WO2020253860A1 - Aryl phosphorus oxide derivative inhibitor, preparation method therefor and use thereof - Google Patents

Aryl phosphorus oxide derivative inhibitor, preparation method therefor and use thereof Download PDF

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Publication number
WO2020253860A1
WO2020253860A1 PCT/CN2020/097362 CN2020097362W WO2020253860A1 WO 2020253860 A1 WO2020253860 A1 WO 2020253860A1 CN 2020097362 W CN2020097362 W CN 2020097362W WO 2020253860 A1 WO2020253860 A1 WO 2020253860A1
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alkyl
substituted
group
cycloalkyl
halogen
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PCT/CN2020/097362
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French (fr)
Chinese (zh)
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高鹏
王少宝
孙广俊
修文华
谭松良
蔡家强
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN202080004102.4A priority Critical patent/CN112469713B/en
Publication of WO2020253860A1 publication Critical patent/WO2020253860A1/en

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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to an aryl phosphorus oxide derivative inhibitor and a preparation method and application thereof.
  • EGFR Extracellular Growth Factor Receptor
  • EGF epidermal growth factor
  • TGF ⁇ transforming growth factor ⁇
  • the activated EGFR forms a homodimer on the cell membrane, or forms a heterodimer with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), causing the key tyrosine in EGFR cells
  • Phosphorylation of acid residues activates downstream signaling pathways in cells and plays an important role in cell proliferation, survival and anti-apoptosis.
  • EGFR activation mutations can lead to excessive activation of EGFR, promote cell transformation into tumor cells, and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis. It is an anti-cancer drug, especially An important target for the development of lung cancer treatment drugs.
  • the first generation of EGFR small molecule inhibitors including gefitinib (Iressa) and erlotinib (Tracet) have shown good efficacy in the treatment of lung cancer. They have been used as first-line drugs for the treatment of EGFR activating mutations ( Including L858R and delE746_A750) non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • Osimertinib (Osimertinib or AZD9291) is a third-generation EGFR TKI inhibitor. It has a high response rate and good therapeutic effect against drug resistance caused by the EGFR T790M mutation. It was approved by the U.S. FDA in November 2015 for accelerated marketing. Clinically, it can effectively treat patients with advanced non-small cell lung cancer with EGFR T790M resistance mutations. Although osimertinib has achieved great success in the clinical treatment of EGFR T790M mutation non-small cell lung cancer, patients still inevitably develop drug resistance after 9 to 14 months of treatment. Studies have shown that up to 20-40% of drug-resistant patients are due to the EGFR C797S mutation.
  • the EGFR C797S mutation converts the cysteine at position 797 to serine, causing osimertinib to fail to form a covalent bond with the EGFR protein, causing drug resistance.
  • EGFR C797S resistance mutations there are no effective inhibitors against EGFR C797S resistance mutations. Therefore, there is an urgent need to develop new and highly active EGFR inhibitors to solve the drug resistance problem caused by the EGFR C797S mutation.
  • EAI0450 a compound resistant to EGFR C797S, belongs to an EGFR allosteric inhibitor. After being combined with EGFR monoclonal antibodies such as cetuximab, it is a model of in vivo pharmacodynamics for L858R/T790M/C797S mutant mice It showed a good anti-tumor effect, but the compound was ineffective as a single agent and could not inhibit the C797S drug resistance mutation containing deIE746_A750, and failed to enter clinical studies. In 2017, Ken Uchibori et al.
  • Lung cancer is a major disease threatening human health, and the mortality rate of lung cancer is the first among all malignant tumors.
  • the incidence of lung cancer is increasing year by year, with about 700,000 new cases each year.
  • my country’s lung cancer cases with EGFR activating mutations account for about 35% of all NSCLC.
  • the use of first or third generation EGFR inhibitors can have a good therapeutic effect, but new drug-resistant mutations will be generated later, so new developments
  • the first generation of anti-drug resistant EGFR inhibitors has huge clinical and market value.
  • the purpose of the present invention is to provide a compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof, and the compound structure is as follows:
  • X 1 or Y 1 are each independently selected from bond, -O-, -NR AA -, -S- or -CR AA R BB -; preferably bond, -O-, -NH-, -NCH 3 -, -S -Or -CH 2 -;
  • R a is selected from hydrogen, deuterium, hydroxy, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, nitro, hydroxy, cyano, alkenyl group, alkynyl group, cycloalkyl group , Heterocyclyl, oxoheterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O) R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -(CH 2 ) n C(O)R CC , -NR
  • R a is linked with ring A1 to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen , Deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , -(CH 2 ) n R CC , aryl and heteroaryl substituted by one or more substituents;
  • R AA or R BB are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, Nitro, cyano, substituted or unsubstituted alkenyl, substituted or
  • R AA or R BB and ring A1 or B1 can be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are any Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents, preferably linked to form a C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 3-6 aryl group Or a 3-6 membered heteroaryl group, more preferably a C 5-6 cycloalkyl group, a 5-6 membered heterocyclic group, a C 5-6 aryl group
  • R CC , R DD or R EE are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, Oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstitute
  • any two of R CC , R DD or R EE may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups , Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • R CC and R DD are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, trimethylsilyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkyl group Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubsti
  • R CC and R DD may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, hetero One or more substituents in the cyclic group, aryl group and heteroaryl group are substituted.
  • a preferred embodiment of the present invention is to provide a compound represented by general formula (IB), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
  • X 1 or Y 1 are each independently selected from -O-, -NR AA -, -S- or -CR AA R BB -, preferably -O-, -NH-, -NCH 3 -, -S- or -CH 2 -;
  • M 2 , M 3 , M 4 or M 5 are each independently selected from N, S, CH, or CR aa , preferably O, S, N or CH;
  • M 0 or M 1 is each independently selected from N, S, CH, NR aa or CR aa R bb when present , preferably O, S, N or CH, more preferably S, N or CH;
  • Ring A is selected from cycloalkyl or aryl, preferably phenyl;
  • Ring D is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group, preferably substituted or unsubstituted C 3-6 ring Alkyl group, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably containing 1-3 nitrogen atoms Or 5-6 membered heteroaryl or heterocyclic group of oxygen atom, more preferably
  • R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group or heteroaryl group, preferably hydrogen, alkyl or halogen, more preferably hydrogen, C 1-6 alkyl, fluorine, chlorine, bromine or iodine, further preferably hydrogen, C 1-3 alkyl, fluorine , Chlorine or bromine;
  • R 1 or R 5 are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, alkene Group, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -(CH 2 ) n C(O)R CC ,
  • R 1 and R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Substituted by one or more substituents among hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH 2 ) n R CC , aryl and heteroaryl;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, mercapto, alkyl substituted Mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetero Aryl, preferably hydrogen, alkyl, haloalkyl, halogen, hydroxy, mercapto, alkoxy, -SR aa or substituted or unsubstituted alkynyl, more preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl Group, halogen, hydroxy, mercapto, C
  • R 3 and R 4 , R 3 and Y 1 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents, preferably substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycle Group, substituted or unsubstituted C 5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably substituted or unsubstituted 5-6
  • R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, oxo group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, Oxo, thio, nitro, cyano, substituted or unsubsti
  • R aa or R bb is linked with a phosphorus atom to form a heterocyclic group or heteroaryl group, wherein the heterocyclic group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group , Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents, preferably 3-6 membered heterocyclic group, more preferably
  • x 0, 1 or 2;
  • y is 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • n 0, 1, or 2.
  • R 1 or R 5 are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, spirocycloalkyl, bridged cycloalkyl, fused ring alkyl, bridged heterocyclyl, spiro hetero Cyclic, fused heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD ,
  • R 1 and R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH 2 ) n R CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n C(O)R CC , aryl and heteroaromatic One or more substituents in the group are substituted.
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
  • M 1 , M 2 and M 3 are the same or different, and are independently selected from O, N, S, CH, NR aa or CR aa R bb ;
  • Ring A is selected from cycloalkyl or aryl
  • R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group or heteroaryl group;
  • R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb ,
  • R 3 and R 4 are the same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb ,
  • R 1 and R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy Substituted by one or more substituents in alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxygen Substitute, nitro, cyano, substituted or unsubstituted alkenyl, substituted or
  • any two of R aa , R bb and R cc may be linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups
  • the group is optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • x 0, 1 or 2;
  • y is 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb ,- NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -( CH 2 ) n C(O)R aa , -NR a
  • R 3 and R 4 are the same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, Alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ;
  • R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb ,
  • R 1 and R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, substituted or unsubstituted heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa is substituted by one or more substituents;
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, trimethylsilyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group Group, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or Unsubstituted amino, oxo, nitro, cyano, substituted or unsub
  • any two of R aa , R bb and R cc may be linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen One of, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Or more substituents;
  • Said It can be a saturated or unsaturated ring.
  • the preferred embodiment of the present invention is to provide a general formula (IA) further represented by the general formula (G):
  • Ring D is selected from heterocyclyl
  • ring B is selected from cycloalkyl, heterocyclic, aryl or heteroaryl; preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused cycloalkane Group, 3-8 membered monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably containing 1-2 N or O atoms 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or fused heterocyclic group; further preferred are the following groups:
  • R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
  • R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl or -(CH 2 ) n OR aa ; or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
  • R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, ring Alkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, hydroxyl, cyano C 1-6 alkyl, C 1-6 alkoxy or oxo;
  • R 5 and R 8 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen Atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy-substituted alkyl, cyano-substituted alkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa ,- (CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb or -(CH 2 ) n NR aa C(O
  • R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R aa , R bb or R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; preferably hydrogen, C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, substituted with one or more halogen atoms, a C 1-6 alkyl group, a substituted or unsubstituted 3-6 membered heterocyclyl or Substituted or unsubstituted C 3-6 cycloalkyl; more preferably hydrogen,
  • y is 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • n1 0, 1, 2, 3 or 4;
  • z 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • u 0, 1, 2, 3 or 4;
  • q 0, 1, or 2.
  • a further preferred embodiment of the present invention is to provide a compound represented by general formula (II), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
  • the present invention also provides a preferred solution, which is a compound represented by general formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • the present invention also provides a preferred solution, and the general formula (G) is further represented by the general formula (G-1):
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (IG), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • u 0, 1, 2, 3 or 4;
  • i 0, 1, or 2.
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (VII), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • the present invention also provides another preferred embodiment, which is the compound represented by (VIII-B), its stereoisomer or its pharmaceutically acceptable salt, and its structure is as follows:
  • Ring F is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group, preferably substituted or unsubstituted C 4-7 cycloalkyl or substituted or unsubstituted 5-7 membered heterocyclic group, further Preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
  • R 12 is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n C(O)R aa , preferably hydrogen, C 1-6 alkyl, substituted or unsubstituted heterocyclic group, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb or -(CH 2 )
  • s 0, 1, 2, 3, or 4.
  • Ring B is selected from 4-6 membered monocyclic heterocyclic groups containing one or two nitrogen atoms or oxygen atoms or one or two nitrogen atoms or oxygen atoms.
  • a 7-9 membered fused ring heterocyclic group preferably a 4-6 membered monocyclic heterocyclic group selected from a nitrogen atom or an oxygen atom or a 7-9 membered fused ring heterocyclic group containing two selected from a nitrogen atom or an oxygen atom base.
  • the present invention also provides a preferred solution.
  • Ring A is selected from the following groups:
  • Ring B is selected from the following groups:
  • the present invention also provides a preferred solution, wherein the compounds represented by the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein the general formula (IB) and the general formula (I):
  • Ring A is selected from the following groups:
  • Ring B is selected from the following groups:
  • the present invention also provides a preferred solution.
  • the ring D is selected from 3-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups, more preferably containing 2-3 5-6 members selected from nitrogen or oxygen atoms. Membered heterocyclic group.
  • the present invention also provides a preferred solution.
  • R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, and halogenated alkyl.
  • R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, and halogenated alkyl.
  • R 9 is selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, cyano substituted C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OC 1-3 alkyl , -(CH 2 ) n C(O)C 1-3 alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n C(O)C 3-6 ring Alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n NC 1-3 -3-6-membered heterocyclic group, -(CH 2 ) n N(C 1- 3 alkyl) 2 , -(CH 2 ) n N
  • R aa , R bb or R cc are each independently selected from hydrogen, C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, one or more halogens Atom-substituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered heterocyclic group or substituted or unsubstituted C 3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, Cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,
  • the present invention also provides a preferred solution, each of the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein:
  • R is selected from hydrogen, halogen or C 1-6 alkyl
  • R 1 is selected from a substituted or unsubstituted 3-12 membered heterocyclic group, -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ;
  • R 3 is selected from hydrogen or halogen
  • R 4 is selected from hydrogen
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
  • R 6 and R 7 are independently selected from hydrogen or 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1 -6 haloalkyl, halogen, hydroxy, amino, cyano, oxo, C 3-8 cycloalkyl, 3-12 heterocyclyl, -(CH 2 ) n R aa , -(CH 2 ) n C( O) R aa and -(CH 2 ) n OR aa are substituted by one or more substituents;
  • R 6 and R 7 are connected to form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, cyano, oxo, C 3-8 cycloalkyl, 3-12 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O) R aa and -(CH 2 ) n OR aa are substituted by one or more substituents;
  • R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo;
  • R 5 and R 8 are linked to form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 Substituted by one or more substituents in haloalkyl, halogen, amino, oxo, cyano and hydroxy;
  • R 9 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano, oxo, hydroxyalkyl, C 3 -8 cycloalkyl, 3-12 membered heterocyclic group, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ;
  • R aa and R bb are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or substituted or unsubstituted C 3-8 ring alkyl.
  • the present invention also provides a preferred solution, each of the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein:
  • Ring D is a 5-6 membered oxygen-containing heterocyclic group; preferably a 5-6 membered dioxyheterocyclic group; more preferably
  • Ring B is a 3-8 membered heterocyclic group; preferably a 3-8 membered monocyclic heterocyclic group or a 3-8 membered bicyclic heterocyclic group;
  • R is selected from hydrogen, halogen or C 1-6 alkyl
  • R 3 is selected from hydrogen, halogen, -SR aa or C 1-6 haloalkyl; more preferably bromine;
  • R 4 is selected from hydrogen
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 5-6 membered heterocyclic group;
  • R 8 is selected from hydrogen
  • R 9 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxy substituted alkyl, C 1-6 cyano substituted alkyl, C 1 -6 haloalkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa R bb ;
  • R aa and R bb are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, or 3-6 membered heterocyclic group.
  • R 3 is selected from hydrogen or halogen
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-4 alkynyl, or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
  • R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo.
  • R 3 is selected from hydrogen or halogen
  • R 5 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 2-3 alkenyl, or C 2-4 alkynyl, or, Two R 5 are connected to form a C 3-6 cycloalkyl group or a 5-6 membered heterocyclic group;
  • R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo.
  • the present invention also relates to a compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
  • R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • i 0, 1, 2, 3 or 4;
  • u 0, 1, 2, 3 or 4;
  • q 0, 1, or 2.
  • the present invention also relates to a compound represented by general formula (A-1), its stereoisomers or pharmaceutically acceptable salts thereof:
  • X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
  • R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
  • R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably C 1- 3 alkyl.
  • R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • i 0, 1, 2, 3 or 4;
  • u 0, 1, 2, 3 or 4;
  • q 0, 1, or 2.
  • the present invention also relates to a compound represented by general formula (A-2), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
  • R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably C 1- 3 alkyl.
  • R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl or -SR aa ;
  • R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, cyano substituted alkyl, alkenyl, alkyne Group, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C
  • two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further Is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, one of -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa or Multiple substituents are substituted; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group; more preferably C 4-6 cycloalkyl, 5
  • R 6 and R 7 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy Substituted by one or more substituents in the group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl,
  • R 6 and R 7 are linked to form an oxo group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group optionally further Is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, ring Alkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
  • R aa , R bb or R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, substituted with one or more halogen atoms, a C 1-6 alkyl group, a substituted or unsubstituted 3-6 membered heterocyclyl or A substituted or unsubstituted C 3-6 cycloalkyl group, more preferably hydrogen, methyl
  • i 0, 1, 2, 3 or 4;
  • u 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • n1 0, 1 or 2;
  • y is 0, 1, 2, 3 or 4;
  • p 0, 1, or 2.
  • the present invention also relates to a method for preparing the compound represented by the general formula (A-1) according to claim 23, its stereoisomers or pharmaceutically acceptable salts thereof, characterized by comprising the following steps:
  • the compound represented by general formula (A) reacts with the compound represented by general formula (A-3) to obtain the target compound represented by general formula (A-1);
  • X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
  • X2 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine.
  • the present invention also relates to a method for preparing the compound represented by the general formula (A-2) according to claim 24, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized by comprising the following steps:
  • the compound represented by general formula (A-1) reacts with the compound represented by general formula (A-4) to obtain the target compound represented by general formula (A-2);
  • X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
  • X3 is halogen, amino, boric acid or boric acid ester; preferably chlorine, bromine or amino.
  • the present invention also relates to a method for preparing the compound represented by the general formula (G-1) according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized by comprising the following steps:
  • the compound represented by general formula (A-2) reacts with the compound containing ring B to obtain the target compound represented by general formula (G-1);
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably C3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, condensed cycloalkyl, 3-8 membered monocyclic ring Heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably 5-7 membered heterocyclic group containing 1-2 N or O atoms, Bridge heterocyclic group, spiro heterocyclic group or condensed heterocyclic group; the following groups are further preferred:
  • the present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which includes a therapeutically effective dose of the compound represented by the general formula and its stereoisomers or pharmaceutically acceptable salts thereof, and a One or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also provides a preferred solution, and also relates to the compounds of the general formulas, and their stereoisomers or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of MEK inhibitors, EGFR inhibitors And EGFR monoclonal antibodies and their combined use in related drugs.
  • the present invention also provides a preferred solution, and also relates to the compounds represented by the general formulas and their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions are used in the preparation of cancer-related diseases Wherein the cancer disease is selected from lung cancer.
  • the present invention further relates to a method for preparing the compound represented by each general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of cancer-related diseases.
  • the present invention also relates to a method for treating cancer-related diseases, which comprises administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof to the mammal.
  • the method involves the treatment of disorders such as cancer.
  • the cancer described in the above method is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma Or myeloma; preferably non-small cell lung cancer.
  • the treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides methods for treating diseases including cancer-related diseases in mammals.
  • the method includes administering to the mammal a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • 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-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate group, the present invention preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "Butylene” refers to -(CH 2 ) 4 -, etc.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, condensed and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • Non-limiting examples include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, nitrogen-containing fused heterocyclic groups, oxygen-containing Monocyclic heterocyclic group, oxygen-containing spiro heterocyclic group or oxygen-containing fused heterocyclic group.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl and piperazinyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heteroalkyl, preferably benzo 3-6 Member cycloalkyl, benzo 3-6 membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or it also contains a three-membered nitrogen-containing fused ring containing a benzene ring .
  • the ring connected with the parent structure is an aryl ring, and non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), where the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DMF N, N-dimethylformamide
  • TFA trifluoroacetic acid
  • MeCN means Otoharu.
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • N-BuLi refers to n-butyl lithium
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by deuterium atoms.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has due biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • the liquid mass spectrometry LC-MS measurement uses an Agilent 1200 Infinity Series mass spectrometer.
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification used for TLC is 0.15mm ⁇ 0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.
  • Step 5 Preparation of (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
  • Step 1 Preparation of 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane
  • the first step (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) two Preparation of methyl phosphine oxidation
  • the second step (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane- 8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
  • the reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the organic solvent was concentrated under reduced pressure and separated by column chromatography.
  • the fourth step (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine-1 -Yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Oxidation preparation
  • the first step preparation of tert-butyl 4-(3-(dimethylamino)azetidine-1-yl)piperidine-1-carboxylate
  • the third step 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine preparation
  • the 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (430mg, 1.04mmol), potassium vinyl trifluoroborate (279mg, 2.08mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (76mg, 0.104mmol), carbonic acid Cesium (1.01g, 3.12mmol) was dissolved in dioxane/water (10mL/1.5mL), replaced with nitrogen three times, heated to 90°C and stirred overnight, water was added to the reaction system, and extracted three times with ethyl acetate.
  • Step 5 Preparation of 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine
  • Example 1 the prepared 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethyl Azetidine-3-amine and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5 -Yl) dimethylphosphine oxidation reaction to prepare the target product (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidine-1 -Yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl ) Dimethylphosphine oxidation.
  • the first step (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3, 4-c]pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Preparation of Dioxin-5-yl) Dimethylphosphine Oxidation
  • Test Example 1 Determination of the inhibitory activity of the compounds of the present invention on EGFR wild-type, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases
  • the purpose of this test case is to test the inhibitory activity of the compound against EGFR wild-type, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases.
  • This experiment uses Cisbio's HTRF kinase assay method (Cisbio#62TK0PEB), the substrate peptides TK and ATP are in the tyrosine kinase EGFR wild type, EGFR del746-750/T790M/C797S or EGFR L858R/T790M/C797S mutation
  • the catalytic reaction occurs under the existing conditions, and the substrate is phosphorylated.
  • the activity of the kinase is characterized by measuring the content of the phosphorylated substrate generated in the reaction, and it is concluded that the compound is against EGFR wild-type, EGFR del746-750/T790M/C797S or EGFR L858R / T790M / C797S mutant half maximal inhibitory concentration IC 50 of inhibition of kinase activity.
  • the compound of the examples of the present invention has a strong inhibitory effect on the kinase activity of EGFR mutations, but has a small inhibitory effect on the activity of EGFR wild-type kinase.
  • the inhibition of EGFR mutant/wild type kinase activity is highly selective.
  • Test Example 2 Determination of the kinase inhibitory activity of the compounds of the present invention on EGFR del746-750/C797S and EGFR L858R/C797S mutations
  • the purpose of this test case is to test the inhibitory activity of the compound against EGFR del746-750/C797S and EGFR L858R/C797S mutant kinases.
  • This experiment uses Cisbio's HTRF kinase assay method (Cisbio#62TK0PEB).
  • the substrate peptides TK and ATP undergo a catalytic reaction in the presence of tyrosine kinase EGFR del746-750/C797S or EGFR L858R/C797S mutations.
  • the substrate is phosphorylated, the activity of the kinase is characterized by measuring the content of the phosphorylated substrate generated in the reaction, and the half inhibitory concentration IC 50 of the compound's inhibition of EGFR del746-750/C797S or EGFR L858R/C797S mutant kinase activity is obtained .
  • ddH 2 O then add 1-5 ⁇ L to each well diluted 0.5-5 nM 4 ⁇ EGFR del746-750/C797S or EGFR in Dilution buffer (5 ⁇ kinase buffer, MgCl 2 6.65mM, MnCl 2 1.33mM, DTT 1.33mM)
  • Dilution buffer 5 ⁇ kinase buffer, MgCl 2 6.65mM, MnCl 2 1.33mM, DTT 1.33mM
  • L858R/C797S mutant kinase solution add 1 ⁇ 5 ⁇ L of Dilution buffer to the negative control wells, add 1 ⁇ 5 ⁇ L of 4 ⁇ M 4 ⁇ Substrate TK solution prepared in 10 ⁇ Dilution buffer to all wells, and finally add 1 ⁇ 5 ⁇ L of diluted Dilution buffer 24 ⁇ M 4 ⁇ ATP solution starts the reaction.
  • the compound of the examples shown in the present invention has a strong inhibitory effect on the kinase activity of EGFR del746-750/C797S or EGFR L858R/C797S mutation
  • the purpose of this test case is to test the compound's inhibitory activity on cell proliferation.
  • CTG CELL TITER-GLO
  • Ba/F3 EGFR del746-750/T790M/C797S
  • A431 cells On the first day, spread 90 ⁇ L of A431 cell suspension in a 96-well test plate, the number of cells per well is 3000, and the negative control does not add cells, and the plate is placed at 37°C with 5% CO 2 Cultivate overnight in an incubator. On the second day, add 10 ⁇ L of the diluted compound solution to each well, add only 10 ⁇ L of medium containing DMSO to the positive and negative control wells, and place the plate in a carbon dioxide incubator for 72 hours.
  • the compound of the example of the present invention has a good inhibitory effect in the inhibition test of Ba/F3 (EGFR del746-750/T790M/C797S) mutant cell proliferation activity, but has a weaker effect on A431 cells.
  • comparative data shows that the compounds of the series of examples of the present invention have high selectivity in inhibiting the proliferation activity of Ba/F3 (EGFR del746-750/T790M/C797S) mutant cells.
  • Test Example 4 Determination of the inhibitory effect of the compound of the present invention on cell EGFR phosphorylation
  • the purpose of this test case is to test the compound's inhibitory activity on cell EGFR phosphorylation.
  • Microplate shaker (88880024) was purchased from Thermo Scientific TM company, centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, microplate reader was purchased from American Biotech company, and the model was SynergyH1 full function Microplate reader.
  • Phospho-EGFR (Tyr1068) LANCE Ultra TR-FRET Cellular Detection Kit (Perkin Elmer TRF4016C) contains (5X) LANCE Ultra Lysis Buffer 1, LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody, Ultra Ultra labeled Anti-EGFR Antibody, EGF (Thermo fisher PHG0311);
  • the Ba/F3 (EGFR del746-750/T790M/C797S) cell line was used to activate the EGFR signaling pathway through EGF stimulation to detect the inhibitory activity of the compound on its downstream EGFR (Y1068) phosphorylation, and obtain the compound half of the EGFR signaling pathway activity inhibitory concentration IC 50.
  • LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody (PerkinElmer) with a final concentration of 0.5 nM
  • LANCE Ultra ULight-labeled Anti-EGFR Antibody (PerkinElmer) with a final concentration of 5 nM were added, and incubated overnight at room temperature.
  • the microplate reader measures the 665nm fluorescence signal value of each plate well, calculates the inhibition rate from the fluorescence signal value, and obtains the IC 50 of the compound by curve fitting according to the inhibition rate of different concentrations.
  • Example number Ba/F3(EGFR del746-750/T790M/C797S)pEGFR IC 50 (nM) Example 1 0.06 Example 2 0.39 Example 12 2.57 Example 13 1.65 Example 15 5.00 Example 16 0.21 Example 20 1.74 Example 38 1.15 Example 42 6.93 Example 48 2.65 Example 52 5.00 Example 57 0.82 Example 58 0.95 Example 59 2.63 Example 60 1.57 Example 61 0.88 Example 65 0.11
  • the compound of the embodiment shown in the present invention has a good inhibitory effect on EGFR phosphorylation of Ba/F3 (EGFR del746-750/T790M/C797S) cells.
  • Balb/C mice were used as the test animals to study the pharmacokinetic behavior of the compound examples in the plasma of mice administered orally at a dose of 5 mg/kg.
  • the example compounds of the present invention are self-made.
  • Balb/C Mouse (6 mice/example), male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
  • mice (6 mice/example), male; p.o. after fasting overnight, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.
  • Mass spectrometry conditions AB Sciex API 4000 mass spectrometer
  • a solution is 0.1% formic acid aqueous solution
  • B solution is acetonitrile
  • FA is the formate of the corresponding compound.
  • Test Example 6 In vivo efficacy test of the compound of the present invention
  • NOD/SCID mice, 6-8 weeks, ⁇ purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • PC9 EGFR Del19/T790M/C797S cells were cultured in RPMI1640 medium containing 10% fetal calf serum. Collect PC9 (EGFR Del19/T790M/C797S) cells in the exponential growth phase.
  • mice were inoculated with 1 ⁇ 10 7 PC9 (EGFR Del19/T790M/C797S) cells subcutaneously on the right back (right back of the mouse, subcutaneous near the forelimb), and the cells were resuspended in 1:1 PBS and Matrigel ( 0.1ml/head), and regularly observe tumor growth.
  • the day of tumor cell inoculation is defined as day 0.
  • a,day7 measured tumor volume data and selected mice with tumor volume in the range of 100-200mm 3 , according to the average volume of 140mm 3 , randomized administration according to tumor size and mouse body weight.
  • test drug administration method: oral administration; administration volume: 10 mL/kg; administration frequency: 1 time/day; administration period: 21 days; vehicle: 0.5% HPMC).
  • TGI% [1-(T i -T 0 )/(C i -C 0 )] ⁇ 100%; where T i is the tumor volume on the i day of the administration group , T 0 is the tumor volume on the day of the administration group, C i is the tumor volume on the i day of the solvent control group, and C 0 is the tumor volume on the day of the solvent control group.
