WO2024153161A1 - 取代的氨基嘧啶类大环化合物、其制备方法及其在医药上的应用 - Google Patents

取代的氨基嘧啶类大环化合物、其制备方法及其在医药上的应用 Download PDF

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WO2024153161A1
WO2024153161A1 PCT/CN2024/072923 CN2024072923W WO2024153161A1 WO 2024153161 A1 WO2024153161 A1 WO 2024153161A1 CN 2024072923 W CN2024072923 W CN 2024072923W WO 2024153161 A1 WO2024153161 A1 WO 2024153161A1
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group
cycloalkyl
general formula
alkyl
heteroaryl
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French (fr)
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贾敏强
吴婷
李心
贺峰
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Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present disclosure belongs to the field of medicine and relates to a substituted aminopyrimidine macrocyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and its use as a therapeutic agent, in particular, its use as an EGFR inhibitor and its use in the preparation of a drug for treating and/or preventing EGFR-mediated or dependent diseases or conditions.
  • a substituted aminopyrimidine macrocyclic compound represented by general formula (I) a preparation method thereof, a pharmaceutical composition containing the compound and its use as a therapeutic agent, in particular, its use as an EGFR inhibitor and its use in the preparation of a drug for treating and/or preventing EGFR-mediated or dependent diseases or conditions.
  • Lung cancer is one of the most common malignant tumors. According to statistics, the cancer with the highest incidence rate in the world in 2018 is lung cancer, with 2.094 million new lung cancer patients. In 2018, the number of lung cancer cases in China was 868,000, with an incidence rate of 0.062%, accounting for 41.4% of the global number of cases.
  • Non-small cell lung cancer is the most common type of lung cancer, accounting for about 85% of the total number of lung cancers.
  • Epidermal growth factor receptor (EGFR) belongs to the family of cell surface receptors with tyrosine kinase activity. EGFR mutation is the most common driver gene for non-small cell lung cancer. About 40% of Chinese non-small cell lung cancer patients have EGFR mutations, while 11-16% of patients in Western countries have EGFR mutations. About 90% of EGFR mutations are deletions in exon 19 (Del19 mutations) and L858R point mutations in exon 21.
  • EGFR small molecule inhibitors have been approved for marketing and have been successfully used in the treatment of non-small cell lung cancer with EGFR mutations, becoming one of the main treatments for patients with advanced non-small cell lung cancer.
  • the first-generation EGFR tyrosine kinase inhibitors represented by gefitinib and erlotinib, are reversibly binding targeted drugs that inhibit activation by competing with ATP to bind to the EGFR kinase domain.
  • gefitinib and erlotinib are reversibly binding targeted drugs that inhibit activation by competing with ATP to bind to the EGFR kinase domain.
  • most patients will develop drug resistance after 10-12 months of treatment, and about 50% of patients develop drug resistance due to the secondary mutation of T790M.
  • the second-generation EGFR tyrosine kinase inhibitors represented by afatinib, are irreversible targeted drugs, but they cannot solve the problem of T790M mutation resistance, and the lack of selectivity for wild-type EGFR makes the compounds more toxic.
  • the emergence of the third-generation EGFR tyrosine kinase inhibitor osimertinib has overcome the drug resistance caused by the EGFR T790M gene mutation, and has weak inhibition of wild-type EGFR and good selectivity, and has achieved great success in clinical practice. However, new drug resistance will occur after 9-14 months of use. Studies have revealed that 6-26% of patients have C797X or other EGFR-dependent gene mutations (JAMA Oncol. 2018, 4, 1527-1534; Br J Cancer. 2019 Oct; 121(9): 725-737.).
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:
  • Ring Cy is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • L 0 is selected from O, S, NR a , alkylene, -O-alkylene-, -alkylene-O-, -NR a -alkylene- and -alkylene-NR a -; wherein the alkylene is optionally substituted with one or more R 01 ;
  • Each R C is the same or different and is independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, alkenyl, alkynyl, cyano, nitro, NR 20 R 21 , C(O)NR 20 R 21 , NR 22 C(O)R 24 , NR 22 C(O)NR 20 R 21 , C(O)R 24 , C(O)OR 24 , OC(O)R 24 , S(O) r R 24 , S(O) r OR 24 , OS(O) r R 24 , S(O) r NR 20 R 21 , NR 22 S(O) r R 24 , cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylalkyl, heterocyclylalkyl, aryl, aryloxy, arylalkyl and heteroaryl; wherein the
  • R4 and R5 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a NR25R26 group, a C(O)NR25R26 group , a NR25C (O) R27 group, a NR25C (O ) NR25R26 group, a C(O) R27 group, a C(O) OR27 group, an OC(O) R27 group, a S (O) rR27 group, a S(O)rOR27 group, an OS(O)rR27 group , a S (O) rNR25R26 group, a NR25S ( O ) rR27 group , cycloalkyl, heterocyclyl,
  • R 4 , R 5 and the carbon atoms to which they are connected together form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more R 01 ;
  • L1 is selected from a bond, O, S, NR L , S(O) r , C(O), C(O) NR L , NR L C(O), C(O)O, OC(O), S(O) r NR L , NR L C(O) NR L , (CR L1 R L2 ) m , alkenyl and alkynyl; wherein the alkenyl is optionally substituted with one or more R 02 ;
  • L 2 is -(CR L3 R L4 ) n1 -R L5 -(CR L6 R L7 ) n2 -;
  • L3 is selected from O, S and CR L8 R L9 ;
  • R L5 is selected from a bond, O, S, NR L11 , S(O) r , C(O), C(O)NR L11 , NR L11 C(O), C(O)O, OC(O), NR L11 C(O)NR L11 , alkenyl and alkynyl; wherein the alkenyl and alkynyl are each independently optionally substituted with one or more R 02 ;
  • Each of RL1 , RL2 , RL3, RL4 , RL6 , RL7 , RL8 and RL9 is the same or different and is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy , hydroxy, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are independently substituted with one or more R02 ;
  • RL1 , RL2 and the same carbon atom to which they are attached together form a cycloalkyl or heterocyclic group
  • RL3 , RL4 and the same carbon atom to which they are attached together form a cycloalkyl or heterocyclic group
  • RL6 , RL7 and the same carbon atom to which they are attached together form a cycloalkyl or heterocyclic group
  • the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R02 ;
  • Z1 is N or CR Z1 ;
  • Z2 is N or CR Z2 ;
  • Z3 is N or CR Z3 ;
  • R Z1 , R Z2 and R Z3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a hydroxyalkoxy group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a NR 30 R 31 , a C(O)NR 30 R 31 , a NR 32 C(O)R 33 , a NR 32 C(O)NR 30 R 31 , a C(O)R 33 , a C(O)OR 33 , an OC(O)R 33 , a S(O) r R 33 , a S(O) r OR 33 , an OS(O) r R 33 , a S(O) r NR 30 R 31 , a NR 32
  • J1 and J2 are the same or different and are each independently selected from a bond, O, S, Oalkylene, alkyleneO, C(O), C(O)alkylene, alkyleneC(O), C(O)N(R J ), N(R J )C(O), N(R J )C(O)N(R J ), S(O) r , S(O) r N(R J ), N(R J )S(O) r , N(R J ), N(R J )alkylene, alkyleneN(R J ), alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R 03 ;
  • J3 is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, hydroxyalkoxy, alkenyl, alkynyl, cyano, nitro, NR40R41 , C(O ) NR40R41 , NR42C ( O ) R43 , NR42C (O) NR40R41 , C(O) R43 , C(O) OR43 , OC(O )R43, S(O)rR43, S(O)rOR43, OS(O)rR43 , S ( O)rNR40R41, NR42S ( O ) rR43 , cycloalkyl , heterocyclic , aryl and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substitute
  • Ra and Rb are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group and heterocyclic groups;
  • Each of R10 , R11 , R12 , R16 , R24 , R27 , R33 and R43 is the same or different and is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are independently optionally substituted by one or more R04 ;
  • each of R13 , R14 , R15 , R20 , R21 , R22 , R25, R26 , RL , RL11 , R30 , R31 , R32 , RJ , R40 , R41 and R42 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more R04 ;
  • R10 , R11 and the phosphine atom to which they are connected form a heterocyclic group, or R13 , R14 and the nitrogen atom to which they are connected form a heterocyclic group, or R20 , R21 and the nitrogen atom to which they are connected form a heterocyclic group, or R25 , R26 and the nitrogen atom to which they are connected form a heterocyclic group, or R30 , R31 and the nitrogen atom to which they are connected form a heterocyclic group, or R40 , R41 and the nitrogen atom to which they are connected form a heterocyclic group, and the heterocyclic groups are each independently optionally substituted by one or more R04 ;
  • each of R 01 , R 02 , R 03 and R 04 is the same or different and is each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, hydroxyalkoxy, cyano, alkenyl, alkynyl, NR c R d , C(O)NR c R d , alkylene NR c R d , alkylene C(O)NR c R d , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy,
  • Each R c and R d is the same or different and is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group and a heterocyclic group; wherein the alkyl group, the alkoxy group, the cycloalkyl group and the heterocyclic group are each independently optionally substituted by one or more R*;
  • R c , R d and the nitrogen atom to which they are attached together form a heterocyclic group optionally substituted by one or more R*;
  • R* is each independently selected from halogen, hydroxy, alkenyl, alkynyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • s is selected from 0, 1, 2, 3, 4, 5 and 6;
  • r is selected from 0, 1 and 2;
  • n1, n2 and m are the same or different and are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: Not for
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: ring Cy is a 6- to 10-membered aryl group or a 5- to 14-membered heteroaryl group; preferably, ring Cy is selected from phenyl, naphthyl, quinolyl and quinoxalyl; more preferably, ring Cy is phenyl.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: Selected from L 1 is connected to the key with *;
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group , a cyano group, a nitro group, a NR20R21, a C(O) NR20R21 , a NR22C (O) R24 , a NR22C(O)NR20R21, a C(O)R24, a C(O)OR24, an OC(O)R24 , a S ( O ) rR24 , a S(O) rOR24 , an OS(O ) rR24 , a S(O) rNR20R21 , a NR22S (O) rR24 , cycloalkyl, heterocyclyl, cycloal
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group , a cyano group, a nitro group, a NR20R21, a C(O) NR20R21 , a NR22C (O) R24 , a NR22C(O)NR20R21, a C(O)R24, a C(O)OR24, an OC(O)R24 , a S ( O ) rR24 , a S(O) rOR24 , an OS(O ) rR24 , a S(O) rNR20R21 , a NR22S (O) rR24 , cycloalkyl, heterocyclyl, cycloal
  • R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group (preferably a C 1-6 alkyl group, more preferably a methyl group);
  • R 3 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group (preferably a hydrogen atom and a halogen, more preferably a hydrogen atom);
  • L 1 is connected to a bond with *;
  • for L 1 is connected to a bond with *.
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group , a cyano group, a nitro group, a NR20R21, a C(O) NR20R21 , a NR22C (O) R24 , a NR22C(O)NR20R21, a C(O)R24, a C(O)OR24, an OC(O)R24 , a S ( O ) rR24 , a S(O) rOR24 , an OS(O ) rR24 , a S(O) rNR20R21 , a NR22S (O) rR24 , cycloalkyl, heterocyclyl, cycloal
  • R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and 3 to 6 membered cycloalkyl; L 1 is connected to the bond with *; R 1 and Ra are as defined in the general formula (I);
  • R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group, and L 1 is connected to a bond marked with *.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein L 0 is NR a ; Ra is as defined in the general formula (I); preferably, L 0 is NR a , Ra is a hydrogen atom or a C 1-6 alkyl group; more preferably, L 0 is NH.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R Z3 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 haloalkoxy and a C 1-6 hydroxyalkyl; preferably, R Z3 is a hydrogen atom.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein L 0 is NR a , Ra is as defined in the general formula (I); and/or Z 3 is CH.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II), or a pharmaceutically acceptable salt thereof:
  • R2 and R3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, alkenyl, alkynyl, cyano, nitro, NR20R21 , C( O ) NR20R21 , NR22C (O ) R24 , NR22C(O) NR20R21 , C(O) R24 , C(O ) OR24 , OC(O ) R24 , S(O) rR24 , S ( O) rOR24 , OS(O) rR24 , S(O) rNR20R21 , NR22S(O) rR24 , cycloalkyl , heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylalkyl , heterocyclylalkyl , aryl , aryloxy, arylalky
  • R 3 is a bond, and R 3 is connected to L 1 ;
  • L1 , L2 , L3 , R1 , Ra , R4 , R5 , Rb , Z1 , Z2 , J1 , J2 , J3 , R20 , R21 , R22 , R24 , R01 , RC and r are as defined in the general formula (I).
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein: Selected from Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; t is 0, 1, 2, 3, 4 or 5; L 1 is connected to the bond with *, or to ring B; R 1 , R 2 , R 3 and RC are as defined in general formula (II); preferably, for R 1 and R 2 are as defined in the general formula (II); L 1 is connected to a bond with *; more preferably, for R 1 is -N(R 15 )S(O) 2 R 16 ; R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group; L 1 is connected to a bond marked with *.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof is middle, for L 1 is connected to the key with *.
  • ring B is selected from 5- or 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl; preferably, ring B is selected from phenyl, pyridyl and pyrazinyl.
  • the fragment (B2) is X1 is CH, CRb1 or N, RC and Rb1 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, hydroxy, C2-6 alkenyl, C2-6 alkynyl, cyano, 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl; t is 0, 1 or 2; R1 is as defined in the general formula (II); L1 is connected to the bond with *.
  • the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,
  • R2 is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group , a NR20R21 group, a C(O) NR20R21 group , a NR22C(O) R24 group, a NR22C(O) NR20R21 group, a C(O) R24 group, a C( O ) OR24 group, an OC(O) R24 group, a S(O) rR24 group, a S(O) rOR24 group, an OS(O) rR24 group, a S(O) rNR20R21 group , and a NR22S (O) rR24 group .
  • R1 , R4 , R5 , Ra , Rb , Z1 , Z2 , L1 , L2 , L3 , J1 , J2 , J3 , R20 , R21 , R22 , R24 , R01 and r are as defined in the general formula (I).
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof,
  • R2 and R3 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group , a cyano group, a nitro group, a NR20R21, a C(O) NR20R21 , a NR22C (O) R24 , a NR22C(O)NR20R21, a C(O)R24, a C(O)OR24, an OC(O)R24 , a S ( O ) rR24 , a S(O) rOR24 , an OS(O ) rR24 , a S(O) rNR20R21 , a NR22S (O) rR24 , cycloalkyl, heterocyclyl, cycloal
  • R 1 , R 4 , R 5 , Ra , R b , Z 1 , Z 2 , L 1 , L 2 , L 3 , J 1 , J 2 , J 3 , R 20 , R 21 , R 22 , R 24 , R 01 and r are as defined in the general formula (I).
  • L1 is a bond or O; preferably, L1 is O.
  • R L5 is a bond.
  • n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably, n1 is 1, 2, 3, 4, 5, 6, 7 or 8; more preferably, n1 is 3, 4, 5 or 6; further preferably, n1 is 3, 4 or 5; in some embodiments, n1 is 4.
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein L 2 is (CR L3 RL4 ) n1 , n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; RL3 and RL4 are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; preferably, L 2 is a C 1-10 alkylene group; more preferably, L 2 is a C 2-8 alkylene group; in some embodiments, L 2 is a C 3-6 alkylene group; in some embodiments, L 2 is selected from (CH 2 ) 3 , CH 2 C(CH 3 ) 2 CH 2 CH 2 , (CH 2 ) 4 and (CH 2 ) 5 ; most preferably, L 2 is selected from From (CH 2 ) 3 , (CH 2 ) 4 and (CH 2 ) 5 .
  • L 3 is O or S; preferably, L 3 is O.
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein L 1 is a bond or O, and/or L 2 is (CR L3 RL4 ) n1 , n1 is 3, 4, 5 or 6; RL3 and RL4 are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl; and/or L 3 is O; in some embodiments, L 1 is O, and/or L 2 is selected from (CH 2 ) 3 , CH 2 C(CH 3 ) 2 CH 2 CH 2 , (CH 2 ) 4 and (CH 2 ) 5 , and/or L 3 is O.
  • the compounds represented by the general formula (I), (II), (III), (III') or their pharmaceutically acceptable salts wherein RL3 and RL4 are each independently selected from hydrogen atom, halogen and C1-6 alkyl; in some embodiments, RL3 and RL4 are each independently hydrogen atom or C1-6 alkyl; in some embodiments, RL3 and RL4 are each independently hydrogen atom or methyl; preferably, RL3 and RL4 are hydrogen atoms.
  • R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a 3- to 6-membered cycloalkyl group (preferably, R 15 and R 16 are the same or different and are each independently a C 1-6 alkyl group).
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom, a C 1-6 alkyl group and a 3 to 6-membered cycloalkyl group; preferably, R 15 and R 16 are the same or different and are each independently a C 1-6 alkyl group or a 3 to 6-membered cycloalkyl group; in some embodiments, R 15 and R 16 are the same or different and are each independently a C 1-6 alkyl group.
  • R 15 and R 16 are methyl groups.
  • the compounds represented by the general formula (I), (II), (III), (III') or their pharmaceutically acceptable salts wherein Z1 is CRZ1 , RZ1 is selected from the group consisting of hydrogen atom, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and C1-6 hydroxyalkoxy; and/or Z2 is CRZ2 , RZ2 is selected from the group consisting of hydrogen atom, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy and 3 to 6 membered cycloalkyl; preferably, Z1 is CRZ1 , RZ1 is a hydrogen atom or a C1-6 alkoxy; and/or Z2 is CRZ2 , RZ2 is a hydrogen atom or a halogen.
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein R Z2 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 haloalkoxy and a 3 to 6 membered cycloalkyl; preferably, R Z2 is a hydrogen atom or a halogen; more preferably, R Z2 is a hydrogen atom.
  • J 1 is a 5- or 6 - membered heterocyclic group; more preferably, J 1 is a piperidinyl group or a piperazinyl group; in some embodiments, J 1 is a piperidinyl group; most preferably, J 1 is The key with an * is connected to J 2 .
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group; wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 , R 03 is as defined in the general formula (I); preferably, Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group; wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 , R 03 is selected from oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl and C 1-6 hydroxyalkyl; more preferably, ring C is a 5- or 6-membered nitrogen-containing heterocyclic group, wherein the 5- or 6-membered nitrogen-containing heterocyclic group is optionally substituted with one or more R 03 , R 03 is selected from oxo, hydroxyl, halogen, C 1-6 alkyl, C
  • J 3 is a C 1-6 alkyl group; most preferably, J 3 is a methyl group; in some embodiments, J 3 is selected from a hydrogen atom , a C 1-6 alkyl group, a 3 to 6 membered heterocyclic group, and a -C 1-6 alkylene - 3 to 6 membered cycloalkyl group, wherein the 3 to 6 membered cycloalkyl group is optionally substituted with one or more cyano groups; in some embodiments, J 3 is selected from a hydrogen atom, a methyl group,
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein J1 is a 5- or 6-membered heterocyclic group optionally substituted by one or more R03 ; J2 is a 5- or 6-membered heterocyclic group optionally substituted by one or more R03 ; R03 is selected from oxo, hydroxyl, halogen, C1-6 alkyl, C1-6 haloalkyl and C1-6 hydroxyalkyl; J3 is selected from hydrogen atom, C1-6 alkyl, 3 to 6-membered heterocyclic group and -C1-6 alkylene-3 to 6-membered cycloalkyl; the 3 to 6-membered cycloalkyl is optionally substituted by one or more cyano groups; in some embodiments, J1 is a 5- or 6-membered heterocyclic group; J2 is a 5- or 6-membered heterocyclic group; J3 is selected from hydrogen atom,
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein -J 1 -J 2 -J 3 is -3 to 12-membered heterocyclyl-3 to 12-membered heterocyclyl, wherein the 3 to 12-membered heterocyclyl is independently substituted by one or more substituents selected from oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl and C 1-6 hydroxyalkyl; preferably, -J 1 -J 2 -J 3 is -5 or 6-membered heterocyclyl-5 or 6-membered heterocyclyl, wherein the 5 or 6-membered heterocyclyl is independently substituted by one or more substituents selected from oxo, hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6
  • each RC is the same or different and is independently selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl and C1-6 hydroxyalkyl; in some embodiments, each RC is the same or different and is independently selected from halogen, C1-6 alkyl and C1-6 haloalkyl; in some embodiments, RC is halogen; in some embodiments, RC is F.
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein R 10 , R 11 , R 12 , R 24 , R 27 , R 33 and R 43 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group; preferably, R 10 , R 11 , R 12 , R 16 , R 24 , R 27 , R 33 and R 43 are the same or different and are each independently a hydrogen atom or a methyl group.
