇体积比为10：1)得到实施例37化合物(100mg)。LCMS(ESI)m/z:384.9[M+H] +. 1H NMR(400MHz,DMSO)δ8.65(d,J＝8.2Hz,1H),7.61(m,4H),7.35(d,J＝7.2Hz,2H),6.62(s,1H),5.05(m,1H),3.86(m,4H)。
第三步：室温下，醋酸1滴加入到上述化合物(50mg,0.13mmol)，甲醛水溶液(208mg,0.286mmol)的甲醇(10mL)溶液中。反应混合液室温下反应1小时，氰基硼氢化钠(53mg,0.832mmol)加入反应液中，继续室温反应1小时，溶剂旋干，乙酸乙酯(100mL)溶解，饱和碳酸氢钠溶液(100mL)洗，干燥，过滤，有机相旋干,粗产物经HPLC制备得到实施例38化合物(12.8mg)。LCMS(ESI)m/z:399.0[M+H] +. 1H NMR(400MHz,DMSO)δ8.64(d,J＝8.5Hz,1H),8.45(d,J＝5.7Hz,1H),7.70-7.56(m,4H),7.36(d,J＝7.1Hz,2H),6.63(s,1H),4.78(m,1H),3.64(m,2H),3.46-3.38(m,2H),2.33(s,3H)。
实施例39：4-((1-异丙基氮杂环丁烷-3-基)氨基)-2-氧代-1-苯基-7-三氟甲基-1，2-二氢喹啉-3-甲氰
Figure PCTCN2021119638-appb-000060
室温下，滴加一滴醋酸到实施例37化合物(50mg,0.13mmol)，丙酮(23mg,0.39mmol)的甲醇(10mL)溶液中，反应混合液在室温下反应2小时。氰基硼氢化钠(25mg,0.39mmol)加入到反应液中，继续室温反应2小时。LCMS检测原料消失。减压浓缩去除溶剂，乙酸乙酯(100mL)溶解后，加入水(100mL)。用乙酸乙酯(100mL)萃取2次，合并的有机相干燥后减压浓缩,所得粗产物经HPLC制备分离得到白色固体实施例39化合物(19.5mg)。LCMS(ESI)m/z:427.0[M+H] +。 1H NMR(400MHz,DMSO)δ8.64(d,J＝8.0Hz,1H),8.41(s,1H),7.65-7.55(m,4H),7.36-7.34(d,J＝8.0Hz,2H),6.63(s,1H),4.71-4.68(m,1H),3.61-3.57(m,2H),3.32-3.30(m,2H),2.40-2.33(m,1H),0.9(d,J＝6.8Hz,6H)。
实施例40：4-((1-乙酰基氮杂环丁烷-3-基)氨基)-2-氧代-1-苯基-7-三氟甲基-1，2-二氢喹啉-3-甲氰
Figure PCTCN2021119638-appb-000061
室温下，向实施例37化合物(50mg,0.13mmol)，1-乙基-3(3-二甲基丙胺)碳二亚胺EDCI(50mg,0.26mmol)，1-羟基苯并***HOBT(26mg,0.195mmol)的二氯甲烷(10mL)溶液中，加入乙酸(32mg,0.52mmol)。反应混合液在室温下搅拌3小时。LCMS检测反应完全。二氯甲烷(100mL)稀释反应液，混合物溶液用饱和食盐水(100mL)洗。分离的有机相用无水硫酸钠干燥后，减压浓缩,粗产物经HPLC制备分离得到白色固体实施例40化合物(30.8mg)。LCMS(ESI)m/z:426.9[M+H] +。 1H NMR(400MHz,DMSO)δ8.60-8.57(m,2H),7.69-7.56(m,4H),7.37-7.35(d,J＝8.0Hz,2H),6.64(s,1H),5.02(m,1H),4.57-4.52(m,1H),4.40-4.36(m,1H),4.28-4.24(m,1H),4.19-4.18(m,1H),1.83(s,3H)。
以不同的脂肪胺为原料，参照实施例1-3的方法合成，得到实施例41-43：
Figure PCTCN2021119638-appb-000062
实施例44：1-(4-氯苯)-2-氧代-4-((3-氧代环丁基)氨基)-7-(三氟甲基)-1,2-二氢喹啉-3-甲氰
Figure PCTCN2021119638-appb-000063
第一步：室温下，草酰氯(7.24g,57.02mmol)加入到氰乙酸(2.4g,28.51mmol)的二氯甲烷(30mL)中,再加入五滴N,N-二甲基甲酰胺，反应混合液在此温度下反应2小时。另一个反应瓶中，氢化钠(342.1mg,8.553mmol)加入到2-((4-氯苯)氨基)-4-三氟甲基苯甲酸甲酯(940mg,2.851mmol)的N,N-二甲基甲酰胺(30mL)中，反应半小时后，加入上面制得的氰乙酰氯浓缩液，反应室温过夜。LCMS检测到反应产物为主，乙酸乙酯(200mL)稀释反应液，饱和氯化钠水溶液洗涤有机相。分离的有机相经无水硫酸钠干燥后，减压浓缩。所得粗产品经硅胶柱层析(洗脱剂:二氯甲烷/甲醇体积比为10:1)纯化得到浅红色固体中间体化合物(520mg)。LCMS(ESI)m/z:364.9[M+H] +. 1H NMR(400MHz,DMSO)δ8.17(d,J＝8.1Hz,1H),7.67-7.61(m,2H),7.38-7.34(m,2H),7.33(d,J＝2.0Hz,1H),6.54(s,1H).