  • test data is as follows:

Abstract

The present invention relates to an aryl phosphorus oxide derivative inhibitor, a preparation method therefor and the use thereof. In particular, the present invention relates to a compound represented by general formula (IA), a preparation method therefor, a pharmaceutical composition containing the compound, and the use of same as an EGFR inhibitor in the treatment of tumor-related diseases.

Description

芳基磷氧化物类衍生物抑制剂、其制备方法和应用Aryl phosphorus oxide derivative inhibitor, preparation method and application thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及一种芳基磷氧化物类衍生物抑制剂及其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to an aryl phosphorus oxide derivative inhibitor and a preparation method and application thereof.
背景技术Background technique
EGFR(Epidermal Growth Factor Receptor)是跨膜受体酪氨酸激酶ErbB家族中的一员，通过与其配体表皮生长因子(EGF)或转化生长因子α(TGFα)结合激活。激活的EGFR在细胞膜上形成同源二聚体，或与家族中其它受体(如ErbB-2，ErbB-3，或ErbB-4)形成异源二聚体，引起EGFR细胞内关键的酪氨酸残基磷酸化，从而激活细胞内下游信号通路，在细胞增殖、生存及抗凋亡中起重要作用。EGFR的激活突变、过表达或基因扩增等可导致EGFR的过度激活，促进细胞向肿瘤细胞转化，并在肿瘤细胞的增殖、侵袭、转移以及血管形成中起重要作用，是抗癌药物特别是肺癌治疗药物开发的重要靶点。EGFR (Epidermal Growth Factor Receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases and is activated by binding to its ligand epidermal growth factor (EGF) or transforming growth factor α (TGFα). The activated EGFR forms a homodimer on the cell membrane, or forms a heterodimer with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), causing the key tyrosine in EGFR cells Phosphorylation of acid residues activates downstream signaling pathways in cells and plays an important role in cell proliferation, survival and anti-apoptosis. EGFR activation mutations, overexpression or gene amplification can lead to excessive activation of EGFR, promote cell transformation into tumor cells, and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis. It is an anti-cancer drug, especially An important target for the development of lung cancer treatment drugs.
第一代EGFR小分子抑制剂包括吉非替尼(易瑞沙)和厄洛替尼(特罗凯)在肺癌治疗中显示出良好的疗效，己作为一线药物用于治疗伴随EGFR激活突变(包括L858R和delE746_A750)的非小细胞肺癌(NSCLC)。但经第一代小分子EGFR抑制剂治疗10-12月后，几乎所有的NSCLC患者对第一代小分子抑制剂均产生耐药性，其耐药机制中有半数以上是由于EGFR看门基因残基T790M的继发突变导致。The first generation of EGFR small molecule inhibitors including gefitinib (Iressa) and erlotinib (Tracet) have shown good efficacy in the treatment of lung cancer. They have been used as first-line drugs for the treatment of EGFR activating mutations ( Including L858R and delE746_A750) non-small cell lung cancer (NSCLC). However, after 10-12 months of treatment with the first-generation small molecule EGFR inhibitor, almost all NSCLC patients are resistant to the first-generation small molecule inhibitor, and more than half of the resistance mechanism is due to the EGFR gatekeeper gene Caused by a secondary mutation of residue T790M.
奥希替尼(Osimertinib或AZD9291)是第三代EGFR TKI抑制剂，针对EGFR T790M突变导致的耐药具有高响应率和良好治疗效果，并于2015年11月获得美国FDA加速批准上市，其在临床上能有效治疗EGFR T790M耐药突变的晚期非小细胞肺癌患者。尽管奥希替尼在临床上治疗EGFR T790M突变的非小细胞肺癌取得了巨大的成功，患者在经过9～14个月治疗后仍不可避免出现了耐药的现象。经研究表明，高达20～40％的耐药患者耐药是由于EGFR C797S突变导致。EGFR C797S突变使797位的半肮氨酸转变为丝氨酸，导致奥希替尼无法与EGFR蛋白形成共价结合健，从而引起耐药。目前临床还没有针对EGFR C797S耐药突变的有效抑制剂。因此，迫切需要开发新型高活性的EGFR抑制剂以解决EGFR C797S突变导致的药物耐药性问题。Osimertinib (Osimertinib or AZD9291) is a third-generation EGFR TKI inhibitor. It has a high response rate and good therapeutic effect against drug resistance caused by the EGFR T790M mutation. It was approved by the U.S. FDA in November 2015 for accelerated marketing. Clinically, it can effectively treat patients with advanced non-small cell lung cancer with EGFR T790M resistance mutations. Although osimertinib has achieved great success in the clinical treatment of EGFR T790M mutation non-small cell lung cancer, patients still inevitably develop drug resistance after 9 to 14 months of treatment. Studies have shown that up to 20-40% of drug-resistant patients are due to the EGFR C797S mutation. The EGFR C797S mutation converts the cysteine at position 797 to serine, causing osimertinib to fail to form a covalent bond with the EGFR protein, causing drug resistance. At present, there are no effective inhibitors against EGFR C797S resistance mutations. Therefore, there is an urgent need to develop new and highly active EGFR inhibitors to solve the drug resistance problem caused by the EGFR C797S mutation.
诺华公司报道了针对EGFR C797S耐药的化合物EAI0450，属于一种EGFR变构抑制剂，在联合EGFR单抗药物如西妥昔单抗后，对L858R/T790M/C797S突变的小鼠体内药效模型中显示了较好的抗肿瘤效果，但该化合物单药无效且不能抑制含deIE746_A750的C797S耐药突变，未能进入临床研究。2017年Ken Uchibori等报道了Brigatinib(AP26113)和EGFR单抗(如西妥昔单抗)联用，能克服C797S这个突变导致的第三代EGFR抑制剂耐药，在PC9(EGFR-C797S/T790M/de119) 小鼠药效模型显示了良好的抗肿瘤药效，但Brigatinib同样面临单药体外活性低和体内无显著抗肿瘤活性，同样未有进一步临床研究。Novartis reported that EAI0450, a compound resistant to EGFR C797S, belongs to an EGFR allosteric inhibitor. After being combined with EGFR monoclonal antibodies such as cetuximab, it is a model of in vivo pharmacodynamics for L858R/T790M/C797S mutant mice It showed a good anti-tumor effect, but the compound was ineffective as a single agent and could not inhibit the C797S drug resistance mutation containing deIE746_A750, and failed to enter clinical studies. In 2017, Ken Uchibori et al. reported that the combination of Brigatinib (AP26113) and EGFR monoclonal antibodies (such as cetuximab) can overcome the third-generation EGFR inhibitor resistance caused by the mutation of C797S. /de119) The mouse pharmacodynamic model showed good anti-tumor efficacy, but Brigatinib also faced low single-agent in vitro activity and no significant anti-tumor activity in vivo, and there was no further clinical research.
肺癌是威胁人类健康的重大疾病，肺癌死亡率己占所有恶性肿瘤首位。在我国，肺癌发病率逐年上升，每年新发病例70万左右。我国肺癌伴有EGFR激活性突变的病例占所有NSCLC约35％左右，使用第一代或第三代EGFR抑制剂能起到良好的治疗效果，但后期都会产生新的耐药突变，因此开发新一代抗耐药的EGFR抑制剂具有巨大的临床和市场价值。Lung cancer is a major disease threatening human health, and the mortality rate of lung cancer is the first among all malignant tumors. In my country, the incidence of lung cancer is increasing year by year, with about 700,000 new cases each year. my country’s lung cancer cases with EGFR activating mutations account for about 35% of all NSCLC. The use of first or third generation EGFR inhibitors can have a good therapeutic effect, but new drug-resistant mutations will be generated later, so new developments The first generation of anti-drug resistant EGFR inhibitors has huge clinical and market value.
发明内容Summary of the invention
本发明的目的在于提供一种通式(IA)所示的化合物、其立体异构体或其药学上可接受盐，其化合物结构如下：The purpose of the present invention is to provide a compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof, and the compound structure is as follows:
Figure PCTCN2020097362-appb-000001
Figure PCTCN2020097362-appb-000001
其中：among them:
X 1或Y 1各自独立的选自键、-O-、-NR AA-、-S-或-CR AAR BB-；优选键、-O-、-NH-、-NCH 3-、-S-或-CH 2-； X 1 or Y 1 are each independently selected from bond, -O-, -NR AA -, -S- or -CR AA R BB -; preferably bond, -O-, -NH-, -NCH 3 -, -S -Or -CH 2 -;
环A1、环B1或环C1各自独立的选自环烷基、杂环基、芳基或杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) nP(＝O)R CCR DD、-(CH 2) nP(＝S)R CCR DD、-(CH 2) nS(O) mR CC、-(CH 2) nOR CC、-(CH 2) nNR CCR DD、-(CH 2) nNR CCC(O)R DD、-NR CCC(O)R DD、-C(O)NR CCR DD、-NR CCS(O) mR DD、-(CH 2) nS(O) mNR CCR DD、-(CH 2) nC(O)R CC、-NR CCC(O)OR DD、-(CH 2) nS(O) mR CC或-(CH 2) nNR CCS(O) mR DD中的一个或多个取代基所取代； Ring A1, Ring B1, or Ring C1 are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, Nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic Group, substituted or unsubstituted heteroaryl, -(CH 2 ) n P(=O)R CC R DD , -(CH 2 ) n P(=S)R CC R DD , -(CH 2 ) n S (O) m R CC , -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)R DD , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -(CH 2 ) n C(O)R CC , -NR CC C(O)OR DD , -(CH 2 ) n S(O) m R CC or -(CH 2 ) n NR CC S(O) m R DD in one or more of the substituents replace;
R a选自氢、氘、羟基、氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、芳基、杂芳基、-(CH 2) nOR CC、-(CH 2) nNR CCR DD、-(CH 2) nNR CCC(O)R DD、-NR CCC(O)NR DDR EE、-C(O)NR CCR DD、-NR CCS(O) mR DD、-(CH 2) nS(O) mNR CCR DD、-(CH 2) nC(O)R CC、-NR CCC(O)OR DD、-(CH 2) nS(O) mR CC或-(CH 2) nNR CCS(O) mR DD；-(CH 2) mNR CCR DD、-(CH 2) mNR CCC(O)R DD、，其中所述的羟基、氨基烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、氘、烷基、卤代烷基、卤素、取代或未取代的氨基、氧代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、卤代烷氧基、羟烷基、-(CH 2) nC(O)R CC、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的氧代杂环基、螺环烷基、桥环烷基或稠环烷基 中的一个或多个取代基所取代； R a is selected from hydrogen, deuterium, hydroxy, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, nitro, hydroxy, cyano, alkenyl group, alkynyl group, cycloalkyl group , Heterocyclyl, oxoheterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O) R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -(CH 2 ) n C(O)R CC , -NR CC C(O)OR DD , -(CH 2 ) n S(O) m R CC or -(CH 2 ) n NR CC S(O ) m R DD ; -(CH 2 ) m NR CC R DD , -(CH 2 ) m NR CC C(O)R DD , wherein the hydroxy, aminoalkyl, haloalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl, optionally further selected from deuterium, deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxyl, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, -(CH 2 ) n C(O)R CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted Among substituted heterocyclic groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted oxoheterocyclic groups, spirocyclic alkyl groups, bridged cycloalkyl groups or fused ring alkyl groups Substituted by one or more substituents;
或者，R a与环A1链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、-(CH 2) nR CC、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R a is linked with ring A1 to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen , Deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , -(CH 2 ) n R CC , aryl and heteroaryl substituted by one or more substituents;
R AA或R BB各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R AA or R BB are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, alkenyl group, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, Nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted One or more substituents in the heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;
或者，R AA或R BB与环A1或B1可链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选链接形成一个C 3-6环烷基、3-6元杂环基、C 3-6芳基或3-6元杂芳基，更优选C 5-6环烷基、5-6元杂环基、C 5-6芳基或5-6元杂芳基； Alternatively, R AA or R BB and ring A1 or B1 can be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are any Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents, preferably linked to form a C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 3-6 aryl group Or a 3-6 membered heteroaryl group, more preferably a C 5-6 cycloalkyl group, a 5-6 membered heterocyclic group, a C 5-6 aryl group or a 5-6 membered heteroaryl group;
R CC、R DD或R EE各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R CC , R DD or R EE are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, Oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted Or substituted by one or more substituents in an unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
或者，R CC、R DD或R EE任意两个可链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, any two of R CC , R DD or R EE may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups , Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
m为0、1或2；且m is 0, 1 or 2; and
n为0、1或2。n is 0, 1, or 2.
本发明一个优选的实施方案中，环A1、环B1或环C1各自独立的选自环烷 基、杂环基、芳基或杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) nP(＝O)R CCR DD、-(CH 2) nP(＝S)R CCR DD、-(CH 2) nS(O) mnR CC、-(CH 2) nOR CC、-(CH 2) nNR CCR DD、-(CH 2) nNR CCC(O)R DD、-NR CCC(O)R DD、-C(O)NR CCR DD、-NR CCS(O) mR DD、-(CH 2) nS(O) mNR CCR DD、-(CH 2) nC(O)R CC、-NR CCC(O)OR DD、-(CH 2) nS(O) mR CC、-(CH 2) nNR CCS(O) mR DD或-(CH 2) nC≡CR CC中的一个或多个取代基所取代； In a preferred embodiment of the present invention, ring A1, ring B1 or ring C1 are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl , Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero Cyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH 2 ) n P(=O)R CC R DD , -(CH 2 ) n P(=S)R CC R DD , -(CH 2 ) n S(O) mn R CC , -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)R DD , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -( CH 2 ) n C(O)R CC , -NR CC C(O)OR DD , -(CH 2 ) n S(O) m R CC , -(CH 2 ) n NR CC S(O) m R DD Or -(CH 2 ) n C≡CR CC substituted by one or more substituents;
R CC和R DD各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、三甲基硅基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R CC and R DD are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, trimethylsilyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkyl group Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkane Substituted by one or more substituents in the group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;
或者，R CC和R DD可链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。 Alternatively, R CC and R DD may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, hetero One or more substituents in the cyclic group, aryl group and heteroaryl group are substituted.
本发明一个优选的实施方案在于提供通式(IB)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：A preferred embodiment of the present invention is to provide a compound represented by general formula (IB), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
Figure PCTCN2020097362-appb-000002
Figure PCTCN2020097362-appb-000002
其中：among them:
X 1或Y 1各自独立的选自-O-、-NR AA-、-S-或-CR AAR BB-，优选-O-、-NH-、-NCH 3-、-S-或-CH 2-； X 1 or Y 1 are each independently selected from -O-, -NR AA -, -S- or -CR AA R BB -, preferably -O-, -NH-, -NCH 3 -, -S- or -CH 2 -;
M 2、M 3、M 4或M 5存在或不存在，存在时各自独立的选自N、S、CH、或CR aa，优选O、S、N或CH； The presence or absence of M 2 , M 3 , M 4 or M 5 , when present, are each independently selected from N, S, CH, or CR aa , preferably O, S, N or CH;
M 0或M 1存在或不存在，存在时各自独立的选自N、S、CH、NR aa或CR aaR bb，优选O、S、N或CH，更优选S、N或CH； The presence or absence of M 0 or M 1 is each independently selected from N, S, CH, NR aa or CR aa R bb when present , preferably O, S, N or CH, more preferably S, N or CH;
环A选自环烷基或芳基，优选苯基；Ring A is selected from cycloalkyl or aryl, preferably phenyl;
环D选自取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选取代或未取代的C 3-6环烷基、取代或未取代的3-6元杂环基、取代或未取代的C 5-6芳基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子或氧原子的5-6元杂芳基或杂环基，进一步优选
Figure PCTCN2020097362-appb-000003
Figure PCTCN2020097362-appb-000004
Ring D is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group, preferably substituted or unsubstituted C 3-6 ring Alkyl group, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably containing 1-3 nitrogen atoms Or 5-6 membered heteroaryl or heterocyclic group of oxygen atom, more preferably
Figure PCTCN2020097362-appb-000003
Figure PCTCN2020097362-appb-000004
R独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，优选氢、烷基或卤素，更优选氢、C 1-6烷基、氟、氯、溴或碘，进一步优选氢、C 1-3烷基、氟、氯或溴； R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group or heteroaryl group, preferably hydrogen, alkyl or halogen, more preferably hydrogen, C 1-6 alkyl, fluorine, chlorine, bromine or iodine, further preferably hydrogen, C 1-3 alkyl, fluorine , Chlorine or bromine;
R 1或R 5各自独立的选自氢、氘、氧、氮、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、芳基、杂芳基、-(CH 2) nOR CC、-(CH 2) nNR CCR DD、-(CH 2) nNR CCC(O)R DD、-NR CCC(O)NR DDR EE、-C(O)NR CCR DD、-NR CCS(O) mR DD、-(CH 2) nS(O) mNR CCR DD、-(CH 2) nC(O)R CC、-NR CCC(O)OR DD、-(CH 2) nS(O) mR CC或-(CH 2) nNR CCS(O) mR DD；其中所述的氧、氮、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、氘、烷基、卤代烷基、卤素、取代或未取代的氨基、氧代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、卤代烷氧基、羟烷基、-(CH 2) nC(O)R CC、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的氧代杂环基、螺环烷基、桥环烷基或稠环烷基中的一个或多个取代基所取代； R 1 or R 5 are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, alkene Group, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -(CH 2 ) n C(O)R CC , -NR CC C(O)OR DD , -(CH 2 ) n S(O) m R CC or -(CH 2 ) n NR CC S(O) m R DD ; wherein the oxygen, nitrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, Deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, haloalkyl Oxy, hydroxyalkyl, -(CH 2 ) n C(O)R CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted Substituted by one or more substituents in the heteroaryl group, substituted or unsubstituted oxoheterocyclic group, spirocyclic alkyl group, bridged cycloalkyl group or fused ring alkyl group;
或者，R 1和R 5，或两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、-(CH 2) nR CC、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 1 and R 5 , or two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Substituted by one or more substituents among hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH 2 ) n R CC , aryl and heteroaryl;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) mR aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m R aa ;
R 3和R 4各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、巯基、烷基取代巯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选氢、烷基、卤代烷基、卤素、羟基、巯基、烷氧基、-SR aa或取代或未取代的炔基，更优选氢、C 1-6烷基、 C 1-6卤代烷基、卤素、羟基、巯基、C 1-6烷氧基、-SR aa、C 2-6炔基、C 2-6烯基，所述C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-SR aa、C 2-6炔基、C 2-6烯基，任选进一步被C 3-6环烷基、C 1-6烷基或卤素所取代，优选氢、氯、溴、-SCH 3、
Figure PCTCN2020097362-appb-000005
Figure PCTCN2020097362-appb-000006
环丙基或-CF 3； R 3 and R 4 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, mercapto, alkyl substituted Mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetero Aryl, preferably hydrogen, alkyl, haloalkyl, halogen, hydroxy, mercapto, alkoxy, -SR aa or substituted or unsubstituted alkynyl, more preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl Group, halogen, hydroxy, mercapto, C 1-6 alkoxy, -SR aa , C 2-6 alkynyl, C 2-6 alkenyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -SR aa , C 2-6 alkynyl, C 2-6 alkenyl, optionally further substituted by C 3-6 cycloalkyl, C 1-6 alkyl or halogen, preferably Hydrogen, chlorine, bromine, -SCH 3 ,
Figure PCTCN2020097362-appb-000005
Figure PCTCN2020097362-appb-000006
Cyclopropyl or -CF 3 ;
或者，R 3和R 4、R 3和Y 1链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选取代或未取代的C 3-6环烷基、取代或未取代的3-6元杂环基、取代或未取代的C 5-6芳基或取代或未取代的5-6元杂芳基，更优选取代或未取代的含1-2个N、O或S原子的5-6元杂芳基，进一步优选取代或未取代的吡咯基、取代或未取代的噻唑基、取代或未取代的吡啶基或取代或未取代的苯基； Alternatively, R 3 and R 4 , R 3 and Y 1 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents, preferably substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycle Group, substituted or unsubstituted C 5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably substituted or unsubstituted 5-6 membered group containing 1-2 N, O or S atoms Heteroaryl, further preferably substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridyl or substituted or unsubstituted phenyl;
R aa或R bb各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、氧代基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代，优选氢、烷基、环烷基、杂环基、氧代基或硫代基，更优选C 1-6烷基、C 3-6环烷基、3-6元杂环基、氧代基或硫代基，进一步优选甲基、乙基、丙基、氧代基或硫代基； R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, oxo group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, Oxo, thio, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted ring Alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl are substituted by one or more substituents, preferably hydrogen, alkyl, cycloalkyl, hetero Cyclic group, oxo group or thio group, more preferably C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, oxo or thio group, more preferably methyl, ethyl Group, propyl group, oxo group or thio group;
或者，R aa或R bb与磷原子链接形成一个杂环基或杂芳基，其中所述的杂环基和杂芳基，任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选3-6元杂环基，更优选
Figure PCTCN2020097362-appb-000007
Alternatively, R aa or R bb is linked with a phosphorus atom to form a heterocyclic group or heteroaryl group, wherein the heterocyclic group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group , Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents, preferably 3-6 membered heterocyclic group, more preferably
Figure PCTCN2020097362-appb-000007
x为0、1或2；x is 0, 1 or 2;
y为0、1、2、3或4；y is 0, 1, 2, 3 or 4;
q为0、1或2；q is 0, 1 or 2;
m为0、1或2。m is 0, 1, or 2.
本发明进一步优选的实施方案中，R 1或R 5各自独立的选自氢、氘、氧、氮、 烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、螺环烷基、桥环烷基、稠环烷基、桥杂环基、螺杂环基、稠杂环基、芳基、杂芳基、-(CH 2) nOR CC、-(CH 2) nNR CCR DD、-(CH 2) nNR CCC(O)R DD、-NR CCC(O)NR DDR EE、-C(O)NR CCR DD、-NR CCS(O) mR DD、-(CH 2) nS(O) mNR CCR DD、-(CH 2) nC(O)R CC、-NR CCC(O)OR DD、-(CH 2) nS(O) mR CC、-(CH 2) nNR CCS(O) mR DD或-(CH 2) nC≡CR CC；其中所述的氧、氮、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、氘、烷基、卤代烷基、卤素、取代或未取代的氨基、氧代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、卤代烷氧基、羟烷基、-(CH 2) nC(O)R CC、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的氧代杂环基、螺环烷基、桥环烷基或稠环烷基中的一个或多个取代基所取代； In a further preferred embodiment of the present invention, R 1 or R 5 are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, Nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, spirocycloalkyl, bridged cycloalkyl, fused ring alkyl, bridged heterocyclyl, spiro hetero Cyclic, fused heterocyclic, aryl, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD ,- (CH 2 ) n C(O)R CC , -NR CC C(O)OR DD , -(CH 2 ) n S(O) m R CC , -(CH 2 ) n NR CC S(O) m R DD or -(CH 2 ) n C≡CR CC ; wherein the oxygen, nitrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from deuterium, Deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, haloalkyl Oxy, hydroxyalkyl, -(CH 2 ) n C(O)R CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted Substituted by one or more substituents in the heteroaryl group, substituted or unsubstituted oxoheterocyclic group, spirocyclic alkyl group, bridged cycloalkyl group or fused ring alkyl group;
或者，R 1和R 5，或两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、-(CH 2) nR CC、-(CH 2) nNR CCR DD、-(CH 2) nC(O)R CC、芳基和杂芳基中的一个或多个取代基所取代。 Alternatively, R 1 and R 5 , or two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH 2 ) n R CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n C(O)R CC , aryl and heteroaromatic One or more substituents in the group are substituted.
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中，通式(I)所示的化合物结构如下：The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
Figure PCTCN2020097362-appb-000008
Figure PCTCN2020097362-appb-000008
其中：among them:
M 1、M 2和M 3各自相同或者不同，各自独立的选自O、N、S、CH、NR aa或CR aaR bb； M 1 , M 2 and M 3 are the same or different, and are independently selected from O, N, S, CH, NR aa or CR aa R bb ;
环A选自环烷基或芳基；Ring A is selected from cycloalkyl or aryl;
R独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group or heteroaryl group;
R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa或-(CH 2) nNR aaS(O) mR bb，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂 芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基中的一个或多个取代基所取代； R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa S(O) m R bb , wherein the alkyl group, alkyl halide Group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl , Alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl Is substituted by one or more substituents in;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) mR aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m R aa ;
R 3和R 4相同或不同，且各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基； R 3 and R 4 are the same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 5选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa或-(CH 2) nNR aaS(O) mR bb； R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa S(O) m R bb ;
或者，R 1和R 5、或两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 1 and R 5 , or two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy Substituted by one or more substituents in alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R aa、R bb和R cc各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R aa , R bb and R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxygen Substitute, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Substituted by one or more substituents in the unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;
或者，R aa、R bb和R cc中任意两个可链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, any two of R aa , R bb and R cc may be linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups The group is optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
x为0、1或2；x is 0, 1 or 2;
y为0、1、2、3或4；y is 0, 1, 2, 3 or 4;
q为0、1或2；q is 0, 1 or 2;
n为0、1或2；且n is 0, 1 or 2; and
m为0、1或2。m is 0, 1, or 2.
本发明进一步优选的实施方案中，R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nC≡CR CC，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、氧代基、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基中的一个或多个取代基所取代； In a further preferred embodiment of the present invention, R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb ,- NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -( CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb Or -(CH 2 ) n C≡CR CC , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen, deuterium, oxo, Alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted Or substituted by one or more substituents in an unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
R 3和R 4相同或不同，且各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa； R 3 and R 4 are the same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, Alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ;
R 5选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nC≡CR aa； R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb or -(CH 2 ) n C≡ CR aa ;
或者，R 1和R 5，或两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、取代或未取代的杂环基、芳基、杂芳基、-(CH 2) nR aa、-(CH 2) nNR aaR bb和-(CH 2) nC(O)R aa中的一个或多个取代基所取代； Alternatively, R 1 and R 5 , or two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, substituted or unsubstituted heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa is substituted by one or more substituents;
R aa、R bb和R cc各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、三甲基硅基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R aa , R bb and R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, trimethylsilyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group Group, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or Unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl are substituted by one or more substituents;
或者，R aa、R bb和R cc中任意两个可链接形成一个环烷基、杂环基、芳基或杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、 芳基和杂芳基中的一个或多个取代基所取代； Alternatively, any two of R aa , R bb and R cc may be linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen One of, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Or more substituents;
所述
Figure PCTCN2020097362-appb-000009
可以为饱和或不饱和环。 Said
Figure PCTCN2020097362-appb-000009
It can be a saturated or unsaturated ring.