  • the compound represented by the general formula (I), (II), (III), (III') or a pharmaceutically acceptable salt thereof wherein each R 13 , R 14 , R 20 , R 21 , R 22 , R 25 , R 26 , RL , RL11 , R 30 , R 31 , R 32 , R J , R 40 , R 41 and R 42 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl group.
  • each R 01 , R 02 , R 03 and R 04 are the same or different, and are each independently selected from oxo, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl, C 1-6 hydroxyalkyl and C 1-6 hydroxyalkoxy; preferably, each R 01 , R 02 , R 03 and R 04 are the same or different, and are each independently selected from oxo, hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; more preferably, each R 01 , R 02 , R 03 and R 04 are the same or different, and are each independently selected from oxo, hydroxyl, halogen, C 1-6 alkyl, C 1-6 halo
  • the compounds represented by the general formula (I), (II), (III), and (III') are or a pharmaceutically acceptable salt thereof, wherein R 03 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 haloalkoxy, hydroxy, C 1-6 hydroxyalkyl and 3 to 6 membered cycloalkyl; the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups; in some embodiments, R 03 is 3 to 6 membered cycloalkyl; the 3 to 6 membered cycloalkyl is optionally substituted with one or more cyano groups; in some embodiments, R 03 is
  • each RL1 , RL2 , RL6 , RL7 , RL8 and RL9 are the same or different and are each independently a hydrogen atom or a C1-6 alkyl group; preferably each RL1 , RL2 , RL6 , RL7 , RL8 and RL9 are hydrogen atoms.
  • the compounds represented by the general formula (I), (II), (III), (III') or their pharmaceutically acceptable salts wherein R* is independently selected from halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R* is cyano.
  • R 2 is a hydrogen atom;
  • L 1 is a bond or O;
  • L 2 is (CH 2 ) n1 , n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • L 3 is O or S;
  • R 4 is a hydrogen atom;
  • R 5 is a halogen; Ra and R b are both hydrogen atoms;
  • Z 1 is CR Z1 , R Z1 is a hydrogen atom or a C 1-6 alkoxy
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein L0 is NH; ring Cy is phenyl; RC is halogen; s is 0 or 1; R1 is -N( R15 )S(O) 2R16 ; R15 and R16 are the same or different and are each independently selected from a hydrogen atom, a C1-6 alkyl group and a 3- to 6-membered cycloalkyl group; Rb is a hydrogen atom; R4 is a hydrogen atom; R5 is halogen; L1 is O; L2 is ( CRL3RL4 ) n1 , n1 is 3, 4, 5 or 6; RL3 and RL4 are each independently selected from a hydrogen atom, a halogen and a C1-6 alkyl group; L3 is O; Z1 is CRZ1 , RZ1 is a hydrogen atom or a C1-6 alkoxy group; Z2 is CRZ
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, in for R1 is -N( R15 )S(O) 2R16 ;
  • R15 and R16 are the same or different and are each independently selected from a hydrogen atom, a C1-6 alkyl group and a 3- to 6-membered cycloalkyl group;
  • R2 is a hydrogen atom;
  • R3 is a hydrogen atom or a halogen;
  • Ra and Rb are both hydrogen atoms;
  • R4 is a hydrogen atom;
  • R5 is a halogen;
  • L1 is O;
  • L2 is ( CRL3RL4 ) n1 , n1 is 3, 4, 5 or 6;
  • RL3 and RL4 are each independently selected from a hydrogen atom, a halogen and a C1-6 alkyl group;
  • L3 is O;
  • Z1 is CRZ1 ,
  • RZ1 is a hydrogen atom or
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein for R1 is -N ( R15 )S(O) 2R16 ; R15 and R16 are the same or different and are independently C1-6 alkyl; R2 is a hydrogen atom; R3 is a hydrogen atom or a halogen; Ra and Rb are both hydrogen atoms; R4 is a hydrogen atom; R5 is a halogen; L1 is O; L2 is a C3-6 alkylene group; L3 is O; Z1 is CRZ1 , RZ1 is a C1-6 alkoxy group; Z2 is CH; Z3 is CH; -J1 - J2 - J3 is f is 0 or 1; Q is selected from CH 2 , O and NJ 3a ; J 3a is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered heterocyclic group and a -C
  • the compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof wherein R 1 is -N(R 15 )S(O) 2 R 16 ; R 15 and R 16 are the same or different and are each independently a C 1-6 alkyl group; R 2 is a hydrogen atom; R 3 is a hydrogen atom or a halogen; L 1 is O; L 2 is (CR L3 R L4 ) n1 , n1 is 3, 4, 5 or 6; R L3 and R L4 are each independently selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; L 3 is O; R 4 is a hydrogen atom; R 5 is a halogen; Ra and R b are both hydrogen atom; Z 1 is CR Z1 , R Z1 is a hydrogen atom or a C 1-6 alkoxy group; Z 2 is CR Z2 , R Z2 is a hydrogen atom or a halogen; -
  • the compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof wherein R 1 is -N(CH 3 )S(O) 2 CH 3 ; R 2 is a hydrogen atom; R 3 is a hydrogen atom or a halogen; L 1 is O; L 2 is selected from (CH 2 ) 3 , CH 2 C(CH 3 ) 2 CH 2 CH 2 , (CH 2 ) 4 and (CH 2 ) 5 ; L 3 is O; R 4 is a hydrogen atom; R 5 is a halogen; Ra and R b are both hydrogen atoms; Z 1 is CR Z1 , R Z1 is a C 1-6 alkoxy group; Z 2 is CH; -J 1 -J 2 -J 3 is selected from Table A Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a pharmaceutically acceptable salt thereof:
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , Z 1 , Z 2 , Z 3 , L 0 , L 1 , L 2 , L 3 , J 1 , J 2 and s are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof:
  • R1 , R2 , R3 , R4 , R5 , Ra , Rb , Z1 , Z2 , L1 , L2 , L3 , J1 and J2 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , Z 1 , Z 2 , L 1 , L 2 , L 3 , J 1 and J 2 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III'A) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , Z 1 , Z 2 , L 1 , L 2 , L 3 , J 1 and J 2 are as defined in the general formula (III′).
  • the compound represented by the general formula (IA), the general formula (IIA), the general formula (IIIA) or the general formula (III'A) or a pharmaceutically acceptable salt thereof wherein: Not for
  • Another aspect of the present disclosure relates to a compound represented by general formula (Ia) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , R 03 , Z 1 , Z 2 , Z 3 , L 0 , L 1 , L 2 , L 3 , J 1 and s are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIa) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIa) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III'a) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ; R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III').
  • Another aspect of the present disclosure relates to a compound represented by general formula (Ib) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S; preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , R 03 , RL , Z 1 , Z 2 , Z 3 , L 0 , J 1 and s are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIb) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S, preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 and J 1 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIb) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S; preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 and J 1 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III'b) or a salt thereof:
  • PG is an amino protecting group, preferably Boc
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S; preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 and J 1 are as defined in the general formula (III′).
  • Another aspect of the present disclosure relates to a compound represented by general formula (Ibb) or a salt thereof:
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S; preferably O;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , RL , Z 1 , Z 2 , Z 3 , L 0 , J 1 , J 2 , J 3 and s are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIbb) or a salt thereof:
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S, preferably O;
  • R1 , R2 , R3 , R4 , R5 , Ra , Rb , RL , Z1 , Z2 , J1 , J2 and J3 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a compound represented by general formula (IIIbb) or a salt thereof:
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S; preferably O;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , RL , Z 1 , Z 2 , J 1 , J 2 and J 3 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a compound represented by general formula (III'bb) or a salt thereof:
  • L 1 is selected from O, S and NR L ; preferably O;
  • L 3 is O or S; preferably O;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , Z 1 , Z 2 , J 1 , J 2 and J 3 are as defined in the general formula (III′).
  • Typical compounds or salts thereof (preferably pharmaceutically acceptable salts) disclosed herein include but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof and an aldehyde or ketone compound or a salt thereof undergo a reductive amination reaction to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , R 03 , Z 1 , Z 2 , Z 3 , L 0 , L 1 , L 2 , L 3 , J 1 and s are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIA) or a pharmaceutically acceptable salt thereof and an aldehyde or ketone compound or a salt thereof undergo a reductive amination reaction to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIA) or a pharmaceutically acceptable salt thereof undergoes a reductive amination reaction with an aldehyde or ketone compound or a salt thereof (preferably an aldehyde, more preferably formaldehyde) to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III') or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (III'A) or a pharmaceutically acceptable salt thereof undergoes a reductive amination reaction with an aldehyde or ketone compound or a salt thereof (preferably an aldehyde, more preferably formaldehyde) to obtain a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III′).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the above general formula (IA) or a pharmaceutically acceptable salt thereof, the method comprising:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , R 03 , Z 1 , Z 2 , Z 3 , L 0 , L 1 , L 2 , L 3 , J 1 and s are as defined in the general formula (IA).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IIA) or a pharmaceutically acceptable salt thereof, the method comprising:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (IIA).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IIIA) or a pharmaceutically acceptable salt thereof, the method comprising:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (IIIA).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III'A) or a pharmaceutically acceptable salt thereof, the method comprising:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III'A).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (Ia) or a salt thereof, the method comprising:
  • the compound represented by the general formula (Ib) or its salt and the compound represented by the general formula (Ic) or its salt undergo a nucleophilic substitution reaction to obtain the compound represented by the general formula (Ia) or its salt;
  • PG is an amino protecting group, preferably Boc; X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S; preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , RL , R 03 , Z 1 , Z 2 , Z 3 , L 0 , L 2 , J 1 and s are as defined in the general formula (Ia).
  • Another aspect of the present disclosure relates to a method for preparing the compound or salt represented by the above general formula (IIa), the method comprising:
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S; preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 , L 2 and J 1 are as defined in the general formula (IIa).
  • Another aspect of the present disclosure relates to a method for preparing the compound or salt represented by the above general formula (IIIa).
  • the law includes:
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S; preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 , L 2 and J 1 are as defined in the general formula (IIIa).
  • Another aspect of the present disclosure relates to a method for preparing the compound or salt represented by the above general formula (III'a), the method comprising:
  • the compound represented by the general formula (III'b) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (Ic) or its salt to obtain the compound represented by the general formula (III'a) or its salt;
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 , L 2 and J 1 are as defined in the general formula (III'a).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (Ibb) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (Ic) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , RL , Z 1 , Z 2 , Z 3 , L 0 , L 2 , J 1 , J 2 , J 3 and s are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIbb) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (Ic) or its salt to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • R1 , R2 , R3 , R4 , R5 , Ra , Rb , RL , Z1 , Z2 , L2 , J1 , J2 and J3 are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IIIbb) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (Ic) or its salt to obtain the compound represented by the general formula (III) or its pharmaceutically acceptable salt;
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • R1 , R2 , R4 , R5 , Ra , Rb, RL , Z1 , Z2 , L2 , J1 , J2 and J3 are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III') or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (III'bb) or its salt and the compound represented by the general formula (Ic) or its salt undergo nucleophilic removal.
  • the substitution reaction is performed to obtain a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof;
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , RL , Z 1 , Z 2 , L 2 , J 1 , J 2 and J 3 are as defined in the general formula (III′).
  • compositions which contains a compound of the present disclosure represented by the general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of compounds shown in general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of drugs for inhibiting EGFR activity.
  • the present disclosure further relates to the use of compounds represented by the general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of EGFR inhibitors.
  • the present disclosure further relates to the use of compounds shown in the general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of drugs for treating and/or preventing diseases or conditions mediated by or dependent on EGFR.
  • the present disclosure further relates to the use of compounds of the general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) and shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of drugs for treating and/or preventing cancer;
  • the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer and thyroid cancer; further preferably lung cancer; more preferably non-small cell lung cancer.
  • the present disclosure also relates to a method for treating and/or preventing EGFR-mediated or dependent diseases or conditions, which comprises administering to a patient in need thereof a compound of the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method for inhibiting EGFR protein activity, which comprises administering to a patient in need thereof a compound represented by the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also relates to a method for treating and/or preventing cancer, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer Cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, renal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer and thyroid
  • the present disclosure further relates to a compound shown in the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.
  • the present disclosure further relates to a compound shown in the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as an EGFR inhibitor.
  • the present disclosure further relates to a compound as shown in the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting EGFR protein activity.
  • the present disclosure further relates to a compound as shown in the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and/or preventing diseases or conditions mediated by or dependent on EGFR.
  • the present disclosure further relates to compounds shown in the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, which are used for inhibiting EGFR protein activity.
  • the present disclosure further relates to compounds shown in the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are used for treating and/or preventing diseases or conditions mediated by or dependent on EGFR.
  • the present disclosure further relates to a compound of the above-mentioned general formula (I), (II), (III), (III'), (IA), (IIA), (IIIA), (III'A) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and/or preventing cancer;
  • the cancer is selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer and thyroid cancer; further preferably lung cancer; more preferably non-small cell lung
  • the EGFR-mediated or dependent disease or condition described in the present disclosure is cancer; the disease or condition is preferably selected from squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, liver cancer, kidney cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, glioma, neuroblastoma, melanoma, sarcoma, endometrial cancer, testicular cancer and thyroid cancer; further preferably lung cancer; more preferably non-small cell lung cancer.
  • Lung cancer in the present disclosure includes small cell lung cancer and non-small cell lung cancer; preferably non-small cell lung cancer.
  • the cancer described in the present disclosure preferably has an EGFR protein with L858R mutation.
  • the cancer described in the present disclosure is preferably an EGFR protein with a 19del mutation.
  • the cancer described in the present disclosure is preferably an EGFR protein with T790M mutation.
  • the cancer described in the present disclosure preferably has an EGFR protein with a C797X mutation.
  • the cancer described in the present disclosure preferably has EGFR protein with L858R and T790M mutations.
  • the cancer described in the present disclosure preferably has EGFR protein with 19del and T790M mutations.
  • the cancer described in the present disclosure preferably has EGFR protein with L858R and C797X mutations.
  • the cancer described in the present disclosure preferably has EGFR protein with 19del and C797X mutations.
  • the cancer described in the present disclosure preferably has EGFR protein with T790M and C797X mutations.
  • the cancer described in the present disclosure preferably has EGFR protein with L858R, T790M and C797X mutations.
  • the cancer described in the present disclosure preferably has EGFR protein with 19del, T790M and C797X mutations.
  • the C797X mutation described in the present disclosure is preferably a C797S mutation; wherein X represents any amino acid including S.
  • the active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form in which a patient can self-administer a single dose.
  • the unit dosage form of the disclosed compound or composition may be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations.
  • suitable unit doses may be in the range of 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient can be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations.
  • Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets can be uncoated or can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a long period of time.
  • Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.
  • Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil.
  • the oil suspension may contain a thickener.
  • the above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil, a mineral oil or a mixture thereof.
  • a suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may also contain a sweetener, a flavoring agent, a preservative and an antioxidant.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions disclosed herein may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion may be injected into the patient's bloodstream by local mass injection.
  • a continuous intravenous drug delivery device may be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.
  • compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques.
  • Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents.
  • sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used.
  • fatty acids can also be used to prepare injections.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.
  • alkyl refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C1-10 alkyl), and preferably an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 alkyl).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., C 1-10 alkylene group), preferably an alkylene group having 1 to 8 carbon atoms (i.e., C 1-8 alkylene group); in some embodiments, an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 alkylene group); in some embodiments, an alkylene group having 3 to 6 carbon atoms (i.e., C 3-6 alkylene group); in some embodiments, an alkylene group having 3 to 5 carbon atoms (i.e., C 3-5 alkylene group); more preferably an alkylene group having 2 to 7 carbon atoms (i.e., C 2-7 alkylene group) or an alkylene group having 1, 2 or 3 carbon atoms (i.e., C 1-3 alkylene group).