第二步：室温下，N,N-二异丙基乙胺(99.39mg,5.699mmol)加入到上述中间体化合物(520mg,1.426mmol)的三氯氧磷(8mL)中,氮气保护下反应混合液在100℃下反应2小时。LCMS检测没有原料，大部分都转化为所需要的产物。减压旋蒸除去多余的三氯氧磷，粗产物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯体积比为4:1)纯化得到浅黄色固体中间体化合物(200mg)。LCMS(ESI)m/z:382.9[M+H] +.
第三步：室温下，3-氨基环丁烷-1-酮(190mg,1.570mmol)加入到上述中间体化合物(120mg,0.314mmol),N,N,-二异丙基乙胺(122mg,0.942mmol)的四氢呋喃(5mL)中,反应混合液在20度下反应2小时。LCMS检测没有原料，大部分都转化为所需要的产物。减压旋蒸除去多余的四氢呋喃，用乙酸乙酯(100mL)稀释反应液，饱和氯化钠水溶液洗涤有机相。分离的有机相分经无水硫酸钠干燥后，减压浓缩，所得粗产品经HPLC制备纯化得到白色固体实施例44化合物(90mg)。LCMS(ESI):m/z 431.9[M+H] +。 1H NMR(400MHz,DMSO)δ8.58(d,J＝8.7Hz,1H),8.53(d,J＝6.2Hz,1H),7.79-7.62(m,3H),7.47-7.34(m,2H),6.68(s,1H),5.13-4.99(m,1H),3.59(d,J＝6.4Hz,4H)。
实施例45a和45b：1-(4-氯苯)-4-((反式-3-氟环丁基)氨基)-2-氧代-7-三氟甲基-1,2-二氢喹啉-3-甲氰和1-(4-氯苯)-4-((顺式-3-氟环丁基)氨基)-2-氧代-7-三氟甲基-1,2-二氢喹啉-3-甲氰
Figure PCTCN2021119638-appb-000064
第一步：室温下，硼氢化钠(31mg,0.810mmol)加入到实施例44化合物(70mg,0.16 mmol)的乙醇(5mL)中,反应混合液在20度下反应2小时。LCMS检测没有原料，大部分都转化为所需要的产物。减压旋蒸除去多余的乙醇，乙酸乙酯(100mL)稀释反应液，用饱和氯化钠溶液洗涤有机相。分离的有机相经无水硫酸钠干燥，减压浓缩后，所得粗产品经HPLC制备纯化后得到白色固体实施例31化合物(55mg)。LCMS(ESI):m/z 433.9[M+H] +. 1H NMR(400MHz,DMSO)δ8.63(m,1H),8.26(m,1H),7.68(m,3H),7.42(d,J＝8.6Hz,2H),6.64(s,1H),5.23(m,1H),4.78(m,1H),4.41-4.27(m,1H),2.82-2.62(m,2H),2.39-2.25(m,2H).
第二步：室温下，二乙胺基三氟化硫(1mL)加入到上述化合物(35mg,0.081mmol)的二氯甲烷(5mL)中,反应混合液在20度下反应2小时。LCMS检测没有原料，大部分都转化为所需要的产物。碳酸氢钠淬灭反应，二氯甲烷(100mL)稀释反应液，饱和氯化钠溶液洗涤有机相，分离的有机相经无水硫酸钠干燥，减压浓缩得到白色固体实施例45化合物(28mg)。LCMS(ESI)m/z:435.9/437.9[M+H] +。
该粗品经Prep-TLC制备(洗脱剂：氯仿/甲醇体积比为10:1)纯化后得到白色固体实施例45a(Rf＝0.4,2.39mg)和实施例45b(Rf＝0.3,3.12mg)。
分析条件：分析柱(Waters SunFire C18，4.6*50mm，5um)；梯度(5％-95％乙腈/0.1％甲酸/水，3.0min，流速2.0mL/min，2.6min)；柱温：40℃；检测波长：254nM。
化合物45a:LCMS(Rt＝1.894min)(ESI)m/z:435.9[M+H] +。 1H NMR(400MHz,DMSO)δ8.60(d,J＝8.5Hz,1H),8.43-8.27(m,1H),7.69(t,J＝7.8Hz,3H),7.42(d,J＝8.6Hz,2H),6.65(s,1H),5.00(m,1H),4.44-4.31(m,1H),3.05-2.89(m,2H),2.79-2.58(m,2H)。
化合物45b：LCMS(Rt＝1.872min)(ESI)m/z:435.9[M+H] +。 1H NMR(400MHz,DMSO)δ8.57(d,J＝8.6Hz,1H),8.31(s,1H),7.69(t,J＝9.2Hz,3H),7.42(d,J＝8.6Hz,2H),6.65(s,1H),5.54-5.22(m,1H),4.97(s,1H),2.90-2.65(m,4H).