本发明优选的实施方案为提供一种通式(IA)进一步为通式(G)所示：The preferred embodiment of the present invention is to provide a general formula (IA) further represented by the general formula (G):
Figure PCTCN2020097362-appb-000010
Figure PCTCN2020097362-appb-000010
其中：among them:
环D选自杂环基；Ring D is selected from heterocyclyl;
环B存在或不存在，存在时选自环烷基、杂环基、芳基或杂芳基；优选C 3-8单环环烷基、桥环烷基、螺环烷基、稠环烷基、3-8元单环杂环基、桥杂环基、螺杂环基、稠杂环基、芳基或3-8元杂芳基；更优选含1-2个N或O原子的5-7元杂环基、桥杂环基、螺杂环基或稠杂环基；进一步优选以下基团： The presence or absence of ring B is selected from cycloalkyl, heterocyclic, aryl or heteroaryl; preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused cycloalkane Group, 3-8 membered monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably containing 1-2 N or O atoms 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or fused heterocyclic group; further preferred are the following groups:
Figure PCTCN2020097362-appb-000011
Figure PCTCN2020097362-appb-000011
R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选 氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 4选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 5选自氢、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基或-(CH 2) nOR aa；或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl or -(CH 2 ) n OR aa ; or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
R 8选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、羟基、氰基C 1-6烷基、C 1-6烷氧基或氧代基； R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, ring Alkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, hydroxyl, cyano C 1-6 alkyl, C 1-6 alkoxy or oxo;
或者，R 5和R 8链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 5 and R 8 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen Atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
R 9选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基、杂芳基、羟基取代的烷基、氰基取代的烷基、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-(CH 2) nC(O)R aa、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nNR aaC(O)R bb； R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy-substituted alkyl, cyano-substituted alkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa ,- (CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb or -(CH 2 ) n NR aa C(O)R bb ;
优选氢、卤素、羟基、C 1-6烷基、C 1-6烷基氰基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-6环烷基、C 3-6杂环基、C 1-6羟基取代的烷基、C 1-6氰基取代的烷基、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-(CH 2) nC(O)R aa、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nNR aaC(O)R bb； Preferably hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkyl cyano, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1 -6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 1-6 hydroxy substituted alkyl, C 1-6 cyano substituted alkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa ,- (CH 2 ) n NR aa S(O) m R bb or -(CH 2 ) n NR aa C(O)R bb ;
进一步优选氢、卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 1-3羟基取代的烷基、C 1-3氰基取代的烷基、-(CH 2) nOC 1-3烷基、-(CH 2) nC(O)C 1-3烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nC(O)C 3-6环烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nNC 1-3-3-6元杂环基、-(CH 2) nN(C 1-3烷基) 2、-(CH 2) nNHC 1-3烷基、-(CH 2) nN(C 1-3烷基)、-(CH 2) nNHC(O)C 1-3烷基或-(CH 2) nS(O) 2C 1-3烷基；更优选氢、甲基、乙基、羧基、-CH 2OH、HOCH 2CH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、(CH 3) 2SO 2-、CH 3CH 2O-、CH 3CH 2NH-、CH 3(O)C(CH 3)N-、CH 3(O)CNH-、(CH 3CH 2)(CH 3)N-、CH 3(O)C-、CH 3O(O)C-、环丙基或甲酰基； More preferably hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3 -6 cycloalkyl, C 3-6 heterocyclyl, C 1-3 hydroxy substituted alkyl, C 1-3 cyano substituted alkyl, -(CH 2 ) n OC 1-3 alkyl, -( CH 2 ) n C(O)C 1-3 alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n C(O)C 3-6 cycloalkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n NC 1-3 -3-6-membered heterocyclic group, -(CH 2 ) n N(C 1-3 alkyl ) 2 , -(CH 2 ) n NHC 1-3 alkyl, -(CH 2 ) n N(C 1-3 alkyl), -(CH 2 ) n NHC(O)C 1-3 alkyl or- (CH 2 ) n S(O) 2 C 1-3 alkyl; more preferably hydrogen, methyl, ethyl, carboxyl, -CH 2 OH, HOCH 2 CH 2 -, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 2 FCH 2 -, CNCH 2 -, (CH 3 ) 2 N-, (CH 3 CH 2 ) 2 N-, (CH 3 ) 2 SO 2 -, CH 3 CH 2 O-, CH 3 CH 2 NH-, CH 3 (O)C(CH 3 )N-, CH 3 (O)CNH-, (CH 3 CH 2 )(CH 3 )N-, CH 3 (O)C-, CH 3 O (O) C-, cyclopropyl or formyl;
R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、 氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R aa、R bb或R cc各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基；优选氢、C 1-6烷基、取代或未取代的C 1-6烷氧基、一个或多个卤原子取代的C 1-6烷基、取代或未取代的3-6元杂环基或取代或未取代的C 3-6环烷基；更优选氢、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、三甲基硅基、氟、氯、溴、
Figure PCTCN2020097362-appb-000012
R aa , R bb or R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; preferably hydrogen, C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, substituted with one or more halogen atoms, a C 1-6 alkyl group, a substituted or unsubstituted 3-6 membered heterocyclyl or Substituted or unsubstituted C 3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine ,
Figure PCTCN2020097362-appb-000012
y为0、1、2、3或4；y is 0, 1, 2, 3 or 4;
n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
m1为0、1、2、3或4；m1 is 0, 1, 2, 3 or 4;
z为0、1、2、3或4；z is 0, 1, 2, 3 or 4;
p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
u为0、1、2、3或4；且u is 0, 1, 2, 3 or 4; and
q为0、1或2。q is 0, 1, or 2.
本发明更进一步优选的实施方案在于提供一种通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：A further preferred embodiment of the present invention is to provide a compound represented by general formula (II), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
Figure PCTCN2020097362-appb-000013
Figure PCTCN2020097362-appb-000013
本发明还提供了一种优选方案，其为通式(IV)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：The present invention also provides a preferred solution, which is a compound represented by general formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097362-appb-000014
Figure PCTCN2020097362-appb-000014
本发明还提供了一种优选方案，通式(G)进一步为通式(G-1)所示：The present invention also provides a preferred solution, and the general formula (G) is further represented by the general formula (G-1):
Figure PCTCN2020097362-appb-000015
Figure PCTCN2020097362-appb-000015
本发明还提供另一优选的实施方案，其为通式(IG)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：The present invention also provides another preferred embodiment, which is a compound represented by general formula (IG), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097362-appb-000016
Figure PCTCN2020097362-appb-000016
其中：among them:
R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
u为0、1、2、3或4；且u is 0, 1, 2, 3 or 4; and
i为0、1或2。i is 0, 1, or 2.
本发明还提供另一优选的实施方案，其为通式(VII)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：The present invention also provides another preferred embodiment, which is a compound represented by general formula (VII), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097362-appb-000017
Figure PCTCN2020097362-appb-000017
本发明还提供另一优选的实施方案，其为(VIII-B)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：The present invention also provides another preferred embodiment, which is the compound represented by (VIII-B), its stereoisomer or its pharmaceutically acceptable salt, and its structure is as follows:
Figure PCTCN2020097362-appb-000018
Figure PCTCN2020097362-appb-000018
其中：among them:
环F选自取代或未取代的环烷基或取代或未取代的杂环基，优选取代或未取代的C 4-7环烷基或取代或未取代的5-7元杂环基，进一步优选哌啶基、四氢吡咯基、环丁基、环戊基、环己基、四氢呋喃基或四氢吡喃基； Ring F is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group, preferably substituted or unsubstituted C 4-7 cycloalkyl or substituted or unsubstituted 5-7 membered heterocyclic group, further Preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
R 12选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) nR aa、-(CH 2) nNR aaR bb或-(CH 2) nC(O)R aa，优选氢、C 1-6烷基、取代或未取代的杂环基、-(CH 2) nR aa、-(CH 2) nNR aaR bb或-(CH 2) nC(O)R aa； R 12 is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n C(O)R aa , preferably hydrogen, C 1-6 alkyl, substituted or unsubstituted heterocyclic group, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n C(O)R aa ;
s为0、1、2、3或4。s is 0, 1, 2, 3, or 4.
本发明还提供了一种优选方案，环B选自含有一个或两个选自氮原子或氧原子的4-6元单环杂环基或含有一个或两个选自氮原子或氧原子的7-9元稠环杂环基，优选含有一个选自氮原子或氧原子的4-6元单环杂环基或含有两个选自氮原子或氧原子的7-9元稠环杂环基。The present invention also provides a preferred solution. Ring B is selected from 4-6 membered monocyclic heterocyclic groups containing one or two nitrogen atoms or oxygen atoms or one or two nitrogen atoms or oxygen atoms. A 7-9 membered fused ring heterocyclic group, preferably a 4-6 membered monocyclic heterocyclic group selected from a nitrogen atom or an oxygen atom or a 7-9 membered fused ring heterocyclic group containing two selected from a nitrogen atom or an oxygen atom base.
本发明还提供了一种优选方案，所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其中通式(IB)以及通式(I)中：The present invention also provides a preferred solution. The compounds represented by the general formulae, their stereoisomers or their pharmaceutically acceptable salts, wherein in the general formula (IB) and the general formula (I):
环A选自如下基团：Ring A is selected from the following groups:
Figure PCTCN2020097362-appb-000019
Figure PCTCN2020097362-appb-000019
通式(G)、通式(G-1)、通式(IG)以及通式(VII)中：In general formula (G), general formula (G-1), general formula (IG) and general formula (VII):
环B选自如下基团：Ring B is selected from the following groups:
Figure PCTCN2020097362-appb-000020
Figure PCTCN2020097362-appb-000020
本发明还提供了一种优选方案，所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其中通式(IB)以及通式(I)：The present invention also provides a preferred solution, wherein the compounds represented by the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein the general formula (IB) and the general formula (I):
环A选自如下基团：Ring A is selected from the following groups:
Figure PCTCN2020097362-appb-000021
Figure PCTCN2020097362-appb-000021
通式(G)、通式(G-1)、通式(IG)以及通式(VII)中，In general formula (G), general formula (G-1), general formula (IG) and general formula (VII),
环B选自如下基团：Ring B is selected from the following groups:
Figure PCTCN2020097362-appb-000022
Figure PCTCN2020097362-appb-000022
Figure PCTCN2020097362-appb-000023
Figure PCTCN2020097362-appb-000023
本发明还提供了一种优选方案，所述环D选自3-8元杂环基；优选5-6元杂环基，更优选含有2-3个选自氮或氧原子的5-6元杂环基。The present invention also provides a preferred solution. The ring D is selected from 3-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups, more preferably containing 2-3 5-6 members selected from nitrogen or oxygen atoms. Membered heterocyclic group.
本发明还提供了一种优选方案，所述的各通式、其立体异构体或其药学上可接受的盐，其中，R 9选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nC(O)R aa、-(CH 2) nC(O)OR aa、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-(CH 2) nNR aaC(O)R bb或-(CH 2) nS(O) mR aa； The present invention also provides a preferred solution. The general formulas, their stereoisomers, or their pharmaceutically acceptable salts, wherein R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, and halogenated alkyl. Group, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl , -(CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n NR aa C(O)R bb or -(CH 2 ) n S(O) m R aa ;
优选氢、氘、C 1-6烷基、C 1-6烷基氰基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、卤素、羟基、C 1-6羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nOR aa、-(CH 2) nC(O)R aa、-(CH 2) nNR aaR bb、-(CH 2) nC(O)OR aa、-(CH 2) nNR aaC(O)R bb或-(CH 2) nS(O) mR aa； Preferably hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl cyano, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n NR aa C(O)R bb or -(CH 2 ) n S(O) m R aa ;
进一步优选氢、氘、C 1-3烷基、C 1-3烷基氰基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、羟基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nOC 1-3烷基、-(CH 2) nC(O)C 1-3烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nC(O)C 3-6环烷基、-(CH 2) nC(O)OR aa、-(CH 2) nNHC 3-6环烷基、-(CH 2) nN(C 1-3烷基) 2、-(CH 2) nNHC 1-3烷基、-(CH 2) nN(C 1-3烷基)(C 3-6环烷基)、-(CH 2) nN(C 1-3烷基)(C 3-6杂环基)、-(CH 2) nN(C 1-3烷基)C(O)C 1-3烷基、-(CH 2) nNHC(O)C 1-3烷基、-(CH 2) nSC 1-3烷基、-(CH 2) nS(O)C 1-3烷基或-(CH 2) nS(O) 2C 1-3烷基。 More preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkyl cyano, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, hydroxy , C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OC 1-3 alkyl, -(CH 2 ) n C(O)C 1 -3 alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n C(O)C 3-6 cycloalkyl, -(CH 2 ) n C(O) OR aa , -(CH 2 ) n NHC 3-6 cycloalkyl, -(CH 2 ) n N(C 1-3 alkyl) 2 , -(CH 2 ) n NHC 1-3 alkyl, -(CH 2 ) n N(C 1-3 alkyl)(C 3-6 cycloalkyl), -(CH 2 ) n N(C 1-3 alkyl)(C 3-6 heterocyclyl), -(CH 2 ) n N(C 1-3 alkyl) C(O)C 1-3 alkyl, -(CH 2 ) n NHC(O)C 1-3 alkyl, -(CH 2 ) n SC 1-3 Alkyl group, -(CH 2 ) n S(O)C 1-3 alkyl group or -(CH 2 ) n S(O) 2 C 1-3 alkyl group.
本发明还提供了一种更优选方案，R 9选自氢、卤素、羟基、C 1-3烷基、氰基取代的C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nOC 1-3烷基、-(CH 2) nC(O)C 1-3烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nC(O)C 3-6环烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nNC 1-3-3-6元杂环基、-(CH 2) nN(C 1-3烷基) 2、-(CH 2) nNHC 1-3烷基、-(CH 2) nN(C 1-3烷基)、-(CH 2) nNHC(O)C 1-3烷基或-(CH 2) nS(O) 2C 1-3烷基； The present invention also provides a more preferred solution, R 9 is selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, cyano substituted C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OC 1-3 alkyl , -(CH 2 ) n C(O)C 1-3 alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n C(O)C 3-6 ring Alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n NC 1-3 -3-6-membered heterocyclic group, -(CH 2 ) n N(C 1- 3 alkyl) 2 , -(CH 2 ) n NHC 1-3 alkyl, -(CH 2 ) n N(C 1-3 alkyl), -(CH 2 ) n NHC(O)C 1-3 alkyl Group or -(CH 2 ) n S(O) 2 C 1-3 alkyl;
优选氢、甲基、乙基、羧基、-CH 2OH、HOCH 2CH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、(CH 3) 2SO 2-、CH 3CH 2O-、CH 3CH 2NH-、CH 3(O)C(CH 3)N-、CH 3(O)CNH-、(CH 3CH 2)(CH 3)N-、CH 3(O)C-、CH 3O(O)C-、环丙基或甲酰基。 Preferably hydrogen, methyl, ethyl, carboxyl, -CH 2 OH, HOCH 2 CH 2 -, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 2 FCH 2 -, CNCH 2 -, (CH 3 ) 2 N-, (CH 3 CH 2 ) 2 N-, (CH 3 ) 2 SO 2 -, CH 3 CH 2 O-, CH 3 CH 2 NH-, CH 3 (O)C(CH 3 )N-, CH 3 (O)CNH-, (CH 3 CH 2 )(CH 3 )N-, CH 3 (O)C-, CH 3 O(O)C-, cyclopropyl or formyl.
本发明还提供了一种优选方案，R aa、R bb或R cc各自独立的选自氢、C 1-6烷基、取代或未取代的C 1-6烷氧基、一个或多个卤原子取代的C 1-6烷基、取代或未取代的3-6元杂环基或取代或未取代的C 3-6环烷基；更优选氢、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、三甲基硅基、氟、氯、溴、
Figure PCTCN2020097362-appb-000024
Figure PCTCN2020097362-appb-000025
The present invention also provides a preferred solution, R aa , R bb or R cc are each independently selected from hydrogen, C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, one or more halogens Atom-substituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered heterocyclic group or substituted or unsubstituted C 3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, Cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,
Figure PCTCN2020097362-appb-000024
Figure PCTCN2020097362-appb-000025
本发明还提供了一种优选方案，所述的各通式、其立体异构体或其药学上可接受的盐，其中，The present invention also provides a preferred solution, each of the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein:
R选自氢、卤素或C 1-6烷基； R is selected from hydrogen, halogen or C 1-6 alkyl;
R 1选自取代的或未取代的3-12元杂环基、-(CH 2) nOR aa或-(CH 2) nNR aaR bb； R 1 is selected from a substituted or unsubstituted 3-12 membered heterocyclic group, -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) mR aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m R aa ;
R 3选自氢或卤素； R 3 is selected from hydrogen or halogen;
R 4选自氢； R 4 is selected from hydrogen;
R 5选自氢、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基、卤素、氰基或-(CH 2) nOR aa，或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
R 6和R 7自独立的选自氢或3-12元杂环基，其中所述的3-12元杂环基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基、氧代基、C 3-8环烷基、3-12杂环基、-(CH 2) nR aa、-(CH 2) nC(O)R aa和-(CH 2) nOR aa中的一个或多个取代基所取代； R 6 and R 7 are independently selected from hydrogen or 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1 -6 haloalkyl, halogen, hydroxy, amino, cyano, oxo, C 3-8 cycloalkyl, 3-12 heterocyclyl, -(CH 2 ) n R aa , -(CH 2 ) n C( O) R aa and -(CH 2 ) n OR aa are substituted by one or more substituents;
或者，R 6和R 7相连形成一个3-12元杂环基，其中所述的3-12元杂环基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基、氧代基、C 3-8环烷基、3-12杂环基、-(CH 2) nOR aa、-(CH 2) nC(O)R aa和-(CH 2) nOR aa中的一个或多个取代基所取代； Alternatively, R 6 and R 7 are connected to form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 Haloalkyl, halogen, hydroxy, amino, cyano, oxo, C 3-8 cycloalkyl, 3-12 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O) R aa and -(CH 2 ) n OR aa are substituted by one or more substituents;
R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基或氧代基； R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo;
或者，R 5和R 8链接形成一个C 3-8环烷基，其中所述的C 3-8环烷基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、氨基、氧代基、氰基和羟基中的一个或多个取代基所取代； Alternatively, R 5 and R 8 are linked to form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 Substituted by one or more substituents in haloalkyl, halogen, amino, oxo, cyano and hydroxy;
R 9选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基、氧代基、羟烷基、C 3-8环烷基、3-12元杂环基、-(CH 2) nC(O)R aa、-(CH 2) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb； R 9 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano, oxo, hydroxyalkyl, C 3 -8 cycloalkyl, 3-12 membered heterocyclic group, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ;
R aa和R bb各自独立地选自氢、氘、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基或取代或未取代的C 3-8环烷基。 R aa and R bb are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or substituted or unsubstituted C 3-8 ring alkyl.
本发明还提供了一种优选方案，所述的各通式、其立体异构体或其药学上可接受的盐，其中，The present invention also provides a preferred solution, each of the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein:
环D为5-6元含氧杂环基；优选5-6元含双氧杂环基；更优选
Figure PCTCN2020097362-appb-000026
Ring D is a 5-6 membered oxygen-containing heterocyclic group; preferably a 5-6 membered dioxyheterocyclic group; more preferably
Figure PCTCN2020097362-appb-000026
环B为3-8元杂环基；优选3-8元单环杂环基或3-8元并环杂环基；跟优选
Figure PCTCN2020097362-appb-000027
Ring B is a 3-8 membered heterocyclic group; preferably a 3-8 membered monocyclic heterocyclic group or a 3-8 membered bicyclic heterocyclic group;
Figure PCTCN2020097362-appb-000027
R选自氢、卤素或C 1-6烷基； R is selected from hydrogen, halogen or C 1-6 alkyl;
R 2选自-(CH 2) nP(＝O)R aaR bb； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb ;
R 3选自氢、卤素、-SR aa或C 1-6卤代烷基；更优选溴； R 3 is selected from hydrogen, halogen, -SR aa or C 1-6 haloalkyl; more preferably bromine;
R 4选自氢； R 4 is selected from hydrogen;
R 5选自氢、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基、卤素、氰基或-(CH 2) nOR aa，或者，两个R 5相连形成一个C 3-8环烷基或5-6元杂环基； R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 5-6 membered heterocyclic group;
R 8选自氢； R 8 is selected from hydrogen;
R 9选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6羟基取代烷基、C 1-6氰基取代烷基、C 1-6卤代烷基、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nC(O)R aa、-(CH 2) nS(O) mR aa或-(CH 2) nNR aaR bb； R 9 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxy substituted alkyl, C 1-6 cyano substituted alkyl, C 1 -6 haloalkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa R bb ;
R aa和R bb各自独立地选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基或3-6元杂环基。 R aa and R bb are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, or 3-6 membered heterocyclic group.
本发明还提供了一种更优选方案，通式(I)、通式(G)、通式(G-1)、通式(IG)以及通式(VII)中，The present invention also provides a more preferred solution. In general formula (I), general formula (G), general formula (G-1), general formula (IG) and general formula (VII),
R 2选自-P(＝O)(CH 3) 2或-P(＝S)(CH 3) 2； R 2 is selected from -P(=O)(CH 3 ) 2 or -P(=S)(CH 3 ) 2 ;
R 3选自氢或卤素； R 3 is selected from hydrogen or halogen;
R 5选自氢、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 2-6烯基、或C 2-4炔基，或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-4 alkynyl, or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基或氧代基。 R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo.
本发明还提供了一种更优选方案，通式(I)、通式(G)、通式(G-1)、通式(IG)以及通式(VII)中，The present invention also provides a more preferred solution. In general formula (I), general formula (G), general formula (G-1), general formula (IG) and general formula (VII),
R 2选自-P(＝O)(CH 3) 2或-P(＝S)(CH 3) 2； R 2 is selected from -P(=O)(CH 3 ) 2 or -P(=S)(CH 3 ) 2 ;
R 3选自氢或卤素； R 3 is selected from hydrogen or halogen;
R 5选自氢、卤素、氰基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基、C 2-3烯基、或C 2-4炔基，或者，两个R 5相连形成一个C 3-6环烷基或5-6元杂环基； R 5 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 2-3 alkenyl, or C 2-4 alkynyl, or, Two R 5 are connected to form a C 3-6 cycloalkyl group or a 5-6 membered heterocyclic group;
R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基或氧代基。 R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo.
本发明还涉及一种通式(A)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020097362-appb-000028
Figure PCTCN2020097362-appb-000028
其中：among them:
R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
i为0、1、2、3或4；i is 0, 1, 2, 3 or 4;
u为0、1、2、3或4；且u is 0, 1, 2, 3 or 4; and
q为0、1或2。q is 0, 1, or 2.
本发明还涉及一种通式(A-1)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a compound represented by general formula (A-1), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020097362-appb-000029
Figure PCTCN2020097362-appb-000029
其中：among them:
X1为卤素、氨基、硼酸或硼酸酯；优选氯或溴；X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
R aa或R bb各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选C 1-3烷基。 R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably C 1- 3 alkyl.
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、 杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 4选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
i为0、1、2、3或4；i is 0, 1, 2, 3 or 4;
u为0、1、2、3或4；且u is 0, 1, 2, 3 or 4; and
q为0、1或2。q is 0, 1, or 2.
本发明还涉及一种通式(A-2)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a compound represented by general formula (A-2), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020097362-appb-000030
Figure PCTCN2020097362-appb-000030
其中：among them:
R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
R aa或R bb各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选C 1-3烷基。 R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably C 1- 3 alkyl.
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基、C 1-6卤代烷基或-SR aa； R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl or -SR aa ;
R 4选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 5选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、氰基取代的烷基、烯基、炔基、环烷基、杂环基、芳 基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nC≡CR aa，优选氢、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、氰基、氰基取代的烷基、烯基、炔基、-NR aaC(O)R bb或-(CH 2) nC≡CR aa，更优选氢、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、卤素、氨基、硝基、氰基、氰基取代的烷基、C 2-4烯基、C 2-4炔基、-NR aaC(O)R bb或-(CH 2) nC≡CR aa，进一步优选氢、甲基、乙基、丙基、甲氧基、乙氧基、乙烯基、乙炔基、氰基、氨基、硝基、氟、氯、溴、卤代甲基、卤代乙基、-CH 2CN、-NR aaC(O)R bb或-(CH 2) nC≡CR aa； R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, cyano substituted alkyl, alkenyl, alkyne Group, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb or- (CH 2 ) n C≡CR aa , preferably hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, cyano, cyano substituted alkyl, alkenyl, alkynyl, -NR aa C (O)R bb or -(CH 2 ) n C≡CR aa , more preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, amino, nitro, Cyano, cyano-substituted alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -NR aa C(O)R bb or -(CH 2 ) n C≡CR aa , more preferably hydrogen, methyl Group, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyano, amino, nitro, fluorine, chlorine, bromine, halomethyl, haloethyl, -CH 2 CN , -NR aa C(O)R bb or -(CH 2 ) n C≡CR aa ;
或者，两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nR aa、-(CH 2) nNR aaR bb和-(CH 2) nC(O)R aa中的一个或多个取代基所取代；优选C 3-6环烷基、3-6元杂环基；更优选C 4-6环烷基、5-6元杂环基；进一步优选环丁基、环戊基、哌啶基、四氢吡咯基、四氢呋喃基或四氢吡喃基； Alternatively, two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further Is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, one of -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa or Multiple substituents are substituted; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group; more preferably C 4-6 cycloalkyl, 5-6 membered heterocyclic group; more preferably cyclobutyl, cyclopentyl , Piperidinyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydropyranyl;
R 6和R 7各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 6 and R 7 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy Substituted by one or more substituents in the group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，R 6和R 7链接形成一个氧代基、环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 6 and R 7 are linked to form an oxo group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group optionally further Is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
R 8选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、环烷基、杂环基、芳基或杂芳基；优选氢、C 1-6烷基、C 1-6烷氧基、卤素、羟基、氰基或氧代基； R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, ring Alkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
R aa、R bb或R cc各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选氢、C 1-6烷基、取代或未取代的C 1-6烷氧基、一个或多个卤原子取代的C 1-6烷基、取代或未取代的3-6元杂环基或取代或未取代 的C 3-6环烷基，更优选氢、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、三甲基硅基、氟、氯、溴、
Figure PCTCN2020097362-appb-000031
R aa , R bb or R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, substituted with one or more halogen atoms, a C 1-6 alkyl group, a substituted or unsubstituted 3-6 membered heterocyclyl or A substituted or unsubstituted C 3-6 cycloalkyl group, more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine ,
Figure PCTCN2020097362-appb-000031
i为0、1、2、3或4；i is 0, 1, 2, 3 or 4;
u为0、1、2、3或4；u is 0, 1, 2, 3 or 4;
q为0、1或2；q is 0, 1 or 2;
n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
m为0、1或2；m is 0, 1 or 2;
m1为0、1或2；m1 is 0, 1 or 2;
y为0、1、2、3或4；且y is 0, 1, 2, 3 or 4; and
p为0、1或2。p is 0, 1, or 2.
本发明还涉及一种制备根据权利要求23所述的通式(A-1)所示的化合物、其立体异构体或其药学上可接受盐的方法，其特征在于包含如下步骤：The present invention also relates to a method for preparing the compound represented by the general formula (A-1) according to claim 23, its stereoisomers or pharmaceutically acceptable salts thereof, characterized by comprising the following steps:
Figure PCTCN2020097362-appb-000032
Figure PCTCN2020097362-appb-000032
通式(A)所示的化合物与通式(A-3)所示的化合物反应，得到通式(A-1)所示的目标化合物；The compound represented by general formula (A) reacts with the compound represented by general formula (A-3) to obtain the target compound represented by general formula (A-1);
其中：among them:
X1为卤素、氨基、硼酸或硼酸酯；优选氯或溴；X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
X2为卤素、氨基、硼酸或硼酸酯；优选氯或溴。X2 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine.
本发明还涉及一种制备根据权利要求24所述的通式(A-2)所示的化合物、其立体异构体或其药学上可接受盐的方法，其特征在于包含如下步骤：The present invention also relates to a method for preparing the compound represented by the general formula (A-2) according to claim 24, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized by comprising the following steps:
Figure PCTCN2020097362-appb-000033
Figure PCTCN2020097362-appb-000033
通式(A-1)所示的化合物与通式(A-4)所示的化合物反应，得到通式(A-2)所示的目标化合物；The compound represented by general formula (A-1) reacts with the compound represented by general formula (A-4) to obtain the target compound represented by general formula (A-2);
其中：among them:
X1为卤素、氨基、硼酸或硼酸酯；优选氯或溴；X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
X3为卤素、氨基、硼酸或硼酸酯；优选氯、溴或氨基。X3 is halogen, amino, boric acid or boric acid ester; preferably chlorine, bromine or amino.
本发明还涉及一种制备根据权利要求10所述的通式(G-1)所示的化合物、其立体异构体或其药学上可接受盐的方法，其特征在于包含如下步骤：The present invention also relates to a method for preparing the compound represented by the general formula (G-1) according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized by comprising the following steps:
Figure PCTCN2020097362-appb-000034
Figure PCTCN2020097362-appb-000034
通式(A-2)所示的化合物与含环B的化合物反应，得到通式(G-1)所示的目标化合物；The compound represented by general formula (A-2) reacts with the compound containing ring B to obtain the target compound represented by general formula (G-1);
环B选自环烷基、杂环基、芳基或杂芳基；优选C3-8单环环烷基、桥环烷基、螺环烷基、稠环烷基、3-8元单环杂环基、桥杂环基、螺杂环基、稠杂环基、芳基或3-8元杂芳基；更优选含1-2个N或O原子的5-7元杂环基、桥杂环基、螺杂环基或稠杂环基；进一步优选以下基团：Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably C3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, condensed cycloalkyl, 3-8 membered monocyclic ring Heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably 5-7 membered heterocyclic group containing 1-2 N or O atoms, Bridge heterocyclic group, spiro heterocyclic group or condensed heterocyclic group; the following groups are further preferred:
Figure PCTCN2020097362-appb-000035
Figure PCTCN2020097362-appb-000035
本发明还提供了一种优选方案，还涉及一种药用组合物，其包括治疗有效剂量的所示的各通式所示化合物及其立体异构体或其药学上可接受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。The present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which includes a therapeutically effective dose of the compound represented by the general formula and its stereoisomers or pharmaceutically acceptable salts thereof, and a One or more pharmaceutically acceptable carriers, diluents or excipients.