  • Non-limiting examples include: -CH2- , -CH( CH3 )-, -C( CH3 ) 2- , -CH2CH2-, -CH(CH2CH3 ) - , -CH2CH ( CH3 )-, -CH2C ( CH3 ) 2- , -CH2CH2CH2- , -CH2CH2CH2CH2-, CH2C( CH3 ) 2CH2CH2 , and ( CH2 ) 5 , etc.
  • the alkylene group may be substituted or unsubstituted , and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkenyl).
  • the alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., C2-6 alkenyl).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc.
  • the alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C2-6 alkynyl).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and the substituent is preferably selected from D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. one or more.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl), a cycloalkyl group having 4 to 7 ring atoms (i.e., 4 to 7-membered cycloalkyl) or a cycloalkyl group having 5 or 6 ring atoms (i.e., 5 or 6-membered cycloalkyl); most preferably a cycloalkyl group having 5 or 6 ring atoms.
  • Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -O-O-, -O-S- or -S-S-), provided that at least one all-carbon ring is contained and the connection point is on the all-carbon ring, and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl).
  • nitrogen may be optionally oxidized, i.e., to form nitrogen oxides
  • the spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl).
  • the spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 7-yuan/5-yuan or 7-yuan/6-yuan monospiro
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl).
  • the fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl).
  • the condensed cycloalkyl includes bicyclic condensed cycloalkyl and polycyclic condensed cycloalkyl (such as tricyclic condensed cycloalkyl, tetracyclic condensed cycloalkyl, etc.), preferably bicyclic condensed cycloalkyl or tricyclic condensed cycloalkyl, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yu
  • connection points can be at any position
  • bridged cycloalkyl refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl).
  • the bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl).
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl.
  • Non-limiting examples include:
  • connection point can be at any position.
  • the cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl).
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group), a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group) or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms.
  • Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.
  • the polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocycl
  • the spiro heterocyclic radical preferably has a spiro heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), and more preferably has a spiro heterocyclic radical of 7 to 11 ring atoms (i.e., a 7 to 11-membered spiro heterocyclic radical).
  • the spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring
  • the fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably has a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 6-yuan/3-yuan, 6-yu
  • bridged heterocyclic group refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S-, or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups).
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups.
  • Non-limiting examples include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated ⁇ electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group).
  • the aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group).
  • the monocyclic aromatic group is, for example, phenyl.
  • Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc.
  • the polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein The point of attachment is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to refer to the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
  • the aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated ⁇ electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S-, or -S-S-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl).
  • a monocyclic heteroaromatic ring i.e., a monocyclic hetero
  • the heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), and more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).
  • the monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system.
  • Non-limiting examples include:
  • the heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyloxy refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to an -O-heterocyclyl group wherein the heterocyclyl group is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • alkoxyalkyl refers to an alkyl group substituted by one or more alkoxy groups, wherein alkoxy and alkyl are as defined above.
  • aryloxy refers to an -O-aryl group in which aryl is as defined above.
  • arylalkyl refers to an alkyl group substituted with one or more aryl groups, wherein alkoxy and aryl are as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • TBS refers to tert-butyldimethylsilyl.
  • amino protecting group refers to a group that is easily removed and introduced on an amino group in order to keep the amino group unchanged when other parts of the molecule are reacted.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxy Carbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the disclosed compounds may exist in specific stereoisomeric forms.
  • stereoisomer refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers).
  • the substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques.
  • An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers.
  • the separation of enantiomers and diastereoisomers is usually completed by chromatography.
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.
  • tautomer or "tautomeric form” refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, that is, in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses.
  • isotopes that can be introduced into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I , etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • deuterium D When a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium (i.e., at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • Examples of compounds having an abundance of deuterium (i.e., at least 15% deuterium incorporation) that is greater than the natural abundance of deuterium may be at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation
  • deuterium incorporation at least 4500 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times more abundant in deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times more abundant in deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times more abundant in deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times more abundant in deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times more abundant in deuterium (ie, at least 99% deuterium incorporation), at least 6633.3 times more abundant in deuterium (ie, at least 99.5% deuterium incorporation), or more abundant in deuterium.
  • C 1-6 alkyl optionally substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • substitution refers to one or more hydrogen atoms in a group, preferably 1, 2 or 3, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents.
  • substitutions by experiment or theory) without undue effort.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
  • the method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof and an aldehyde or ketone compound or a salt thereof undergo a reductive amination reaction under acidic conditions in the presence of a reducing agent to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • Ring Cy, R 1 , R 4 , R 5 , R b , R 03 , RC , Z 1 , Z 2 , Z 3 , L 0 , L 1 , L 2 , L 3 , J 1 and s are as defined in the general formula (I).
  • the method for preparing the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IIA) or a pharmaceutically acceptable salt thereof and an aldehyde or ketone compound or a salt thereof undergo a reductive amination reaction under acidic conditions in the presence of a reducing agent to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (II).
  • the method for preparing the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IIIA) or a pharmaceutically acceptable salt thereof and an aldehyde or ketone compound or a salt thereof undergo a reductive amination reaction under acidic conditions in the presence of a reducing agent to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III).
  • the method for preparing the compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (III'A) or a pharmaceutically acceptable salt thereof and an aldehyde or ketone compound or a salt thereof undergo a reductive amination reaction under acidic conditions in the presence of a reducing agent to obtain a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • J3 is selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R03 ; preferably, J3 is C1-6 alkyl, more preferably, J3 is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III′).
  • the method for preparing the compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , R 03 , Z 1 , Z 2 , Z 3 , L 0 , L 1 , L 2 , L 3 , J 1 and s are as defined in the general formula (IA).
  • the method for preparing the compound represented by the general formula (IIA) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (IIA).
  • the method for preparing the compound represented by the general formula (IIIA) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (IIIA).
  • the method for preparing the compound represented by the general formula (III'A) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • PG is an amino protecting group, preferably Boc
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , R 03 , Z 1 , Z 2 , L 1 , L 2 , L 3 and J 1 are as defined in the general formula (III'A).
  • the method for preparing the compound represented by the general formula (Ia) or a salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (Ib) or its salt and the compound represented by the general formula (Ic) or its salt undergo nucleophilic substitution reaction in the presence of a catalyst under alkaline conditions to obtain the compound represented by the general formula (Ia) or its salt;
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , RL , R 03 , Z 1 , Z 2 , Z 3 , L 0 , L 2 , J 1 and s are as defined in the general formula (Ia).
  • the method for preparing the compound represented by the general formula (IIa) or a salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IIb) or its salt and the compound represented by the general formula (Ic) or its salt undergo nucleophilic substitution reaction in the presence of a catalyst under alkaline conditions to obtain the compound represented by the general formula (IIa) or its salt;
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 , L 2 and J 1 are as defined in the general formula (IIa).
  • the method for preparing the compound represented by the general formula (IIIa) or a salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IIIb) or its salt and the compound represented by the general formula (Ic) or its salt undergo a nucleophilic substitution reaction in the presence of a catalyst under alkaline conditions to obtain the compound represented by the general formula (IIIa) or its salt;
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 , L 2 and J 1 are as defined in the general formula (IIIa).
  • the method for preparing the compound represented by the general formula (III'a) or a salt thereof disclosed herein comprises the following steps:
  • PG is an amino protecting group, preferably Boc
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • J2 is * key is connected to J 1 ;
  • Ring C is a 3- to 12-membered nitrogen-containing heterocyclic group, wherein the 3- to 12-membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 03 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , Ra , R b , RL , R 03 , Z 1 , Z 2 , L 2 and J 1 are as defined in the general formula (III'a).
  • the method for preparing the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (Ibb) or its salt and the compound represented by the general formula (Ic) or its salt undergo nucleophilic substitution reaction in the presence of a catalyst under alkaline conditions to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • Ring Cy, R 1 , R 4 , R 5 , R b , RC , RL , Z 1 , Z 2 , Z 3 , L 0 , L 2 , J 1 , J 2 , J 3 and s are as defined in the general formula (I).
  • the method for preparing the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • the compound represented by the general formula (IIbb) or its salt and the compound represented by the general formula (Ic) or its salt undergo nucleophilic substitution reaction in the presence of a catalyst under alkaline conditions to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • R1 , R2 , R3 , R4 , R5 , Ra , Rb , RL , Z1 , Z2 , L2 , J1 , J2 and J3 are as defined in the general formula (II).
  • the method for preparing the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • R1 , R2 , R4 , R5 , Ra , Rb, RL , Z1 , Z2 , L2 , J1 , J2 and J3 are as defined in the general formula (III).
  • the method for preparing the compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:
  • X2 and X3 are the same or different and are each independently a halogen; preferably X2 and X3 are both bromine atoms;
  • L 1 is selected from O, S and NR L , preferably O;
  • L 3 is O or S, preferably O;
  • R 1 , R 2 , R 4 , R 5 , Ra , R b , RL , Z 1 , Z 2 , L 2 , J 1 , J 2 and J 3 are as defined in the general formula (III′).
  • the reagent providing alkaline conditions includes organic bases and inorganic bases
  • the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably, the reagent providing alkaline conditions described in Schemes 9 to 16 is potassium carbonate (preferably anhydrous potassium carbonate).
  • the acidic condition can be provided by an acid added in the reaction, or provided by an acid generated in situ in the reaction; the acid includes but is not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Ti(i-PrO) 3 , BF 3 ⁇ Et 2 O Me 3 SiCl and TMSOTf and mixtures thereof.
  • the acid includes but is not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanes
  • the reagent providing acidic conditions in Schemes 1 to 4 is acetic acid (preferably glacial acetic acid).
  • the reactions of Schemes 5 to 8 are carried out under acidic conditions, and the reagent providing the acidic conditions is preferably a 1,4-dioxane solution of hydrogen chloride.
  • the catalyst described in Schemes IX to XVI is a phase transfer catalyst, such as tetrabutylammonium iodide.
  • the reducing agent includes but is not limited to sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium acetylborohydride, etc., preferably sodium triacetoxyborohydride or sodium cyanoborohydride; more preferably sodium cyanoborohydride.
  • the aldehyde and ketone compounds include but are not limited to formaldehyde, oxetan-3-one and 1-formylcyclopropane-1-carbonitrile; preferably formaldehyde.
  • the reaction in the above steps is preferably carried out in a solvent, and the solvent used is not limited to: pyridine, ethylene glycol Dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.
  • the solvent used is not limited to: pyridine, ethylene glycol Dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS/MS instrument (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparation was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, Darui Chemicals and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • reaction solution was concentrated, and the residue was dissolved in N,N-dimethylformamide and prepared by high performance liquid chromatography (Gilson-GX-281, elution system: 10 mmol/L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 35%-55%, flow rate: 30 mL/min) to obtain the title compound 4 (20.6 mg, yield: 53%).
  • reaction solution was concentrated, and the resulting residue was dissolved in N,N-dimethylformamide and subjected to high performance liquid phase preparation (SHIMADZU LC, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-65%, flow rate: 30 mL/min) to obtain the title compound 5 (12.2 mg, yield: 31%).
  • high performance liquid phase preparation SHIMADZU LC, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 40%-65%, flow rate: 30 mL/min
  • Example 2 The synthetic route of Example 1 was adopted, and the compound 1e in the fourth step was replaced by N-(2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-fluoro-5-hydroxyphenyl)-N-methylmethanesulfonamide (prepared by the known method “Intermediate 22 on page 26 of the specification of KR102524856B1”), and the final product was prepared by high performance liquid chromatography (Gilson-GX-281, elution system: 10 mmol/L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 30%-65%, flow rate: 30 mL/min) to give the title compound 6 (2.0 mg, yield: 24%).
  • Gilson-GX-281 elution system: 10 mmol/L aqueous solution of ammonium bicarbonate and acetonitrile, acetonitrile gradient: 30%-65%, flow rate: 30
  • reaction solution was filtered and subjected to high performance liquid chromatography (Gilson-GX-281, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-80%, flow rate: 30 mL/min) to obtain the title compound 8 (50 mg, yield: 13%).
  • Example 8 The synthetic route of Example 8 was adopted, and the first step 8a was replaced by 4-(pyrrol-1-yl)piperidine (Shanghai Haohong Biopharmaceutical Technology Co., Ltd.), and the title compound 9 (65 mg, yield: 13%) was obtained by high performance liquid chromatography (Gilson-GX-281, elution system: 10 mmol/L ammonium bicarbonate aqueous solution and acetonitrile, acetonitrile gradient: 45%-75%, flow rate: 30 mL/min).
  • Test Example 1 Proliferation inhibition assay of the disclosed compounds on BaF3/EGFR L858R-T790M-C797S, BaF3/EGFR L858R-C797S, H1975/EGFR L858R-T790M and HCC827/EGFR Del19 cells
  • BaF3/EGFR L858R-T790M-C797S (also recorded as BaF3/LTC, KC-0122) was purchased from Kangyuan Bochuang; BaF3/EGFR L858R-C797S (also recorded as BaF3/LC, CBP73047) was purchased from Nanjing Kebai; H1975/EGFR L858R-T790M (also recorded as H1975/LT, CRL-5908) was purchased from ATCC; HCC827/EGFR Del19 (also recorded as HCC827/D, CRL-2868) was purchased from ATCC.
  • RPMI1640 culture medium (Mei Lun, PWL015)
  • H1975/LT and HCC827/D Based on the cell counting results, dilute the cells to the corresponding plating density with 1640 medium containing 10% FBS, and seed the cells in 384-well culture plates at a density of 300 and 600 cells per well, respectively, with 20 ⁇ L per well.
  • BaF3/LTC and BaF3/LC Based on the cell counting results, dilute the cells to the corresponding plating density with 1640 medium containing 10% FBS, and seed the cells in 384-well culture plates at a density of 400 cells per well, 20 ⁇ L per well.
  • the starting concentration of the compound is 3.3 mM.
  • Each compound is diluted 3-fold with DMSO to 10 concentration points (the highest concentration of different compounds can be adjusted accordingly according to the different IC 50 ). For example, in a 96-well round-bottomed drug plate, 3 ⁇ L of the compound is diluted in 6 ⁇ L of DMSO.
  • the inhibition rate of each concentration of the compound was calculated using the following formula, and XLfit was used to perform curve fitting based on the logarithmic concentration and inhibition rate of the compound and calculate the IC 50 value.
  • Inhibition rate (%) 100-100 ⁇ (RLU compound -RLU blank control ) / (RLU solvent control -RLU blank control )
  • the disclosed compounds have significant proliferation inhibitory activity on BaF3/LTC, BaF3/LC, H1975/LT and HCC827/D cells.
  • SD rats were used as test animals, and the LC/MS/MS method was used to determine the drug concentrations in the plasma of SD rats at different times after oral gavage (i.g.) and intravenous injection (i.v.) of the example compounds, to study the pharmacokinetic behavior of the disclosed compounds in SD rats and evaluate their pharmacokinetic characteristics.
  • test compound A certain amount was weighed respectively, and 5% DMSO + 5% Tween 80 + 90% normal saline was added to prepare a 0.2 mg/mL colorless clear solution.
  • Intragastric administration group the dosage was 2.0 mg/kg, and the administration volume was 10 mL/kg.
  • Intravenous injection group the dosage was 1.0 mg/kg, and the administration volume was 5 mL/kg.
  • 0.2 mL of blood was collected from the rat's orbit, placed in an EDTA anticoagulant tube, centrifuged at 10000 rpm for 2 minutes (4°C) to separate the plasma, and stored under dry ice or at -80°C for testing. All processes were operated under ice bath conditions and completed within 1 hour. Food and water were resumed 2 hours after administration.
  • Determination of the content of the test compound in the plasma of SD rats after administration of different compounds Take 50 ⁇ L of SD rat and mouse plasma samples at different times after administration, add 25 ⁇ L of diclofenac sodium (1 ⁇ g/mL), 450 ⁇ L of acetonitrile, vortex mix, and centrifuge at 3700 rpm for 10 minutes. Take the supernatant for LC/MS/MS analysis.
  • the disclosed compounds have high blood concentration and exposure in SD mice and have pharmacokinetic advantages.