以不同脂肪胺为原料，参照上述实施例的方法合成，得到实施例46-63：
Figure PCTCN2021119638-appb-000065
Figure PCTCN2021119638-appb-000066
Figure PCTCN2021119638-appb-000067
Figure PCTCN2021119638-appb-000068
以不同的脂肪胺为原料，参照上述实施例的方法合成，得到实施例64-71：
Figure PCTCN2021119638-appb-000069
Figure PCTCN2021119638-appb-000070
以不同的脂肪胺如环丁烷胺、氮杂环丁胺为原料，参照上述实施例1-3,38等的方法合成，得到实施例72-76；
Figure PCTCN2021119638-appb-000071
Figure PCTCN2021119638-appb-000072
实施例77a和77b的制备
Figure PCTCN2021119638-appb-000073
第一步：室温下，草酰氯(4.97g,37.0mmol)加入到2-氯-6-三氟甲基烟酸(4.17g,18.5mmol)的二氯甲烷(150mL)中,加3滴N,N-二甲基甲酰胺，反应混合液在此温度下反应2小时。另一个反应瓶中，氢化钠(3.7g,61.66mmol)加入到N-(4-氯苯)-2-氰基乙酰胺(3g,15.42mmol)的N,N-二甲基甲酰胺(80mL)中，反应半小时后，加入上面制得的反应浓缩液，反应在室温下搅拌过夜。LCMS检测到反应产物为主，乙酸乙酯(200mL)稀释反应液后，饱和氯化钠溶液洗涤有机相。分离的有机相分，用无水硫酸钠干燥后，减压浓缩。所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/甲醇体积比为20:1到10:1)纯化得到浅红色固体化合物(4.1g,粗品)。LCMS(ESI)m/z:366.0[M+H] +。 1H NMR(400MHz,DMSO)δ8.49(d,J＝7.8Hz,1H),7.58-7.49(m,3H),7.31-7.23(m,2H).
第二步：室温下，N,N-二异丙基乙胺(5.8g,44.84mmol)加入到上述中间体化合物(4.1g,11.21mmol)的三氯氧磷(20mL)中,氮气保护下反应混合液在100℃下反应2小时。LCMS检测没有原料，大部分都转化为所需要的产物。减压旋蒸除去多余的三氯氧磷，剩余物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯体积比为4:1)纯化得到浅黄色固体中间体化合物(1.68g)。LCMS(ESI)m/z:383.9/385.9[M+H] +。 1H NMR(400MHz,DMSO)δ8.81(d,J＝8.1Hz,1H),7.97(d,J＝8.2Hz,1H),7.69-7.62(m,2H),7.43-7.36(m,2H)。
第三步：室温下，3-氨基-环丁基-1酮(152mg,1.25mmol)加入到上述中间体化合物(50mg,0.13mmol)，N,N-二异丙基乙胺(162mg,1.25mmol)的四氢呋喃(5mL)中,反应混 合液在20℃下反应2小时。LCMS检测没有原料，大部分都转化为所需要的产物。减压旋蒸除去多余的四氢呋喃后，用乙酸乙酯(100mL)稀释反应液，饱和氯化钠溶液洗涤有机相。分离的有机相经无水硫酸钠干燥后，减压浓缩，所得粗产物经HPLC制备纯化后得到实施例77a(白色固体，9.7mg)。LCMS(ESI)m/z:433.0[M+H] +。 1H NMR(400MHz,DMSO)δ9.02(d,J＝8.3Hz,1H),8.63(d,J＝6.1Hz,1H),7.90(d,J＝8.3Hz,1H),7.62-7.54(m,2H),7.36-7.29(m,2H),5.04(m,1H),3.64-3.51(m,4H).
第四步：在冰浴冷却下，甲基溴化镁(50mg,0.3mmol)滴加到上述中间体化合物(100mg,0.23mmol)的四氢呋喃(10mL)溶液中。在冰浴冷却下反应1小时。向反应液中加入水(70mL)，然后用乙酸乙酯(100mL)萃取2次。合并的有机相用无水硫酸钠干燥，过滤后，减压浓缩，所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/甲醇体积比为10:1)纯化得到实施例77b化合物(白色固体，70mg)。LC-MS(ESI)m/z:449.1/451.1[M+H] +. 1H NMR(400MHz,DMSO)δ9.07(m,1H),8.46(m,1H),8.87-8.83(m,1H),7.56(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),5.16(s,1H),4.42(m,1H),2.62-2.38(m,4H),1.33(s,3H)。
以不同的脂肪胺如环丁烷胺、氮杂环丁胺为原料，参照实施例1-3、45a/45b、77a/77b等的方法合成，得到实施例78-85；
Figure PCTCN2021119638-appb-000074
Figure PCTCN2021119638-appb-000075
实施例86和87：1-(4-氯苯)-4-(((顺式)-3-氟-(3-甲基环丁基)氨基)-2-氧代-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲氰和1-(4-氯苯)-4-(((反式)-3-氟-(3-甲基环丁基)氨基)-2-氧代-7-(三氟甲基)-1,2-二氢-1,8-萘啶-3-甲氰
Figure PCTCN2021119638-appb-000076
室温下，将二乙胺基三氟化硫(84mg,0.65mmol)加入到上述实施例77b化合物(50mg,0.13mmol)二氯甲烷(10mL)溶液中。反应混合液在室温下反应2小时。二氯甲烷(100 mL)稀释反应液，再加入水(100mL)，然后用二氯甲烷(100mL)萃取2次。合并的有机相经无水硫酸钠干燥后，减压浓缩。所得粗产品经Prep-TLC(洗脱剂：氯仿/甲醇体积比为4:1)纯化得到实施例86化合物(白色固体，1.52mg)和实施例87化合物(白色固体，1.12mg)。
分析条件：分析柱(Waters SunFire C18，4.6*50mm，5um)；梯度(5％-95％乙腈/0.1％甲酸/水，3.0min，流速2.0mL/min，2.6min)；柱温：40℃；检测波长：254nM。
实施例86:LCMS(Rt＝1.867min)(ESI)m/z:451.0[M+H] +。 1H NMR(400MHz,DMSO)δ9.03(d,J＝8.3Hz,1H),8.50(d,J＝6.6Hz,1H),7.87(d,J＝8.3Hz,1H),7.57(d,J＝8.6Hz,2H),7.31(d,J＝8.6Hz,2H),4.46(m,1H),2.82-2.69(m,4H),1.49(d,J＝22.4Hz,3H).