本发明还提供了一种优选方案，还涉及所述的各通式化合物、及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备MEK抑制剂、EGFR抑制剂和EGFR单抗及其联用相关药物中的应用。The present invention also provides a preferred solution, and also relates to the compounds of the general formulas, and their stereoisomers or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of MEK inhibitors, EGFR inhibitors And EGFR monoclonal antibodies and their combined use in related drugs.
本发明还提供了一种优选方案，还涉及所述的各通式所示的化合物及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治癌症相关疾病中的应用；其中所述癌症疾病选自肺癌。The present invention also provides a preferred solution, and also relates to the compounds represented by the general formulas and their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions are used in the preparation of cancer-related diseases Wherein the cancer disease is selected from lung cancer.
本发明进一步涉及各通式所示的化合物、其立体异构体或其药学上可接受的 盐，或其药物组合物在制备治疗癌症相关疾病的方法。The present invention further relates to a method for preparing the compound represented by each general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of cancer-related diseases.
本发明还涉及治疗癌症相关疾病的方法，其包括向所述哺乳动物施用治疗有效量的本发明的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The present invention also relates to a method for treating cancer-related diseases, which comprises administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof to the mammal.
在一些实施方案中，本方法涉及诸如癌症相关病症的治疗。In some embodiments, the method involves the treatment of disorders such as cancer.
以上方法所述的癌症选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤或骨髓瘤；优选非小细胞肺癌。The cancer described in the above method is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma Or myeloma; preferably non-small cell lung cancer.
本文提供的治疗方法包括向受试者施用治疗有效量的本发明的化合物。在一个实施方案中，本发明提供了治疗哺乳动物中包括癌症相关疾病症的方法。该方法包括向所述哺乳动物施用治疗有效量的本发明的化合物，或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods for treating diseases including cancer-related diseases in mammals. The method includes administering to the mammal a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
发明的详细说明Detailed description of the invention
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。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、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。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、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、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨 基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms The alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms. 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, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred is a lower alkyl group containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate group, the present invention preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。 The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means -CH 2 -, "ethylene" means -(CH 2 ) 2 -, "propylene" Refers to -(CH 2 ) 3 -, "Butylene" refers to -(CH 2 ) 4 -, etc. The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、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、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, condensed and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2020097362-appb-000036
Figure PCTCN2020097362-appb-000036
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：It also contains a spirocycloalkyl group in which a single spirocycloalkyl group and a heterocycloalkyl group share a spiro atom. Non-limiting examples include:
Figure PCTCN2020097362-appb-000037
Figure PCTCN2020097362-appb-000037
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2020097362-appb-000038
Figure PCTCN2020097362-appb-000038
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2020097362-appb-000039
Figure PCTCN2020097362-appb-000039
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；进一步优选包含1-3氮原子的3-8元杂环基，最优选5-6元杂环基，任选地，被1-2个氧原子、硫原子、氧代基取代，包括含氮单环杂环基、含氮螺杂环基、含氮稠杂环基、含氧单环杂环基、含氧螺杂环基或含氧稠杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; further preferably 3-8 membered heterocyclic groups containing 1-3 nitrogen atoms, most preferably 5-6 The membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, nitrogen-containing fused heterocyclic groups, oxygen-containing Monocyclic heterocyclic group, oxygen-containing spiro heterocyclic group or oxygen-containing fused heterocyclic group.
单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选哌啶基和哌嗪基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂 原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:
Figure PCTCN2020097362-appb-000040
Figure PCTCN2020097362-appb-000040
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2020097362-appb-000041
Figure PCTCN2020097362-appb-000041
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure PCTCN2020097362-appb-000042
Figure PCTCN2020097362-appb-000042
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
Figure PCTCN2020097362-appb-000043
等。
Figure PCTCN2020097362-appb-000043
Wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并3-8元环烷基、苯并3-8元杂烷基，优选苯并3-6元环烷基、苯并3-6元杂烷基，其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heteroalkyl, preferably benzo 3-6 Member cycloalkyl, benzo 3-6 membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or it also contains a three-membered nitrogen-containing fused ring containing a benzene ring .
其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The ring connected with the parent structure is an aryl ring, and non-limiting examples include:
Figure PCTCN2020097362-appb-000044
Figure PCTCN2020097362-appb-000044
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为***基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有选***基、吡咯基、噻吩基、噻唑基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2020097362-appb-000045
Figure PCTCN2020097362-appb-000045
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如： 烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" refers to (CH≡C-), where the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“氨基”指-NH 2。 "Amino" refers to -NH 2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2。 "Nitro" refers to -NO 2 .
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" means ethyl acetate.
“MeOH”指甲醇。"MeOH" means methanol.
“DMF”指N、N-二甲基甲酰胺。"DMF" refers to N, N-dimethylformamide.
“TFA”指三氟乙酸。"TFA" refers to trifluoroacetic acid.
“MeCN”指乙晴。"MeCN" means Otoharu.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N,N-dimethylacetamide.
“Et 2O”指***。 "Et 2 O" means diethyl ether.
“DCE”指1,2二氯乙烷。"DCE" means 1,2 dichloroethane.
“DIPEA”指N，N-二异丙基乙胺。"DIPEA" refers to N,N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。 "Pd 2 (dba) 3 "refers to tris(dibenzylideneacetone) dipalladium.
“Dppf”指1,1’-双二苯基膦二茂铁。"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamide.
“MeLi”指甲基锂。"MeLi" refers to methyl lithium.
“n-BuLi”指正丁基锂。"N-BuLi" refers to n-butyl lithium.
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。 "NaBH(OAc) 3 "means sodium triacetoxyborohydride.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by deuterium atoms.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明 包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)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(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。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。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has due biological activity.
具体实施方式Detailed ways
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.
实施例Example
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。The liquid mass spectrometry LC-MS measurement uses an Agilent 1200 Infinity Series mass spectrometer. HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification used for TLC is 0.15mm～0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm～0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.
中间体的制备1Preparation of intermediate 1
(6-氨基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备Preparation of (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000046
Figure PCTCN2020097362-appb-000046
第一步：2-溴-6-甲氧基-3-硝基苯酚的制备Step 1: Preparation of 2-bromo-6-methoxy-3-nitrophenol
Figure PCTCN2020097362-appb-000047
Figure PCTCN2020097362-appb-000047
往2-甲氧基-5-硝基苯酚(2g,11.8mmol)的DCM(20mL)溶液中加入NBS(2.1g,11.8mmol)，室温搅拌一小时后，向反应中加入CH 2Cl 2与水分液，有机相减压浓缩后柱层析分离得到标题化合物2-溴-6-甲氧基-3-硝基苯酚(1.5g,收率:51％)。 To 2-methoxy-5-nitrophenol (2g, 11.8mmol) in DCM (20mL) was added NBS (2.1g, 11.8mmol), after stirring for one hour at room temperature, CH 2 Cl 2 and The aqueous liquid and the organic phase were concentrated under reduced pressure and separated by column chromatography to obtain the title compound 2-bromo-6-methoxy-3-nitrophenol (1.5 g, yield: 51%).
MS m/z(ESI):245.9[M-H] -. MS m/z(ESI): 245.9[MH] - .
第二步：3-溴-4-硝基苯-1,2-二酚的制备Step 2: Preparation of 3-bromo-4-nitrobenzene-1,2-diphenol
Figure PCTCN2020097362-appb-000048
Figure PCTCN2020097362-appb-000048
-78℃下往2-溴-6-甲氧基-3-硝基苯酚(500mg,2.0mmol)的二氯甲烷溶液(5mL)中，加入BBr 3(1M,2.6mL,2.6mmol)的二氯甲烷溶液，搅拌2小时后，缓慢升至室温，搅拌过夜。冷却至0℃，向反应中缓慢滴加MeOH(5ml)，有机相减压浓缩后柱层析分离得到标题化合物3-溴-4-硝基苯-1,2-二酚(410mg,收率:87％)。 To the dichloromethane solution (5mL) of 2-bromo-6-methoxy-3-nitrophenol (500mg, 2.0mmol) at -78℃, add BBr 3 (1M, 2.6mL, 2.6mmol) The methyl chloride solution was stirred for 2 hours, then slowly warmed to room temperature and stirred overnight. After cooling to 0°C, MeOH (5ml) was slowly added dropwise to the reaction. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 3-bromo-4-nitrobenzene-1,2-diphenol (410mg, yield : 87%).
MS m/z(ESI):231.9[M-H] -. MS m/z(ESI): 231.9[MH] - .
第三步：5-溴-6-硝基-2,3-二氢苯并[b][1,4]二噁英的制备The third step: Preparation of 5-bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin
Figure PCTCN2020097362-appb-000049
Figure PCTCN2020097362-appb-000049
3-溴-4-硝基苯-1,2-二酚(410mg,1.75mmol)，碳酸钾(0.73g,5.26mmol)，1,2-二溴乙烷(1.32g,7.0mmol)混合于DMF(5mL)中，在90℃下搅拌过夜，冷却，加入大量乙酸乙酯稀释。有机相用饱和食盐水洗涤多次，然后无水硫酸钠干燥，减压浓缩有机溶剂后柱层析得到标题化合物5-溴-6-硝基-2,3-二氢苯并[b][1,4]二噁英(200mg,收率：44％)。3-Bromo-4-nitrobenzene-1,2-diphenol (410mg, 1.75mmol), potassium carbonate (0.73g, 5.26mmol), 1,2-dibromoethane (1.32g, 7.0mmol) were mixed in In DMF (5 mL), stir overnight at 90°C, cool, and dilute with a large amount of ethyl acetate. The organic phase was washed with saturated brine several times, and then dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and then column chromatography to obtain the title compound 5-bromo-6-nitro-2,3-dihydrobenzo[b][ 1,4] Dioxin (200 mg, yield: 44%).
MS m/z(ESI):257.9[M-H] -. MS m/z(ESI): 257.9[MH] - .
第四步：5-溴-2,3-二氢苯并[b][1,4]二噁英-6-胺的制备Step 4: Preparation of 5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine
Figure PCTCN2020097362-appb-000050
Figure PCTCN2020097362-appb-000050
5-溴-6-硝基-2,3-二氢苯并[b][1,4]二噁英(200mg,0.77mmol)溶于乙醇(9mL)和水(3mL)，加入还原铁粉(343mg,6.1mmol)和氯化铵(82mg,1.5mmol)，回流反应3h。反应液过滤，滤液减压浓缩后得到标题化合物5-溴-2,3-二氢苯并[b][1,4]二噁英-6-胺(170mg,收率:96％)。5-Bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin (200mg, 0.77mmol) dissolved in ethanol (9mL) and water (3mL), added reduced iron powder (343mg, 6.1mmol) and ammonium chloride (82mg, 1.5mmol), react under reflux for 3h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (170 mg, yield: 96%).
MS m/z(ESI):230.2[M+H] +. MS m/z(ESI): 230.2[M+H] + .
第五步：(6-氨基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备Step 5: Preparation of (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000051
Figure PCTCN2020097362-appb-000051
5-溴-2,3-二氢苯并[b][1,4]二噁英-6-胺(0.16g,0.7mmol)，二甲基氧化磷(108mg,1.39mmol)，磷酸钾(295mg,1.39mmol)混合于N,N-二甲基甲酰胺(5mL)中，加入醋酸钯(31mg,0.14mmol)和Xantphos(161mg,0.28mmol)，N2除氧5分钟，然后微波加热至145℃反应3小时。反应冷却至室温，减压浓缩有机溶剂后柱层析分离得到标题化合物(6-氨基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(83mg,收率:52％)。5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.16g, 0.7mmol), dimethyl phosphorous oxide (108mg, 1.39mmol), potassium phosphate ( 295mg, 1.39mmol) was mixed in N,N-dimethylformamide (5mL), palladium acetate (31mg, 0.14mmol) and Xantphos (161mg, 0.28mmol) were added, N2 deoxygenated for 5 minutes, and then heated to 145 in microwave React at °C for 3 hours. The reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Phosphine oxidation (83mg, yield: 52%).
1H NMR(400MHz,CDCl 3)δ1.72(s,3H),1.75(s,3H),4.09-4.13(m,2H),4.15-4.23(m,2H),5.41-5.85(m,2H),6.07-6.15(m,1H),6.72(d，J＝6.8,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.72 (s, 3H), 1.75 (s, 3H), 4.09-4.13 (m, 2H), 4.15-4.23 (m, 2H), 5.41-5.85 (m, 2H) ), 6.07-6.15 (m, 1H), 6.72 (d, J=6.8, 1H);
MS m/z(ESI):228.2[M+H] +. MS m/z(ESI): 228.2[M+H] + .
中间体的制备2Preparation of intermediate 2
2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)苯胺2-Methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline
Figure PCTCN2020097362-appb-000052
Figure PCTCN2020097362-appb-000052
第一步：8-(5-甲氧基-2-甲基-4-硝基苯基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷的制备Step 1: Preparation of 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane
Figure PCTCN2020097362-appb-000053
Figure PCTCN2020097362-appb-000053
往1-氟-5-甲氧基-2-甲基-4-硝基苯(1.1g,5.9mmol)和4-哌啶酮缩乙二醇(3.4g,23.9mmol)的DMSO(15mL)溶液中加入K 2CO 3(1.6g,11.9mmol)，120℃搅拌过夜。反应液冷却至室温，减压浓缩有机溶剂后柱层析分离得到标题化合物8-(5-甲氧基-2-甲基-4-硝基苯基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(1.3g,收率:71％)。 To 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.1g, 5.9mmol) and 4-piperidone ethylene ketal (3.4g, 23.9mmol) in DMSO (15mL) K 2 CO 3 (1.6 g, 11.9 mmol) was added to the solution, and stirred at 120°C overnight. The reaction solution was cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8 -Azaspiro[4.5]decane (1.3g, yield: 71%).
MS m/z(ESI):309.2[M+H] +. MS m/z(ESI): 309.2[M+H] + .
第二步：2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)苯胺的制备Step 2: Preparation of 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline
Figure PCTCN2020097362-appb-000054
Figure PCTCN2020097362-appb-000054
8-(5-甲氧基-2-甲基-4-硝基苯基)-1,4-二氧杂-8-氮杂螺[4.5]癸烷(500mg,1.62mmol)溶于甲醇(10mL)，四氢呋喃(3mL)中，加入Pd/C(100mg)，氢气氛围下室温搅拌5h。反应液过滤，滤液减压浓缩后得到标题化合物2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)苯胺(433mg,收率:96％)。8-(5-Methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (500mg, 1.62mmol) dissolved in methanol ( 10mL), tetrahydrofuran (3mL), add Pd/C (100mg), and stir at room temperature for 5h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (433mg, yield: 96%).
MS m/z(ESI):279.2[M+H] +. MS m/z(ESI): 279.2[M+H] + .
实施例1Example 1
(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000055
Figure PCTCN2020097362-appb-000055
第一步：(6-((5-溴-2-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备The first step: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) two Preparation of methyl phosphine oxidation
Figure PCTCN2020097362-appb-000056
Figure PCTCN2020097362-appb-000056
室温条件下，5-溴-2,4-二氯嘧啶(2.27g,10mmol)，(6-氨基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(2.27g,10mmol)，磷酸钾(2.76g,20mmol)混合于叔戊醇(20mL)中，微波90℃反应1h。反应冷却至室温，减压浓缩有机溶剂后柱层析分离得到标题化合物(6-((5-溴-2-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(3.25g,收率:78％)。At room temperature, 5-bromo-2,4-dichloropyrimidine (2.27g, 10mmol), (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl ) Dimethyl phosphine oxidation (2.27 g, 10 mmol), potassium phosphate (2.76 g, 20 mmol) was mixed in tert-amyl alcohol (20 mL), and reacted in a microwave at 90° C. for 1 h. The reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b] [1,4] Dioxin-5-yl)dimethylphosphine oxide (3.25g, yield: 78%).
1H NMR(400MHz,DMSO-d 6)δ1.81(s,3H),1.85(s,3H),4.24-4.39(m,4H),7.13(d,J＝9.2Hz,1H),7.89-7.98(m,1H),8.44(d,J＝1.8Hz,1H),12.26(s,1H)； 1 H NMR (400MHz, DMSO-d 6 ) δ 1.81 (s, 3H), 1.85 (s, 3H), 4.24-4.39 (m, 4H), 7.13 (d, J = 9.2 Hz, 1H), 7.89- 7.98(m,1H), 8.44(d,J=1.8Hz,1H), 12.26(s,1H);
MS m/z(ESI):417.9[M+H] +. MS m/z(ESI): 417.9[M+H] + .
第二步：(6-((5-溴-2-((2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备The second step: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane- 8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000057
Figure PCTCN2020097362-appb-000057
室温条件下，(6-((5-溴-2-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(1.0g,2.4mmol)，2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5] 癸烷-8-基)苯胺(1.0g,3.6mmol)，对甲苯磺酸(0.62g,3.6mmol)混合于乙二醇(40mL)中，升温至90℃反应2h。反应冷却至室温，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，分离有机相并用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤干燥剂后减压浓缩有机溶剂，柱层析分离得到标题化合物(6-((5-溴-2-((2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(1.34g,收率:85％)。At room temperature, (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) two Methylphosphine oxide (1.0g, 2.4mmol), 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5] decane-8-yl)aniline (1.0g, 3.6mmol), p-toluenesulfonic acid (0.62g, 3.6mmol) was mixed in ethylene glycol (40mL), heated to 90°C and reacted for 2h. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the organic solvent was concentrated under reduced pressure and separated by column chromatography. The title compound (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8 -Yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (1.34g, Yield: 85%).
1H NMR(400MHz,DMSO-d 6)δ1.74-1.85(m,10H),2.14(s,3H),2.91(t,J＝5.4Hz,4H),3.77(s,3H),3.93(s,4H),4.24(s,2H),4.32(s,2H),6.73(s,1H),6.81(d,J＝9.2Hz,1H),7.46(s,1H),7.94(d,J＝15.0Hz,2H),8.10(s,1H),11.62(s,1H)； 1 H NMR (400MHz, DMSO-d 6 )δ1.74-1.85 (m, 10H), 2.14 (s, 3H), 2.91 (t, J = 5.4 Hz, 4H), 3.77 (s, 3H), 3.93 ( s, 4H), 4.24 (s, 2H), 4.32 (s, 2H), 6.73 (s, 1H), 6.81 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 7.94 (d, J =15.0Hz, 2H), 8.10 (s, 1H), 11.62 (s, 1H);
MS m/z(ESI):660.2[M+H] +. MS m/z(ESI): 660.2[M+H] + .
第三步：1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-酮的制备The third step: 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6 -Yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one
Figure PCTCN2020097362-appb-000058
Figure PCTCN2020097362-appb-000058
室温条件下，(6-((5-溴-2-((2-甲氧基-5-甲基-4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(1.34g,2.03mmol)混合于醋酸/水(12mL/12mL)中，升温至90℃反应2h。反应冷却至室温，减压浓缩反应液，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，过滤干燥剂后减压浓缩有机溶剂，柱层析分离得到标题化合物1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(1.2g,收率:96％)。At room temperature, (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane- 8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (1.34g , 2.03mmol) was mixed in acetic acid/water (12mL/12mL), and the temperature was raised to 90°C for 2h. The reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was filtered, the organic solvent was concentrated under reduced pressure, and the title was obtained by column chromatography. Compound 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (1.2 g, yield: 96%).
MS m/z(ESI):616.2[M+H] +. MS m/z(ESI): 616.2[M+H] + .
第四步：(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备The fourth step: (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine-1 -Yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Oxidation preparation
Figure PCTCN2020097362-appb-000059
Figure PCTCN2020097362-appb-000059
室温条件下，1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(0.8g,1.3mmol)，3-(甲氧基甲基)吖丁啶三氟醋酸盐(0.42g,1.95mmol)和醋酸(0.1mL)混溶于二氯乙烷(20mL)中，搅拌30分钟，加入三乙酰氧基硼氢化钠(0.55g,2.6mmol)室温搅拌过夜。加入饱和碳酸氢钠水溶液，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤干燥剂后减压浓缩有机溶剂，柱层析分离得到标题化合物(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(0.56g,收率:62％)。At room temperature, 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6 -Amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (0.8g, 1.3mmol), 3-(methoxymethyl) Azetidine trifluoroacetate (0.42g, 1.95mmol) and acetic acid (0.1mL) were mixed in dichloroethane (20mL), stirred for 30 minutes, and sodium triacetoxyborohydride (0.55g, 2.6 mmol) Stir at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the organic solvent was concentrated under reduced pressure. The title compound (6-((5-bromo-2- ((2-Methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidine- 4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (0.56g, yield: 62%).
1H NMR(400MHz,DMSO-d 6)δ1.26-1.38(m,2H),1.69-1.77(m,2H),1.78(s,3H),1.81(s,3H),2.07-2.22(m,4H),2.56-2.66(m,3H),2.83-2.92(m,1H),2.96-3.05(m,2H),3.15-3.19(m,2H),3.23-3.27(m,3H),3.42-3.46(m,2H),3.76(s,3H),4.07-4.13(m,1H),4.24(s,2H),4.32(s,2H),6.69(s,1H),6.80(d,J＝9.0Hz,1H),7.43(s,1H),7.91-7.98(m,2H),8.10(s,1H),11.62(s,1H)； 1 H NMR (400MHz, DMSO-d 6 ) δ1.26-1.38 (m, 2H), 1.69-1.77 (m, 2H), 1.78 (s, 3H), 1.81 (s, 3H), 2.07-2.22 (m ,4H),2.56-2.66(m,3H),2.83-2.92(m,1H),2.96-3.05(m,2H),3.15-3.19(m,2H),3.23-3.27(m,3H),3.42 -3.46(m,2H),3.76(s,3H),4.07-4.13(m,1H), 4.24(s,2H), 4.32(s,2H), 6.69(s,1H), 6.80(d,J ＝9.0Hz,1H),7.43(s,1H),7.91-7.98(m,2H),8.10(s,1H),11.62(s,1H);
MS m/z(ESI):701.2[M+H] +. MS m/z(ESI):701.2[M+H] + .
实施例2Example 2
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methyl Oxidation of oxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine
Figure PCTCN2020097362-appb-000060
Figure PCTCN2020097362-appb-000060
第一步:叔-丁基4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-羧酸酯的制备The first step: preparation of tert-butyl 4-(3-(dimethylamino)azetidine-1-yl)piperidine-1-carboxylate
Figure PCTCN2020097362-appb-000061
Figure PCTCN2020097362-appb-000061
室温条件下，将叔-丁基4-羰基哌啶-1-羧酸酯(500mg，2.51mmol)和N,N-二甲基吖丁啶-3-胺(302mg，3.01mmol)溶于1,2-二氯乙烷(15mL)中，加入2滴醋酸，搅拌5分钟，加入三乙酰氧基硼氢化钠(1.06g，5.02mmol)，室温搅拌过夜，然后加入饱和碳酸氢钠溶液淬灭反应，用二氯甲烷萃取三次。合并有机相，有机相用无水硫酸钠干燥，过滤干燥剂后减压浓缩有机溶剂后柱层析分离得到标题化合物叔-丁基4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-羧酸酯(610mg,收率:86％)。At room temperature, dissolve tert-butyl 4-carbonylpiperidine-1-carboxylate (500mg, 2.51mmol) and N,N-dimethylazetidine-3-amine (302mg, 3.01mmol) in 1 , 2-Dichloroethane (15mL), add 2 drops of acetic acid, stir for 5 minutes, add sodium triacetoxyborohydride (1.06g, 5.02mmol), stir overnight at room temperature, then add saturated sodium bicarbonate solution to quench The reaction was extracted three times with dichloromethane. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter the desiccant, concentrate the organic solvent under reduced pressure, and separate by column chromatography to obtain the title compound tert-butyl 4-(3-(dimethylamino)azetidine-1- Yl)piperidine-1-carboxylate (610 mg, yield: 86%).
1H NMR(400MHz,CDCl 3)δ1.14-1.23(m,2H),1.44(s,9H),1.62-1.70(m,2H),2.12(s,6H),2.81-2.89(m,6H),3.48-3.53(m,2H),4.03-3.87(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.14-1.23 (m, 2H), 1.44 (s, 9H), 1.62-1.70 (m, 2H), 2.12 (s, 6H), 2.81-2.89 (m, 6H) ), 3.48-3.53 (m, 2H), 4.03-3.87 (m, 2H);
MS m/z(ESI):284.1[M+H] +. MS m/z(ESI): 284.1[M+H] + .
第二步:N,N-二甲基-1-(哌啶-4-基)吖丁啶-3-胺的制备Step 2: Preparation of N,N-dimethyl-1-(piperidin-4-yl)azetidine-3-amine
Figure PCTCN2020097362-appb-000062
Figure PCTCN2020097362-appb-000062
室温条件下，将叔-丁基4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-羧酸酯(610mg，2.16mmol)溶于盐酸二氧六环(10mL)中，室温搅拌过夜，减压浓缩有机溶剂后得到标题化合物N,N-二甲基-1-(哌啶-4-基)吖丁啶-3-胺粗品直接用于下一步反应。At room temperature, dissolve tert-butyl 4-(3-(dimethylamino)azetidine-1-yl)piperidine-1-carboxylate (610mg, 2.16mmol) in dioxane hydrochloride (10mL After stirring at room temperature overnight, the organic solvent was concentrated under reduced pressure to obtain the title compound N,N-dimethyl-1-(piperidin-4-yl)azetidine-3-amine crude product and used directly in the next reaction.
MS m/z(ESI):184.1[M+H] +. MS m/z(ESI): 184.1[M+H] + .
第三步:1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺的制备The third step: 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine preparation
Figure PCTCN2020097362-appb-000063
Figure PCTCN2020097362-appb-000063
室温条件下，将1-溴-2-氟-4-甲氧基-5-硝基苯(300mg,1.2mmol)N,N-二甲基-1-(哌啶-4-基)吖丁啶-3-胺粗品(220mg,1.2mmol)和碳酸钾(497mg,3.6mmol)溶于N,N-二甲基甲酰胺(8mL)中，升温至60℃搅拌过夜，向反应体系中加入水，用乙酸乙酯萃取三次。合并有机相，然后有机相用无水硫酸钠干燥，过滤干燥剂，减压浓缩有机溶剂后柱层析分离得到标题化合物1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(430mg,收率:87％)。At room temperature, the 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (300mg, 1.2mmol) N,N-dimethyl-1-(piperidin-4-yl)azetidine The crude pyridine-3-amine (220mg, 1.2mmol) and potassium carbonate (497mg, 3.6mmol) were dissolved in N,N-dimethylformamide (8mL), heated to 60℃ and stirred overnight, and water was added to the reaction system , Extracted three times with ethyl acetate. The organic phases were combined, and then the organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 1-(1-(2-bromo-5-methoxy-4-nitro (Phenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (430 mg, yield: 87%).
MS m/z(ESI):413.1[M+H] +. MS m/z(ESI): 413.1[M+H] + .
第四步:1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺的制备The fourth step: 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine Preparation
Figure PCTCN2020097362-appb-000064
Figure PCTCN2020097362-appb-000064
室温条件下，将1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(430mg,1.04mmol)，乙烯基三氟硼酸钾(279mg,2.08mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(76mg,0.104mmol)，碳酸铯(1.01g,3.12mmol)溶于二氧六环/水(10mL/1.5mL)中，氮气置换三次，升温至90℃搅拌过夜，向反应体系中加入水，用乙酸乙酯萃取三次。合并有机相，然后有机相用无水硫酸钠干燥，过滤干燥剂，减压浓缩有机溶剂后柱层析分离得到标题化合物1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(230mg,收率:61％)。At room temperature, the 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (430mg, 1.04mmol), potassium vinyl trifluoroborate (279mg, 2.08mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (76mg, 0.104mmol), carbonic acid Cesium (1.01g, 3.12mmol) was dissolved in dioxane/water (10mL/1.5mL), replaced with nitrogen three times, heated to 90°C and stirred overnight, water was added to the reaction system, and extracted three times with ethyl acetate. The organic phases were combined, and then the organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 1-(1-(5-methoxy-4-nitro-2- Vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (230 mg, yield: 61%).
MS m/z(ESI):361.1[M+H] +. MS m/z(ESI): 361.1[M+H] + .