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Abstract

本公开涉及取代的氨基嘧啶类大环化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的取代的氨基嘧啶类大环化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是作为EGFR抑制剂的用途和在制备用于治疗和/或预防由EGFR介导的或依赖性的疾病或病症的药物中的用途。

Description

取代的氨基嘧啶类大环化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种通式(I)所示的取代的氨基嘧啶类大环化合物、其制备方法、含有该化合物的药物组合物以及其作为治疗剂的用途，特别是作为EGFR抑制剂的用途和在制备用于治疗和/或预防由EGFR介导的或依赖性的疾病或病症的药物中的用途。
背景技术
肺癌是最为常见的恶性肿瘤之一。据统计2018年全球发病率最高的癌症是肺癌，有209.4万人为新发肺癌患者。中国2018年肺癌发病人数是86.8万人，发病率是0.062％，发病人数占全球的41.4％。非小细胞肺癌是最常见的肺癌类型，发病率约占肺癌总数的85％左右。表皮生长因子受体(Epidermal growth factor receptor,EGFR)属于具有酪氨酸激酶活性的细胞表面受体家族。EGFR突变是最常见的非小细胞肺癌驱动基因，大约40％的中国非小细胞肺癌患者存在EGFR突变，而11-16％的西方国家病人存在EGFR突变。EGFR的突变形式大约90％是19号外显子的缺失(Del19突变)和21号外显子的L858R点突变。
多个EGFR小分子抑制剂已经被批准上市，成功应用于具有EGFR突变的非小细胞肺癌的治疗，成为晚期非小细胞肺癌病人的主要治疗手段之一。第一代EGFR酪氨酸激酶抑制剂以吉非替尼和厄洛替尼为代表是可逆结合的靶向性药物，通过与ATP竞争结合EGFR激酶的结构域，达到抑制其活化的效果。但是大多数病人在经过10-12月的治疗后，会产生耐药，大约50％的病人耐药是由于产生了T790M的二次突变。第二代EGFR酪氨酸激酶抑制剂以阿法替尼为代表是不可逆的靶向药物，但是不能够解决T790M突变耐药问题，并且由于对于野生型EGFR缺少选择性使得化合物毒性较大。第三代EGFR酪氨酸激酶抑制剂奥希替尼的出现克服了由于EGFR T790M基因突变导致的耐药，且对野生型EGFR的抑制较弱、选择性好，在临床上取得了巨大成功，但是使用9-14个月之后会产生新的耐药，研究揭示6-26％的病人产生了C797X或其它EGFR依赖的基因突变(JAMA Oncol.2018,4,1527-1534；Br J Cancer.2019Oct；121(9):725-737.)。
目前在市场上尚缺少针对EGFR C797S基因突变的单独用药有效的EGFR抑制剂，因此有必要开发新的用于非小细胞肺癌的治疗手段。已公开的EGFR抑制剂化合物的专利申请包括WO2022204544A1、WO2022211573A1、WO2022208454A1、WO2022206797A1和WO2021216440A1等。
发明内容
本公开的目的是提供一种通式(I)所示的化合物，或其可药用的盐：
其中：
环Cy选自环烷基、杂环基、芳基和杂芳基；
L0选自O、S、NRa、亚烷基、-O-亚烷基-、-亚烷基-O-、-NRa-亚烷基-和-亚烷基-NRa-；其中所述的亚烷基任选被一个或多个R01所取代；
R1选自-P(O)R10R11、-S(O)2R12、-S(O)R12、-C(O)R12、-S(O)2NR13R14、-S(O)NR13R14、-C(O)NR13R14、-S(O)(＝NR15)R12、-N(R15)S(O)R12、-N(R15)S(O)2R16和-N(R15)C(O)R12；
各个RC相同或不同，且各自独立地选自氧代基、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
R4和R5相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR25R26、C(O)NR25R26、NR25C(O)R27、NR25C(O)NR25R26、C(O)R27、C(O)OR27、OC(O)R27、S(O)rR27、S(O)rOR27、OS(O)rR27、S(O)rNR25R26、NR25S(O)rR27、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
或者R4、R5及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基；所述环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
L1选自键、O、S、NRL、S(O)r、C(O)、C(O)NRL、NRLC(O)、C(O)O、OC(O)、S(O)rNRL、NRLC(O)NRL、(CRL1RL2)m、烯基和炔基；其中所述的烯基任选被一个或多个R02所取代；
L2为-(CRL3RL4)n1-RL5-(CRL6RL7)n2-；
L3选自O、S和CRL8RL9；
RL5选自键、O、S、NRL11、S(O)r、C(O)、C(O)NRL11、NRL11C(O)、C(O)O、OC(O)、NRL11C(O)NRL11、烯基和炔基；其中所述的烯基和炔基各自独立地任选被一个或多个R02所取代；
各个RL1、RL2、RL3、RL4、RL6、RL7、RL8和RL9相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；
或者RL1、RL2及与其相连的同一碳原子一起形成环烷基或杂环基，或者RL3、RL4及与其相连的同一碳原子一起形成环烷基或杂环基，或者RL6、RL7及与其相连的同一碳原子一起形成环烷基或杂环基，或者RL8、RL9及与其相连的同一碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被一个或多个R02所取代；
Z1为N或CRZ1；
Z2为N或CRZ2；
Z3为N或CRZ3；
RZ1、RZ2和RZ3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、羟烷氧基、烯基、炔基、氰基、硝基、NR30R31、C(O)NR30R31、NR32C(O)R33、NR32C(O)NR30R31、C(O)R33、C(O)OR33、OC(O)R33、S(O)rR33、S(O)rOR33、OS(O)rR33、S(O)rNR30R31、NR32S(O)rR33、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
或者Z1、Z2及其连接的取代基一起形成环烷基、杂环基、芳基和杂芳基；所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
J1和J2相同或不同，且各自独立地选自键、O、S、O亚烷基、亚烷基O、C(O)、C(O)亚烷基、亚烷基C(O)、C(O)N(RJ)、N(RJ)C(O)、N(RJ)C(O)N(RJ)、S(O)r、S(O)rN(RJ)、N(RJ)S(O)r、N(RJ)、N(RJ)亚烷基、亚烷基N(RJ)、亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
J3选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、羟烷氧基、烯基、炔基、氰基、硝基、NR40R41、C(O)NR40R41、NR42C(O)R43、NR42C(O)NR40R41、C(O)R43、C(O)OR43、OC(O)R43、S(O)rR43、S(O)rOR43、OS(O)rR43、S(O)rNR40R41、NR42S(O)rR43、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
Ra和Rb相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基 和杂环基；
各个R10、R11、R12、R16、R24、R27、R33和R43相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R04所取代；
各个R13、R14、R15、R20、R21、R22、R25、R26、RL、RL11、R30、R31、R32、RJ、R40、R41和R42相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R04所取代；
或者R10、R11及与其相连的膦原子一起形成杂环基，或者R13、R14及与其相连的氮原子一起形成杂环基，或者R20、R21及与其相连的氮原子一起形成杂环基，或者R25、R26及与其相连的氮原子一起形成杂环基，或者R30、R31及与其相连的氮原子一起形成杂环基，或者R40、R41及与其相连的氮原子一起形成杂环基，所述的杂环基各自独立地任选被一个或多个R04所取代；
各个R01、R02、R03和R04相同或不同，且各自独立地选自氧代基、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、羟烷氧基、氰基、烯基、炔基、NRcRd、C(O)NRcRd、亚烷基NRcRd、亚烷基C(O)NRcRd、硝基、环烷基、杂环基、环烷基烷基、杂环基烷基、环烷基氧基、杂环基氧基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、亚烷基、环烷基、杂环基、环烷基烷基、杂环基烷基、环烷基氧基、杂环基氧基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；
各个Rc和Rd相同或不同，且各自独立地选自氢原子、烷基、烷氧基、环烷基和杂环基；其中所述的烷基、烷氧基、环烷基和杂环基各自独立地任选被一个或多个R*所取代；
或者Rc、Rd及与其相连的氮原子一起形成任选被一个或多个R*所取代的杂环基；
R*各自独立地选自卤素、羟基、烯基、炔基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；
s选自0、1、2、3、4、5和6；
r选自0、1和2；且
n1、n2和m相同或不同，且各自独立地选自0、1、2、3、4、5、6、7、8、9和10。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：条件是不为
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：环Cy为6至10元芳基或5至14元杂芳基；优选地，环Cy选自苯基、萘基、喹啉基和喹喔啉基；更优选地，环Cy为苯基。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：选自L1连接至带*的键；
R2和R3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；或者R2、R3及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被1、2、3或4个RC所取代，且L1连接至带*的键或连接至R2、R3形成的环上；R1、Ra、R20、R21、R22、R24、R01、RC和r如通式(I)中所定义；
在一些实施方案中，为L1连接至带*的键；
R2和R3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；R1、Ra、R20、R21、R22、R24、R01和r如通式(I)中所定义；
在一些实施方案中，为R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基(优选为C1-6烷基，更优选为甲基)；R3选自氢原子、卤素和C1-6烷基(优选为氢原子和卤素，更优选为氢原子)；L1与带*的键连接；
在一些实施方案中，为L1与带*的键连接。本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：为L1连接至带*的键；
R2和R3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；或者R2、R3及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被1、2、3或4个RC所取代，且L1连接至带*的键或连接至R2、R3形成的环上；R1、Ra、R20、R21、R22、R24、R01、RC和r如通式(I)中所定义；
优选地，为R2选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；L1与带*的键连接；R1和Ra如通式(I)中所定义；
进一步优选地，为R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基，L1与带*的键连接。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：为L1与带*的键连接。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中L0为NRa；Ra如通式(I)中所定义；优选地，L0为NRa，Ra为氢原子或C1-6烷基；更优选地，L0为NH。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Z3为CRZ3，RZ3如通式(I)中所定义；优选地，Z3为CRZ3，RZ3选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和C1-6羟烷基；更优选地，Z3为CH。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中RZ3选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和C1-6羟烷基；优选地，RZ3为氢原子。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中L0为NRa，Ra如通式(I)中所定义；和/或Z3为CH。
本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物，或其可药用的盐：
其中，
R2和R3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、 NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
或者，R3为键，且R3与L1连接；
或者R2、R3及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被1、2、3或4个RC所取代，且L1连接至苯环或连接至R2、R3形成的环上；
L1、L2、L3、R1、Ra、R4、R5、Rb、Z1、Z2、J1、J2、J3、R20、R21、R22、R24、R01、RC和r如通式(I)中所定义。
本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中，选自环B选自环烷基、杂环基、芳基和杂芳基；t为0、1、2、3、4或5；L1连接至带*的键，或连接至环B；R1、R2、R3和RC如通式(II)中所定义；优选地，为R1和R2如通式(II)中所定义；L1连接至带*的键；更优选地，为R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；L1连接至带*的键。
本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其 中，为L1连接至带*的键。
本公开的一些实施方案中，片段(B2)中，环B选自5或6元杂环基、苯基和5或6元杂芳基；优选地，环B选自苯基、吡啶基和吡嗪基。
本公开的一些实施方案中，所述片段(B2)为X1为CH、CRb1或N，RC和Rb1各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、羟基、C2-6烯基、C2-6炔基、氰基、3至12元环烷基和3至12元杂环基；t为0、1或2；R1如通式(II)中所定义；L1连接至带*的键。
在本公开的一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐，
其中，
R2选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
R1、R4、R5、Ra、Rb、Z1、Z2、L1、L2、L3、J1、J2、J3、R20、R21、R22、R24、R01和r如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(III’)所示的化合物或其可药用的盐，
其中，
R2和R3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
R1、R4、R5、Ra、Rb、Z1、Z2、L1、L2、L3、J1、J2、J3、R20、R21、R22、R24、R01和r如通式(I)中所定义。在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中Ra和Rb相同或不同，且各自独立地为氢原子或C1-6烷基；优选地，Ra和Rb均为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中L1为键或O；优选地，L1为O。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中RL5为键。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中n2为0、1、2、3或4；优选地，n2为0。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中n1为1、2、3、4、5、6、7、8、9或10；优选地，n1为1、2、3、4、5、6、7或8；更优选地，n1为3、4、5或6；进一步优选地，n1为3、4或5；在一些实施方案中，n1为4。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中L2为(CRL3RL4)n1，n1为1、2、3、4、5、6、7、8、9或10；RL3和RL4各自独立地选自氢原子、卤素和C1-6烷基；优选地，L2为C1-10亚烷基；更优选地，L2为C2-8亚烷基；在一些实施方案中，L2为C3-6亚烷基；在一些实施方案中，L2选自(CH2)3、CH2C(CH3)2CH2CH2、(CH2)4和(CH2)5；最优选地，L2选 自(CH2)3、(CH2)4和(CH2)5。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中L2为(CH2)n1，n1为1、2、3、4、5、6、7、8、9或10。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)所示的化合物或其可药用的盐，其中L3为O或S；优选地，L3为O。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中L1为键或O，和/或L2为(CRL3RL4)n1，n1为3、4、5或6；RL3和RL4各自独立地选自氢原子、卤素和C1-6烷基；和/或L3为O；在一些实施方案中，L1为O，和/或L2选自(CH2)3、CH2C(CH3)2CH2CH2、(CH2)4和(CH2)5，和/或L3为O。在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中L1为键或O，和/或L2为C1-10亚烷基，和/或L3为O或S；优选地，L1为O，和/或L2选自(CH2)3、(CH2)4和(CH2)5，和/或L3为O。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中RL3和RL4各自独立地选自氢原子、卤素和C1-6烷基；在一些实施方案中，RL3和RL4各自独立地为氢原子或C1-6烷基；一些实施方案中，RL3和RL4各自独立地为氢原子或甲基；优选地，RL3和RL4为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐或(B0)至(B4)片段，其中R1为-P(O)R10R11或-N(R15)S(O)2R16；R10、R11、R15和R16如通式(I)中所定义；优选地，R1为-P(O)R10R11或-N(R15)S(O)2R16；R10、R11、R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；更优选地，R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基(优选地，R15和R16相同或不同，且各自独立地为C1-6烷基)。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐或(B0)至(B4)片段，其中R1为-N(CH3)S(O)2CH3。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；优选地，R15和R16相同或不同，且各自独立地为C1-6烷基或3至6元环烷基；一些实施方案中，R15和R16相同或不同，且各自独立地为C1-6烷基。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R15和R16为甲基。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐或(B0)片段和(B1)片段，其中R2选自氢原子、卤素、C1-6烷基、 C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟烷基和3至6元环烷基；优选地，R2为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III’)所示的化合物或其可药用的盐和(B1)片段，其中R3选自氢原子、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟烷基和3至6元环烷基；在一些实施方案中，R3选自氢原子、卤素和C1-6烷基；在一些实施方案中，R3为氢原子或卤素；在一些实施方案中，R3为氢原子或F；在一些实施方案中，R3为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R4为氢原子或C1-6烷基；优选地，R4为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R5选自氢原子、卤素和C1-6烷基；优选地，R5为卤素；更优选地，R5为溴原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R4为氢原子；和/或R5为卤素。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中Z1为CRZ1，RZ1如通式(I)中所定义；优选地，Z1为CRZ1，RZ1选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和C1-6羟烷氧基；进一步优选地，Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；在一些实施方案中，Z1为CRZ1，RZ1为C1-6烷氧基；更优选地，Z1为CH或C-OCH3；最优选地，Z1为C-OCH3。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中Z2为CRZ2，RZ2如通式(I)中所定义；优选地，Z2为CRZ2，RZ2选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；进一步优选地，Z2为CRZ2，RZ2为氢原子或卤素；最优选地，Z2为CH。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中Z1为CRZ1，RZ1选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和C1-6羟烷氧基；和/或Z2为CRZ2，RZ2选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；优选地，Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；和/或Z2为CRZ2，RZ2为氢原子或卤素。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中RZ1选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和C1-6羟烷氧基；优选地，RZ1为氢原子或C1-6烷氧基；更优选地，RZ1为C1-6烷氧基；最优选地，RZ1为甲氧基。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中RZ2选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；优选地，RZ2为氢原子或卤素；更优选地，RZ2为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中J1选自键、N(RJ)、-N(RJ)-C1-6亚烷基-、3至12元环烷基和3至12元杂环基；其中所述的3至12元环烷基和3至12元杂环基各自独立地任选被一个或多个R03所取代，R03和RJ如通式(I)中所定义；优选地，J1为任选被一个或多个R03所取代的3至12元杂环基，R03选自氧代基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基和C1-6羟烷基；更优选地，J1为任选被一个或多个R03所取代的5或6元杂环基，R03选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；在一些实施方案中，J1为5或6元杂环基；更优选地，J1为哌啶基或哌嗪基；在一些实施方案中，J1为哌啶基；最优选地，J1为带*的键与J2连接。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中J2选自键、C1-6亚烷基、C(O)和3至12元杂环基；其中所述的3至12元杂环基任选被一个或多个R03所取代，R03如通式(I)中所定义；优选地，J2为任选被一个或多个R03所取代的3至12元杂环基，R03选自氧代基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基和C1-6羟烷基；更优选地，J2为任选被一个或多个R03所取代的5或6元杂环基，R03选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；更优选地，J2为哌啶基或哌嗪基；在一些实施方案中，J2为5或6元杂环基；在一些实施方案中，J2选自哌嗪基、吡咯烷基和吗啡啉基；在一些实施方案中，J2选自 *键与J3相连；最优选地，J2为
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中J2为*键与J1相连；
其中：环C为3至12元含氮杂环基；其中所述的3至12元含氮杂环基任选被一个或多个R03所取代，R03如通式(I)中所定义；优选地，环C为3至12元含氮杂环基；其中所述的3至12元含氮杂环基任选被一个或多个R03所取代，R03选自 氧代基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基和C1-6羟烷基；更优选地，环C为5或6元含氮杂环基，其中所述的5或6元含氮杂环基任选被一个或多个R03所取代，R03选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；在一些实施方案中，环C为5或6元含氮杂环基；在一些实施方案中，环C为6元含氮杂环基；更优选地，环C为哌啶基或哌嗪基；在一些实施方案中，环C为哌嗪基；最优选地，环C为
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中J3选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、羟基、C1-6羟烷基、C1-6羟烷氧基、NR40R41、C(O)NR40R41、C(O)R43、S(O)2R43、3至12元环烷基和3至12元杂环基；其中所述3至12元环烷基和3至12元杂环基各自独立地任选被一个或多个R03所取代，R03、R40、R41和R43如通式(I)中所定义；优选地，J3选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、羟基和C1-6羟烷基；更优选地，J3为C1-6烷基；最优选地，J3为甲基；在一些实施方案中，J3选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代；在一些实施方案中，J3选自氢原子、甲基、
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中J1为任选被一个或多个R03所取代的5或6元杂环基；J2为任选被一个或多个R03所取代的5或6元杂环基；R03选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；J3选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基；所述3至6元环烷基任选被一个或多个氰基取代；在一些实施方案中，J1为5或6元杂环基；J2为5或6元杂环基；J3选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代；在一些实施方案中，-J1-J2-J3为f为0或1；Q选自CH2、O和N-J3a；J3a选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代；在一些实施方案中，-J1-J2-J3选自
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中J3a选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代；在一些实施方案中，J3a选自C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代；在一些实施方案中，J3a选自甲基、
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中-J1-J2-J3为-3至12元杂环基-3至12元杂环基，所述的3至12元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基和C1-6羟烷基中的一个或多个取代基所取代；优选地，-J1-J2-J3为-5或6元杂环基-5或6元杂环基，所述的5或6元杂环基各自独立地任选被选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基中的一个或多个取代基所取代；更优选地，-J1-J2-J3为
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中各个RC相同或不同，且各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；在一些实施方案中，各个RC相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；在一些实施方案中，RC为卤素；在一些实施方案中，RC为F。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R10、R11、R12、R24、R27、R33和R43相同或不同，且各自独立地为氢原子或C1-6烷基；优选地，R10、R11、R12、R16、R24、R27、R33和R43相同或不同，且各自独立地为氢原子或甲基。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中各个R13、R14、R20、R21、R22、R25、R26、RL、RL11、R30、R31、R32、RJ、R40、R41和R42相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中各个R01、R02、R03和R04相同或不同，且各自独立地选自氧代基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基、C1-6羟烷基和C1-6羟烷氧基；优选地，各个R01、R02、R03和R04相同或不同，且各自独立地选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；更优选地，各个R01、R02、R03和R04相同或不同，且各自独立地选自羟基、卤素、C1-6烷基和C1-6卤代烷基。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物 或其可药用的盐，其中R03选自卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基、C1-6羟烷基和3至6元环烷基；所述3至6元环烷任选被一个或多个氰基取代；在一些实施方案中，R03为3至6元环烷基；所述3至6元环烷任选被一个或多个氰基取代；在一些实施方案中，R03为
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中各个RL1、RL2、RL6、RL7、RL8和RL9相同或不同，且各自独立地为氢原子或C1-6烷基；优选地各个RL1、RL2、RL6、RL7、RL8和RL9均为氢原子。
在本公开的一些实施方案中，所述的通式(I)、(II)、(III)、(III’)所示的化合物或其可药用的盐，其中R*各自独立地选自卤素、氰基、C1-6烷基和C1-6卤代烷基；在一些实施方案中，R*为氰基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中s为0、1或2，优选为0。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中s为0或1；在一些实施方案中，s为1。在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；R2为氢原子；L1为键或O；L2为(CH2)n1，n1为1、2、3、4、5、6、7、8、9或10；L3为O或S；R4为氢原子；R5为卤素；Ra和Rb均为氢原子；Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；Z2为CRZ2，RZ2为氢原子或卤素；-J1-J2-J3为-5或6元杂环基-5或6元杂环基，所述的5或6元杂环基各自独立地任选被选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基中的一个或多个取代基所取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中L0为NH；环Cy为苯基；RC为卤素；s为0或1；R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；Rb为氢原子；R4为氢原子；R5为卤素；L1为O；L2为(CRL3RL4)n1，n1为3、4、5或6；RL3和RL4各自独立地选自氢原子、卤素和C1-6烷基；L3为O；Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；Z2为CRZ2，RZ2为氢原子或卤素；Z3为CH；J1为5或6元杂环基；J2为5或6元杂环基；J3选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐， 其中为R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；R2为氢原子；R3为氢原子或卤素；Ra和Rb均为氢原子；R4为氢原子；R5为卤素；L1为O；L2为(CRL3RL4)n1，n1为3、4、5或6；RL3和RL4各自独立地选自氢原子、卤素和C1-6烷基；L3为O；Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；Z2为CRZ2，RZ2为氢原子或卤素；Z3为CH；J1为5或6元杂环基；J2为5或6元杂环基；J3选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代。在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中为R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地为C1-6烷基；R2为氢原子；R3为氢原子或卤素；Ra和Rb均为氢原子；R4为氢原子；R5为卤素；L1为O；L2为C3-6亚烷基；L3为O；Z1为CRZ1，RZ1为C1-6烷氧基；Z2为CH；Z3为CH；-J1-J2-J3为f为0或1；Q选自CH2、O和N-J3a；J3a选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基，所述3至6元环烷基任选被一个或多个氰基取代。
在本公开的一些实施方案中，所述的通式(III’)所示的化合物或其可药用的盐，其中R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地为C1-6烷基；R2为氢原子；R3为氢原子或卤素；L1为O；L2为(CRL3RL4)n1，n1为3、4、5或6；RL3和RL4各自独立地选自氢原子、卤素和C1-6烷基；L3为O；R4为氢原子；R5为卤素；Ra和Rb均为氢原子；Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；Z2为CRZ2，RZ2为氢原子或卤素；-J1-J2-J3为f为0或1；Q选自CH2、O和N-J3a；J3a选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基；所述3至6元环烷基任选被一个或多个氰基取代。
在本公开的一些实施方案中，所述的通式(III’)所示的化合物或其可药用的盐，其中R1为-N(CH3)S(O)2CH3；R2为氢原子；R3为氢原子或卤素；L1为O；L2选自(CH2)3、CH2C(CH3)2CH2CH2、(CH2)4和(CH2)5；L3为O；R4为氢原子；R5为卤素；Ra和Rb均为氢原子；Z1为CRZ1，RZ1为C1-6烷氧基；Z2为CH；-J1-J2-J3选自 表A本公开的典型化合物包括但不限于：