实施例87:LCMS(Rt＝1.855min)(ESI)m/z:451.0[M+H] +。 1H NMR(400MHz,DMSO)δ9.02(d,J＝8.0Hz,1H),8.40(m,1H),7.87(d,J＝7.8Hz,1H),7.57(d,J＝8.5Hz,2H),7.31(d,J＝8.4Hz,2H),4.92(m,1H),2.85-2.76(m,2H),2.70-2.55(m,2H),1.55(d,J＝20Hz,3H).
以不同的脂肪胺如环丁烷胺、氮杂环丁胺为原料，参照实施例1-3、77、87等的方法合成，得到实施例88-103；
Figure PCTCN2021119638-appb-000077
Figure PCTCN2021119638-appb-000078
Figure PCTCN2021119638-appb-000079
参考专利文献WO2020123395A1的合成方法合成下面对比化合物1-4。
Figure PCTCN2021119638-appb-000080
Figure PCTCN2021119638-appb-000081
测试例1MAT2a酶抑制活性测试
采用Colorimetric Assay测试实施例化合物对MAT2a的酶抑制活性，测试步骤如下：1)、利用标准反应缓冲液(Tris,pH 8.0,50mM KCl,15mM MgCl 2,300uM EDTA,0.005％w/v的牛血洁白蛋白)配置10个化合物浓度梯度：受试化合物测试浓度为10uM起始，3倍稀释,10个浓度，单孔测试。在384孔板中梯度稀释成100倍终浓度的10个不同浓度的溶液。然后用Echo 550转移250nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加250nL的100％DMSO。2)、用标准反应缓冲液配制1.67倍终浓度的酶溶液。3)、在化合物孔和阳性对照孔分别加15μL的1.67倍终浓度的酶溶液；在阴性对照孔中加15μL的标准反应缓冲液。4)、1000rpm离心60秒，振荡混匀后孵育15分钟。5)、用标准反应缓冲液配制2.5倍终浓度的底物混合溶液。6)、加入10μL的2.5倍终浓度的底物混合溶液，起始反应。7)、将384孔板1000rpm离心60秒，振荡混匀后孵育150分钟。8)、加入50μL Biomol终止反应，1000rpm离心60秒后孵育15分钟。读取OD620，处理数据。9)、数据分析：计算公式％Inhibition＝(OD 620_max–OD 620_sample)/(OD 620_max–OD 620_min)x 100；其中：OD 620_sample是样品孔吸光值；OD 620_min：阴性对照孔吸光值，代表没有酶活孔的读数；OD 620_max：阳性对照孔吸光值，代表没有化合物抑制孔的读数。10)、拟合量效曲线：以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。
结果：本发明大部分实施例化合物具有较高的MAT2a抑制活性，IC 50均小于200nM，部分实施例的IC 50甚至小于20nM,明显优于对比化合物3和4。(A<100nM，100nM≤B<500nM，C≥500nM)
编号 MAT2a IC 50(nM) 编号 MAT2a IC 50(nM) 编号 MAT2a IC 50(nM)
1 119.7 2 75.5 3 69.9
4 C 5 B 6 C
7 C 8 B 9 C
10 C 11 C 12 B
13 C 14 C 15 C
16 C 17 C 18 C
19 C 20 C 21 76.9
22 C 23 C 24 407
25 17.1 26 20.8 27 32.2
28 305 29 31.9 30 74.6
31 16.6 32 A 33 178
34 17.3 35 42.0 36 56.7
37 B 38 19.1 39 B
40 38.6 41 25.5 42 C
43 13.3 44 18.5 45 A
45a 16.3 45b 16.1 46 A
47 A 48 A 49 B
50 20.8 51 A 52 24
53 B 54 31.6 55 48.7
56 38.6 57 B 58 B
59 B 60 B 61 20.8
62 A 63 A 64 33
65 B 66 B 67 A
68 A 69 A 70 A
71 A 72 15.3 73 23.5
74 23.1 75 A 76 A
77a/77b 18.6/20.1 78 A 79 A
80 A 81 13.6 82 17.2
83 16.3 84 17.3 85 15.8
86 16.3 87 14.7 88 15.7
89 B 90 B 91 A
92 A 93 32 94 76
95 B 96 25.1 97 26.5
98 A 99 41 100 B
101 77.9 102 65.5 103 B
104 B 对照1 10.9 对照2 11.1
对照3 B 对照4 39.1    
测试例2：实施例化合物对HCT-116 wt和HCT-116 MTAP-细胞的增殖抑制作用。
1)、实验试剂
Figure PCTCN2021119638-appb-000082
2、细胞株
细胞系 培养类型 来源 培养基
HCT116 MTAP 贴壁型 Horizon RPMI-1640+10％FBS
HCT116wt 贴壁型 Horizon RPMI-1640+10％FBS
3、测试方法：1)取处于对数生长期的HCT-116 wt/HCT116 MTAP-细胞(Horizon)按合适密度接种至96孔培养板中，每孔80μL，培养过夜后，加入不同浓度的化合物作用4hr，并设定溶剂对照组(阴性对照)。2)待化合物作用细胞120hr后，化合物对细胞增殖的影响采用CTG细胞计数试剂盒检测，每孔加入40μL CTG试剂，置于37℃培养箱中放置60min后，用PerkinElmer公司的Multilabel Reader酶标仪读数。3)采用以下公式计算化合物对肿瘤细胞生长的抑制率(％):抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC 50值采用酶标仪随机附带软件GraphPad Prism5以四参数法回归求得。
结果：本发明大部分实施例化合物对HCT-116 MTAP-细胞增殖抑制IC 50小于1uM，如实施例25、26、34、45b、72、77a、81、82、83、85、86、88等的抑制活性IC 50更是小于200nM，明显优于对比化合物4；并且本发明部分实施例化合物对HCT-116 wt细胞的增殖抑制活性IC 50大于5uM，显示了较高的细胞选择性。
Figure PCTCN2021119638-appb-000083
Figure PCTCN2021119638-appb-000084
测试例3：实施例化合物的ADMET测试
(1)代谢稳定性试验：用体系为150μL的肝微粒体(终浓度0.5mg/mL)进行代谢稳定性温孵，体系含NADPH(终浓度1mM)、1μM受试化合物和阳性对照咪达***或阴性对照阿替洛尔，分别在0min、5min、10min、20min和30min用含替硝唑的乙腈终止反应，涡旋10min，15000rmp离心10min，取50μL上清于96孔板中进样。通过测定原药的相对减少量计算化合物代谢稳定性。