第五步:1-(1-(4-氨基-2-乙基-5-甲氧苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺的制备Step 5: Preparation of 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine
Figure PCTCN2020097362-appb-000065
Figure PCTCN2020097362-appb-000065
室温条件下，将1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(230mg,0.64mmol)溶于甲醇(10mL)中，氮气置换三次，加入钯/碳(46mg)，氢气氛下室温搅拌过夜，过滤除去催化剂，减压浓缩有机溶剂得到标题化合物1-(1-(4-氨基-2-乙基-5-甲氧苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(210mg,收率:98％)。At room temperature, the 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3- Amine (230mg, 0.64mmol) was dissolved in methanol (10mL), replaced with nitrogen three times, palladium/carbon (46mg) was added, stirred overnight under hydrogen atmosphere at room temperature, the catalyst was removed by filtration, and the organic solvent was concentrated under reduced pressure to obtain the title compound 1-(1 -(4-Amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (210 mg, yield: 98%).
MS m/z(ESI):333.1[M+H] +. MS m/z(ESI): 333.1[M+H] + .
参考实施例1的第二步，将制备得到的1-(1-(4-氨基-2-乙基-5-甲氧苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺与(6-((5-溴-2-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化反应制备目标产物(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化。Referring to the second step of Example 1, the prepared 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethyl Azetidine-3-amine and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5 -Yl) dimethylphosphine oxidation reaction to prepare the target product (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidine-1 -Yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl ) Dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ0.98-1.07(m,3H),1.47-1.60(m,2H),1.87(s,3H),1.91(s,3H),1.96-2.05(m,2H),2.24(s,6H),2.50-2.59(m,2H),2.71-2.83(m,4H),3.03-3.10(m,2H),3.12-3.19(m,1H),3.47-3.58(m,2H),3.84(d,J＝1.7Hz,2H),3.90-3.97(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.77(s,1H),6.88-6.94(m,1H),7.75(d,J＝1.6Hz,1H),7.79-7.84(m,1H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.98-1.07 (m, 3H), 1.47-1.60 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.96-2.05 (m, 2H), 2.24 (s, 6H), 2.50-2.59 (m, 2H), 2.71-2.83 (m, 4H), 3.03-3.10 (m, 2H), 3.12-3.19 (m, 1H), 3.47-3.58 ( m,2H),3.84(d,J=1.7Hz,2H),3.90-3.97(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.77(s,1H) ,6.88-6.94(m,1H),7.75(d,J=1.6Hz,1H),7.79-7.84(m,1H),8.07(s,1H);
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例3Example 3
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-8-氟-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000066
Figure PCTCN2020097362-appb-000066
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-8-氟-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference implementation Example 2.
MS m/z(ESI):732.2[M+H] +. MS m/z(ESI): 732.2[M+H] + .
实施例4Example 4
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-7-氟-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000067
Figure PCTCN2020097362-appb-000067
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-7-氟-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference implementation Example 2.
MS m/z(ESI):732.2[M+H] +. MS m/z(ESI): 732.2[M+H] + .
实施例5Example 5
(6-((5-溴-2-((5-乙基-3-氟-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000068
Figure PCTCN2020097362-appb-000068
(6-((5-溴-2-((5-乙基-3-氟-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Phenyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference implementation Example 2.
MS m/z(ESI):732.2[M+H] +. MS m/z(ESI): 732.2[M+H] + .
实施例6Example 6
(6-((5-溴-2-((3-乙基-2-氟-6-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000069
Figure PCTCN2020097362-appb-000069
(6-((5-溴-2-((3-乙基-2-氟-6-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Phenyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference implementation Example 2.
MS m/z(ESI):732.2[M+H] +. MS m/z(ESI): 732.2[M+H] + .
实施例7Example 7
(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000070
Figure PCTCN2020097362-appb-000070
(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备方法参照实施例1。(5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):696.2[M+H] +. MS m/z(ESI): 696.2[M+H] + .
实施例8Example 8
(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,2-二氟苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000071
Figure PCTCN2020097362-appb-000071
(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,2-二氟苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备方法参照实施例1。(5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidized preparation method refer to Example 1.
MS m/z(ESI):732.2[M+H] +. MS m/z(ESI): 732.2[M+H] + .
实施例9Example 9
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000072
Figure PCTCN2020097362-appb-000072
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin For the preparation method of -5-yl)dimethylphosphine oxidation, refer to Example 1.
MS m/z(ESI):726.3[M+H] +. MS m/z(ESI): 726.3[M+H] + .
实施例10Example 10
(6-((5-氯-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin -5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000073
Figure PCTCN2020097362-appb-000073
(6-((5-氯-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin For the preparation method of -5-yl)dimethylphosphine oxidation, refer to Example 1.
MS m/z(ESI):682.3[M+H] +. MS m/z(ESI): 682.3[M+H] + .
实施例11Example 11
(6-((2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((2-Methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo(b)(1, 4] Preparation of dioxin-5-yl) dimethyl phosphine oxidation
Figure PCTCN2020097362-appb-000074
Figure PCTCN2020097362-appb-000074
(6-((2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((2-Methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo(b)(1, 4] Refer to Example 1 for the preparation method of dioxin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):716.3[M+H] +. MS m/z(ESI): 716.3[M+H] + .
实施例12Example 12
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097362-appb-000075
Figure PCTCN2020097362-appb-000075
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备方法参照实施例1。2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Example 1.
1H NMR(400MHz,CD 3OD)δ1.49-1.51(m,3H),1.91-1.93(m,9H),2.12(s,3H),2.57-2.59(m,1H),2.69-2.72(m,2H),2.78-2.80(m,2H),2.89-2.93(m,1H),3.12-3.15(m,2H),3.78-3.81(m,2H),3.84(s,3H),4.33-4.36(m,4H),6.72(s,1H),6.91-6.95(m,1H),7.70-7.76(m,1H),7.88-7.91(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.49-1.51 (m, 3H), 1.91-1.93 (m, 9H), 2.12 (s, 3H), 2.57-2.59 (m, 1H), 2.69-2.72 ( m, 2H), 2.78-2.80 (m, 2H), 2.89-2.93 (m, 1H), 3.12-3.15 (m, 2H), 3.78-3.81 (m, 2H), 3.84 (s, 3H), 4.33- 4.36 (m, 4H), 6.72 (s, 1H), 6.91-6.95 (m, 1H), 7.70-7.76 (m, 1H), 7.88-7.91 (m, 1H), 8.06 (s, 1H);
MS m/z(ESI):696.2[M+H] +. MS m/z(ESI): 696.2[M+H] + .
实施例13Example 13
2-(1-(1-(4-((5-氯-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备2-(1-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097362-appb-000076
Figure PCTCN2020097362-appb-000076
2-(1-(1-(4-((5-氯-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备方法参照实施例1。2-(1-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxin -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Example 1.
1H NMR(400MHz,CD 3OD)δ1.46-1.49(m,2H),1.90-1.93(m,8H),2.15-2.19(m,3H),2.37-2.39(m,1H),2.62-2.78(m,4H),2.85-2.89(m,1H),3.06-3.21(m,4H),3.63-3.66(m,2H),3.83(s,3H),4.32-4.38(m,4H),6.72(s,1H),6.89-6.91(m,1H),7.69-7.73(m,1H),7.96-8.10(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ1.46-1.49 (m, 2H), 1.90-1.93 (m, 8H), 2.15-2.19 (m, 3H), 2.37-2.39 (m, 1H), 2.62 2.78 (m, 4H), 2.85-2.89 (m, 1H), 3.06-3.21 (m, 4H), 3.63-3.66 (m, 2H), 3.83 (s, 3H), 4.32-4.38 (m, 4H), 6.72(s,1H), 6.89-6.91(m,1H), 7.69-7.73(m,1H), 7.96-8.10(m,2H);
MS m/z(ESI):652.3[M+H] +. MS m/z(ESI): 652.3[M+H] + .
实施例14Example 14
2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl )Amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetyl Preparation of Nitriles
Figure PCTCN2020097362-appb-000077
Figure PCTCN2020097362-appb-000077
2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备方法参照实施例1。2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl )Amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetyl Refer to Example 1 for the preparation method of nitrile.
MS m/z(ESI):686.3[M+H] +. MS m/z(ESI): 686.3[M+H] + .
实施例15Example 15
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000078
Figure PCTCN2020097362-appb-000078
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference implementation example 1.
1H NMR(400MHz,CD 3OD)δ1.54-1.61(m,2H),1.89-1.91(m,6H),2.07-2.08(m,2H),2.12(s,3H),2.30(s,6H),2.72-2.79(m,2H),3.04-3.06(m,2H),3.15-3.18(m,2H),3.82-3.88(m,5H),4.05-4.18(m,2H),4.32-4.39(m,4H),6.71(s,1H),6.90-6.93(m,1H),7.71(s,1H),7.88-7.92(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.54-1.61 (m, 2H), 1.89-1.91 (m, 6H), 2.07-2.08 (m, 2H), 2.12 (s, 3H), 2.30 (s, 6H), 2.72-2.79(m, 2H), 3.04-3.06(m, 2H), 3.15-3.18(m, 2H), 3.82-3.88(m, 5H), 4.05-4.18(m, 2H), 4.32- 4.39 (m, 4H), 6.71 (s, 1H), 6.90-6.93 (m, 1H), 7.71 (s, 1H), 7.88-7.92 (m, 1H), 8.06 (s, 1H);
MS m/z(ESI):700.2[M+H] +. MS m/z(ESI): 700.2[M+H] + .
实施例16Example 16
(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000079
Figure PCTCN2020097362-appb-000079
(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation method refer to Example 1 .
1H NMR(400MHz,CD 3OD)δ1.22(t,J＝7.0Hz,3H),1.53-1.64(m,2H),1.87(s,3H),1.90(s,3H),2.00-2.08(m,2H),2.11(s,3H),2.64-2.75(m,2H),2.91-3.01(m, 1H),3.11-3.18(m,2H),3.48-3.57(m,2H),3.73-3.79(m,2H),3.83(s,3H),4.15-4.23(m,2H),4.25-4.38(m,5H),6.70(s,1H),6.89(d,J＝9.1Hz,1H),7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.22 (t, J = 7.0 Hz, 3H), 1.53-1.64 (m, 2H), 1.87 (s, 3H), 1.90 (s, 3H), 2.00-2.08 (m,2H),2.11(s,3H),2.64-2.75(m,2H),2.91-3.01(m,1H),3.11-3.18(m,2H),3.48-3.57(m,2H),3.73 -3.79(m,2H),3.83(s,3H),4.15-4.23(m,2H),4.25-4.38(m,5H),6.70(s,1H),6.89(d,J=9.1Hz,1H ), 7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H);
MS m/z(ESI):701.2[M+H] +. MS m/z(ESI):701.2[M+H] + .
实施例17Example 17
(S)-(6-((5-溴-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000080
Figure PCTCN2020097362-appb-000080
(S)-(6-((5-溴-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(S)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 1 for the method.
1H NMR(400MHz,CD 3OD)δ1.80-1.83(m,2H),1.88-1.90(m,6H),2.09-2.11(m,6H),2.30(s,1H),2.62(s,6H),2.72-2.79(m,3H),3.14-3.18(m,4H),3.25-3.29(m,1H),3.34-3.47(m,2H),3.83(s,3H),4.31-4.33(m,4H),6.69(s,1H),6.88-6.91(m,1H),7.70(s,1H),7.87-7.89(m,1H),8.05(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.80-1.83 (m, 2H), 1.88-1.90 (m, 6H), 2.09-2.11 (m, 6H), 2.30 (s, 1H), 2.62 (s, 6H), 2.72-2.79 (m, 3H), 3.14-3.18 (m, 4H), 3.25-3.29 (m, 1H), 3.34-3.47 (m, 2H), 3.83 (s, 3H), 4.31-4.33 ( m,4H),6.69(s,1H),6.88-6.91(m,1H),7.70(s,1H),7.87-7.89(m,1H),8.05(s,1H);
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例18Example 18
(R)-(6-((5-溴-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000081
Figure PCTCN2020097362-appb-000081
(R)-(6-((5-溴-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(R)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 1 for the method.
1H NMR(400MHz,CD 3OD)δ1.80-1.83(m,2H),1.88-1.90(m,6H),2.09-2.11(m,6H),2.30(s,1H),2.62(s,6H),2.72-2.79(m,3H),3.14-3.18(m,4H),3.25-3.29(m,1H),3.34-3.47(m,2H),3.83(s,3H),4.31-4.33(m,4H),6.69(s,1H),6.88-6.91(m,1H),7.70(s,1H),7.87-7.89(m,1H),8.05(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.80-1.83 (m, 2H), 1.88-1.90 (m, 6H), 2.09-2.11 (m, 6H), 2.30 (s, 1H), 2.62 (s, 6H), 2.72-2.79 (m, 3H), 3.14-3.18 (m, 4H), 3.25-3.29 (m, 1H), 3.34-3.47 (m, 2H), 3.83 (s, 3H), 4.31-4.33 ( m,4H),6.69(s,1H),6.88-6.91(m,1H),7.70(s,1H),7.87-7.89(m,1H),8.05(s,1H);
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例19Example 19
(S)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000082
Figure PCTCN2020097362-appb-000082
(S)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(S)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference Example 1.
1H NMR(400MHz,CD 3OD)δ1.22(t,J＝7.0Hz,3H),1.90-1.96(m,8H),2.15(s,3H),2.22-2.28(m,4H),2.75-2.82(m,2H),3.18-3.22(m,3H),3.41-3.46(m,3H),3.50-3.59(m,4H),3.84(s,3H),4.25-4.38(m,5H),6.71(s,1H),6.91-6.96(m,1H),7.73(s,1H),7.90-7.93(m,1H),8.06(s,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.22(t,J=7.0Hz,3H),1.90-1.96(m,8H),2.15(s,3H),2.22-2.28(m,4H),2.75 -2.82(m,2H),3.18-3.22(m,3H),3.41-3.46(m,3H),3.50-3.59(m,4H),3.84(s,3H),4.25-4.38(m,5H) ,6.71(s,1H),6.91-6.96(m,1H),7.73(s,1H),7.90-7.93(m,1H),8.06(s,1H);
MS m/z(ESI):715.2[M+H] +. MS m/z(ESI): 715.2[M+H] + .
实施例20Example 20
(R)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000083
Figure PCTCN2020097362-appb-000083
(R)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(R)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference Example 1.
1H NMR(400MHz,CD 3OD)δ1.22(t,J＝7.0Hz,3H),1.90-1.96(m,8H),2.15(s,3H),2.22-2.28(m,4H),2.75-2.82(m,2H),3.18-3.22(m,3H),3.41-3.46(m,3H),3.50-3.59(m,4H),3.84(s,3H),4.25-4.38(m,5H),6.71(s,1H),6.91-6.96(m,1H),7.73(s,1H),7.90-7.93(m,1H),8.06(s,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.22(t,J=7.0Hz,3H),1.90-1.96(m,8H),2.15(s,3H),2.22-2.28(m,4H),2.75 -2.82(m,2H),3.18-3.22(m,3H),3.41-3.46(m,3H),3.50-3.59(m,4H),3.84(s,3H),4.25-4.38(m,5H) ,6.71(s,1H),6.91-6.96(m,1H),7.73(s,1H),7.90-7.93(m,1H),8.06(s,1H);
MS m/z(ESI):715.2[M+H] +. MS m/z(ESI): 715.2[M+H] + .
实施例21Example 21
(6-((5-氯-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000084
Figure PCTCN2020097362-appb-000084
(6-((5-氯-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference implementation example 1.
1H NMR(400MHz,CD 3OD)δ1.53-1.56(m,2H),1.89-1.91(m,6H),1.98-2.01(m,2H),2.14(s,3H),2.23(s,6H),2.69-2.71(m,3H),3.06-3.22(m,3H),3.40-3.51(m,2H),3.79-3.91(m,5H),4.22-4.38(m,4H),6.72(s,1H),6.89-6.91(m,1H),7.70(s,1H),7.95(s,1H),8.03-8.09(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.53-1.56 (m, 2H), 1.89-1.91 (m, 6H), 1.98-2.01 (m, 2H), 2.14 (s, 3H), 2.23 (s, 6H), 2.69-2.71 (m, 3H), 3.06-3.22 (m, 3H), 3.40-3.51 (m, 2H), 3.79-3.91 (m, 5H), 4.22-4.38 (m, 4H), 6.72 ( s,1H),6.89-6.91(m,1H),7.70(s,1H),7.95(s,1H),8.03-8.09(m,1H);
MS m/z(ESI):656.2[M+H] +. MS m/z(ESI): 656.2[M+H] + .
实施例22Example 22
(6-((5-氯-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000085
Figure PCTCN2020097362-appb-000085
(6-((5-氯-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Chloro-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1 .
MS m/z(ESI):657.2[M+H] +. MS m/z(ESI): 657.2[M+H] + .
实施例23Example 23
(S)-(6-((5-氯-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(S)-(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000086
Figure PCTCN2020097362-appb-000086
(S)-(6-((5-氯-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(S)-(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 1 for the method.
MS m/z(ESI):670.2[M+H] +. MS m/z(ESI): 670.2[M+H] + .
实施例24Example 24
(R)-(6-((5-氯-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(R)-(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000087
Figure PCTCN2020097362-appb-000087
(R)-(6-((5-氯-2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(R)-(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy (-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 1 for the method.
MS m/z(ESI):670.2[M+H] +. MS m/z(ESI): 670.2[M+H] + .
实施例25Example 25
(S)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(S)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000088
Figure PCTCN2020097362-appb-000088
(S)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(S)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference Example 1.
MS m/z(ESI):671.2[M+H] +. MS m/z(ESI): 671.2[M+H] + .
实施例26Example 26
(R)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(R)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000089
Figure PCTCN2020097362-appb-000089
(R)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(R)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method reference Example 1.
MS m/z(ESI):671.2[M+H] +. MS m/z(ESI): 671.2[M+H] + .
实施例27Example 27
(6-((2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide Preparation
Figure PCTCN2020097362-appb-000090
Figure PCTCN2020097362-appb-000090
(6-((2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide Refer to Example 1 for the preparation method.
MS m/z(ESI):690.2[M+H] +. MS m/z(ESI): 690.2[M+H] + .
实施例28Example 28
(6-((2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino )-5-(Trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000091
Figure PCTCN2020097362-appb-000091
(6-((2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino )-5-(Trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 1 for the method.
MS m/z(ESI):691.2[M+H] +. MS m/z(ESI): 691.2[M+H] + .
实施例29Example 29
(S)-(6-((2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(S)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097362-appb-000092
Figure PCTCN2020097362-appb-000092
(S)-(6-((2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(S)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.
MS m/z(ESI):704.2[M+H] +. MS m/z(ESI): 704.2[M+H] + .
实施例30Example 30
(R)-(6-((2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(R)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097362-appb-000093
Figure PCTCN2020097362-appb-000093
(R)-(6-((2-((4-(4-(3-(二甲氨基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧 化的制备方法参照实施例1。(R)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.
MS m/z(ESI):704.2[M+H] +. MS m/z(ESI): 704.2[M+H] + .
实施例31Example 31
(S)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(S)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Oxidation preparation
Figure PCTCN2020097362-appb-000094
Figure PCTCN2020097362-appb-000094
(S)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(S)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.
MS m/z(ESI):705.2[M+H] +. MS m/z(ESI):705.2[M+H] + .
实施例32Example 32
(R)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(R)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Oxidation preparation
Figure PCTCN2020097362-appb-000095
Figure PCTCN2020097362-appb-000095
(R)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨 基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(R)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.
MS m/z(ESI):705.2[M+H] +. MS m/z(ESI):705.2[M+H] + .
实施例33Example 33
(6-((5-溴-2-((7-甲氧基-2-(四氢呋喃-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000096
Figure PCTCN2020097362-appb-000096
(6-((5-溴-2-((7-甲氧基-2-(四氢呋喃-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((7-methoxy-2-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation method refer to Example 1.
MS m/z(ESI):630.2[M+H] +. MS m/z(ESI): 630.2[M+H] + .
实施例34Example 34
(6-((5-溴-2-((7-甲氧基-2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6- (Yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000097
Figure PCTCN2020097362-appb-000097
(6-((5-溴-2-((7-甲氧基-2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((7-methoxy-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6- (Yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation method refer to Example 1.
MS m/z(ESI):643.2[M+H] +. MS m/z(ESI):643.2[M+H] + .
实施例35Example 35
(6-((5-溴-2-((7-甲氧基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)-2, Preparation of 3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000098
Figure PCTCN2020097362-appb-000098
(6-((5-溴-2-((7-甲氧基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)-2, Refer to Example 1 for the preparation method of 3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):560.1[M+H] +. MS m/z(ESI): 560.1[M+H] + .
实施例36Example 36
(6-((5-溴-2-((6-甲氧基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)-2, Preparation of 3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000099
Figure PCTCN2020097362-appb-000099
(6-((5-溴-2-((6-甲氧基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)-2, Refer to Example 1 for the preparation method of 3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):560.1[M+H] +. MS m/z(ESI): 560.1[M+H] + .
实施例37Example 37
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097362-appb-000100
Figure PCTCN2020097362-appb-000100
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦硫化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine sulfide preparation method refer to Example 2.
MS m/z(ESI):730.2[M+H] +. MS m/z(ESI): 730.2[M+H] + .
实施例38Example 38
(6-((5-溴-2-((4-(4-(3-(乙基(甲基)氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide preparation
Figure PCTCN2020097362-appb-000101
Figure PCTCN2020097362-appb-000101
(6-((5-溴-2-((4-(4-(3-(乙基(甲基)氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide Refer to Example 1 for the preparation method.
1H NMR(400MHz,CD 3OD)δ1.14(t,J＝7.2Hz,3H),1.52-1.63(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.09(m,2H),2.12(s,3H),2.29(s,3H),2.48-2.57(m,2H),2.66-2.77(m,2H),2.83-2.93(m,1H),3.08-3.18(m,2H),3.38-3.45(m,1H),3.63-3.71(m,2H),3.84(s,3H),4.00-4.07(m,2H),4.22-4.40(m,4H),6.71(s,1H),6.88-6.95(m,1H),7.71(s,1H),7.85-7.92(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.14 (t, J = 7.2Hz, 3H), 1.52-1.63 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.09 (m, 2H), 2.12 (s, 3H), 2.29 (s, 3H), 2.48-2.57 (m, 2H), 2.66-2.77 (m, 2H), 2.83-2.93 (m, 1H), 3.08-3.18 (m, 2H), 3.38-3.45 (m, 1H), 3.63-3.71 (m, 2H), 3.84 (s, 3H), 4.00-4.07 (m, 2H), 4.22-4.40 (m, 4H), 6.71 (s,1H),6.88-6.95(m,1H),7.71(s,1H),7.85-7.92(m,1H),8.06(s,1H);
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例39Example 39
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基-1,4-重氮基庚环-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide preparation
Figure PCTCN2020097362-appb-000102
Figure PCTCN2020097362-appb-000102
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基-1,4-重氮基庚环-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide Refer to Example 1 for the preparation method.
1H NMR(400MHz,CD 3OD)δ1.73-1.84(m,2H),1.85-1.97(m,8H),2.00-2.10(m,2H),2.14(s,3H),2.64-2.74(m,2H),2.78-2.86(m,4H),3.01-3.07(m,2H),3.09-3.18(m,4H),3.19-3.23(m,2H),3.25-3.29(m,2H),3.83(s,3H),4.25-4.39(m,4H),6.70(s,1H),6.90(d,J＝9.1Hz,1H),7.68(s,1H),7.86-7.93(m,1H),8.05(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.73-1.84 (m, 2H), 1.85-1.97 (m, 8H), 2.00-2.10 (m, 2H), 2.14 (s, 3H), 2.64-2.74 ( m,2H),2.78-2.86(m,4H),3.01-3.07(m,2H),3.09-3.18(m,4H),3.19-3.23(m,2H),3.25-3.29(m,2H), 3.83(s,3H),4.25-4.39(m,4H),6.70(s,1H),6.90(d,J=9.1Hz,1H),7.68(s,1H),7.86-7.93(m,1H) ,8.05(s,1H);
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例40Example 40
(6-((2-((4-(4-(1,4-噁吖庚环-4-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-溴嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino )-5-Bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000103
Figure PCTCN2020097362-appb-000103
(6-((2-((4-(4-(1,4-噁吖庚环-4-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)-5-溴嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino )-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1 .
1H NMR(400MHz,CD 3OD)δ1.84-1.94(m,8H),2.02-2.10(m,4H),2.15(s,3H),2.69-2.79(m,2H),3.08-3.26(m,7H),3.80-3.88(m,7H),4.26-4.39(m,4H),6.72(s,1H),6.91(d,J＝9.1Hz,1H),7.70(s,1H),7.86-7.92(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.84-1.94 (m, 8H), 2.02-2.10 (m, 4H), 2.15 (s, 3H), 2.69-2.79 (m, 2H), 3.08-3.26 ( m,7H),3.80-3.88(m,7H),4.26-4.39(m,4H),6.72(s,1H),6.91(d,J=9.1Hz,1H),7.70(s,1H),7.86 -7.92(m,1H),8.06(s,1H);
MS m/z(ESI):701.2[M+H] +. MS m/z(ESI):701.2[M+H] + .
实施例41Example 41
(6-((2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation
Figure PCTCN2020097362-appb-000104
Figure PCTCN2020097362-appb-000104
(6-((2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized The preparation method refers to Example 2.
1H NMR(400MHz,CD 3OD)δ0.94-1.04(m,3H),1.51-1.60(m,2H),1.84(s,3H),1.88(s,3H),1.98-2.07(m,2H),2.26(s,6H),2.46-2.55(m,2H),2.70-2.81(m,2H),3.04-3.12(m,2H),3.17-3.23(m,2H),3.57-3.65(m,2H),3.84(s,3H),3.99(t,J＝8.1Hz,2H),4.26-4.33(m,2H),4.33-4.41(m,2H),6.77(s,1H),6.89(d,J＝9.1Hz,1H),7.54-7.64(m,1H),7.72(s,1H),8.25(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.94-1.04 (m, 3H), 1.51-1.60 (m, 2H), 1.84 (s, 3H), 1.88 (s, 3H), 1.98-2.07 (m, 2H), 2.26(s, 6H), 2.46-2.55(m, 2H), 2.70-2.81(m, 2H), 3.04-3.12(m, 2H), 3.17-3.23(m, 2H), 3.57-3.65( m, 2H), 3.84 (s, 3H), 3.99 (t, J = 8.1 Hz, 2H), 4.26-4.33 (m, 2H), 4.33-4.41 (m, 2H), 6.77 (s, 1H), 6.89 (d,J=9.1Hz,1H),7.54-7.64(m,1H),7.72(s,1H),8.25(s,1H);
MS m/z(ESI):704.2[M+H] +. MS m/z(ESI): 704.2[M+H] + .
实施例42Example 42
2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-5-(甲硫基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl )Amino)-5-(methylthio)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Preparation
Figure PCTCN2020097362-appb-000105
Figure PCTCN2020097362-appb-000105
2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)-5-(甲硫基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备方法参照实施例1。2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl )Amino)-5-(methylthio)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Refer to Example 1 for the preparation method.
1H NMR(400MHz,CD 3OD)δ1.51-1.61(m,2H),1.87(s,3H),1.91(s,3H), 1.99-2.07(m,2H),2.13(s,3H),2.29(s,3H),2.67-2.76(m,2H),2.81-2.95(m,3H),3.07-3.19(m,3H),3.65-3.73(m,2H),3.85(s,3H),4.02-4.10(m,2H),4.26-4.31(m,4H),6.72(s,1H),6.91(d,J＝9.1Hz,1H),7.75(s,1H),7.89-7.96(m,1H),8.11(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.51-1.61 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.13 (s, 3H) ,2.29(s,3H),2.67-2.76(m,2H),2.81-2.95(m,3H),3.07-3.19(m,3H),3.65-3.73(m,2H),3.85(s,3H) ,4.02-4.10(m,2H),4.26-4.31(m,4H),6.72(s,1H),6.91(d,J=9.1Hz,1H),7.75(s,1H),7.89-7.96(m ,1H),8.11(s,1H);
MS m/z(ESI):664.2[M+H] +. MS m/z(ESI): 664.2[M+H] + .
实施例43Example 43
(6-((2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-(甲硫基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000106
Figure PCTCN2020097362-appb-000106
(6-((2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-(甲硫基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 2 for the method.