本公开的另一方面涉及一种通式(IA)所示的化合物或其可药用的盐：
其中，
环Cy、R1、R4、R5、Rb、RC、Z1、Z2、Z3、L0、L1、L2、L3、J1、J2和s如通式(I)中所定义。
本公开的另一方面涉及一种通式(IIA)所示的化合物或其可药用的盐：
其中，
R1、R2、R3、R4、R5、Ra、Rb、Z1、Z2、L1、L2、L3、J1和J2如通式(II)中所定义。
本公开的另一方面涉及一种通式(IIIA)所示的化合物或其可药用的盐：
其中，
R1、R2、R4、R5、Ra、Rb、Z1、Z2、L1、L2、L3、J1和J2如通式(III)中所定义。
本公开的另一方面涉及一种通式(III’A)所示的化合物或其可药用的盐：
其中，
R1、R2、R3、R4、R5、Ra、Rb、Z1、Z2、L1、L2、L3、J1和J2如通式(III’)中所定义。
本公开的一些实施方案中，所述的通式(IA)、通式(IIA)、通式(IIIA)或通式(III’A)所示的化合物或其可药用的盐，其中：条件是不为
本公开的另一方面涉及一种通式(Ia)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
环Cy、R1、R4、R5、Rb、RC、R03、Z1、Z2、Z3、L0、L1、L2、L3、J1和s如通式(I)中所定义。
本公开的另一方面涉及一种通式(IIa)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(II)中所定义。
本公开的另一方面涉及一种通式(IIIa)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；R1、R2、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III)中所定义。
本公开的另一方面涉及一种通式(III’a)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III’)中所定义。
本公开的一些实施方案中，所述的通式(Ia)、通式(IIa)、通式(IIIa)或通式(III’a)所示的化合物或其盐(优选可药用的盐)，其中：条件是不为
本公开的另一方面涉及一种通式(Ib)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
L1选自O、S和NRL；优选为O；
L3为O或S；优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
环Cy、R1、R4、R5、Rb、RC、R03、RL、Z1、Z2、Z3、L0、J1和s如通式(I)中所定义。
本公开的另一方面涉及一种通式(IIb)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
L1选自O、S和NRL；优选为O；
L3为O或S，优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、RL、R03、Z1、Z2和J1如通式(II)中所定义。
本公开的另一方面涉及一种通式(IIIb)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
L1选自O、S和NRL；优选为O；
L3为O或S；优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R4、R5、Ra、Rb、RL、R03、Z1、Z2和J1如通式(III)中所定义。
本公开的另一方面涉及一种通式(III’b)所示的化合物或其盐：
其中，
PG为氨基保护基，优选为Boc；
L1选自O、S和NRL；优选为O；
L3为O或S；优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、RL、R03、Z1、Z2和J1如通式(III’)中所定义。
本公开的另一方面涉及一种通式(Ibb)所示的化合物或其盐：
其中，
L1选自O、S和NRL；优选为O；
L3为O或S；优选为O；
环Cy、R1、R4、R5、Rb、RC、RL、Z1、Z2、Z3、L0、J1、J2、J3和s如通式(I)中所定义。
本公开的另一方面涉及一种通式(IIbb)所示的化合物或其盐：
其中，
L1选自O、S和NRL；优选为O；
L3为O或S，优选为O；
R1、R2、R3、R4、R5、Ra、Rb、RL、Z1、Z2、J1、J2和J3如通式(II)中所定义。
本公开的另一方面涉及一种通式(IIIbb)所示的化合物或其盐：
其中，
L1选自O、S和NRL；优选为O；
L3为O或S；优选为O；
R1、R2、R4、R5、Ra、Rb、RL、Z1、Z2、J1、J2和J3如通式(III)中所定义。
本公开的另一方面涉及一种通式(III’bb)所示的化合物或其盐：
其中，
L1选自O、S和NRL；优选为O；
L3为O或S；优选为O；
R1、R2、R3、R4、R5、Ra、Rb、RL、Z1、Z2、J1、J2和J3如通式(III’)中所定义。
在本公开一些实施方案中，所述的通式(Ia)、(IIa)、(IIIa)、(III’a)、(Ib)、(IIb)、(IIIb)、(III’b)所示的化合物或其盐(优选可药用的盐)，其中J2为*键与J1相连；其中：环C为3至12元含氮杂环基；其中所述的3至12元含氮杂环基任选被一个或多个R03所取代，R03选自氧代基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、羟基和C1-6羟烷基；优选地，环C为5或6元含氮杂环基，其中所述的5或6元含氮杂环基任选被一个或多个R03所取代，R03选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；在一些实施方案中，环C为5或6元含氮杂环基；在一些实施方案中，环C为6元含氮杂环基；更优选地，环C为哌啶基或哌嗪基；在一些实施方案中，环C为哌嗪基；最优选地，环C为
表B本公开的典型化合物或其盐(所述盐优选可药用的盐)包括但不限于：