结果：本发明实施例化合物对各种属(如大鼠、小鼠、狗、猴、人)肝微粒体稳定性较高，半衰期大于30min，如实施例化合物25、43、83、85、86、88等。
Figure PCTCN2021119638-appb-000085
Figure PCTCN2021119638-appb-000086
测试例4：实施例化合物在小鼠体内药代动力学参数测试
6只雄性SPF级Balb c小鼠(上海西普尔-必凯实验动物)分成两组，受试化合物配置成合适溶液或混悬液；一组静脉注射给药，一组口服给药。经颈静脉穿刺采血，每个样品采集约0.2mL/时间点，肝素钠抗凝，采血时间点如下：给药前及给药后5、15和30min，1、2、4、6、8和24h；血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)，收集的血浆分析前存放于-80℃。血浆样品采用LC-MS/MS进行分析。
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数AUC 0-t、AUC 0-∞、MRT 0-∞、C max、T max、T 1/2和V d等参数及其平均值和标准差。此外，生物利用度(F)将通过下面的公式进行计算。
Figure PCTCN2021119638-appb-000087
对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到Cmax以前取样的样品应以零值计算，在达到C max以后取样点样品应以无法定量(BLQ)计算。
结果显示，本发明实施例化合物显示了较好的药代动力学性质，代表性实施例的药代参数如下所示。
实施例25的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000088
Figure PCTCN2021119638-appb-000089
实施例43的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000090
实施例72的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000091
实施例83的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000092
实施例85的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000093
Figure PCTCN2021119638-appb-000094
实施例86的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000095
实施例88的小鼠PK数据结果如下：
Figure PCTCN2021119638-appb-000096
测试例5：实施例化合物对人结肠癌HCT116 MTAP -/-裸鼠皮下异种移植瘤体内生长的抑制作用
(1)BALB/c nude小鼠(6-8周龄，上海灵畅生物科技有限公司)饲养于SPF环境，温度20～25℃，相对湿度30～70％，12：12h光暗照明；自由饮水及采食。试验处理前动物进行适应性饲养；(2)HCT116 MTAP -/-细胞(Horizon)体外培养扩增，收取对数生长期细胞重悬于无血清RPMI1640培养液中，调整细胞浓度到1.33×10 7/mL；(3)用1mL注射器将细胞悬液注入BALB/c nude小鼠前右肢腋窝皮下，每只动物注射150μL；定期观察动物及移植瘤生长情况；(4)待平均肿瘤体积生长至100～150mm 3左右时，淘汰体积过大、过小或肿瘤形状不规则的动物，采用随机区组法分组；溶剂对照组每天一次灌胃给予溶剂(1％HPMC)；给药组每天一次灌胃给与不同体积的1％HPMC药物混悬液；(5)给药期间，每周测量2次瘤径、称量动物体重，观察动物生活状态，对异常状况进行记 录；若给药期间测量肿瘤体积超过2000mm 3时，动物进行安乐处死；(6)试验结束时，采用CO 2对动物实施安乐死，剥取皮下肿瘤组织称重后拍照，计算瘤重抑瘤率；对动物进行大体解剖，肉眼观察动物脏器有无异常，并记录；(7)肿瘤体积(tumor volume，TV)：计算公式为TV＝1/2×a×b 2，其中，a表示肿瘤长径；b表示肿瘤短径。相对肿瘤体积(relative tumor volume,RTV)：计算公式为RTV＝V t/V initial×100(％)；其中，V initial为分组给药时(即d initial)测量所得肿瘤体积，V t为每一次测量时的肿瘤体积。相对肿瘤增殖率T/C(％)：计算公式为T/C(％)＝(T RTV/C RTV)×100％；其中，T RTV表示治疗组的相对肿瘤体积，C RTV表示溶剂对照组的相对肿瘤体积；肿瘤体积抑瘤率(GI)：计算公式为GI＝[1–(TV t–TV initial)/(CV t–CV initial)]×100％；其中，TV t表示治疗组每次测量时的瘤体积；TV initial表示分组给药时治疗组的瘤体积；CV t表示溶剂对照组每次测量时的瘤体积；CV initial表示分组给药时溶剂对照组的瘤体积。动物体重下降率：计算公式为体重下降率＝100％×(BW initial–BW final)/BW initial；其中，BW initial表示分组给药时动物体重；BW final表示试验结束时动物体重。瘤重抑制率(IR)：计算公式为：IR＝(WC–WT)/WC×100％；其中，WC表示溶剂对照组瘤重；WT表示治疗组瘤重。(8)统计分析方法：试验数据用Microsoft Office Excel 2010软件进行计算和相关统计学处理。数据除特别说明外，用均数±标准误(Mean±S.E)表示，两组间比较采用t-检验。
结果表明，本发明实施例对人结肠癌HCT116 MTAP -/-裸鼠皮下异种移植瘤具有明显的生长抑制作用，如实施例25，34，43，83，85，86，88在30mg/kg～300mg/kg剂量下，连续35天每天灌胃给药一次，剂量依赖性地抑制HCT116 MTAP -/-裸鼠皮下异种移植瘤的生长(抑瘤率为30％～93％)，并且动物体重与溶剂对照组相比无明显差异。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (12)

  1. 一种如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，
    Figure PCTCN2021119638-appb-100001
    式中：
    Ar选自5-12元单环或并环芳基、被1-3个Rn取代的单环或并环芳基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”和被1-3个Rn取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”；
    所述的Rn独立地选自氘、卤素、氰基、酰胺、磺酰胺、羟基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基、-NRz 1Rz 2、烯基、炔基、3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、3-12元环烷基醚、3-12元杂环烷基醚、5-10元单环或并环芳基和“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”；或者上述任意两个Rn可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和或芳香的环系；Rz 1和Rz 2独立地选自H和C 1-C 12烷基；