1H NMR(400MHz,CD 3OD)δ1.01(t,J＝7.5Hz,3H),1.51-1.63(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.08(m,2H),2.24-2.32(m,9H),2.50-2.58(m,2H),2.70-2.80(m,2H),2.85-2.96(m,1H),3.03-3.13(m,2H),3.20-3.28(m,1H),3.64-3.71(m,2H),3.85(s,3H),3.98-4.08(m,2H),4.25-4.40(m,4H),6.77(s,1H),6.91(d,J＝9.1Hz,1H),7.79-7.88(m,2H),8.12(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.01 (t, J = 7.5Hz, 3H), 1.51-1.63 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.08 (m, 2H), 2.24-2.32 (m, 9H), 2.50-2.58 (m, 2H), 2.70-2.80 (m, 2H), 2.85-2.96 (m, 1H), 3.03-3.13 (m, 2H) , 3.20-3.28 (m, 1H), 3.64-3.71 (m, 2H), 3.85 (s, 3H), 3.98-4.08 (m, 2H), 4.25-4.40 (m, 4H), 6.77 (s, 1H) ,6.91(d,J=9.1Hz,1H),7.79-7.88(m,2H),8.12(s,1H);
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例44Example 44
(6-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000107
Figure PCTCN2020097362-appb-000107
(6-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation method refer to Example 2.
MS m/z(ESI):710.2[M+H] +. MS m/z(ESI): 710.2[M+H] + .
实施例45Example 45
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine- Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000108
Figure PCTCN2020097362-appb-000108
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation method Refer to Example 2.
1H NMR(400MHz,CD 3OD)δ1.02(t,J＝7.5Hz,3H),1.53-1.64(m,2H),1.87(s,3H),1.91(s,3H),2.02-2.09(m,2H),2.49-2.60(m,2H),2.71-2.81(m,2H),2.97-3.13(m,4H),3.44(s,3H),3.52(d,J＝4.5Hz,2H),3.84(s,3H),3.87-3.91(m,2H),4.08(t,J＝9.4Hz,2H),4.26-4.33(m,2H),4.33-4.40(m,2H),6.77(s,1H),6.91(d,J＝9.2Hz,1H),7.77(s,1H),7.79-7.84(m,1H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.02 (t, J = 7.5 Hz, 3H), 1.53-1.64 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.02-2.09 (m,2H),2.49-2.60(m,2H),2.71-2.81(m,2H),2.97-3.13(m,4H),3.44(s,3H),3.52(d,J=4.5Hz,2H ), 3.84 (s, 3H), 3.87-3.91 (m, 2H), 4.08 (t, J = 9.4 Hz, 2H), 4.26-4.33 (m, 2H), 4.33-4.40 (m, 2H), 6.77 ( s, 1H), 6.91 (d, J = 9.2 Hz, 1H), 7.77 (s, 1H), 7.79-7.84 (m, 1H), 8.07 (s, 1H);
MS m/z(ESI):715.2[M+H] +. MS m/z(ESI): 715.2[M+H] + .
实施例46Example 46
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin -6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097362-appb-000109
Figure PCTCN2020097362-appb-000109
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)吖丁啶-3-基)乙酰腈的制备方法参照实施例2。2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin -6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Example 2.
1H NMR(400MHz,CD 3OD)δ1.01(t,J＝7.5Hz,3H),1.50-1.60(m,2H),1.87(s,3H),1.91(s,3H),1.96-2.04(m,2H),2.50-2.58(m,2H),2.71-2.79(m,2H),2.80-2.87(m,3H),3.03-3.12(m,3H),3.58-3.68(m,2H),3.84(s,3H),3.97-4.06(m,2H),4.25-4.31(m,4H),6.76(s,1H),6.90(d,J＝9.1Hz,1H),7.74-7.83(m,2H),8.07(s,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.01(t,J=7.5Hz,3H),1.50-1.60(m,2H),1.87(s,3H),1.91(s,3H),1.96-2.04 (m, 2H), 2.50-2.58 (m, 2H), 2.71-2.79 (m, 2H), 2.80-2.87 (m, 3H), 3.03-3.12 (m, 3H), 3.58-3.68 (m, 2H) ,3.84(s,3H),3.97-4.06(m,2H),4.25-4.31(m,4H),6.76(s,1H),6.90(d,J=9.1Hz,1H),7.74-7.83(m ,2H),8.07(s,1H);
MS m/z(ESI):710.2[M+H] +. MS m/z(ESI): 710.2[M+H] + .
实施例47Example 47
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-(三氟甲基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide preparation
Figure PCTCN2020097362-appb-000110
Figure PCTCN2020097362-appb-000110
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-(三氟甲基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide Refer to Example 1 for the preparation method.
1H NMR(400MHz，CD 3OD)δ1.51-1.62(m,2H),1.88(s,3H),1.91(s,3H),2.00-2.07(m,2H),2.28(s,6H),2.85(t,J＝11.3Hz,2H),2.91-3.02(m,1H),3.04-3.12(m,2H),3.21-3.27(m,1H),3.67-3.75(m,2H),3.94(s,3H),4.02-4.08(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.89(d,J＝9.1Hz,1H),7.07(s,1H),7.81-7.86(m,1H),8.13(s,1H),8.21(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.51-1.62(m,2H),1.88(s,3H),1.91(s,3H),2.00-2.07(m,2H),2.28(s,6H) ,2.85(t,J=11.3Hz,2H),2.91-3.02(m,1H),3.04-3.12(m,2H),3.21-3.27(m,1H),3.67-3.75(m,2H),3.94 (s,3H),4.02-4.08(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.89(d,J=9.1Hz,1H),7.07(s,1H) ),7.81-7.86(m,1H),8.13(s,1H),8.21(s,1H);
MS m/z(ESI):754.2[M+H] +. MS m/z(ESI): 754.2[M+H] + .
实施例48Example 48
(5-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000111
Figure PCTCN2020097362-appb-000111
(5-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备方法参照实施例1。(5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidized preparation method refer to Example 1.
1H NMR(400MHz,CD 3OD)δ1.58-1.61(m,2H),1.86-1.88(m,6H),1.90-1.92(m,1H),2.04-2.07(m,2H),2.12-2.15(m,3H),2.20-2.37(m,6H),2.70-2.75(m,2H),2.92-2.95(m,1H),3.13-3.16(m,2H),3.61-3.77(m,2H),3.84(s,3H),3.97-4.14(m,2H),6.07(s,2H),6.71(s,1H),6.92-6.95(m,1H),7.70(s,1H),7.74-7.87(m,1H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.58-1.61 (m, 2H), 1.86-1.88 (m, 6H), 1.90-1.92 (m, 1H), 2.04-2.07 (m, 2H), 2.12 2.15 (m, 3H), 2.20-2.37 (m, 6H), 2.70-2.75 (m, 2H), 2.92-2.95 (m, 1H), 3.13-3.16 (m, 2H), 3.61-3.77 (m, 2H) ), 3.84 (s, 3H), 3.97-4.14 (m, 2H), 6.07 (s, 2H), 6.71 (s, 1H), 6.92-6.95 (m, 1H), 7.70 (s, 1H), 7.74 7.87(m,1H),8.07(s,1H);
MS m/z(ESI):686.2[M+H] +. MS m/z(ESI): 686.2[M+H] + .
实施例49Example 49
(5-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methyl Oxidation of oxyphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine
Figure PCTCN2020097362-appb-000112
Figure PCTCN2020097362-appb-000112
(5-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备方法参照实施例2。(5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methyl (Oxyphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidized preparation method refer to Example 2.
1H NMR(400MHz,CD 3OD)δ1.01(t,J＝7.2Hz,3H),1.41-1.58(m,2H),1.86-1.89(m,6H),2.01-2.03(m,2H),2.25(s,6H),2.52-2.55(m,2H),2.76-2.78(m,3H),3.05-3.08(m,2H),3.12-3.24(m,1H),3.57-3.59(m,2H),3.84(s,3H),3.96-3.99(m,2H),6.07(s,2H),6.76(s,1H),6.91-6.93(m,1H),7.61-7.78(m,2H),8.08(s,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.01(t,J=7.2Hz,3H),1.41-1.58(m,2H),1.86-1.89(m,6H),2.01-2.03(m,2H) ,2.25(s,6H),2.52-2.55(m,2H),2.76-2.78(m,3H),3.05-3.08(m,2H),3.12-3.24(m,1H),3.57-3.59(m, 2H), 3.84 (s, 3H), 3.96-3.99 (m, 2H), 6.07 (s, 2H), 6.76 (s, 1H), 6.91-6.93 (m, 1H), 7.61-7.78 (m, 2H) ,8.08(s,1H);
MS m/z(ESI):700.2[M+H] +. MS m/z(ESI): 700.2[M+H] + .
实施例50Example 50
(6-((2-((5-溴-4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)-5-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((5-Bromo-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino )-5-Chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000113
Figure PCTCN2020097362-appb-000113
(6-((2-((5-溴-4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)-5-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((5-Bromo-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino )-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation method refer to Example 1 .
MS m/z(ESI):720.2[M+H] +. MS m/z(ESI): 720.2[M+H] + .
实施例51Example 51
(6-((2-((5-溴-4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)-5-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((2-((5-Bromo-4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)- Preparation of 5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000114
Figure PCTCN2020097362-appb-000114
(6-((2-((5-溴-4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)-5-氯嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((5-Bromo-4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)- For the preparation method of 5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation, refer to Example 1.
MS m/z(ESI):721.2[M+H] +. MS m/z(ESI): 721.2[M+H] + .
实施例52Example 52
(6-((5-氯-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methyl Oxidation of oxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine
Figure PCTCN2020097362-appb-000115
Figure PCTCN2020097362-appb-000115
(6-((5-氯-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methyl Oxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidized preparation method Reference Example 2.
1H NMR(400MHz,CD 3OD)δ0.96-1.11(m,3H),1.48-1.63(m,2H),1.88(s,3H),1.91(s,3H),1.99-2.08(m,2H),2.27(s,6H),2.50-2.64(m,2H),2.66-2.96(m,4H),3.04-3.12(m,2H),3.16-3.25(m,2H),3.55-3.66(m,2H),3.85(s,3H),3.94-4.05(m,2H),4.23-4.31(m,2H),4.33-4.40(m,2H),6.78(s,1H),6.86-6.93(m,1H),7.76 (d,J＝4.4Hz,1H),7.93-8.01(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.96-1.11 (m, 3H), 1.48-1.63 (m, 2H), 1.88 (s, 3H), 1.91 (s, 3H), 1.99-2.08 (m, 2H), 2.27(s, 6H), 2.50-2.64(m, 2H), 2.66-2.96(m, 4H), 3.04-3.12(m, 2H), 3.16-3.25(m, 2H), 3.55-3.66( m, 2H), 3.85 (s, 3H), 3.94-4.05 (m, 2H), 4.23-4.31 (m, 2H), 4.33-4.40 (m, 2H), 6.78 (s, 1H), 6.86-6.93 ( m,1H),7.76 (d,J=4.4Hz,1H),7.93-8.01(m,2H);
MS m/z(ESI):670.2[M+H] +. MS m/z(ESI): 670.2[M+H] + .
实施例53Example 53
(6-((5-溴-2-((4-(4-(3-氟-3-(羟甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide preparation
Figure PCTCN2020097362-appb-000116
Figure PCTCN2020097362-appb-000116
(6-((5-溴-2-((4-(4-(3-氟-3-(羟甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide Refer to Example 1 for the preparation method.
1H NMR(400MHz,DMSO-d 6)δ1.35-1.38(m,2H),1.79-1.81(m,8H),2.11(s,3H),2.22-2.25(m,1H),2.58-2.71(m,3H),2.96-3.01(m,5H),3.68-2.71(m,2H),3.76(s,3H),4.28-4.31(m,4H),6.70(s,1H),6.80-6.83(m,1H),7.43(s,1H),7.93-7.95(m 2H),8.10(s,1H),11.62(s,1H)； 1 H NMR (400MHz, DMSO-d 6 ) δ1.35-1.38 (m, 2H), 1.79-1.81 (m, 8H), 2.11 (s, 3H), 2.22-2.25 (m, 1H), 2.58-2.71 (m, 3H), 2.96-3.01 (m, 5H), 3.68-2.71 (m, 2H), 3.76 (s, 3H), 4.28-4.31 (m, 4H), 6.70 (s, 1H), 6.80-6.83 (m,1H),7.43(s,1H),7.93-7.95(m 2H),8.10(s,1H),11.62(s,1H);
MS m/z(ESI):705.2[M+H] +. MS m/z(ESI):705.2[M+H] + .
实施例54Example 54
(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(羟甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)piperidin-1-yl) -2-Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000117
Figure PCTCN2020097362-appb-000117
(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(羟甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯 基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)piperidin-1-yl) -2-Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxidation preparation Refer to Example 2 for the method.
1H NMR(400MHz,CD 3OD)δ1.02(t,J＝7.6Hz,3H),1.49-1.64(m,2H),1.87(s,3H),1.91(s,3H),2.00(d,J＝13.4Hz,2H),2.54(q,J＝7.5Hz,2H),2.75(t,J＝11.5Hz,3H),3.07(d,J＝11.7Hz,2H),3.71-3.85(m,7H),3.97(dd,J＝15.7,10.4Hz,2H),4.29(s,2H),4.36(s,2H),6.77(s,1H),6.90(d,J＝9.1Hz,1H),7.75(s,1H),7.81(dd,J＝9.2,4.5Hz,1H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.02 (t, J = 7.6 Hz, 3H), 1.49-1.64 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.00 (d ,J=13.4Hz,2H),2.54(q,J=7.5Hz,2H),2.75(t,J=11.5Hz,3H),3.07(d,J=11.7Hz,2H),3.71-3.85(m ,7H),3.97(dd,J=15.7,10.4Hz,2H),4.29(s,2H),4.36(s,2H),6.77(s,1H),6.90(d,J=9.1Hz,1H) ,7.75(s,1H),7.81(dd,J=9.2,4.5Hz,1H), 8.07(s,1H);
MS m/z(ESI):719.2[M+H] +. MS m/z(ESI): 719.2[M+H] + .
实施例55Example 55
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,2-二甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097362-appb-000118
Figure PCTCN2020097362-appb-000118
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,2-二甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.
MS m/z(ESI):728.2[M+H] +. MS m/z(ESI): 728.2[M+H] + .
实施例56Example 56
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-3,3-二甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097362-appb-000119
Figure PCTCN2020097362-appb-000119
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-3,3-二甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.
MS m/z(ESI):728.2[M+H] +. MS m/z(ESI): 728.2[M+H] + .
实施例57Example 57
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- Preparation of 5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000120
Figure PCTCN2020097362-appb-000120
第一步：(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备The first step: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3, 4-c]pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Preparation of Dioxin-5-yl) Dimethylphosphine Oxidation
Figure PCTCN2020097362-appb-000121
Figure PCTCN2020097362-appb-000121
室温条件下，1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(0.25g,0.41mmol)，(3aR,6aS)-六氢-1H-呋喃并[3,4-c]吡咯(0.07g,0.61mmol)和醋酸(3滴)混溶于二氯乙烷(10mL)中，搅拌30分钟，加入三乙酰氧基硼氢化钠(0.17g,0.81mmol)，室温搅拌过夜，向反应液中加入饱和碳酸氢钠水溶液，用二氯甲烷萃取，分离有机相，用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化(0.17g,收率:58％)。At room temperature, 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxin-6 -Amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (0.25g, 0.41mmol), (3aR,6aS)-hexahydro- 1H-furo[3,4-c]pyrrole (0.07g, 0.61mmol) and acetic acid (3 drops) are miscible in dichloroethane (10mL), stirred for 30 minutes, add sodium triacetoxyborohydride ( 0.17g, 0.81mmol), stirred overnight at room temperature, added saturated aqueous sodium bicarbonate to the reaction solution, extracted with dichloromethane, separated the organic phase, dried with anhydrous sodium sulfate, filtered, concentrated the organic solvent under reduced pressure, and column chromatography The title compound (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3, 4-c]pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Dioxin-5-yl)dimethylphosphine oxidation (0.17g, yield: 58%).
1H NMR(400MHz,DMSO-d 6)δ1.49-1.62(m,2H),1.78(s,3H),1.81(s,3H),1.89-1.95(m,2H),2.04-2.15(m,4H),2.38-2.43(m,2H),2.58-2.72(m,6H),3.02-3.07(m,2H),3.35-3.43(m,2H),3.72-3.80(m,5H),4.24(s,2H),4.32(s,2H),6.70(s,1H),6.80(d,J＝8.8Hz,1H),7.43(s,1H),7.91-7.97(m,2H),8.10(s,1H),11.62(s,1H)； 1 H NMR (400MHz, DMSO-d 6 ) δ 1.49-1.62 (m, 2H), 1.78 (s, 3H), 1.81 (s, 3H), 1.89-1.95 (m, 2H), 2.04-2.15 (m ,4H),2.38-2.43(m,2H),2.58-2.72(m,6H),3.02-3.07(m,2H),3.35-3.43(m,2H),3.72-3.80(m,5H),4.24 (s, 2H), 4.32 (s, 2H), 6.70 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.91-7.97 (m, 2H), 8.10 ( s,1H),11.62(s,1H);
MS m/z(ESI):713.2[M+H] +. MS m/z(ESI): 713.2[M+H] + .
实施例58Example 58
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- Preparation of 5-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000122
Figure PCTCN2020097362-appb-000122
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- Refer to Example 2 for the preparation method of 5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.03(t,J＝7.6Hz,3H),1.87-1.91(m,8H),2.17-2.19(m,2H),2.56-2.58(m,2H),2.77-2.79(m,2H),2.90(s,3H),3.08-3.11(m4H),3.65-3.68(m,4H),3.83-3.86(m,5H),4.32-4.35(m,4H),6.76(s,1H),6.91-6.93(m,1H),7.80-7.83(m,2H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.03 (t, J = 7.6Hz, 3H), 1.87-1.91 (m, 8H), 2.17-2.19 (m, 2H), 2.56-2.58 (m, 2H) ,2.77-2.79(m,2H),2.90(s,3H),3.08-3.11(m4H),3.65-3.68(m,4H),3.83-3.86(m,5H),4.32-4.35(m,4H) ,6.76(s,1H),6.91-6.93(m,1H),7.80-7.83(m,2H),8.07(s,1H);
MS m/z(ESI):727.2[M+H] +. MS m/z(ESI): 727.2[M+H] + .
实施例59Example 59
(6-((5-溴-2-((5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzene Preparation of oxofura-7-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine
Figure PCTCN2020097362-appb-000123
Figure PCTCN2020097362-appb-000123
第一步：5-甲基-2,3-二氢苯并呋喃的制备Step 1: Preparation of 5-methyl-2,3-dihydrobenzofuran
Figure PCTCN2020097362-appb-000124
Figure PCTCN2020097362-appb-000124
往5-甲基苯并呋喃(3.0g,22.7mmol)的甲醇溶液(30mL)中加入Pd/C(300mg,10wt％)，在氢气氛下，常温常压，搅拌过夜。用硅藻土滤除不溶物，滤液减压浓缩有机溶剂，柱层析分离得到标题化合物5-甲基-2,3-二氢苯并呋喃(2.70g,收率:89％)。Pd/C (300 mg, 10 wt%) was added to a methanol solution (30 mL) of 5-methylbenzofuran (3.0 g, 22.7 mmol), and stirred overnight under a hydrogen atmosphere at room temperature and pressure. The insoluble matter was filtered off with Celite, the filtrate was concentrated under reduced pressure and the organic solvent was concentrated, and column chromatography was separated to obtain the title compound 5-methyl-2,3-dihydrobenzofuran (2.70 g, yield: 89%).
第二步：5-甲基-7-硝基-2,3-二氢苯并呋喃的制备Step 2: Preparation of 5-methyl-7-nitro-2,3-dihydrobenzofuran
Figure PCTCN2020097362-appb-000125
Figure PCTCN2020097362-appb-000125
冰水浴下，往5-甲基-2,3-二氢苯并呋喃(2.70g,20.1mmol)的TFA溶液(40mL)里分批加入NaNO 2(1.36g,19.7mmol)，然后继续在冰水浴下搅拌两小时。向反应中加入冰水，然后用DCM萃取多次，合并有机相，依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物5-甲基-7-硝基-2,3-二氢苯并呋喃(900mg,收率:25％)。 Under an ice-water bath, add NaNO 2 (1.36g, 19.7mmol) to the TFA solution (40mL) of 5-methyl-2,3-dihydrobenzofuran (2.70g, 20.1mmol) in batches, and then continue to place it on ice. Stir under water bath for two hours. Ice water was added to the reaction, and then extracted with DCM for several times. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution and saturated brine successively, separated the organic phase and dried with anhydrous sodium sulfate, filtered, and concentrated the organic solvent under reduced pressure. Chromatographic separation gave the title compound 5-methyl-7-nitro-2,3-dihydrobenzofuran (900mg, yield: 25%).
第三步：5-甲基-2,3-二氢苯并呋喃-7-胺的制备The third step: Preparation of 5-methyl-2,3-dihydrobenzofuran-7-amine
Figure PCTCN2020097362-appb-000126
Figure PCTCN2020097362-appb-000126
往5-甲基-7-硝基-2,3-二氢苯并呋喃(900mg,5.03mmol)的甲醇溶液(30mL)中加入Pd/C(100mg,10wt％)，在氢气氛下，常温常压，搅拌过夜。用硅藻土滤除不溶物，滤液浓缩，柱层析分离得到标题化合物5-甲基-2,3-二氢苯并呋喃-7-胺(670mg,收率:89％)。To 5-methyl-7-nitro-2,3-dihydrobenzofuran (900mg, 5.03mmol) in methanol (30mL) was added Pd/C (100mg, 10wt%), under a hydrogen atmosphere, at room temperature At normal pressure, stir overnight. The insoluble matter was filtered off with Celite, the filtrate was concentrated, and the column chromatography was separated to obtain the title compound 5-methyl-2,3-dihydrobenzofuran-7-amine (670 mg, yield: 89%).
MS m/z(ESI):150.1[M+H] +. MS m/z(ESI): 150.1[M+H] + .
第四步：4-溴-5-甲基-2,3-二氢苯并呋喃-7-胺的制备Step 4: Preparation of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine
Figure PCTCN2020097362-appb-000127
Figure PCTCN2020097362-appb-000127
-30℃下，往5-甲基-2,3-二氢苯并呋喃-7-胺(650mg,4.36mmol)的DMF溶液(20mL)里分批加入NBS(466mg,2.62mmol)，反应缓慢升至室温，并在室温下继续搅拌两小时。用EtOAc稀释反应液后，用饱和食盐水洗涤多次，滤液用无水硫酸钠干燥，减压浓缩有机溶剂，柱层析分离得到标题化合物4-溴-5-甲基-2,3-二氢苯并呋喃-7-胺(600mg,收率:60％)。At -30℃, add NBS (466mg, 2.62mmol) to the DMF solution (20mL) of 5-methyl-2,3-dihydrobenzofuran-7-amine (650mg, 4.36mmol) in batches, the reaction is slow Warm to room temperature and continue stirring at room temperature for two hours. After diluting the reaction solution with EtOAc, it was washed with saturated brine several times, the filtrate was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the title compound 4-bromo-5-methyl-2,3-di was obtained by column chromatography. Hydrobenzofuran-7-amine (600mg, yield: 60%).
MS m/z(ESI):228.0[M+H] +. MS m/z(ESI): 228.0[M+H] + .
第五步：N-(4-溴-5-甲基-2,3-二氢苯并呋喃-7-基)乙酰胺的制备Step 5: Preparation of N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide
Figure PCTCN2020097362-appb-000128
Figure PCTCN2020097362-appb-000128
冰水浴下，往4-溴-5-甲基-2,3-二氢苯并呋喃-7-胺(400mg,1.75mmol)的二氯甲烷溶液(10mL)里依次滴加入乙酸酐(0.233mL,2.46mmol)和DIPEA(0.864mL,5.25mmol)，反应然后缓慢升至室温，并在室温下继续搅拌两小时。减压浓缩反应液，柱层析分离纯化得到标题化合物N-(4-溴-5-甲基-2,3-二氢苯并呋喃-7-基)乙酰胺(385mg,收率:81％)。Under ice water bath, to 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine (400mg, 1.75mmol) in dichloromethane (10mL) was added dropwise acetic anhydride (0.233mL) , 2.46 mmol) and DIPEA (0.864 mL, 5.25 mmol), the reaction was then slowly raised to room temperature, and stirring was continued for two hours at room temperature. The reaction solution was concentrated under reduced pressure, and separated and purified by column chromatography to obtain the title compound N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide (385 mg, yield: 81%) ).
MS m/z(ESI):270.0[M+H] +. MS m/z(ESI): 270.0[M+H] + .
第六步：N-(5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-基)乙酰胺的制备The sixth step: N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl ) Preparation of acetamide
Figure PCTCN2020097362-appb-000129
Figure PCTCN2020097362-appb-000129
往N-(4-溴-5-甲基-2,3-二氢苯并呋喃-7-基)乙酰胺(385mg,1.43mmol)和1-甲基-4-(哌啶-4-基)哌嗪(783mg,4.28mmol)的THF溶液(10mL)里，依次加入醋酸钯(48mg,0.215mmol)、Johnphos(128mg,0.430mmol)和LiHMDS(1M in THF,4.3mL)，氮气保护下，微波115℃下反应2小时。反应冷却至室温，浓缩反应液，柱层析分离得到标题化合物N-(5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-基)乙酰胺(225mg,收率:42％)。To N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide (385mg, 1.43mmol) and 1-methyl-4-(piperidin-4-yl) ) Piperazine (783mg, 4.28mmol) in THF (10mL), add palladium acetate (48mg, 0.215mmol), Johnphos (128mg, 0.430mmol) and LiHMDS (1M in THF, 4.3mL) in sequence, under nitrogen React under microwave at 115°C for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and column chromatography was separated to obtain the title compound N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2 ,3-Dihydrobenzofuran-7-yl)acetamide (225mg, yield: 42%).
MS m/z(ESI):373.3[M+H] +. MS m/z(ESI): 373.3[M+H] + .
第七步：5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-胺的制备Step 7: Preparation of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-amine
Figure PCTCN2020097362-appb-000130
Figure PCTCN2020097362-appb-000130
往N-(5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-基)乙酰胺(125mg,0.336mmol)的乙醇溶液(10mL)里小心加入浓硫酸(1mL)，加热回流下搅拌一小时，冷却，浓缩，用DCM溶解，再依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，干燥，柱层析，得标题化合物5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-胺(80mg,收率:72％)。To N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)acetamide (125mg, 0.336mmol) ethanol solution (10mL) was carefully added concentrated sulfuric acid (1mL), heated under reflux and stirred for one hour, cooled, concentrated, dissolved in DCM, and then washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn. After drying and column chromatography, the title compound 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7 -Amine (80mg, yield: 72%).
MS m/z(ESI):331.2[M+H] +. MS m/z(ESI): 331.2[M+H] + .
Figure PCTCN2020097362-appb-000131
Figure PCTCN2020097362-appb-000131
(6-((5-溴-2-((5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢苯并呋喃-7-基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzene Preparation method of oxyfuran-7-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Refer to Example 1.
1H NMR(400MHz,CD 3OD)δ1.70(d,J＝12.0Hz,2H),1.87(s,3H),1.91(s,3H),2.00(d,J＝13.2Hz,3H),2.16(s,3H),2.53(s,3H),2.60-2.65(m,1H),2.73-3.17(m,13H),4.27(s,2H),4.34(d,J＝4.3Hz,2H),4.48(t,J＝8.6Hz,2H),6.84(d,J＝9.3Hz,1H),7.30(s,1H),7.97(d,J＝9.3Hz,1H),8.03(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.70 (d, J = 12.0 Hz, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.00 (d, J = 13.2 Hz, 3H), 2.16(s,3H),2.53(s,3H),2.60-2.65(m,1H),2.73-3.17(m,13H), 4.27(s,2H), 4.34(d,J=4.3Hz,2H) ,4.48(t,J=8.6Hz,2H),6.84(d,J=9.3Hz,1H),7.30(s,1H),7.97(d,J=9.3Hz,1H),8.03(s,1H) ；
MS m/z(ESI):712.2[M+H] +. MS m/z(ESI): 712.2[M+H] + .
实施例60Example 60
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的制备1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4 -c) Preparation of pyrrole-2(1H)-yl)ethane-1-one
Figure PCTCN2020097362-appb-000132
Figure PCTCN2020097362-appb-000132
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的制备方法参照实施例1。1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4 -c] The preparation method of pyrrole-2(1H)-yl)ethane-1-one refers to Example 1.