本公开另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)，发生还原胺化反应得到通式(I)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
环Cy、R1、R4、R5、Rb、RC、R03、Z1、Z2、Z3、L0、L1、L2、L3、J1和s如通式(I)中所定义。
本公开另一方面涉及一种制备上述通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)，发生还原胺化反应得到通式(II)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(II)中所定义。
本公开另一方面涉及一种制备上述通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)发生还原胺化反应得到通式(III)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
R1、R2、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III)中所定义。
本公开另一方面涉及一种制备上述通式(III’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(III’A)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)发生还原胺化反应得到通式(III’)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III’)中所定义。
本公开另一方面涉及一种制备上述通式(IA)所示的化合物或其可药用的盐的方法，该方法包括：
通式(Ia)所示的化合物或其盐脱去保护基，得到通式(IA)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
环Cy、R1、R4、R5、Rb、RC、R03、Z1、Z2、Z3、L0、L1、L2、L3、J1和s如通式(IA)中所定义。
本公开另一方面涉及一种制备上述通式(IIA)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIa)所示的化合物或其盐脱去保护基，得到通式(IIA)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(IIA)中所定义。
本公开另一方面涉及一种制备上述通式(IIIA)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIa)所示的化合物或其盐脱去保护基，得到通式(IIIA)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(IIIA)中所定义。
本公开另一方面涉及一种制备上述通式(III’A)所示的化合物或其可药用的盐的方法，该方法包括：
通式(III’a)所示的化合物或其盐脱去保护基，得到通式(III’A)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III’A)中所定义。
本公开另一方面涉及一种制备上述通式(Ia)所示的化合物或其盐的方法，该方法包括：
通式(Ib)所示的化合物或其盐和通式(Ic)所示的化合物或其盐，发生亲核取代反应，得到通式(Ia)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S；优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
环Cy、R1、R4、R5、Rb、RC、RL、R03、Z1、Z2、Z3、L0、L2、J1和s如通式(Ia)中所定义。
本公开另一方面涉及一种制备上述通式(IIa)所示的化合物或盐的方法，该方法包括：
通式(IIb)所示的化合物或其盐和通式(Ic)所示的化合物或其盐，发生亲核取代反应，得到通式(IIa)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S；优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、RL、R03、Z1、Z2、L2和J1如通式(IIa)中所定义。
本公开另一方面涉及一种制备上述通式(IIIa)所示的化合物或盐的方法，该方 法包括：
通式(IIIb)所示的化合物或其盐和通式(Ic)所示的化合物或其盐，发生亲核取代反应，得到通式(IIIa)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S；优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R4、R5、Ra、Rb、RL、R03、Z1、Z2、L2和J1如通式(IIIa)中所定义。
本公开另一方面涉及一种制备上述通式(III’a)所示的化合物或盐的方法，该方法包括：
通式(III’b)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，发生亲核取代反应得到通式(III’a)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、RL、R03、Z1、Z2、L2和J1如通式(III’a)中所定义。
本公开另一方面涉及一种制备上述通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(Ibb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，发生亲核取代反应得到通式(I)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
环Cy、R1、R4、R5、Rb、RC、RL、Z1、Z2、Z3、L0、L2、J1、J2、J3和s如通式(I)中所定义。
本公开另一方面涉及一种制备上述通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIbb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，发生亲核取代反应得到通式(II)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
R1、R2、R3、R4、R5、Ra、Rb、RL、Z1、Z2、L2、J1、J2和J3如通式(II)中所定义。
本公开另一方面涉及一种制备上述通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIbb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，发生亲核取代反应得到通式(III)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
R1、R2、R4、R5、Ra、Rb、RL、Z1、Z2、L2、J1、J2和J3如通式(III)中所定义。
本公开另一方面涉及一种制备上述通式(III’)所示的化合物或其可药用的盐的方法，该方法包括：
通式(III’bb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，发生亲核取 代反应得到通式(III’)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
R1、R2、R4、R5、Ra、Rb、RL、Z1、Z2、L2、J1、J2和J3如通式(III’)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备用于抑制EGFR活性的药物中的用途。
本公开进一步涉及通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备EGFR抑制剂中的用途。
本公开进一步涉及通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备用于治疗和/或预防由EGFR介导的或依赖性的疾病或病症的药物中的用途。
本公开进一步涉及通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备用于治疗和/或预防癌症的药物中的用途；优选地，所述的癌症选自鳞状细胞癌、基底细胞癌、腺癌、肝癌、肾癌、膀胱癌、乳腺癌、宫颈癌、结直肠癌、食管癌、头颈癌、鼻咽癌、口腔癌、唾液腺癌、肾癌、肺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、白血病、淋巴瘤、神经胶质瘤、神经母细胞瘤、黑素瘤、肉瘤、子宫内膜癌、睾丸癌和甲状腺癌；进一步优选为肺癌；更优选为非小细胞肺癌。
本公开还涉及一种治疗和/或预防由EGFR介导的或依赖性的疾病或病症的方法，其包括给予所需患者上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种抑制EGFR蛋白活性的方法，其包括给予所需患者上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防癌症的方法，其包括给予所需患者上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物；优选地，所述的癌症选自鳞状细胞癌、基底细胞癌、腺癌、肝癌、肾癌、膀胱癌、乳腺癌、宫颈癌、结直肠癌、食管癌、头颈 癌、鼻咽癌、口腔癌、唾液腺癌、肾癌、肺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、白血病、淋巴瘤、神经胶质瘤、神经母细胞瘤、黑素瘤、肉瘤、子宫内膜癌、睾丸癌和甲状腺癌；进一步优选为肺癌；更优选为非小细胞肺癌。
本公开进一步涉及一种上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作药物。
本公开进一步涉及一种上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作EGFR抑制剂。
本公开进一步涉及一种上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作抑制EGFR蛋白活性的药物。
本公开进一步涉及一种上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作治疗和/或预防由EGFR介导的或依赖性的疾病或病症的药物。
本公开进一步涉及上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于抑制EGFR蛋白活性。
本公开进一步涉及上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防由EGFR介导的或依赖性的疾病或病症。
本公开进一步涉及一种上述通式(I)、(II)、(III)、(III’)、(IA)、(IIA)、(IIIA)、(III’A)或表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防癌症；优选地，所述的癌症选自鳞状细胞癌、基底细胞癌、腺癌、肝癌、肾癌、膀胱癌、乳腺癌、宫颈癌、结直肠癌、食管癌、头颈癌、鼻咽癌、口腔癌、唾液腺癌、肾癌、肺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、白血病、淋巴瘤、神经胶质瘤、神经母细胞瘤、黑素瘤、肉瘤、子宫内膜癌、睾丸癌和甲状腺癌；进一步优选为肺癌；更优选为非小细胞肺癌。
优选地，本公开中所述的由EGFR介导的或依赖性的疾病或病症为癌症；所述的疾病或病症优选选自鳞状细胞癌、基底细胞癌、腺癌、肝癌、肾癌、膀胱癌、乳腺癌、宫颈癌、结直肠癌、食管癌、头颈癌、鼻咽癌、口腔癌、唾液腺癌、肾癌、肺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、白血病、淋巴瘤、神经胶质瘤、神经母细胞瘤、黑素瘤、肉瘤、子宫内膜癌、睾丸癌和甲状腺癌；进一步优选为肺癌；更优选为非小细胞肺癌。
本公开中的肺癌包括小细胞肺癌和非小细胞肺癌；优选为非小细胞肺癌。
本公开所述的癌症优选为具有L858R突变的EGFR蛋白。
本公开所述的癌症优选为具有19del突变的EGFR蛋白。
本公开所述的癌症优选为具有T790M突变的EGFR蛋白。
本公开所述的癌症优选为具有C797X突变的EGFR蛋白。
本公开所述的癌症优选为具有L858R和T790M突变的EGFR蛋白。
本公开所述的癌症优选为具有19del和T790M突变的EGFR蛋白。
本公开所述的癌症优选为具有L858R和C797X突变的EGFR蛋白。
本公开所述的癌症优选为具有19del和C797X突变的EGFR蛋白。
本公开所述的癌症优选为具有T790M和C797X突变的EGFR蛋白。
本公开所述的癌症优选为具有L858R、T790M和C797X突变的EGFR蛋白。
本公开所述的癌症优选为具有19del、T790M和C797X突变的EGFR蛋白。
本公开所述的C797X突变优选为C797S突变；其中X代表包括S的任何氨基酸。
可将活性化合物制成适合于通过任何适当途径给药的形式，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。
作为一般性指导，合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-10烷基)，优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5- 二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至10个碳原子的亚烷基(即C1-10亚烷基)，优选具有1至8个碳原子的亚烷基(即C1-8亚烷基)；在一些实施方案中，具有1至6个碳原子的亚烷基(即C1-6亚烷基)；在一些实施方案中，具有3至6个碳原子的亚烷基(即C3-6亚烷基)；在一些实施方案中，具有3至5个碳原子的亚烷基(即C3-5亚烷基)；更优选具有2至7个碳原子的亚烷基(即C2-7亚烷基)或具有1、2或3个碳原子的亚烷基(即C1-3亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、CH2C(CH3)2CH2CH2和(CH2)5等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的 一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环系统(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)、4至7个环原子的环烷基(即4至7元环烷基)或5或6个环原子的环烷基(即5或6元环烷基)；最优选具有5或6个环原子的环烷基。
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环系统，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：
其连接点可在任意位置；
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环系统，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：
，其连接点可在任意位置；
等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环系统，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：
其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环系统(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)、4至7个环原子的杂环基(即4至7元杂环基)或5或6个环原子的杂环基(即5或6元杂环基)；最优选具有5或6个环原子的杂环基。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、氮杂环丁烷基、吗啉基、硫代吗啉基和高哌嗪基等。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至11个环原子的螺杂环基(即7至11元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环系统，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：
等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环系统，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环系统(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中 连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环系统中的环原子个数，非限制性的实例包括：
等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环系统(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环系统中的环原子个数。非限制性的实例包括：
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基氧基”指-O-环烷基，其中环烷基如上所定义。
术语“杂环基氧基”指-O-杂环基，其中杂环基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基、烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基、烷基如上所定义。
术语“烷氧基烷基”指烷基被一个或多个烷氧基取代，其中烷氧基、烷基如上所定义。
术语“芳基氧基”指-O-芳基，其中芳基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中烷氧基、芳基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“羟烷氧基”指烷氧基被一个或多个羟基取代，其中烷氧基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
TBS指叔丁基二甲基硅基。
术语“酰胺基”指-CONH2。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧 羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。
术语“醛酮类化合物”是指含有羰基(C＝O)的化合物，非限制性的实例包括：甲醛、乙醛、丙酮、氧杂环丁-3-酮和1-甲酰基环丙烷-1-甲腈等。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐或其同位素取代物。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包 含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
当一个位置被特别地指定为氘D时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即至少15％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘(即至少15％的氘掺入)、至少2000倍的丰度的氘(即至少30％的氘掺入)、至少3000倍的丰度的氘(即至少45％的氘掺入)、至少3340倍的丰度的氘(即至少50.1％的氘掺入)、至少3500倍的丰度的氘(即至少52.5％的氘掺入)、至少4000倍的丰度的氘(即至少60％的氘掺入)、至少4500倍的丰度的氘(即至少67.5％的氘掺入)、至少5000倍的丰度的氘(即至少75％的氘掺入)、至少5500倍的丰度的氘(即至少82.5％的氘掺入)、至少6000倍的丰度的氘(即至少90％的氘掺入)、至少6333.3倍的丰度的氘(即至少95％的氘掺入)、至少6466.7倍的丰度的氘(即至少97％的氘掺入)、至少6600 倍的丰度的氘(即至少99％的氘掺入)、至少6633.3倍的丰度的氘(即至少99.5％的氘掺入)或更高丰度的氘。
“任选的”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选被卤素或者氰基取代的C1-6烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素或氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，优选1、2或3个，更优选1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)在酸性条件下，在还原剂存在下，发生还原胺化反应得到通式(I)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
环Cy、R1、R4、R5、Rb、R03、RC、Z1、Z2、Z3、L0、L1、L2、L3、J1和s如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)在酸性条件下，在还原剂存在下，发生还原胺化反应得到通式(II)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)在酸性条件下，在还原剂存在下，发生还原胺化反应得到通式(III)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
R1、R2、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III)中所定义。
方案四
本公开通式(III’)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(III’A)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)在酸性条件下，在还原剂存在下，发生还原胺化反应得到通式(III’)所示的化合物或其可药用的盐；
其中，
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III’)中所定义。
方案五
本公开通式(IA)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(Ia)所示的化合物或其盐脱去保护基，得到通式(IA)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
环Cy、R1、R4、R5、Rb、RC、R03、Z1、Z2、Z3、L0、L1、L2、L3、J1和s如通式(IA)中所定义。
方案六
本公开通式(IIA)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIa)所示的化合物或其盐脱去保护基，得到通式(IIA)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(IIA)中所定义。
方案七
本公开通式(IIIA)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIa)所示的化合物或其盐脱去保护基，得到通式(IIIA)所示的化合物或其 可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(IIIA)中所定义。
方案八
本公开通式(III’A)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(III’a)所示的化合物或其盐脱去保护基，得到通式(III’A)所示的化合物或其可药用的盐；
其中，
PG为氨基保护基，优选为Boc；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、R03、Z1、Z2、L1、L2、L3和J1如通式(III’A)中所定义。
方案九
本公开通式(Ia)所示的化合物或其盐的制备方法，包括以下步骤：
通式(Ib)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(Ia)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
环Cy、R1、R4、R5、Rb、RC、RL、R03、Z1、Z2、Z3、L0、L2、J1和s如通式(Ia)中所定义。
方案十
本公开通式(IIa)所示的化合物或其盐的制备方法，包括以下步骤：
通式(IIb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(IIa)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、RL、R03、Z1、Z2、L2和J1如通式(IIa)中所定义。
方案十一
本公开通式(IIIa)所示的化合物或其盐的制备方法，包括以下步骤：
通式(IIIb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(IIIa)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R4、R5、Ra、Rb、RL、R03、Z1、Z2、L2和J1如通式(IIIa)中所定义。
方案十二
本公开通式(III’a)所示的化合物或其盐的制备方法，包括以下步骤：
通式(III’b)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(III’a)所示的化合物或其盐；
其中，
PG为氨基保护基，优选为Boc；
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
J2为*键与J1相连；
环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
R1、R2、R3、R4、R5、Ra、Rb、RL、R03、Z1、Z2、L2和J1如通式(III’a)中所定义。
方案十三
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(Ibb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(I)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
环Cy、R1、R4、R5、Rb、RC、RL、Z1、Z2、Z3、L0、L2、J1、J2、J3和s如通式(I)中所定义。
方案十四
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIbb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(II)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
R1、R2、R3、R4、R5、Ra、Rb、RL、Z1、Z2、L2、J1、J2和J3如通式(II)中所定义。
方案十五
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIbb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(III)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
R1、R2、R4、R5、Ra、Rb、RL、Z1、Z2、L2、J1、J2和J3如通式(III)中所定义。
方案十六
本公开通式(III’)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(III’bb)所示的化合物或其盐与通式(Ic)所示的化合物或其盐，在碱性条件下催化剂存在下发生亲核取代反应得到通式(III’)所示的化合物或其可药用的盐；
其中，
X2和X3相同或不同，且各自独立地为卤素；优选地X2和X3均为溴原子；
L1选自O、S和NRL，优选为O；
L3为O或S，优选为O；
R1、R2、R4、R5、Ra、Rb、RL、Z1、Z2、L2、J1、J2和J3如通式(III’)中所定义。
上述合成方案中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、乙酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；优选地，方案九至十六中所述的提供碱性条件的试剂为碳酸钾(优选为无水碳酸钾)。
上述合成方案中，酸性条件可以由反应中加入的酸提供，或者由反应中现场生成的酸提供；所述酸包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、盐酸的1,4-二氧六环溶液、三氟乙酸、甲酸、乙酸、盐酸、浓硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Ti(i-PrO)3、BF3·Et2O Me3SiCl和TMSOTf及其混合物。
优选地，方案一至四中提供酸性条件的试剂为乙酸(优选冰乙酸)。
优选地，方案五至八在酸性条件下进行反应，且提供酸性条件的试剂优选为氯化氢的1,4-二氧六环溶液。
方案九至十六中所述的催化剂为相转移催化剂，如四丁基碘化铵。
方案一至四中，所述的还原剂包括但不限于三乙酰氧基硼氢化钠、硼氢化钠、硼氢化锂、氰基硼氢化钠和乙酰硼氢化钠等，优选三乙酰氧基硼氢化钠或氰基硼氢化钠；更优选氰基硼氢化钠。
方案一至四中，所述的醛酮类化合物包括但不限于甲醛、氧杂环丁-3-酮和1-甲酰基环丙烷-1-甲腈；优选甲醛。
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇 二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。
waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)
THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、毕得医药、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
N-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺1
第一步
4-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪-1-羧酸叔丁酯1b
将1-溴-2-氟-4-甲氧基-5-硝基苯1a(3g，12.0mmol，江苏艾康生物医药研发有限公司)溶于N,N-二甲基甲酰胺(30mL)中，加入N,N-二异丙基乙胺(3.10g，24.0mmol)，4-(哌啶-4-基)哌嗪-1-羧酸叔丁酯(3.23g，12.0mmol，上海皓鸿生物医药科技有限公司)，升温到90℃反应12小时。待反应冷却到室温后，加入水(30mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，残留物真空干燥，得到粗产品标题化合物1b(5.99g，产率：99％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):499.1[M+1]。
第二步
4-(1-(5-甲氧基-2-(甲氧基羰基)-4-硝基苯基)哌啶-4-基)哌嗪-1-羧酸叔丁酯1c
称取化合物1b(5.99g，11.99mmol)，1,1'-双(二苯基膦)二茂铁二氯化钯(II)(879mg，1.20mmol)和三乙胺(12.2g，120.57mmol)到100mL单口瓶中，加入N,N-二甲基甲酰胺(15mL)和甲醇(15mL)。一氧化碳置换三次，升温到85℃，在一氧化碳气氛下反应12小时。待反应液冷却到室温后，加水(30mL)，用乙酸乙酯萃取(40mL×3)，合并有机相，有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1c(5.45g，产率：95％)。
MS m/z(ESI):479.2[M+1]。
第三步
4-(1-(4-氨基-5-甲氧基-2-(甲氧基羰基)苯基)哌啶-4-基)哌嗪-1-羧酸叔丁酯1d
将化合物1c(5.4g，11.28mmol)溶于甲醇(30mL)，加入10％干钯碳(360mg，0.34mmol，韶远化学科技(上海)有限公司)。氢气置换三次，氢气气氛反应12小时。反应液用硅藻土过滤，滤液浓缩，残留物真空干燥，得到粗产品标题化合物1d(5.0g，产率：99％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):449.2[M+1]。
第四步
4-(1-(4-((5-溴-4-((4-羟基-2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-(甲氧基羰基)苯基)哌啶-4-基)哌嗪-1-羧酸叔丁酯1f
称取化合物1d(2.3g，5.13mmol)，N-(2-((5-溴-2-氯嘧啶-4-基)氨基)-5-羟基苯基)-N-甲基甲磺酰胺1e(1.8g，4.42mmol，采用专利申请“WO2021216440中说明书第70页的实施例A29”公开的方法制备而得)到100mL单口瓶中，加入异丙醇(150mL)和三氟乙酸(1.18g，10.35mmol)，升温到90℃反应24小时。待反应液冷却到室温，减压浓缩除去溶剂，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1f(2.16g，产率：51％)。
MS m/z(ESI):819.2[M+1]。
第五步
5-((5-溴-4-((4-羟基-2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-(4-(4-(叔丁氧羰基)哌嗪-1-基)哌啶-1-基)-4-甲氧基苯甲酸1g
称取化合物1f(2.16g，2.64mmol)到100mL单口瓶中，加入30mL甲醇、四氢呋喃和水的混合溶剂(V/V/V＝1/1/1)。然后加入氢氧化钠(527mg，13.19mmol)，升温到60℃反应12小时。待反应液冷却到室温，加入1M盐酸溶液调节反应液pH到6-7之间，浓缩反应液，真空干燥，得到粗产品标题化合物1g(1.8g，产率：85％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):803.0[M-1]。
第六步
4-(1-(35-溴-16-甲氧基-52-(N-甲基甲磺酰氨基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-14-基)哌啶-4-基)哌嗪-1-羧酸叔丁酯1h
将化合物1g(350mg，0.43mmol)溶于N,N-二甲基甲酰胺(5mL)，加入1,4-二溴丁烷(100mg，0.46mmol)，无水碳酸钾(180mg，1.30mmol)和四丁基碘化铵(32mg，0.087mmol)，升温到60℃反应12小时。加水(5mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和氯化钠溶液(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1h(185mg，产率：50％)。
MS m/z(ESI):857.2[M-1]。
第七步
N-(35-溴-16-甲氧基-12-氧代-14-(4-(哌嗪-1-基)哌啶-1-基)-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺二盐酸盐1i
将化合物1h(180mg，0.21mmol)溶于二氯甲烷(2mL)中，加入4M氯化氢的1,4-二氧六环溶液(2mL)，反应30分钟。反应液减压浓缩，真空干燥，得到粗产品标题化合物1i(170mg，产率：98％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):757.2[M-1]。
第八步
N-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺1
向50mL单口瓶中加入4mL二氯甲烷和甲醇的混合溶液(V/V＝1/1)，加入化合物1i(167mg，0.20mmol)，无水乙酸钠(82mg，1.00mmol)，反应15分钟，加入35％甲醛水溶液(51mg，0.60mmol)，冰乙酸(36mg，0.60mmol)，反应30分钟，缓慢加入氰基硼氢化钠(24.0mg，0.40mmol)，反应2小时。浓缩反应液，所得残留物用N,N-二甲基甲酰胺溶解，经高效液相制备(Waters 2545，洗脱体系：10mmol/L碳酸 氢铵的水溶液和乙腈，乙腈的梯度：40％-75％，流速：30mL/min)得到标题化合物1(12mg，产率：8％)。
MS m/z(ESI):773.1[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),7.96(s,1H),7.78(s,1H),7.70(s,1H),7.51(d,1H),7.13(s,1H),6.82(d,1H),6.66(s,1H),4.40(t,2H),4.29(t,2H),3.84(s,3H),3.29(s,3H),3.18-3.11(m,2H),3.09(s,3H),3.02(s,3H),2.74-2.21(m,11H),1.88-1.78(m,4H),1.75-1.66(m,2H),1.51-1.41(m,2H)。
实施例2
N-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-氧代-6,10-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十一蕃-52-基)-N-甲基甲磺酰胺2
第一步
4-(1-(35-溴-16-甲氧基-52-(N-甲基甲磺酰氨基)-11-氧代-6,10-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十一蕃-14-基)哌啶-4-基)哌嗪-1-羧酸叔丁酯2a
将化合物1g(250mg，0.31mmol)溶于N,N-二甲基甲酰胺(4mL)，加入1,3-二溴丙烷(60mg，0.30mmol)，无水碳酸钾(130mg，0.94mmol)和四丁基碘化铵(23mg，0.062mmol)，升温到60℃反应12小时。加水(5mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和氯化钠溶液(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物2a(85mg，产率：32％)。
MS m/z(ESI):843.1[M-1]。
第二步
N-(35-溴-16-甲氧基-11-氧代-14-(4-(哌嗪-1-基)哌啶-1-基)-6,10-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十一蕃-52-基)-N-甲基甲磺酰胺二盐酸盐2b
将化合物2a(85mg，0.10mmol)溶于二氯甲烷(2mL)中，加入4M氯化氢的1,4-二氧六环溶液(2mL)，反应30分钟。反应液减压浓缩，真空干燥，得到粗产品标题化合物2b(80mg，产率：99％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):743.1[M-1]。
第三步
N-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-氧代-6,10-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十一蕃-52-基)-N-甲基甲磺酰胺2
向50mL单口瓶中加入4mL二氯甲烷和甲醇的混合溶液(V/V＝1/1)，加入化合物2b(67mg，0.091mmol)，无水乙酸钠(37mg，0.45mmol)，反应15分钟，加入35％甲醛水溶液(23mg，0.27mmol)，冰乙酸(16mg，0.27mmol)，反应30分钟，缓慢加入氰基硼氢化钠(11mg，0.18mmol)，反应2小时。浓缩反应液，所得残留物用N,N-二甲基甲酰胺溶解，经高效液相制备(Waters 2545，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：45％-80％，流速：30mL/min)得到标题化合物2(4mg，产率：6％)。
MS m/z(ESI):757.1[M-1]。
δ1H NMR(500MHz,DMSO-d6)δ8.15(s,1H),7.97(s,1H),7.72(s,1H),7.46(s,1H),7.25(d,1H),7.16(d,1H),6.88(dd,1H),6.61(s,1H),4.34(t,2H),4.28(t,2H),3.85(s,3H),3.30(s,3H),3.18-3.11(m,3H),3.04(s,3H),3.00(s,3H),2.80-2.55(m,4H),2.29-2.16(m,4H),2.10-1.95(m,4H),1.87-1.78(m,2H),1.52-1.42(m,2H)。
实施例3
N-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1基)哌啶-1-基)-13-氧代-6,12-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十三蕃-52-基)-N-甲基甲磺酰胺3