    R 1选自卤素、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基、C 1-C 12单烷基氨基、C 1-C 12双烷基氨基、C 1-C 12的卤代烷基氨基、3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、3-12元环烷基醚、3-12元杂环烷基醚、5-10元单环或并环芳基和“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”；
    R 2选自卤素、氰基、酰胺、磺酰胺、磷酰基、烷基磷氧基、烷基硅基、C 1-C 12卤代烷基和C 1-C 12卤代烷氧基；
    R 3a选自氢、C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12单烷基氨基烷基、C 1-C 12双烷基氨基烷基、环烷基氨基烷基、杂环烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
    R 3b选自C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12单烷基氨基烷基、C 1-C 12双烷基氨基烷基、环烷基氨基烷基、杂环烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
    或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”或被一个或多个Rm 5取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环或并环杂芳基”；
    所述的Rm 1、Rm 2、Rm 3、Rm 4和Rm 5独立地选自氘、氧代(＝O)、卤素、氰基、酰胺、磺酰胺、羟基、脲基、磷酰基、烷基磷氧基、烷基硅基、C 1-C 12烷基、被一个或多个Ry 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基、烯基、炔基、3-12元单环、螺环或桥环的环烷基、被一个或多个Ry 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、-NRz 1Rz 2和
    Figure PCTCN2021119638-appb-100002
    或者上述两个Rm 1、两个Rm 2、两个Rm 3、两个Rm 4或两个Rm 5可以通过碳链或者杂原子构成3-12元的饱和或部分不饱和或芳香的环系；
    Rx选自C 1-C 12烷基和C 1-C 12烷氧基；
    Ry 1独立地为羟基；
    Ry 2独立地选自C 1-C 12烷基和羟基取代C 1-C 12烷基；
    Ry 3独立地选自C 1-C 12烷基和C 1-C 12卤代烷基；
    W、Z、Y分别独立地选自O、S、CR 4和N；其中R 4分别独立地选自氢、氘、卤素、氰基、羟基、酰胺基、磺酰胺基、C 1-C 12烷基、C 1-C 12卤代烷基、C 1-C 12烷基-S-、C 1-C 12烷基-SO-、C 1-C 12烷基-SO 2-、C 1-C 12烷基-O-、C 1-C 12卤代烷基-O-、-NRz 1Rz 2、3-12元环烷基氨基、3-12元杂环烷基氨基、3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、3-12元卤代环烷基或卤代杂环烷基、3-12元环烷基-O-、3-12元卤代环烷基-O-、3-12元杂环烷基-O-、5-12元的单环或并环芳基和5-12元单环或并环杂芳基；
    或者-Y＝Z-可以形成＝CH-、＝N-、-O-、-S-或-NR 5；R 5选自氢、C 1-C 12烷基、3-12元单环、螺环或桥环的环烷基和“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
    上述如式(I)所示的芳环或芳基杂环并吡啶酮类化合物不包含以下化合物：
    Figure PCTCN2021119638-appb-100003
  2. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物满足下述条件中的一种或多种：
    (1)所述的Rn独立地选自卤素、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基；
    (2)R 1选自卤素、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基；
    (3)R 2为氰基；
    (4)R 3a选自氢和C 1-C 12烷基；
    R 3b选自C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12双烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或 桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
    或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”或被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”
    (5)所述的Rm 1、Rm 2、Rm 3和Rm 4独立地选自氧代(＝O)、卤素、氰基、羟基、C 1-C 12烷基、被一个或多个Ry 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、3-8元单环、螺环或桥环的环烷基、被一个或多个Ry 2取代的3-8元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、-NRz 1Rz 2和
    Figure PCTCN2021119638-appb-100004
    (6)Rz 1和Rz 2独立地选自C 1-C 12烷基；
    (7)Y为CH或N；
    (8)Z为CH；
    (9)W为CH或N。
  3. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，Ar选自5-12元单环或并环芳基、被13个Rn取代的单环或并环芳基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”和被1-3个Rn取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”；
    所述的Rn独立地选自卤素、C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基；
    Figure PCTCN2021119638-appb-100005
    为
    Figure PCTCN2021119638-appb-100006
    Figure PCTCN2021119638-appb-100007