1H NMR(400MHz,CD 3OD)δ1.78-1.90(m,5H),1.91(s,3H),2.09(s,3H),2.12-2.22(m,5H),2.73(t,J＝11.8Hz,2H),2.97-3.23(m,7H),3.54-3.67(m,5H),3.75-3.82(m,1H),3.84(s,3H),4.25-4.32(m,2H),4.33-4.39(m,2H),6.71(s,1H),6.91(d,J＝9.1Hz,1H),7.72(s,1H),7.87-7.92(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.78-1.90 (m, 5H), 1.91 (s, 3H), 2.09 (s, 3H), 2.12-2.22 (m, 5H), 2.73 (t, J = 11.8Hz, 2H), 2.97-3.23 (m, 7H), 3.54-3.67 (m, 5H), 3.75-3.82 (m, 1H), 3.84 (s, 3H), 4.25-4.32 (m, 2H), 4.33 -4.39(m,2H),6.71(s,1H),6.91(d,J=9.1Hz,1H),7.72(s,1H),7.87-7.92(m,1H),8.06(s,1H);
MS m/z(ESI):754.2[M+H] +. MS m/z(ESI): 754.2[M+H] + .
实施例61Example 61
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的制备1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c) Preparation of pyrrole-2(1H)-yl)ethane-1-one
Figure PCTCN2020097362-appb-000133
Figure PCTCN2020097362-appb-000133
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的制备方法参照实施例2。1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4- c] Refer to Example 2 for the preparation method of pyrrole-2(1H)-yl)ethane-1-one.
1H NMR(400MHz,CD 3OD)δ1.02(t,J＝7.7Hz,3H),1.81-1.93(m,8H),2.09(s,3H),2.18(d,J＝10.5Hz,2H),2.56(q,J＝7.5Hz,2H),2.78(t,J＝11.6Hz,2H),2.95-3.20(m,7H),3.52-3.68(m,5H),3.77(d,J＝9.6Hz,1H),3.84(s,3H),4.29(s,2H),4.36(s,2H),6.76(s,1H),6.90(d,J＝9.2Hz,1H),7.79-7.83(m,2H),8.07(s,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.02(t,J=7.7Hz,3H),1.81-1.93(m,8H),2.09(s,3H),2.18(d,J=10.5Hz,2H ),2.56(q,J=7.5Hz,2H),2.78(t,J=11.6Hz,2H),2.95-3.20(m,7H),3.52-3.68(m,5H),3.77(d,J= 9.6Hz, 1H), 3.84 (s, 3H), 4.29 (s, 2H), 4.36 (s, 2H), 6.76 (s, 1H), 6.90 (d, J = 9.2 Hz, 1H), 7.79-7.83 ( m,2H),8.07(s,1H);
MS m/z(ESI):768.2[M+H] + MS m/z(ESI):768.2[M+H] +
实施例62Example 62
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-(甲磺酰)六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Preparation of Dioxin-5-yl) Dimethylphosphine Oxidation
Figure PCTCN2020097362-appb-000134
Figure PCTCN2020097362-appb-000134
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-(甲磺酰)六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Refer to Example 1 for the preparation method of dioxin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.85-1.97(m,8H),2.14(s,3H),2.17-2.30(m,2H),2.74(t,J＝11.9Hz,2H),2.96(s,3H),3.04-3.26(m,7H),3.34-3.49(m,3H),3.80-3.91(m,5H),4.28(d,J＝4.9Hz,2H),4.35(d,J＝4.9Hz,2H),6.70(s,1H),6.90(d,J＝9.1Hz,1H),7.72(s,1H),7.88(dd,J＝9.5,4.4Hz,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.85-1.97 (m, 8H), 2.14 (s, 3H), 2.17-2.30 (m, 2H), 2.74 (t, J = 11.9 Hz, 2H), 2.96 (s,3H),3.04-3.26(m,7H),3.34-3.49(m,3H),3.80-3.91(m,5H), 4.28(d,J=4.9Hz,2H), 4.35(d,J ＝4.9Hz,2H),6.70(s,1H),6.90(d,J＝9.1Hz,1H),7.72(s,1H),7.88(dd,J＝9.5,4.4Hz,1H),8.06(s ,1H);
MS m/z(ESI):790.2[M+H] + MS m/z(ESI): 790.2[M+H] +
实施例63Example 63
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-5-(甲磺酰)六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Preparation of Dioxin-5-yl) Dimethylphosphine Oxidation
Figure PCTCN2020097362-appb-000135
Figure PCTCN2020097362-appb-000135
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-5-(甲磺酰)六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4] Refer to Example 2 for the preparation method of dioxin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):804.2[M+H] + MS m/z(ESI): 804.2[M+H] +
实施例64Example 64
(5-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097362-appb-000136
Figure PCTCN2020097362-appb-000136
(5-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备方法参照实施例1。(5-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidized preparation method refer to Example 1.
1H NMR(400MHz,CD 3OD)δ1.23(t,J＝7.1Hz,3H),1.53-1.64(m,2H),1.84(s,3H),1.88(s,3H),2.03-2.14(m,5H),2.72(t,J＝11.7Hz,2H),3.06-3.19(m,3H), 3.49-3.58(m,2H),3.84(s,3H),3.88-3.95(m,2H),4.25-4.38(m,3H),6.07(s,2H),6.71(s,1H),6.93(d,J＝8.7Hz,1H),7.71(s,1H),7.74-7.81(m,1H),8.08(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.23 (t, J = 7.1 Hz, 3H), 1.53-1.64 (m, 2H), 1.84 (s, 3H), 1.88 (s, 3H), 2.03-2.14 (m,5H),2.72(t,J=11.7Hz,2H),3.06-3.19(m,3H), 3.49-3.58(m,2H),3.84(s,3H),3.88-3.95(m,2H) ),4.25-4.38(m,3H),6.07(s,2H),6.71(s,1H),6.93(d,J=8.7Hz,1H),7.71(s,1H),7.74-7.81(m, 1H), 8.08(s, 1H);
MS m/z(ESI):687.2[M+H] +. MS m/z(ESI): 687.2[M+H] + .
实施例65Example 65
(5-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation
Figure PCTCN2020097362-appb-000137
Figure PCTCN2020097362-appb-000137
(5-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的制备方法参照实施例1。(5-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- The preparation method of 5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation refers to Example 1.
1H NMR(400MHz,CD 3OD)δ1.55-1.68(m,2H),1.86-1.89(m,6H),2.09-2.11(m,5H),2.72-2.76(m,2H),3.15-3.18(m,4H),3.45(s,3H),3.52-3.54(m,2H),3.84(s,3H),3.99-4.13(m,2H),4.20-4.31(m,2H),6.07-6.09(m,2H),6.71(s,1H),6.93-6.96(m,1H),7.63-7.88(m,2H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.55-1.68 (m, 2H), 1.86-1.89 (m, 6H), 2.09-2.11 (m, 5H), 2.72-2.76 (m, 2H), 3.15 3.18 (m, 4H), 3.45 (s, 3H), 3.52-3.54 (m, 2H), 3.84 (s, 3H), 3.99-4.13 (m, 2H), 4.20-4.31 (m, 2H), 6.07- 6.09(m,2H),6.71(s,1H),6.93-6.96(m,1H),7.63-7.88(m,2H),8.07(s,1H);
MS m/z(ESI):687.2[M+H] +. MS m/z(ESI): 687.2[M+H] + .
实施例66Example 66
(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)-3,3-二甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Preparation of dimethyl phosphine oxidation
Figure PCTCN2020097362-appb-000138
Figure PCTCN2020097362-appb-000138
(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)-3,3-二甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Refer to Example 1 for the preparation method of dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.35(s,6H),1.50-1.63(m,2H),1.89(s,3H),1.93(s,3H),1.98-2.06(m,2H),2.11(s,3H),2.71(t,J＝11.7Hz,2H),2.92-3.01(m,2H),3.11-3.18(m,2H),3.43(s,3H),3.49-3.54(m,2H),3.74-3.81(m,2H),3.84(s,3H),3.95-4.07(m,4H),6.72(s,1H),6.88(d,J＝9.1Hz,1H),7.74(s,1H),7.87-7.93(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.35 (s, 6H), 1.50-1.63 (m, 2H), 1.89 (s, 3H), 1.93 (s, 3H), 1.98-2.06 (m, 2H) ,2.11(s,3H),2.71(t,J=11.7Hz,2H),2.92-3.01(m,2H),3.11-3.18(m,2H),3.43(s,3H),3.49-3.54(m ,2H),3.74-3.81(m,2H),3.84(s,3H),3.95-4.07(m,4H),6.72(s,1H),6.88(d,J=9.1Hz,1H),7.74( s, 1H), 7.87-7.93 (m, 1H), 8.06 (s, 1H);
MS m/z(ESI):687.2[M+H] +. MS m/z(ESI): 687.2[M+H] + .
实施例67Example 67
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(3-(甲基(噁丁环-3-基)氨基)吖丁啶-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxbutan-3-yl)amino)azetidine- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)bis Preparation of methyl phosphine oxidation
Figure PCTCN2020097362-appb-000139
Figure PCTCN2020097362-appb-000139
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(3-(甲基(噁丁环-3-基)氨基)吖丁啶-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxbutan-3-yl)amino)azetidine- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)bis Refer to Example 1 for the preparation method of methylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.50-1.65(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.07(m,2H),2.11(s,3H),2.22(s,3H),2.64-2.74(m,2H),2.90-3.00(m,1H),3.08-3.18(m,2H),3.37-3.46(m,1H),3.73-3.81(m,3H),3.83(s,3H),3.95-4.04(m,2H),4.24-4.39(m,4H),4.60-4.70(m,4H),6.69(s,1H),6.89(d,J＝9.1Hz,1H),7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.50-1.65 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.11 (s, 3H) ,2.22(s,3H),2.64-2.74(m,2H),2.90-3.00(m,1H),3.08-3.18(m,2H),3.37-3.46(m,1H),3.73-3.81(m, 3H), 3.83 (s, 3H), 3.95-4.04 (m, 2H), 4.24-4.39 (m, 4H), 4.60-4.70 (m, 4H), 6.69 (s, 1H), 6.89 (d, J = 9.1Hz,1H),7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H);
MS m/z(ESI):742.2[M+H] +. MS m/z(ESI): 742.2[M+H] + .
实施例68Example 68
(6-((5-溴-2-((4-(4-(3-氟-3-(2-羟基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)piperidin-1-yl) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)bis Preparation of methyl phosphine oxidation
Figure PCTCN2020097362-appb-000140
Figure PCTCN2020097362-appb-000140
(6-((5-溴-2-((4-(4-(3-氟-3-(2-羟基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)piperidin-1-yl) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)bis Refer to Example 1 for the preparation method of methylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.23-1.25(m,6H),1.63-1.65(m,2H),1.89-1.91(m,6H),2.02-2.21(m,5H),2.71-2.73(m,2H),3.12-3.16(m,3H),3.84(s,3H),4.11-4.13(m 2H),4.36-4.39(m,6H),6.72(s,1H),6.91-6.93(m,1H),7.72(s,1H),7.87-7.89(m,1H),8.06(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.23-1.25 (m, 6H), 1.63-1.65 (m, 2H), 1.89-1.91 (m, 6H), 2.02-2.21 (m, 5H), 2.71 2.73(m,2H),3.12-3.16(m,3H),3.84(s,3H),4.11-4.13(m 2H),4.36-4.39(m,6H),6.72(s,1H),6.91-6.93 (m,1H),7.72(s,1H),7.87-7.89(m,1H),8.06(s,1H);
MS m/z(ESI):733.2[M+H] +. MS m/z(ESI): 733.2[M+H] + .
实施例69Example 69
(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(2-羟基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidine -1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097362-appb-000141
Figure PCTCN2020097362-appb-000141
(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(2-羟基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例2。(6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidine -1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Refer to Example 2 for the preparation method of phosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.03(t,J＝7.6Hz,3H),1.23-1.26(m,6H),1.60-1.65(m,2H),1.91-1.93(m,6H),2.03-2.05(m,2H),2.56-2.58(m,2H),2.75-2.78(m,3H),3.08-3.12(m,2H),3.78-3.96(m,5H),4.12-4.16(m,2H),4.22-4.48(m,4H),6.78(s,1H),6.91-6.93(m,1H),7.63-7.90(m,2H),8.08(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.03 (t, J = 7.6 Hz, 3H), 1.23-1.26 (m, 6H), 1.60-1.65 (m, 2H), 1.91-1.93 (m, 6H) ,2.03-2.05(m,2H),2.56-2.58(m,2H),2.75-2.78(m,3H),3.08-3.12(m,2H),3.78-3.96(m,5H),4.12-4.16( m,2H),4.22-4.48(m,4H),6.78(s,1H),6.91-6.93(m,1H),7.63-7.90(m,2H),8.08(s,1H);
MS m/z(ESI):747.2[M+H] +. MS m/z(ESI): 747.2[M+H] + .
实施例70Example 70
(6-((5-溴-2-((4-(4-(3-(2-氟乙基)-3-羟基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(2-fluoroethyl)-3-hydroxyazetidine-1-yl)piperidin-1-yl)-2- Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Oxidation preparation
Figure PCTCN2020097362-appb-000142
Figure PCTCN2020097362-appb-000142
(6-((5-溴-2-((4-(4-(3-(2-氟乙基)-3-羟基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((4-(4-(3-(2-fluoroethyl)-3-hydroxyazetidine-1-yl)piperidin-1-yl)-2- Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.
1H NMR(400MHz,CD 3OD)δ1.56-1.67(m,2H),1.88(s,3H),1.92(s,3H),2.03-2.11(m,2H),2.12-2.18(m,4H),2.20-2.26(m,1H),2.73(t,J＝11.7Hz,3H),3.11-3.20(m,2H),3.81-3.89(m,4H),4.08-4.14(m,2H),4.25-4.31(m,2H),4.33-4.38(m,2H),4.55-4.66(m,3H),4.75(t,J＝5.6Hz,1H),6.72(s,1H),6.92(d,J＝9.2Hz,1H),7.72(s,1H),7.87-7.93(m,1H),8.07(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.56-1.67 (m, 2H), 1.88 (s, 3H), 1.92 (s, 3H), 2.03-2.11 (m, 2H), 2.12-2.18 (m, 4H), 2.20-2.26 (m, 1H), 2.73 (t, J = 11.7Hz, 3H), 3.11-3.20 (m, 2H), 3.81-3.89 (m, 4H), 4.08-4.14 (m, 2H) ,4.25-4.31(m,2H),4.33-4.38(m,2H),4.55-4.66(m,3H),4.75(t,J=5.6Hz,1H),6.72(s,1H),6.92(d ,J=9.2Hz,1H), 7.72(s,1H), 7.87-7.93(m,1H), 8.07(s,1H);
MS m/z(ESI):719.2[M+H] +. MS m/z(ESI): 719.2[M+H] + .
生物学测试评价Biological test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The following further describes the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.
测试例1、本发明化合物对EGFR野生型、EGFR del746-750/T790M/C797S和EGFR L858R/T790M/C797S突变激酶抑制活性的测定Test Example 1. Determination of the inhibitory activity of the compounds of the present invention on EGFR wild-type, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases
实验目的：该测试例的目的是测试化合物对EGFR野生型、EGFR del746-750/T790M/C797S和EGFR L858R/T790M/C797S突变激酶的抑制活性。Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound against EGFR wild-type, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases.
实验仪器：离心机(5810R)购自Eppendorf公司，移液器购自Eppendorf或Rainin公司，酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。Experimental instrument: a centrifuge (5810R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, and a microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.
实验方法：本实验采用Cisbio公司的HTRF激酶测定方法(Cisbio#62TK0PEB)，底物多肽TK和ATP在酪氨酸激酶EGFR野生型、EGFR del746-750/T790M/C797S或EGFR L858R/T790M/C797S突变存在的条件下发生催化反应，底物被磷酸化，通过测定反应中生成的磷酸化底物的含量来表征激酶的活性，并得出化合物对EGFR野生型、EGFR del746-750/T790M/C797S或EGFR  L858R/T790M/C797S突变激酶活性抑制的半数抑制浓度IC 50。 Experimental method: This experiment uses Cisbio's HTRF kinase assay method (Cisbio#62TK0PEB), the substrate peptides TK and ATP are in the tyrosine kinase EGFR wild type, EGFR del746-750/T790M/C797S or EGFR L858R/T790M/C797S mutation The catalytic reaction occurs under the existing conditions, and the substrate is phosphorylated. The activity of the kinase is characterized by measuring the content of the phosphorylated substrate generated in the reaction, and it is concluded that the compound is against EGFR wild-type, EGFR del746-750/T790M/C797S or EGFR L858R / T790M / C797S mutant half maximal inhibitory concentration IC 50 of inhibition of kinase activity.
具体实验操作如下：The specific experimental operations are as follows:
激酶反应在白色384孔板(Perkin Elmer#6008280)中进行，每孔加入1～5μL用含1％DMSO的ddH 2O稀释的不同浓度的化合物，阳性对照孔加入1～5μL含1％DMSO的ddH 2O，然后每孔加入1～5μL用Dilution buffer(5×激酶缓冲液，MgCl 2 6.65mM，MnCl 2 1.33mM，DTT 1.33mM)稀释的0.5～5nM 4×EGFR野生型、EGFR del746-750/T790M/C797S或EGFR L858R/T790M/C797S突变的激酶溶液，阴性对照孔加入1～5μL的Dilution buffer，所有孔加入1～5μL用10×Dilution buffer配制的4μM 4×底物TK溶液，最后加入1～5μL用Dilution buffer稀释的24μM 4×ATP溶液启动反应，室温反应120分钟后，每孔加入10μL检测液(TK抗体16nM，XL665 0.5μM)室温避光反应20分钟后用BioTek Synergy H1酶标仪检测化学发光值。 Kinase reaction was carried out in a white 384-well plate (Perkin Elmer#6008280), each well was added with 1～5μL of compounds of different concentrations diluted with ddH 2 O containing 1% DMSO, and 1～5μL of 1% DMSO was added to the positive control well. ddH 2 O, and then add 1-5 μL to each well diluted 0.5-5 nM 4×EGFR wild type, EGFR del746-750 in Dilution buffer (5×kinase buffer, MgCl 2 6.65mM, MnCl 2 1.33mM, DTT 1.33mM) /T790M/C797S or EGFR L858R/T790M/C797S mutant kinase solution, add 1～5μL of Dilution buffer to the negative control wells, add 1～5μL of 4μM 4×substrate TK solution prepared with 10×Dilution buffer to all wells, and finally add Start the reaction with 1～5μL 24μM 4×ATP solution diluted with Dilution buffer. After reacting at room temperature for 120 minutes, add 10μL of detection solution (TK antibody 16nM, XL665 0.5μM) to each well and react for 20 minutes in the dark at room temperature, then use BioTek Synergy H1 enzyme label The meter detects the chemiluminescence value.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值，具体数据如下表所示： Calculate the percentage inhibition data of the wells treated with the compound through the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate = 100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC 50 value. The specific data are shown in the following table:
Figure PCTCN2020097362-appb-000143
Figure PCTCN2020097362-appb-000143
Figure PCTCN2020097362-appb-000144
Figure PCTCN2020097362-appb-000144
实验结论：Experimental results:
通过以上方案得出，本发明所示的实施例化合物对EGFR突变的激酶活性具有较强的抑制作用，而对EGFR野生型激酶活性抑制作用较小，对比数据可知，本发明系列实施例化合物对EGFR突变的/野生型激酶活性的抑制具有高选择性。According to the above scheme, the compound of the examples of the present invention has a strong inhibitory effect on the kinase activity of EGFR mutations, but has a small inhibitory effect on the activity of EGFR wild-type kinase. The inhibition of EGFR mutant/wild type kinase activity is highly selective.
测试例2、本发明化合物对EGFR del746-750/C797S和EGFR L858R/C797S突变的激酶抑制活性的测定Test Example 2. Determination of the kinase inhibitory activity of the compounds of the present invention on EGFR del746-750/C797S and EGFR L858R/C797S mutations
实验目的：该测试例的目的是测试化合物对EGFR del746-750/C797S和EGFR L858R/C797S突变激酶的抑制活性。Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound against EGFR del746-750/C797S and EGFR L858R/C797S mutant kinases.
实验仪器：离心机(5810R)购自Eppendorf公司，移液器购自Eppendorf或Rainin公司，酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。Experimental instrument: a centrifuge (5810R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, and a microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.
实验方法：本实验采用Cisbio公司的HTRF激酶测定方法(Cisbio#62TK0PEB)，底物多肽TK和ATP在酪氨酸激酶EGFR del746-750/C797S或EGFR L858R/C797S突变存在的条件下发生催化反应，底物被磷酸化，通过测定反应中生成的磷酸化底物的含量来表征激酶的活性，并得出化合物对EGFR del746-750/C797S或EGFR L858R/C797S突变激酶活性抑制的半数抑制浓度IC 50。 Experimental method: This experiment uses Cisbio's HTRF kinase assay method (Cisbio#62TK0PEB). The substrate peptides TK and ATP undergo a catalytic reaction in the presence of tyrosine kinase EGFR del746-750/C797S or EGFR L858R/C797S mutations. The substrate is phosphorylated, the activity of the kinase is characterized by measuring the content of the phosphorylated substrate generated in the reaction, and the half inhibitory concentration IC 50 of the compound's inhibition of EGFR del746-750/C797S or EGFR L858R/C797S mutant kinase activity is obtained .
具体实验操作如下：The specific experimental operations are as follows:
激酶反应在白色384孔板(Perkin Elmer#6008280)中进行，每孔加入1～5μL用含1％DMSO的ddH 2O稀释的不同浓度的化合物，阳性对照孔加入1～5μL含1％DMSO的ddH 2O，然后每孔加入1～5μL用Dilution buffer(5×激酶缓冲液，MgCl 2 6.65mM，MnCl 2 1.33mM，DTT 1.33mM)稀释的0.5～5nM 4×EGFR del746-750/C797S或EGFR L858R/C797S突变的激酶溶液，阴性对照孔加入1～5μL的Dilution buffer，所有孔加入1～5μL用10×Dilution buffer配制的4μM 4×底物TK溶液，最后加入1～5μL用Dilution buffer稀释的24μM 4×ATP溶液启动反应，室温反应120分钟后，每孔加入10μL检测液(TK抗体16nM,XL665 0.5μM)室温避光反应20分钟后用BioTek Synergy H1酶标仪检测化学发光值。 Kinase reaction was carried out in a white 384-well plate (Perkin Elmer#6008280), each well was added with 1～5μL of compounds of different concentrations diluted with ddH 2 O containing 1% DMSO, and 1～5μL of 1% DMSO was added to the positive control well. ddH 2 O, then add 1-5 μL to each well diluted 0.5-5 nM 4×EGFR del746-750/C797S or EGFR in Dilution buffer (5×kinase buffer, MgCl 2 6.65mM, MnCl 2 1.33mM, DTT 1.33mM) For L858R/C797S mutant kinase solution, add 1～5μL of Dilution buffer to the negative control wells, add 1～5μL of 4μM 4×Substrate TK solution prepared in 10×Dilution buffer to all wells, and finally add 1～5μL of diluted Dilution buffer 24μM 4×ATP solution starts the reaction. After reacting at room temperature for 120 minutes, add 10μL of detection solution (TK antibody 16nM, XL665 0.5μM) to each well and react for 20 minutes in the dark at room temperature, and then use BioTek Synergy H1 microplate reader to detect the chemiluminescence value.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值，具体数据如下表所示： Calculate the percentage inhibition data of the wells treated with the compound through the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate = 100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC 50 value. The specific data are shown in the following table:
Figure PCTCN2020097362-appb-000145
Figure PCTCN2020097362-appb-000145
Figure PCTCN2020097362-appb-000146
Figure PCTCN2020097362-appb-000146
实验结论：Experimental results:
通过以上方案得出，本发明所示的实施例化合物对EGFR del746-750/C797S或EGFR L858R/C797S突变的激酶活性具有较强的抑制作用According to the above scheme, the compound of the examples shown in the present invention has a strong inhibitory effect on the kinase activity of EGFR del746-750/C797S or EGFR L858R/C797S mutation
测试例3:细胞增殖抑制实验Test Example 3: Cell Proliferation Inhibition Experiment
实验目的：该测试例的目的是测试化合物对细胞的增殖抑制活性。Experimental purpose: The purpose of this test case is to test the compound's inhibitory activity on cell proliferation.
实验仪器：移液器购自Eppendorf公司，CO 2培养箱购自美国Thermo公司，酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。 Experimental instrument: the pipette was purchased from Eppendorf, the CO 2 incubator was purchased from the American Thermo company, and the microplate reader was purchased from the American BioTek company, and the model was SynergyH1 full-function microplate reader.
实验方法：本实验采用CTG(CELL TITER-GLO)发光法检测化合物对A431细胞和Ba/F3(EGFR del746-750/T790M/C797S)细胞的增殖抑制活性，并得出化合物对细胞增殖活性的半数抑制浓度IC 50。 Experimental method: In this experiment, CTG (CELL TITER-GLO) luminescence method was used to detect the compound's proliferation inhibitory activity on A431 cells and Ba/F3 (EGFR del746-750/T790M/C797S) cells, and the compound's activity on cell proliferation was half Inhibition concentration IC 50 .
具体实验操作如下：The specific experimental operations are as follows:
对于A431细胞：第一天，在96孔检测板中铺入90μL A431细胞悬液，每孔细胞个数为3000个，其中阴性对照不加细胞，将板放入含5％CO 2的37℃培养箱中培养过夜。第二天，每孔加入10μL梯度稀释好的化合物溶液，阳性和阴性对照孔只加入含DMSO的10μL培养基，将板放入二氧化碳培养箱孵育72小时。培养72h后，向细胞板的每个孔中加入50μL Cell Titer Glo，避光震荡2min后静置10min；之后在BioTek Synergy H1酶标仪检测发光值，通过化学发光信号值计算抑制率，根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 For A431 cells: On the first day, spread 90μL of A431 cell suspension in a 96-well test plate, the number of cells per well is 3000, and the negative control does not add cells, and the plate is placed at 37°C with 5% CO 2 Cultivate overnight in an incubator. On the second day, add 10 μL of the diluted compound solution to each well, add only 10 μL of medium containing DMSO to the positive and negative control wells, and place the plate in a carbon dioxide incubator for 72 hours. After culturing for 72 hours, add 50μL Cell Titer Glo to each well of the cell plate, shake for 2 minutes in the dark, and then stand for 10 minutes; then, the luminescence value is detected on the BioTek Synergy H1 microplate reader, and the inhibition rate is calculated by the chemiluminescence signal value. inhibition rate IC 50 concentrations of the compound obtained by curve fitting.
对于Ba/F3(EGFR del746-750/T790M/C797S)悬浮细胞：For Ba/F3 (EGFR del746-750/T790M/C797S) suspension cells:
在96孔检测板中铺入90μL Ba/F3细胞悬液，每孔细胞个数为3000个，其中阴性对照不加细胞；静置2h后每孔加入10μL梯度稀释好的化合物溶液，阳性和阴性对照孔只加入含DMSO的10μL培养基，放入二氧化碳培养箱培养72小时后同前述A431细胞的方法进行CTG检测。Spread 90μL of Ba/F3 cell suspension in a 96-well test plate, the number of cells in each well is 3000, and the negative control does not add cells; after standing for 2h, add 10μL of the compound solution in each well, positive and negative Only 10μL of medium containing DMSO was added to the control wells, and then placed in a carbon dioxide incubator for 72 hours and then subjected to CTG detection using the same A431 cell method described above.
实验数据处理方法：Experimental data processing method:
通过板上阳性对照孔(DMSO对照孔)和阴性对照孔(不加细胞)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照 值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值，具体数据如下表所示： Calculate the percentage inhibition data of the wells treated with the compound through the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate = 100-[(test compound value-negative control value)]/( Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC 50 value. The specific data are shown in the following table:
Figure PCTCN2020097362-appb-000147
Figure PCTCN2020097362-appb-000147
Figure PCTCN2020097362-appb-000148
Figure PCTCN2020097362-appb-000148
实验结论：Experimental results:
通过以上方案得出，本发明所示的实施例化合物在Ba/F3(EGFR del746-750/T790M/C797S)突变细胞增殖活性的抑制试验中具有良好的抑制作用，而对A431细胞具有较弱的抑制作用，对比数据可知，本发明系列实施例化合物对Ba/F3(EGFR del746-750/T790M/C797S)突变细胞增殖活性的抑制具有高选择性。According to the above scheme, the compound of the example of the present invention has a good inhibitory effect in the inhibition test of Ba/F3 (EGFR del746-750/T790M/C797S) mutant cell proliferation activity, but has a weaker effect on A431 cells. Inhibition effect, comparative data shows that the compounds of the series of examples of the present invention have high selectivity in inhibiting the proliferation activity of Ba/F3 (EGFR del746-750/T790M/C797S) mutant cells.