第一步
4-(1-(35-溴-16-甲氧基-52-(N-甲基甲磺酰氨基)-13-氧代-6,12-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十三蕃-14-基)哌啶-4-基)哌嗪-1-羧酸叔丁酯3a
将化合物1g(100mg，0.12mmol)溶于N,N-二甲基甲酰胺(2mL)，加入1,5-二溴戊烷(30mg，0.13mmol)，无水碳酸钾(51mg，0.37mmol)和四丁基碘化铵(10mg，0.027mmol)，升温到60℃反应12小时。加水(5mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，有机相用饱和氯化钠溶液(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物3a(50mg，产率：46％)。
MS m/z(ESI):871.2[M-1]。
第二步
N-(35-溴-16-甲氧基-13-氧代-14-(4-(哌嗪-1-基)哌啶-1-基)-6,12-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十三蕃-52-基)-N-甲基甲磺酰胺二盐酸盐3b
将化合物3a(50mg，0.057mmol)溶于二氯甲烷(2mL)中，加入4M氯化氢的1,4-二氧六环溶液(2mL)，反应30分钟。反应液减压浓缩，真空干燥，得到粗产品标题化合物3b(48mg，产率：99％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):771.1[M-1]。
第三步
N-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1基)哌啶-1-基)-13-氧代-6,12-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十三蕃-52-基)-N-甲基甲磺酰胺3
向50mL单口瓶中加入2mL二氯甲烷和甲醇的混合溶液(V/V＝1/1)，加入化合物3b(48mg，0.057mmol)，无水乙酸钠(23mg，0.28mmol)，反应15分钟，加入35％甲醛水溶液(15mg，0.17mmol)，冰乙酸(10mg，0.17mmol)，反应30分钟，缓慢加入氰基硼氢化钠(7mg，0.11mmol)，反应2小时。浓缩反应液，所得残留物用N,N-二甲基甲酰胺溶解，经高效液相制备(Waters 2545，洗脱体系：10mmol/L碳酸氢铵 的水溶液和乙腈，乙腈的梯度：40％-60％，流速：30mL/min)得到标题化合物3(1mg，产率：2％)。
MS m/z(ESI):787.1[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),8.14(s,1H),8.03(s,1H),7.69-7.64(m,2H),7.17(d,1H),6.69(s,1H),6.48(dd,1H),4.19(t,2H),4.11(t,2H),3.84(s,3H),3.30-3.26(m,4H),3.15(s,3H),3.06(s,3H),2.75(t,2H),2.39-2.26(m,4H),2.20-2.13(m,3H),2.04-1.95(m,2H),1.87-1.81(m,2H),1.79-1.72(m,2H),1.67-1.54(m,6H),1.50-1.41(m,1H)。
实施例4
N-(35-溴-16-甲氧基-14-(4-(4-(氧杂环丁-3-基)哌嗪-1-基)哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺4
将化合物1i(50mg，0.060mmol)和氧杂环丁-3-酮4a(14mg，0.19mmol，韶远化学科技(上海)有限公司)溶于5mL二氯甲烷和甲醇的混合溶剂(V/V＝4/1)中，加入三乙酰氧基硼氢化钠(20mg，0.094mmol)和无水乙酸钠(32mg，0.39mmol)，反应12小时。加入氰基硼氢化钠(6mg，0.10mmol)，反应1.5小时。浓缩反应液，所得残留物用N,N-二甲基甲酰胺溶解，经高效液相制备(Gilson-GX-281，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：35％-55％，流速：30mL/min)得到标题化合物4(20.6mg，产率：53％)。
MS m/z(ESI):815.2[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),7.95(s,1H),7.78(s,1H),7.69(s,1H),7.50(d,1H),7.13(d,1H),6.82(dd,1H),6.65(s,1H),4.52(t,2H),4.45-4.35(m,4H),4.28(t,2H),3.84(s,3H),3.40-3.35(m,2H),3.14(d,2H),3.09(s,3H),3.02(s,3H), 2.67(t,2H),2.34-2.14(m,5H),2.02-1.97(m,1H),1.88-1.78(m,4H),1.74-1.65(m,2H),1.51-1.40(m,2H),1.32-1.24(m,2H)。
实施例5
N-(35-溴-14-(4-(4-((1-氰基环丙基)甲基)哌嗪-1-基)哌啶-1-基)-16-甲氧基-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺5
将化合物1i(50mg，0.060mmol)和1-甲酰基环丙烷-1-甲腈5a(18mg，0.19mmol，韶远化学科技(上海)有限公司)溶于5mL二氯甲烷和甲醇的混合溶剂(V/V＝4/1)中，加入无水乙酸钠(32mg，0.39mmol)和三乙酰氧基硼氢化钠(20mg，0.094mmol)反应12小时。加入氰基硼氢化钠(6mg，0.10mmol)，反应1.5小时。浓缩反应液，所得残留物用N,N-二甲基甲酰胺溶解，经高效液相制备(SHIMADZU LC，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：40％-65％，流速：30mL/min)得到标题化合物5(12.2mg，产率：31％)。
MS m/z(ESI):838.2[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),7.95(s,1H),7.78(s,1H),7.70(s,1H),7.51(d,1H),7.13(d,1H),6.82(dd,1H),6.65(s,1H),4.40(t,2H),4.29(t,2H),3.84(s,3H),3.15(d,2H),3.10(s,3H),3.03(s,3H),2.68(t,2H),2.60-2.51(m,6H),2.37(s,2H),2.26(t,1H),2.04-1.94(m,1H),1.90-1.78(m,4H),1.75-1.65(m,2H),1.53-1.41(m,3H),1.33-1.25(m,2H),0.94-0.87(m,2H)。
实施例6
N-(35-溴-55-氟-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺6
采用实施例1的合成路线，将第四步中的化合物1e替换为N-(2-((5-溴-2-氯嘧啶-4-基)氨基)-4-氟-5-羟基苯基)-N-甲基甲磺酰胺(采用公知的方法“KR102524856B1中说明书第26页中间体22”制备得到)，终产物经高效液相制备(Gilson-GX-281，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：30％-65％，流速：30mL/min)，得到标题化合物6(2.0mg，产率：24％)。
MS m/z(ESI):791.1[M+1]。
1H NMR(500MHz,DMSO-d6):8.18(s,1H),8.12(s,1H),7.69(s,1H),7.66(s,1H),7.34(s,1H),7.32(d,1H),6.66(s,1H),4.38(t,2H),4.32-4.23(m,2H),3.86(s,3H),3.12(d,2H),2.96(s,3H),2.92(s,3H),2.67-2.63(m,2H),2.59-2.38(m,3H),2.30-2.16(m,5H),2.03-1.95(m,2H),1.89-1.77(m,4H),1.75-1.67(m,2H),1.50-1.40(m,2H),1.32-1.26(m,2H)。
实施例7
N-(35-溴-16-甲氧基-8,8-二甲基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺7

第一步
4-(1-(4-((5-溴-4-((4-羟基-2-(N-甲基甲磺酰胺基)苯基)氨基)嘧啶-2-基)氨基)-2-((3,3-二甲基-4-((甲基磺酰基)氧基)丁氧基)羰基)-5-甲氧基苯基)哌啶-4-基)哌嗪-1-羧酸叔丁酯7b
将化合物1g(177mg，0.20mmol)溶于二甲基亚砜(10mL)，加入2,2-二甲基丁烷-1,4-二基二甲烷磺酸酯7a(90mg，0.33mmol，采用公知的方法“Organic Letters,2019,21(23),9729-9733”制备而得)、无水碳酸钾(61mg，0.44mmol)和四丁基碘化铵(15mg，0.045mmol)，升温到60℃反应12小时。加水(5mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和氯化钠溶液(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7b(150mg，产率：69％)。
MS m/z(ESI):983.2[M+1]。
第二步
4-(1-(35-溴-16-甲氧基-8,8-二甲基-52-(N-甲基甲磺酰胺基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-14-基)哌啶-4-基)哌嗪-1-羧酸叔丁酯7c
将化合物7b(150mg，0.15mmol)溶于二甲基亚砜(5mL)，加入无水碳酸钾(42mg，0.30mmol)，四丁基碘化铵(10mg，0.030mmol)和碘化钠(23mg，0.15mmol)，升温到140℃反应4小时。加水(5mL)，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和氯化钠溶液(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物经高效液相制备(Waters 2545，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：55％-90％，流速：30mL/min)得到标题化合物7c(23mg，产率：17％)。MS m/z(ESI):887.2[M+1]。
第三步
N-(35-溴-16-甲氧基-8,8-二甲基-12-氧代-14-(4-(哌嗪-1-基)哌啶-1-基)-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺二盐酸盐7d
将化合物7c(23mg，0.026mmol)溶于二氯甲烷(1mL)中，加入4M氯化氢的1,4-二氧六环溶液(1mL)，反应30分钟。反应液减压浓缩，真空干燥，得到粗产品标题化合物7d(21mg，产率：94％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):785.5[M-1]。
第四步
N-(35-溴-16-甲氧基-8,8-二甲基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺7
向50mL单口瓶中加入2mL二氯甲烷和甲醇的混合溶剂(V/V＝1/1)，加入化合物7d(24mg，0.024mmol)和35％甲醛水溶液(11mg，0.13mmol)，反应30分钟，缓慢加入三乙酰氧基硼氢化钠(16mg，0.076mmol)，反应1小时。浓缩反应液，所得残留物用N,N-二甲基甲酰胺溶解，经高效液相制备(Waters 2545，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：40％-80％，流速：30mL/min)得到标题化合物7(7mg，产率：34％)。
MS m/z(ESI):801.1[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.94(s,1H),7.66(s,1H),7.41(s,1H),7.23(d,1H),7.10(d,1H),6.79(dd,1H),6.67(s,1H),4.34(t,2H),3.89(s,2H),3.83(s,3H),3.10(d,2H),3.03(s,3H),3.01(s,3H),2.66(t,2H),2.38-2.20(m,5H),2.14(s,3H),2.04-1.94(m,1H),1.84-1.72(m,4H),1.52-1.41(m,3H),1.32-1.24(m,2H),1.05(s,6H)。
实施例8
N-(35-溴-16-甲氧基-14-(4-吗啉基哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺8