    R 1选自卤素、C 1-C 12卤代烷基、C 1-C 12卤代烷氧基和3-10元单环的环烷基；
    R 2为氰基；
    R 3a选自氢和C 1-C 12烷基；
    R 3b选自C 1-C 12烷基、被一个或多个Rm 1取代的C 1-C 12烷基、C 1-C 12双烷基氨基烷基、3-12元单环、螺环或桥环的环烷基、被一个或多个Rm 2取代的3-12元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”和被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
    或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”或被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”；
    所述的Rm 1、Rm 2、Rm 3和Rm 4独立地选自氧代(＝O)、卤素、氰基、羟基、C 1-C 12烷基、被一个或多个Ry 1取代的C 1-C 12烷基、C 1-C 12烷氧基、C 1-C 12卤代烷基、3-8元单环、螺环或桥环的环烷基、被一个或多个Ry 2取代的3-8元单环、螺环或桥环的环烷基、“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”、-NRz 1Rz 2和
    Figure PCTCN2021119638-appb-100008
    Rx为C 1-C 12烷基或C 1-C 12烷氧基；
    Ry 1独立地为羟基；
    Ry 2独立地为C 1-C 12烷基或羟基取代C 1-C 12烷基；
    Ry 3独立地为C 1-C 12烷基或C 1-C 12卤代烷基；
    Rz 1和Rz 2独立地选自C 1-C 12烷基。
  4. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物满足下述条件中的一种或多种：
    (1)Ar、Rn、R 1和R 4中，所述芳基独立地为6-10元单环或并环芳基，例如苯基或萘基；
    (2)Ar、Rn、R 1、R 3a、R 3b和R 4中，所述杂芳基独立地为“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”；
    (3)Rn、R 1、R 2、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5和R 4中，所述卤素独立地为F、Cl、Br或I；
    (4)Rn、Rz 1、Rz 2、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、Rx、Ry 2、Ry 3、R 4和R 5中，所述烷基独立地为C 1-C 6的烷基；
    (5)Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5和Rx中，所述烷氧基独立地为C 1-C 6的烷氧基；
    (6)Rn、R 1、R 2、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、Ry 3和R 4中，所述卤代烷基独立地为C 1-C 6的卤代烷基；
    (7)Rn、R 1、R 2、Rm 1、Rm 2、Rm 3、Rm 4和Rm 5中，所述卤代烷氧基独立地为C 1-C 6的卤代烷氧基；
    (8)Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、R 4和R 5中，所述环烷基为3-6元单环、螺环或桥环的环烷基；
    (9)Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、R 4和R 5中，所述杂环烷基为“杂原子选自N、O和S中的一种或多种，杂原子数为1-3个的3-10元单环、螺环或桥环的杂环烷基”。
  5. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物满足下述条件中的一种或多种：
    (1)Ar、Rn、R 1和R 4中，所述芳基独立地为苯基或萘基；
    (2)Ar中，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的 5-12元单环或并环杂芳基”和被1-3个Rn取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”中的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的5-12元单环或并环杂芳基”独立地为吡啶基(例如
    Figure PCTCN2021119638-appb-100009
    )或咪唑并[1,2-a]吡啶(例如
    Figure PCTCN2021119638-appb-100010
    )；
    (3)Rn、R 1、R 2、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5和R 4中，所述卤素独立地为F或Cl；
    (4)Rn、Rz 1、Rz 2、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、Rx、Ry 2、Ry 3、R 4和R 5中，所述烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    (5)Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5和Rx中，所述烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，例如甲氧基；
    (6)Rn、R 1、R 2、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、Ry 3和R 4中，所述卤代烷基独立地为CF 3或CH 2CF 3；
    (7)Rn、R 1、R 2、Rm 1、Rm 2、Rm 3、Rm 4和Rm 5中，所述卤代烷氧基独立地为OCF 3；
    (8)Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、R 4和R 5中，所述环烷基为3-6元单环的环烷基，例如环丙基或环丁基；
    (9)Rn、R 1、R 3a、R 3b、Rm 1、Rm 2、Rm 3、Rm 4、Rm 5、R 4和R 5中，所述杂环烷基为“杂原子选自N和O中的一种或多种，杂原子数为1-2个的4-10元单环或螺环的杂环烷基”，例如氮杂环丁基(例如
    Figure PCTCN2021119638-appb-100011
    )、氧杂环丁基(例如
    Figure PCTCN2021119638-appb-100012
    )、吡咯烷基(例如
    Figure PCTCN2021119638-appb-100013
    )、哌啶基(例如
    Figure PCTCN2021119638-appb-100014
    )或
    Figure PCTCN2021119638-appb-100015
  6. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物满足下述条件中的一种或多种：
    (1)R 3a、R 3b中，当R 3b为“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述“杂原子选自N、O、P和S中 的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
    Figure PCTCN2021119638-appb-100016
    当R 3b为被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述被一个或多个Rm 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
    Figure PCTCN2021119638-appb-100017
    Figure PCTCN2021119638-appb-100018
    当R 3a和R 3b与其相连的原子一起形成“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
    Figure PCTCN2021119638-appb-100019
    当R 3a和R 3b与其相连的原子一起形成被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”时，所述被一个或多个Rm 4取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
    Figure PCTCN2021119638-appb-100020
    Figure PCTCN2021119638-appb-100021
    (2)Rm 1、Rm 2、Rm 3和Rm 4中，所述“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单环、螺环或桥环的杂环烷基”为
    Figure PCTCN2021119638-appb-100022
    所述被一个或多个Ry 3取代的“杂原子选自N、O、P和S中的一种或多种，杂原子数为1-3个的3-12元单 环、螺环或桥环的杂环烷基”为
    Figure PCTCN2021119638-appb-100023
  7. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物满足下述条件中的一种或多种：
    (1)
    Figure PCTCN2021119638-appb-100024
    为
    Figure PCTCN2021119638-appb-100025
    Figure PCTCN2021119638-appb-100026
    例如
    Figure PCTCN2021119638-appb-100027
    (2)Ar选自苯基、
    Figure PCTCN2021119638-appb-100028
    Rn独立地选自卤素(例如Cl、F)、C 1-C 6卤代烷基(例如CF 3)、C 1-C 6卤代烷氧基(例如OCF 3)和3-6元环烷基(例如环丙基)；
    (3)R 1为Cl或CF 3；
    R 3a为氢；
    R 3b独立地选自C 1-C 6烷基、被1-3个Rm 1取代的C 1-C 6烷基、C 1-C 6双烷基氨基烷基、3-6元单环的环烷基、被1-3个Rm 2取代的3-6元单环的环烷基、“杂原子选自N、O和S中的一种或多种，杂原子数为1-2个的3-6元单环或螺环的杂环烷基”和被1-3个Rm 3取代的“杂原子选自N、O和S中的一种或多种，杂原子数为1-2个的3-6元单环或螺环的杂环烷基”；
    或者，上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N，杂原子数为1-3个的3-5元单环的杂环烷基”或被1-3个Rm 4取代的“杂原子选自N，杂原子数为1-2个的3-5元单环的杂环烷基”，其中，当上述R 3a和R 3b与其相连的原子一起形成“杂原子选自N， 杂原子数为1-3个的5元单环的杂环烷基”或被1-3个Rm 4取代的“杂原子选自N，杂原子数为1-2个的5元单环的杂环烷基”时，Ar为苯基或
    Figure PCTCN2021119638-appb-100029
  8. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物满足下述条件中的一种或多种：
    (1)
    Figure PCTCN2021119638-appb-100030
    为
    Figure PCTCN2021119638-appb-100031
    Figure PCTCN2021119638-appb-100032
    (2)R 1选自Cl、CF 3、OCF 3和环丙基；
    (3)Ar选自苯基、
    Figure PCTCN2021119638-appb-100033
    Figure PCTCN2021119638-appb-100034
    (4)
    Figure PCTCN2021119638-appb-100035
    选自
    Figure PCTCN2021119638-appb-100036
    Figure PCTCN2021119638-appb-100037
  9. 如权利要求1所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，所述如式(I)所示的芳环或芳基杂环并吡啶酮类化合物选自如下任一化合物：
    Figure PCTCN2021119638-appb-100038
    Figure PCTCN2021119638-appb-100039
  10. 一种药物组合物，其特征在于，所述药物组合物包括：
    (1)如权利要求1-9任一项所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，以及
    (2)药学上可接受的载体。
  11. 如权利要求1-9任一项所述的如式(I)所示的芳环或芳基杂环并吡啶酮类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药、或如权利要求10所述的药物组合物在制备药物中的应用；所述药物可为治疗和/或预防与MAT2a或MTAP蛋白活性或表达相关的疾病的药物； 所述药物特别是治疗和/或预防肿瘤或自身免疫性疾病的药物。
  12. 如权利要求11所述的应用，其特征在于，所述的肿瘤独立地选自肺癌、胰腺癌、肝癌、结直肠癌、胆管癌、胆囊癌、脑癌、胃癌、白血病、淋巴癌、黑色素瘤、甲状腺癌、鼻咽癌、胶质瘤、膀胱癌、星形细胞瘤、基底细胞癌、骨肉瘤、头颈癌、软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤和间皮瘤；
    所述的自身免疫性疾病独立地选自甲状腺炎、炎性肠炎、红斑狼仓、纤维化、肌无力、血管炎、银屑病、关节炎、硬皮病和皮炎。
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