第一步
4-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)吗啉8b
将化合物1a(3g，12.0mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入无水碳酸钾(4.14g，30.0mmol)，4-(哌啶-4-基)吗啉8a(2.45g，14.40mmol，上海皓鸿生物医药科技有限公司)，升温到90℃反应12小时。待反应液冷却到室温，加入水(30mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，残留物真空干燥，得到粗产品标题化合物8b(4.3g，产率：89％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):400.0[M+1]。
第二步
4-甲氧基-2-(4-吗啉基哌啶-1-基)-5-硝基苯甲酸甲酯8c
将化合物8b(4.2g，10.49mmol)溶于100mL甲醇和N,N-二甲基甲酰胺的混合溶剂(V/V＝1/1)中，依次加入醋酸钯(117.5mg，0.52mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(607.1mg，1.05mmol)和三乙胺(10.62g，104.9mmol)。一氧化碳置换三次，升温到85℃，在一氧化碳气氛下反应12小时。反应液用硅藻土过滤，滤液浓缩，真空干燥，得到粗产品标题化合物8c(3.49g，产率：95％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):380.1[M+1]。
第三步
5-氨基-4-甲氧基-2-(4-吗啉基哌啶-1-基)苯甲酸甲酯8d
将化合物8c(3.49g，10.0mmol)溶于甲醇(30mL)，加入10％干钯碳(900mg，7.41mmol)。氢气置换三次，氢气氛反应12小时。反应液用硅藻土过滤，滤液浓 缩，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物8d(3.0g，产率：86％)。
MS m/z(ESI):350.1[M+1]。
第四步
5-((5-溴-4-((4-羟基-2-(N-甲基甲磺酰胺基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-吗啉基哌啶-1-基)苯甲酸甲酯8e
称取化合物8d(2.00g，5.72mmol)和化合物1e(2.33g，5.72mmol)到100mL单口瓶中，加入异丙醇(80mL)和三氟乙酸(1.31g，11.45mmol)，升温到90℃反应16小时。待反应液冷却到室温，减压浓缩除去溶剂，所得残留物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物8e(2.2g，产率：52％)。
MS m/z(ESI):720.0[M+1]。
第五步
5-((5-溴-4-((4-羟基-2-(N-甲基甲磺酰胺基)苯基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-吗啉基哌啶-1-基)苯甲酸8f
称取化合物8e(1.5g，2.08mmol)到100mL单口瓶中，加入45mL甲醇、四氢呋喃和水的混合溶剂(V/V/V＝1/1/1)。然后加入氢氧化钠(416mg，10.41mmol)，升温到60℃反应16小时。待反应液冷却到室温，减压浓缩除掉大部分有机溶剂。冰水浴下加入1M盐酸溶液调节反应液pH到6-7之间，过滤，滤饼用少量水淋洗，收集滤饼，真空干燥，得到粗产品标题化合物8f(0.9g，产率：91％)，粗产品不经纯化直接用于下一步反应。
MS m/z(ESI):706.1[M+1]。
第六步
N-(35-溴-16-甲氧基-14-(4-吗啉基哌啶-1-基)-12-氧代-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺8
将化合物8f(350mg，0.50mmol)溶于N,N-二甲基甲酰胺(14mL)，加入1,4-二溴丁烷(107mg，0.50mmol)，无水碳酸钾(205mg，1.49mmol)和四丁基碘化铵(91mg，0.25mmol)，升温到60℃反应4小时。反应液过滤，经高效液相制备(Gilson-GX-281，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：45％-80％，流速：30mL/min)，得到标题化合物8(50mg，产率：13％)。
MS m/z(ESI):760.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.16(s,1H),7.96(s,1H),7.77(s,1H),7.70(s,1H),7.51(d,1H),7.13(d,1H),6.82(dd,1H),6.66(s,1H),4.40(t,2H),4.29(t,2H),3.84(s,3H),3.67-3.50(m,4H),3.18-3.11(m,2H),3.09(s,3H),3.03(s,3H),2.68(t,2H),2.48-2.43(m,2H),2.26-2.15(m,1H),1.91-1.78(m,4H),1.74-1.66(m,2H),1.52-1.39(m,2H),1.28-1.22(m,2H)。
实施例9
N-(35-溴-16-甲氧基-12-氧代-14-(4-(吡咯-1-基)哌啶-1-基)-6,11-二氧杂-2,4-二氮杂-3(2,4)-嘧啶杂-1(1,3),5(1,4)-二苯杂环十二蕃-52-基)-N-甲基甲磺酰胺9
采用实施例8的合成路线，将第一步8a替换为4-(吡咯-1-基)哌啶(上海皓鸿生物医药科技有限公司)，经高效液相制备(Gilson-GX-281，洗脱体系：10mmol/L碳酸氢铵的水溶液和乙腈，乙腈的梯度：45％-75％，流速：30mL/min)，得到标题化合物9(65mg，产率：13％)。
MS m/z(ESI):744.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ8.17(s,1H),7.97(s,1H),7.78(s,1H),7.72(s,1H),7.51(d,1H),7.13(d,1H),6.83(dd,1H),6.68(s,1H),4.40(t,2H),4.30(t,2H),3.85(s,3H),3.15-3.11(m,2H),3.10(s,3H),3.03(s,3H),2.80-2.63(m,5H),1.98-1.92(m,2H),1.90-1.83(m,2H),1.80-1.66(m,6H),1.56-1.48(m,2H),1.31-1.24(m,2H)。
生物学评价
测试例1、本公开化合物对BaF3/EGFR L858R-T790M-C797S、BaF3/EGFR L858R-C797S、H1975/EGFR L858R-T790M和HCC827/EGFR Del19细胞的增殖抑制测定
1.实验材料与仪器
BaF3/EGFR L858R-T790M-C797S(也记作BaF3/LTC，KC-0122)购于康源博创；BaF3/EGFR L858R-C797S(也记作BaF3/LC，CBP73047)购于南京科佰；H1975/EGFR L858R-T790M(也记作H1975/LT，CRL-5908)购于ATCC；HCC827/EGFR Del19(也记作HCC827/D，CRL-2868)购于ATCC。
RPMI1640培养基(美仑,PWL015)
0.25％胰蛋白酶-EDTA(1×)(Gibco，25200-072)
青霉素-链霉素(Gibco，15140-122)
DPBS(1×)(Gibco，14190-144)
FBS(Gibco，10091148)
T75Flask(TITAN,02055020)
384细胞培养板(白色不透明384孔微孔板，无菌和组织培养处理)(PE,6007680)
96孔圆底配药板(未处理)(JET BIOFIL,TCP-002-096)
CellTiter-Glo缓冲液(Promega,G756B)
CellTiter-Glo底物(Promega,G755B)
自动细胞计数仪(Countstar，IC1000)
离心机(Thermo，75004524)
恒温培养箱(Thermo，I160)
EnVision多模式读板仪(PerkinElmer,EnVision 2105)
2.实验方法
2.1贴壁细胞铺板(第0天)
a.显微镜下观察细胞状态，确保细胞的融合度在～90％。
b.弃去细胞的上清，PBS润洗一次，倒去PBS。加入适量胰蛋白酶消化细胞，37℃静置5分钟。
c.用等体积含10％FBS的培养基终止消化，收集细胞悬液。300g，离心3分钟。用适量新鲜培养基悬浮细胞。
d.取重悬的细胞悬液20μL进行计数，确保细胞活率大于90％。
e.H1975/LT和HCC827/D：根据细胞计数结果，用含10％FBS的1640培养基稀释细胞至相应铺板密度，分别按照每孔300、600个细胞的密度将细胞接种于384孔培养板中，每孔20μL。
f.将细胞培养板放在37℃，5％二氧化碳的培养箱中培养过夜。
2.2悬浮细胞铺板(第1天)
a.显微镜下观察细胞状态。
b.收集细胞至15mL离心管中，300g，离心4分钟。用适量新鲜培养基悬浮细胞。
c.取重悬的细胞悬液20μL进行细胞计数，确保细胞活率大于90％。
d.BaF3/LTC和BaF3/LC：根据细胞计数结果，用含10％FBS的1640培养基稀释细胞至相应铺板密度，按照每孔400个细胞的密度将细胞接种于384孔培养板中，每孔20μL。
2.3加药(第1天)
a.化合物起始浓度为3.3mM，用DMSO将每个化合物3倍梯度稀释成10个浓度点(不同化合物最高浓度根据IC50的不同可作相应调整)。例如，在96孔圆底配药板中，将3μL化合物依次梯度稀释至6μL DMSO中。
b.将每个化合物各浓度点按500倍稀释到相应体积1640细胞培液中。
c.向每个细胞板20μL/孔的细胞上清中依次加入20μL上述稀释好的化合物溶液。
d.将加完药的细胞板放置在37℃，5％二氧化碳的培养箱培养。
2.4 CTG检测(第4天)
a.使用前将CellTiter-Glo缓冲液和冻干的CellTiter-Glo底物放置平衡到室温，两者混合充分混匀配制成100mL的CellTiter-Glo试剂(或将已混好的CellTiter-Glo试剂从-20℃拿出平衡到室温)。
b.将待检测的板子从培养箱中取出，平衡至室温，每孔加入20μL CellTiter-Glo试剂。
c.振荡混匀2分钟使细胞充分裂解。
d.室温放置28分钟待信号稳定后在EnVision上进行发光信号值(RLU)的检 测。
2.5 IC50值和最大抑制率计算
a.通过下列公式计算化合物各浓度的抑制率，使用XLfit根据化合物的对数浓度和抑制率进行曲线拟合并计算IC50值。
b.抑制率(％)＝100-100×(RLU化合物-RLU空白对照)/(RLU溶媒对照-RLU空白对照)
本公开化合物生物活性由上述分析所得，计算所得的IC50值。
表1本公开化合物的细胞增殖抑制活性
结论：本公开化合物对BaF3/LTC、BaF3/LC、H1975/LT和HCC827/D细胞具有明显的增殖抑制活性。
测试例2、药代动力学评价
一、SD大鼠试验
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠灌胃(i.g.)和静脉注射(i.v.)给予实施例化合物后不同时刻血浆中的药物浓度，研究本公开化合物在SD大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1、试验药品
化合物1。
2.2、试验动物
SD大鼠8只，雌雄各半，平均分成2组，每组4只，由维通利华实验动物技术有限公司提供；禁食过夜。
2.3、药物配制
分别称取一定量的受试化合物，加5％DMSO+5％吐温80+90％生理盐水，配制成0.2mg/mL无色澄明溶液。
2.4、给药
灌胃给药组：给药剂量为2.0mg/kg，给药体积为10mL/kg。
静脉注射给药组：给药剂量为1.0mg/kg，给药体积为5mL/kg。
3、操作
于给药后5分钟、0.25小时、0.5小时、1.0小时、2.0小时、4.0小时、8.0小时、11.0小时、24.0小时，由大鼠眼眶采血0.2mL，置EDTA抗凝试管中，10000rpm离心2分钟(4℃)分离血浆，干冰下或-80℃下保存待测。所有过程在冰浴条件下操作，并在1小时内完成。给药后2小时恢复进食水。
测定不同的化合物给药后SD大鼠血浆中的待测化合物含量：取给药后各时刻的SD大鼠小鼠血浆样品50μL，加入25μL双氯芬酸钠(1μg/mL)，450μL乙腈，涡旋混合，并在3700rpm下离心10分钟。取上清液进行LC/MS/MS分析。
4、药代动力学参数结果
表2、本公开化合物在SD大鼠体内的药代动力学参数
结论：本公开化合物在SD小鼠体内血药浓度高，暴露量高，具有药代动力学优势。

Claims (19)

  1. 一种通式(I)所示的化合物，或其可药用的盐：
    其中：
    环Cy选自环烷基、杂环基、芳基和杂芳基；
    L0选自O、S、NRa、亚烷基、-O-亚烷基-、-亚烷基-O-、-NRa-亚烷基-和-亚烷基-NRa-；其中所述的亚烷基任选被一个或多个R01所取代；
    R1选自-P(O)R10R11、-S(O)2R12、-S(O)R12、-C(O)R12、-S(O)2NR13R14、-S(O)NR13R14、-C(O)NR13R14、-S(O)(＝NR15)R12、-N(R15)S(O)R12、-N(R15)S(O)2R16和-N(R15)C(O)R12；
    各个RC相同或不同，且各自独立地选自氧代基、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
    R4和R5相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR25R26、C(O)NR25R26、NR25C(O)R27、NR25C(O)NR25R26、C(O)R27、C(O)OR27、OC(O)R27、S(O)rR27、S(O)rOR27、OS(O)rR27、S(O)rNR25R26、NR25S(O)rR27、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
    或者R4、R5及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基；所述环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R01所取代；
    L1选自键、O、S、NRL、S(O)r、C(O)、C(O)NRL、NRLC(O)、C(O)O、OC(O)、S(O)rNRL、NRLC(O)NRL、(CRL1RL2)m、烯基和炔基；其中所述的烯基任选被一个或多个R02所取代；
    L2为-(CRL3RL4)n1-RL5-(CRL6RL7)n2-；
    L3选自O、S和CRL8RL9；
    RL5选自键、O、S、NRL11、S(O)r、C(O)、C(O)NRL11、NRL11C(O)、C(O)O、OC(O)、NRL11C(O)NRL11、烯基和炔基；其中所述的烯基和炔基各自独立地任选被一个或多个R02所取代；
    各个RL1、RL2、RL3、RL4、RL6、RL7、RL8和RL9相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R02所取代；
    或者RL1、RL2及与其相连的同一碳原子一起形成环烷基或杂环基，或者RL3、RL4及与其相连的同一碳原子一起形成环烷基或杂环基，或者RL6、RL7及与其相连的同一碳原子一起形成环烷基或杂环基，或者RL8、RL9及与其相连的同一碳原子一起形成环烷基或杂环基，所述的环烷基或杂环基各自独立地任选被一个或多个R02所取代；
    Z1为N或CRZ1；
    Z2为N或CRZ2；
    Z3为N或CRZ3；
    RZ1、RZ2和RZ3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、羟烷氧基、烯基、炔基、氰基、硝基、NR30R31、C(O)NR30R31、NR32C(O)R33、NR32C(O)NR30R31、C(O)R33、C(O)OR33、OC(O)R33、S(O)rR33、S(O)rOR33、OS(O)rR33、S(O)rNR30R31、NR32S(O)rR33、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、杂环基烷基、杂环基氧基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
    或者Z1、Z2及其连接的取代基一起形成环烷基、杂环基、芳基和杂芳基；所述的环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
    J1和J2相同或不同，且各自独立地选自键、O、S、O亚烷基、亚烷基O、C(O)、C(O)亚烷基、亚烷基C(O)、C(O)N(RJ)、N(RJ)C(O)、N(RJ)C(O)N(RJ)、S(O)r、S(O)rN(RJ)、N(RJ)S(O)r、N(RJ)、N(RJ)亚烷基、亚烷基N(RJ)、亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；
    J3选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、羟烷氧基、烯基、炔基、氰基、硝基、NR40R41、C(O)NR40R41、NR42C(O)R43、NR42C(O)NR40R41、C(O)R43、C(O)OR43、OC(O)R43、S(O)rR43、S(O)rOR43、OS(O)rR43、S(O)rNR40R41、NR42S(O)rR43、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或 多个R03所取代；
    Ra和Rb相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、环烷基和杂环基；
    各个R10、R11、R12、R16、R24、R27、R33和R43相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R04所取代；
    各个R13、R14、R15、R20、R21、R22、R25、R26、RL、RL11、R30、R31、R32、RJ、R40、R41和R42相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R04所取代；
    或者R10、R11及与其相连的膦原子一起形成杂环基，或者R13、R14及与其相连的氮原子一起形成杂环基，或者R20、R21及与其相连的氮原子一起形成杂环基，或者R25、R26及与其相连的氮原子一起形成杂环基，或者R30、R31及与其相连的氮原子一起形成杂环基，或者R40、R41及与其相连的氮原子一起形成杂环基，所述的杂环基各自独立地任选被一个或多个R04所取代；
    各个R01、R02、R03和R04相同或不同，且各自独立地选自氧代基、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、羟烷氧基、氰基、烯基、炔基、NRcRd、C(O)NRcRd、亚烷基NRcRd、亚烷基C(O)NRcRd、硝基、环烷基、杂环基、环烷基烷基、杂环基烷基、环烷基氧基、杂环基氧基、芳基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、亚烷基、环烷基、杂环基、环烷基烷基、杂环基烷基、环烷基氧基、杂环基氧基、芳基和杂芳基各自独立地任选被一个或多个R*所取代；
    各个Rc和Rd相同或不同，且各自独立地选自氢原子、烷基、烷氧基、环烷基和杂环基；其中所述的烷基、烷氧基、环烷基和杂环基各自独立地任选被一个或多个R*所取代；
    或者Rc、Rd及与其相连的氮原子一起形成任选被一个或多个R*所取代的杂环基；
    R*各自独立地选自卤素、羟基、烯基、炔基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；
    s选自0、1、2、3、4、5和6；
    r选自0、1和2；且
    n1、n2和m相同或不同，且各自独立地选自0、1、2、3、4、5、6、7、8、9和10。
  2. 根据权利要求1所述的通式(I)所示的化合物，或其可药用的盐，其中： 选自L1连接至带*的键；
    R2和R3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
    或者R2、R3及与其相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被1、2、3或4个RC所取代，且L1连接至带*的键或连接至R2、R3形成的环上；
    R1、Ra、R20、R21、R22、R24、R01、RC和r如权利要求1中所定义。
  3. 根据权利要求1所述的通式(I)所示的化合物，或其可药用的盐，其中：L0为NRa，Ra如权利要求1中所定义；和/或Z3为CH。
  4. 根据权利要求1至3任一所述的通式(I)所示的化合物，或其可药用的盐，其为通式(III)所示的化合物，或其可药用的盐：
    其中，
    R2选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、烯基、炔基、氰基、硝基、NR20R21、C(O)NR20R21、NR22C(O)R24、NR22C(O)NR20R21、C(O)R24、C(O)OR24、OC(O)R24、S(O)rR24、S(O)rOR24、OS(O)rR24、S(O)rNR20R21、NR22S(O)rR24、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基；其中所述的烷基、烷氧基、烯基、 炔基、环烷基、杂环基、环烷基氧基、杂环基氧基、环烷基烷基、杂环基烷基、芳基、芳基氧基、芳基烷基和杂芳基各自独立地任选被一个或多个R01所取代；
    R1、R4、R5、Ra、Rb、Z1、Z2、L1、L2、L3、J1、J2、J3、R20、R21、R22、R24、R01和r如权利要求1中所定义。
  5. 根据权利要求1至4任一所述的通式(I)所示的化合物，或其可药用的盐，其中：Ra和Rb相同或不同，且各自独立地为氢原子或C1-6烷基；优选地，Ra和Rb均为氢原子。
  6. 根据权利要求1至5任一所述的通式(I)所示的化合物，或其可药用的盐，其中L1为键或O，和/或L2为C1-10亚烷基，和/或L3为O或S。
  7. 根据权利要求1至6任一所述的通式(I)所示的化合物，或其可药用的盐，其中，R1为-N(R15)S(O)2R16；R15和R16相同或不同，且各自独立地选自氢原子、C1-6烷基和3至6元环烷基；优选地，R1为-N(CH3)S(O)2CH3。
  8. 根据权利要求2至7任一所述的通式(I)所示的化合物，或其可药用的盐，其中，R2为氢原子。
  9. 根据权利要求1至8任一所述的通式(I)所示的化合物，或其可药用的盐，其中，R4为氢原子；和/或R5为卤素。
  10. 根据权利要求1至9任一所述的通式(I)所示的化合物，或其可药用的盐，其中：Z1为CRZ1，RZ1选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和C1-6羟烷氧基；和/或Z2为CRZ2，RZ2选自氢原子、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基和3至6元环烷基；优选地，Z1为CRZ1，RZ1为氢原子或C1-6烷氧基；和/或Z2为CRZ2，RZ2为氢原子或卤素。
  11. 根据权利要求1至10任一所述的通式(I)所示的化合物，或其可药用的盐，其中，J1为任选被一个或多个R03所取代的5或6元杂环基；J2为任选被一个或多个R03所取代的5或6元杂环基；R03选自氧代基、羟基、卤素、C1-6烷基、C1-6卤代烷基和C1-6羟烷基；J3选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基；所述3至6元环烷基任选被一个或多个氰基取代；优选地，-J1-J2-J3为f为0或1；Q选自CH2、O和N-J3a；J3a选自氢原子、C1-6烷基、3至6元杂环基和-C1-6亚烷基-3至6元环烷基；所述3至6元环烷基任选被 一个或多个氰基取代；更优选地，-J1-J2-J3选自
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物，或其可药用的盐，其选自以下任一化合物：
  13. 一种通式(IA)所示的化合物或其可药用的盐：
    其中，
    环Cy、R1、R4、R5、Rb、RC、Z1、Z2、Z3、L0、L1、L2、L3、J1、J2和s如权 利要求1中所定义。
  14. 化合物或其可药用的盐，其选自以下结构：

  15. 一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
    通式(IA)所示的化合物或其可药用的盐与醛酮类化合物或其盐(优选为醛，更优选为甲醛)，发生还原胺化反应得到通式(I)所示的化合物或其可药用的盐；
    其中，
    J2为*键与J1相连；
    环C为3至12元含氮杂环基，其中所述的3至12元含氮杂环基任选被一个或多个R03所取代；
    J3选自烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个R03所取代；优选地，J3为C1-6烷基，更优选地，J3为甲基；
    环Cy、R1、R4、R5、Rb、R03、RC、Z1、Z2、Z3、L0、L1、L2、L3、J1和s如权利要求1中所定义。
  16. 一种药物组合物，所述药物组合物含有根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  17. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求16所述的药物组合物在制备EGFR抑制剂中的用途。
  18. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求16所述的药物组合物在制备用于治疗和/或预防由EGFR介导的或依赖性的疾病或病症的药物中的用途。
  19. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求16所述的药物组合物在制备用于治疗和/或预防癌症的药物中的用途；优选地，所述的癌症选自鳞状细胞癌、基底细胞癌、腺癌、肝癌、肾癌、膀胱癌、乳腺癌、宫颈癌、结直肠癌、食管癌、头颈癌、鼻咽癌、口腔癌、唾液腺癌、肾癌、肺癌、卵巢癌、胰腺癌、前列腺癌、胃癌、白血病、淋巴瘤、神经胶质瘤、神经母细胞瘤、黑素瘤、肉瘤、子宫内膜癌、睾丸癌和甲状腺癌；进一步优选为肺癌；更优选为非小细胞肺癌。
PCT/CN2024/072923 2023-01-18 2024-01-18 取代的氨基嘧啶类大环化合物、其制备方法及其在医药上的应用 Ceased WO2024153161A1 (zh)

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