测试例4、本发明化合物对细胞EGFR磷酸化抑制作用的测定Test Example 4. Determination of the inhibitory effect of the compound of the present invention on cell EGFR phosphorylation
实验目的：该测试例的目的是测试化合物对细胞EGFR磷酸化的抑制活性。Experimental purpose: The purpose of this test case is to test the compound's inhibitory activity on cell EGFR phosphorylation.
实验仪器：微孔板振荡器(88880024)购自Thermo Scientific TM公司，离心机(5702R)购自Eppendorf公司，移液器购自Eppendorf公司，酶标仪购自美国Biotech公司，型号为SynergyH1全功能酶标仪。 Experimental instrument: Microplate shaker (88880024) was purchased from Thermo Scientific TM company, centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, microplate reader was purchased from American Biotech company, and the model was SynergyH1 full function Microplate reader.
实验试剂：Phospho-EGFR(Tyr1068)LANCE Ultra TR-FRET Cellular Detection Kit(Perkin Elmer TRF4016C)内含(5X)LANCE Ultra Lysis Buffer 1，LANCE Ultra Eu-labeled Anti-EGFR(Y1068)Antibody，LANCE Ultra ULight-labeled Anti-EGFR Antibody,EGF(Thermo fisher PHG0311)；Experimental reagents: Phospho-EGFR (Tyr1068) LANCE Ultra TR-FRET Cellular Detection Kit (Perkin Elmer TRF4016C) contains (5X) LANCE Ultra Lysis Buffer 1, LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody, Ultra Ultra labeled Anti-EGFR Antibody, EGF (Thermo fisher PHG0311);
实验方法：本实验采用Ba/F3(EGFR del746-750/T790M/C797S)细胞系，通过EGF刺激激活EGFR信号通路，检测化合物对其下游EGFR(Y1068)磷酸化的抑制活性，并得出化合物对EGFR信号通路活性的半数抑制浓度IC 50。 Experimental method: In this experiment, the Ba/F3 (EGFR del746-750/T790M/C797S) cell line was used to activate the EGFR signaling pathway through EGF stimulation to detect the inhibitory activity of the compound on its downstream EGFR (Y1068) phosphorylation, and obtain the compound half of the EGFR signaling pathway activity inhibitory concentration IC 50.
具体实验操作如下：The specific experimental operations are as follows:
384孔检测板中铺入Ba/F3(EGFR del746-750/T790M/C797S)细胞3-12μL，每孔细胞个数为100-300K，加入2μL梯度稀释好的化合物溶液，室温，350rpm,孵育2小时。2小时后加入2μL EGF，EGF终浓度50nM，室温震荡15min。加入2-5μL(5X)LANCE Ultra Lysis Buffer 1溶液，室温震荡2h。2h后加入5μL终浓度为0.5nM的LANCE Ultra Eu-labeled Anti-EGFR(Y1068)Antibody(PerkinElmer)和终浓度为5nM的LANCE Ultra ULight-labeled Anti-EGFR Antibody(PerkinElmer)溶液，室温孵育过夜。酶标仪测定各板孔的665nm荧光信号值，通过荧光信号值计算抑制率，根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 Place 3-12μL of Ba/F3 (EGFR del746-750/T790M/C797S) cells in a 384-well detection plate, the number of cells in each well is 100-300K, add 2μL of the diluted compound solution, room temperature, 350rpm, incubate 2 hour. After 2 hours, add 2μL of EGF, the final concentration of EGF is 50nM, and shake at room temperature for 15min. Add 2-5μL (5X) LANCE Ultra Lysis Buffer 1 solution and shake at room temperature for 2h. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody (PerkinElmer) with a final concentration of 0.5 nM and LANCE Ultra ULight-labeled Anti-EGFR Antibody (PerkinElmer) with a final concentration of 5 nM were added, and incubated overnight at room temperature. The microplate reader measures the 665nm fluorescence signal value of each plate well, calculates the inhibition rate from the fluorescence signal value, and obtains the IC 50 of the compound by curve fitting according to the inhibition rate of different concentrations.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不加细胞)计算 使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值。 Calculate the percentage inhibition data of the wells treated with the compound through the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate = 100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Fitting using GraphPad prism and the corresponding concentrations of the different percent inhibition data to a 4 parameter nonlinear logic formula 50 value was calculated IC.
实施例编号Example number Ba/F3(EGFR del746-750/T790M/C797S)pEGFR IC 50(nM) Ba/F3(EGFR del746-750/T790M/C797S)pEGFR IC 50 (nM)
实施例1Example 1 0.060.06
实施例2Example 2 0.390.39
实施例12Example 12 2.572.57
实施例13Example 13 1.651.65
实施例15Example 15 5.005.00
实施例16Example 16 0.210.21
实施例20Example 20 1.741.74
实施例38Example 38 1.151.15
实施例42Example 42 6.936.93
实施例48Example 48 2.652.65
实施例52Example 52 5.005.00
实施例57Example 57 0.820.82
实施例58Example 58 0.950.95
实施例59Example 59 2.632.63
实施例60Example 60 1.571.57
实施例61Example 61 0.880.88
实施例65Example 65 0.110.11
实验结论：Experimental results:
通过以上方案得出，本发明所示的实施例化合物对Ba/F3(EGFR del746-750/T790M/C797S)细胞的EGFR磷酸化具有良好的抑制作用。According to the above scheme, the compound of the embodiment shown in the present invention has a good inhibitory effect on EGFR phosphorylation of Ba/F3 (EGFR del746-750/T790M/C797S) cells.
测试例5:Balb/C小鼠药代动力学测定Test Example 5: Determination of Balb/C Mouse Pharmacokinetics
5.1研究目的：5.1 Research purpose:
以Balb/C小鼠为受试动物，研究化合物实施例，在5mg/kg剂量下口服给药在小鼠体内血浆的药代动力学行为。Balb/C mice were used as the test animals to study the pharmacokinetic behavior of the compound examples in the plasma of mice administered orally at a dose of 5 mg/kg.
5.2试验方案5.2 Test plan
5.2.1试验药品：5.2.1 Test drugs:
本发明实施例化合物，自制。The example compounds of the present invention are self-made.
5.2.2试验动物：5.2.2 Experimental animals:
Balb/C Mouse(6只/实施例)，雄性，上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006N0.311620400001794)。Balb/C Mouse (6 mice/example), male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
5.2.3制剂处方：5.2.3 Formulation prescription:
0.5％CMC-Na(1％Tween80)，超声溶解，配制为澄清溶液或均一混悬液。0.5% CMC-Na (1% Tween80), dissolve by ultrasonic, prepare as clear solution or homogeneous suspension.
5.2.4给药：5.2.4 Administration:
Balb/C小鼠(6只/实施例)，雄性；禁食一夜后分别p.o.，剂量为5mg/kg，给药体积10mL/kg。Balb/C mice (6 mice/example), male; p.o. after fasting overnight, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.
5.2.5样品采集：5.2.5 Sample collection:
小鼠给药前和给药后，在0、0.5、1、2、4、6、8和24小时，采用眼眶采血0.1mL，置于EDTA-K 2试管中，4℃ 6000rpm离心6min分离血浆，于-80℃保存。 Before and after the administration of the mice, at 0, 0.5, 1, 2 , 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K 2 test tube, and centrifuged at 4°C at 6000 rpm for 6 minutes to separate plasma , Store at -80℃.
5.2.6样品处理：5.2.6 Sample processing:
1)血浆样品40μL加入160μL乙腈沉淀，混合后3500×g离心5～20分钟。1) 40μL of plasma sample was precipitated with 160μL of acetonitrile, mixed and centrifuged at 3500×g for 5-20 minutes.
2)取处理后上清溶液100μL进行LC/MS/MS分析待测化合物的浓度。2) Take 100 μL of the supernatant solution after treatment to analyze the concentration of the test compound by LC/MS/MS.
5.2.7液相分析5.2.7 Liquid phase analysis
●液相条件：Shimadzu LC-20AD泵●Liquid phase conditions: Shimadzu LC-20AD pump
●质谱条件:AB Sciex API 4000质谱仪Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm●Chromatography column: phenomenex Gemiu 5um C18 50×4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈●Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile
●流速：0.8mL/min●Flow rate: 0.8mL/min
●洗脱时间：0-4.0分钟，洗脱液如下：●Elution time: 0-4.0 minutes, the eluent is as follows:
Figure PCTCN2020097362-appb-000149
Figure PCTCN2020097362-appb-000149
5.3试验结果与分析5.3 Test results and analysis
药代动力学主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表：The main pharmacokinetic parameters are calculated with WinNonlin 6.1, and the mouse pharmacokinetic experiment results are shown in the following table:
化合物Compound t max(h) t max (h) C max(ng/mL) C max (ng/mL) AUC 0-t(ng/mL*h) AUC 0-t (ng/mL*h) AUC 0-∞(ng/mL*h) AUC 0-∞ (ng/mL*h) t 1/2(h) t 1/2 (h) MRT 0-∞(h) MRT 0-∞ (h)
实施例1-FAExample 1-FA 2.02.0 19331933 1159311593 1163111631 2.92.9 4.74.7
实施例2-FAExample 2-FA 2.02.0 21132113 2101721017 2138321383 4.04.0 6.36.3
实施例12-FAExample 12-FA 4.04.0 32333233 3881638816 3896738967 2.82.8 6.16.1
实施例13-FAExample 13-FA 2.02.0 27072707 2530425304 2534425344 2.52.5 5.35.3
实施例15-FAExample 15-FA 2.02.0 16801680 1636816368 1651116511 5.65.6 6.06.0
实施例16-FAExample 16-FA 2.02.0 20272027 2517125171 2532825328 3.23.2 6.16.1
实施例20-FAExample 20-FA 1.01.0 12571257 1110411104 1120011200 3.53.5 5.55.5
实施例21-FAExample 21-FA 2.02.0 13401340 1175911759 1184411844 4.24.2 5.65.6
实施例49-FAExample 49-FA 2.02.0 14701470 1234112341 1253512535 4.24.2 6.06.0
实施例52-FAExample 52-FA 2.02.0 23232323 1800918009 1817518175 3.53.5 5.55.5
实施例53-FAExample 53-FA 2.02.0 33273327 2058720587 2059420594 1.81.8 3.83.8
实施例57-FAExample 57-FA 2.02.0 17931793 1673716737 1688016880 3.43.4 5.85.8
实施例59-FAExample 59-FA 2.02.0 11431143 90079007 90449044 3.23.2 5.25.2
实施例67-FAExample 67-FA 2.02.0 22802280 81688168 81788178 1.11.1 3.03.0
注：FA为相应化合物的甲酸盐。Note: FA is the formate of the corresponding compound.
实验结论：Experimental results:
从表中小鼠药代实验结果可以看出，本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。 It can be seen from the mouse pharmacokinetic experiment results in the table that the compounds of the examples of the present invention exhibit good metabolic properties, and both the exposure amount AUC and the maximum blood drug concentration C max perform well.
测试例6:本发明实施例化合物的体内药效试验Test Example 6: In vivo efficacy test of the compound of the present invention
6.1 实验目的6.1 Experimental purpose
通过体内药效实验筛选出药效较为明显且毒副作用较小的化合物。Through in vivo drug efficacy experiments, compounds with more obvious drug effects and less toxic and side effects are screened out.
6.2 实验主要仪器和材料6.2 The main instruments and materials of the experiment
6.2.1 仪器：6.2.1 Instrument:
Figure PCTCN2020097362-appb-000150
Figure PCTCN2020097362-appb-000150
6.2.2 试剂：6.2.2 Reagents:
Figure PCTCN2020097362-appb-000151
Figure PCTCN2020097362-appb-000151
Figure PCTCN2020097362-appb-000152
Figure PCTCN2020097362-appb-000152
6.2.3 动物：6.2.3 Animals:
NOD/SCID小鼠，6-8周，♀，购自江苏集萃药康生物科技有限公司。NOD/SCID mice, 6-8 weeks, ♀, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
6.3 实验步骤6.3 Experimental steps
6.3.1 细胞培养6.3.1 Cell culture
PC9(EGFR Del19/T790M/C797S)细胞培养在含10％胎牛血清的RPMI1640培养液中。收集指数生长期的PC9(EGFR Del19/T790M/C797S)细胞。PC9 (EGFR Del19/T790M/C797S) cells were cultured in RPMI1640 medium containing 10% fetal calf serum. Collect PC9 (EGFR Del19/T790M/C797S) cells in the exponential growth phase.
6.3.2 细胞接种6.3.2 Cell seeding
实验小鼠于右侧背部皮下(小鼠右侧背部，前肢附近的皮下)接种1×10 7PC9(EGFR Del19/T790M/C797S)细胞，细胞重悬在1：1的PBS与基质胶中(0.1ml/只)，定期观察肿瘤生长情况，肿瘤细胞接种当天定义为第0天。 Experimental mice were inoculated with 1×10 7 PC9 (EGFR Del19/T790M/C797S) cells subcutaneously on the right back (right back of the mouse, subcutaneous near the forelimb), and the cells were resuspended in 1:1 PBS and Matrigel ( 0.1ml/head), and regularly observe tumor growth. The day of tumor cell inoculation is defined as day 0.
6.3.3 荷瘤鼠量瘤、分组、给药6.3.3 The amount of tumor, grouping and administration of tumor-bearing mice
a,day7测量肿瘤体积数据，并选择肿瘤体积在100-200mm 3范围的小鼠，按照平均体积140mm 3，根据肿瘤大小和小鼠体重随机分组给药。 a,day7 measured tumor volume data, and selected mice with tumor volume in the range of 100-200mm 3 , according to the average volume of 140mm 3 , randomized administration according to tumor size and mouse body weight.
c,根据分组结果，开始给予测试药物(给药方式：口服给药；给药体积：10mL/kg；给药频率：1次/天；给药周期：21天；溶媒：0.5％HPMC)。c. According to the grouping results, start to administer the test drug (administration method: oral administration; administration volume: 10 mL/kg; administration frequency: 1 time/day; administration period: 21 days; vehicle: 0.5% HPMC).
d,开始给予测试药物后每周两次量瘤、称重。d. Measure and weigh the tumor twice a week after starting the test drug.
e,实验结束后安乐死动物。e. Euthanize the animal after the experiment.
f,用Excel等软件处理数据。化合物抑瘤率TGI(％)的计算：TGI％＝[1-(T i-T 0)/(C i-C 0)]×100％；其中，T i为给药组第i天瘤体积，T 0为给药组分组当天瘤体积，C i为溶剂对照组第i天瘤体积，C 0为溶剂对照组分组当天瘤体积。 f, Use Excel and other software to process data. Calculation of compound tumor inhibition rate TGI (%): TGI%=[1-(T i -T 0 )/(C i -C 0 )]×100%; where T i is the tumor volume on the i day of the administration group , T 0 is the tumor volume on the day of the administration group, C i is the tumor volume on the i day of the solvent control group, and C 0 is the tumor volume on the day of the solvent control group.
6.4 试验数据如下表：6.4 The test data is as follows:
Figure PCTCN2020097362-appb-000153
Figure PCTCN2020097362-appb-000153
6.5 实验结果6.5 Experimental results
从上述结果中可以看出，本专利的上述化合物有较好的抑瘤率，且安全性较好。It can be seen from the above results that the above-mentioned compounds of this patent have better tumor inhibition rate and better safety.

Claims (30)

  1. 通式(IB)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by general formula (IB), its stereoisomer or its pharmaceutically acceptable salt:
    Figure PCTCN2020097362-appb-100001
    Figure PCTCN2020097362-appb-100001
    其中：among them:
    X 1或Y 1各自独立的选自-O-、-NR AA-、-S-或-CR AAR BB-；优选-O-、-NH-、-NCH 3-、-S-或-CH 2-； X 1 or Y 1 are each independently selected from -O-, -NR AA -, -S- or -CR AA R BB -; preferably -O-, -NH-, -NCH 3 -, -S- or -CH 2 -;
    M 2、M 3、M 4或M 5存在或不存在，存在时各自独立的选自N、S、CH或CR aa；优选O、S、N或CH； The presence or absence of M 2 , M 3 , M 4 or M 5 , when present, are each independently selected from N, S, CH or CR aa ; preferably O, S, N or CH;
    M 0或M 1存在或不存在，存在时各自独立的选自N、S、CH、NR aa或CR aaR bb；优选O、S、N或CH，更优选S、N或CH； The presence or absence of M 0 or M 1 is independently selected from N, S, CH, NR aa or CR aa R bb when present ; preferably O, S, N or CH, more preferably S, N or CH;
    环A选自环烷基或芳基，优选苯基；Ring A is selected from cycloalkyl or aryl, preferably phenyl;
    环D选自取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基；优选取代或未取代的C 3-6环烷基、取代或未取代的3-6元杂环基、取代或未取代的C 5-6芳基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子或氧原子的5-6元杂芳基或杂环基，进一步优选
    Figure PCTCN2020097362-appb-100002
    Figure PCTCN2020097362-appb-100003
    Ring D is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; preferably substituted or unsubstituted C 3-6 ring Alkyl group, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably containing 1-3 nitrogen atoms Or 5-6 membered heteroaryl or heterocyclic group of oxygen atom, more preferably
    Figure PCTCN2020097362-appb-100002
    Figure PCTCN2020097362-appb-100003
    R独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，优选氢、烷基或卤素，更优选氢、C 1-6烷基、氟、氯、溴或碘，进一步优选氢、C 1-3烷基、氟、氯或溴； R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group or heteroaryl group, preferably hydrogen, alkyl or halogen, more preferably hydrogen, C 1-6 alkyl, fluorine, chlorine, bromine or iodine, further preferably hydrogen, C 1-3 alkyl, fluorine , Chlorine or bromine;
    R 1或R 5各自独立的选自氢、氘、氧、氮、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、螺环烷基、桥环烷基、稠环烷基、桥杂环基、螺杂环基、稠杂环基、芳基、杂芳基、-(CH 2) nOR CC、-(CH 2) nNR CCR DD、-(CH 2) nNR CCC(O)R DD、-NR CCC(O)NR DDR EE、-C(O)NR CCR DD、-NR CCS(O) mR DD、-(CH 2) nS(O) mNR CCR DD、-(CH 2) nC(O)R CC、-NR CCC(O)OR DD、-(CH 2) nS(O) mR CC或-(CH 2) nNR CCS(O) mR DD； 其中所述的氧、氮、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、氘、烷基、卤代烷基、卤素、取代或未取代的氨基、氧代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、卤代烷氧基、羟烷基、-(CH 2) nC(O)R CC、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的氧代杂环基、螺环烷基、桥环烷基或稠环烷基中的一个或多个取代基所取代； R 1 or R 5 are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, alkene Group, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, spirocycloalkyl, bridged cycloalkyl, fused ring alkyl, bridged heterocyclyl, spiroheterocyclyl, fused heterocyclyl, aryl Group, heteroaryl, -(CH 2 ) n OR CC , -(CH 2 ) n NR CC R DD , -(CH 2 ) n NR CC C(O)R DD , -NR CC C(O)NR DD R EE , -C(O)NR CC R DD , -NR CC S(O) m R DD , -(CH 2 ) n S(O) m NR CC R DD , -(CH 2 ) n C(O) R CC , -NR CC C(O)OR DD , -(CH 2 ) n S(O) m R CC or -(CH 2 ) n NR CC S(O) m R DD ; wherein the oxygen and nitrogen , Alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amino, oxo , Nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, -(CH 2 ) n C(O)R CC , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted oxoheterocyclyl, spirocycloalkyl , Substituted by one or more substituents in bridged cycloalkyl or fused cycloalkyl;
    或者，R 1和R 5，或两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、-(CH 2) nR CC、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 1 and R 5 , or two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Substituted by one or more substituents among hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH 2 ) n R CC , aryl and heteroaryl;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) mR aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m R aa ;
    R 3和R 4各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、巯基、烷基取代巯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选氢、烷基、卤代烷基、卤素、羟基、巯基、烷氧基、-SR aa或取代或未取代的炔基，更优选氢、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、巯基、C 1-6烷氧基、-SR aa、C 2-6炔基、C 2-6烯基，所述C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-SR aa、C 2-6炔基、C 2-6烯基，任选进一步被C 3-6环烷基、C 1-6烷基或卤素所取代，优选氢、氯、溴、-SCH 3、
    Figure PCTCN2020097362-appb-100004
    Figure PCTCN2020097362-appb-100005
    环丙基或-CF 3；     R 3 and R 4 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, mercapto, alkyl substituted Mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted hetero Aryl, preferably hydrogen, alkyl, haloalkyl, halogen, hydroxy, mercapto, alkoxy, -SR aa or substituted or unsubstituted alkynyl, more preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl Group, halogen, hydroxy, mercapto, C 1-6 alkoxy, -SR aa , C 2-6 alkynyl, C 2-6 alkenyl, the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -SR aa , C 2-6 alkynyl, C 2-6 alkenyl, optionally further substituted by C 3-6 cycloalkyl, C 1-6 alkyl or halogen, preferably Hydrogen, chlorine, bromine, -SCH 3 ,
    Figure PCTCN2020097362-appb-100004
    Figure PCTCN2020097362-appb-100005
    Cyclopropyl or -CF 3 ;
    或者，R 3和R 4、R 3和Y 1链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选取代或未取代的C 3-6环烷基、取代或未取代的3-6元杂环基、取代或未取代的C 5-6芳基或取代或未取代的5-6元杂芳基，更优选取代或未取代的含1-2个N、O或S原子的5-6元杂芳基，进一步优选取代或未取代的吡咯基、取代或未取代的噻唑基、取代或未取代的吡啶基或取代或未取代的苯基； Alternatively, R 3 and R 4 , R 3 and Y 1 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents, preferably substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycle Group, substituted or unsubstituted C 5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably substituted or unsubstituted 5-6 membered group containing 1-2 N, O or S atoms Heteroaryl, further preferably substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridyl or substituted or unsubstituted phenyl;
    R aa或R bb各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、氧代基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或 未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代，优选氢、烷基、环烷基、杂环基、氧代基或硫代基，更优选C 1-6烷基、C 3-6环烷基、3-6元杂环基、氧代基或硫代基，进一步优选甲基、乙基、丙基、氧代基或硫代基； R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, oxo group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino , Oxo, thio, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl are substituted by one or more substituents, preferably hydrogen, alkyl, cycloalkyl, Heterocyclic group, oxo group or thio group, more preferably C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, oxo or thio group, more preferably methyl, Ethyl, propyl, oxo, or thio;
    或者，R aa或R bb与磷原子链接形成一个杂环基或杂芳基，其中所述的杂环基和杂芳基，任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代，优选3-6元杂环基，更优选
    Figure PCTCN2020097362-appb-100006
    Alternatively, R aa or R bb is linked with a phosphorus atom to form a heterocyclic group or heteroaryl group, wherein the heterocyclic group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group , Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents, preferably 3-6 membered heterocyclic group, more preferably
    Figure PCTCN2020097362-appb-100006
    x为0-2的整数；x is an integer of 0-2;
    y为0-4的整数；y is an integer from 0-4;
    q为0-2的整数；q is an integer of 0-2;
    m为0-2的整数。m is an integer of 0-2.
  2. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
    Figure PCTCN2020097362-appb-100007
    Figure PCTCN2020097362-appb-100007
    其中：among them:
    M 1、M 2和M 3各自独立的选自O、N、S、CH、NR aa或CR aaR bb； M 1 , M 2 and M 3 are each independently selected from O, N, S, CH, NR aa or CR aa R bb ;
    环A选自环烷基或芳基；Ring A is selected from cycloalkyl or aryl;
    R独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, Heterocyclic group, aryl group or heteroaryl group;
    R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa或-(CH 2) nNR aaS(O) mR bb，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、氧代基、烷基、卤代烷基、卤素、氨基、氧代 基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基中的一个或多个取代基所取代； R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa S(O) m R bb , wherein the alkyl group, alkyl halide Group, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, oxo, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano , Hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted One or more substituents in the substituted heteroaryl group;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) mR aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m R aa ;
    R 3和R 4相同或不同，且各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基； R 3 and R 4 are the same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, amino, nitro, hydroxyl, cyano, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    R 5选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa或-(CH 2) nNR aaS(O) mR bb； R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa S(O) m R bb ;
    或者，R 1和R 5，或两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 1 and R 5 , or two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and Heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
    R aa、R bb和R cc各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R aa , R bb and R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogenated alkyl, alkoxy, hydroxyalkyl, halogenated alkoxy, halogen, cyano, nitro, hydroxyl, Amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxygen Substitute, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Substituted by one or more substituents in the unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;
    或者，R aa、R bb和R cc中任意两个可链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, any two of R aa , R bb and R cc may be linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups The group is optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
    x为0-2的整数；x is an integer of 0-2;
    y为0-4的整数；y is an integer from 0-4;
    q为0-2的整数；q is an integer of 0-2;
    n为0-2的整数；且n is an integer of 0-2; and
    m为0-2的整数。m is an integer of 0-2.
  3. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述通式(IB)进一步为通式(G)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein said general formula (IB) is further represented by general formula (G):
    Figure PCTCN2020097362-appb-100008
    Figure PCTCN2020097362-appb-100008
    其中：among them:
    环D选自杂环基；Ring D is selected from heterocyclyl;
    环B存在或不存在，存在时选自环烷基、杂环基、芳基或杂芳基；优选C 3-8单环环烷基、桥环烷基、螺环烷基、稠环烷基、3-8元单环杂环基、桥杂环基、螺杂环基、稠杂环基、芳基或3-8元杂芳基；更优选含1-2个N或O原子的5-7元杂环基、桥杂环基、螺杂环基或稠杂环基；进一步优选以下基团： The presence or absence of ring B is selected from cycloalkyl, heterocyclic, aryl or heteroaryl; preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused cycloalkane Group, 3-8 membered monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably containing 1-2 N or O atoms 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or fused heterocyclic group; further preferred are the following groups:
    Figure PCTCN2020097362-appb-100009
    Figure PCTCN2020097362-appb-100009
    R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 4选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、 氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 5选自氢、卤素、氰基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基或-(CH 2) nOR aa；或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl or -(CH 2 ) n OR aa ; or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
    R 8选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、羟基、氰基C 1-6烷基、C 1-6烷氧基或氧代基； R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, ring Alkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, hydroxyl, cyano C 1-6 alkyl, C 1-6 alkoxy or oxo;
    或者，R 5和R 8链接形成一个环烷基、杂环基、芳基或杂芳基，任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 5 and R 8 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, optionally further selected from a hydrogen atom, a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, an oxo group , Nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents replace;
    R 9选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基、杂芳基、羟基取代的烷基、氰基取代的烷基、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-(CH 2) nC(O)R aa、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nNR aaC(O)R bb； R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy-substituted alkyl, cyano-substituted alkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa ,- (CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb or -(CH 2 ) n NR aa C(O)R bb ;
    优选地R 9选自氢、卤素、羟基、C 1-6烷基、氰基取代的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-(CH 2) nC(O)R aa、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nNR aaC(O)R bb； Preferably R 9 is selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1- 6 alkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, - (CH 2) n R aa, - (CH 2) n OR aa, - (CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb Or -(CH 2 ) n NR aa C(O)R bb ;
    R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R aa、R bb或R cc各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基； R aa , R bb or R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
    y为0-4的整数；y is an integer from 0-4;
    n为0-4的整数；n is an integer from 0-4;
    m1为0-4的整数；m1 is an integer of 0-4;
    z为0-4的整数；z is an integer of 0-4;
    p为0-4的整数；p is an integer from 0-4;
    u为0-4的整数；且u is an integer from 0-4; and
    q为0-2的整数。q is an integer of 0-2.
  4. 根据权利要求2所述的化合物，其立体异构体或其药学上可接受盐，其 特征在于，所述通式(I)进一步为通式(II)所示：The compound of claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (II):
    Figure PCTCN2020097362-appb-100010
    Figure PCTCN2020097362-appb-100010
  5. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述通式(I)进一步为通式(IV)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 2, wherein said general formula (I) is further represented by general formula (IV):
    Figure PCTCN2020097362-appb-100011
    Figure PCTCN2020097362-appb-100011
  6. 根据权利要求3所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述通式(G)进一步为通式(G-1)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 3, wherein the general formula (G) is further represented by the general formula (G-1):
    Figure PCTCN2020097362-appb-100012
    Figure PCTCN2020097362-appb-100012
  7. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述通式(IA)进一步为通式(IG)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein said general formula (IA) is further represented by general formula (IG):
    Figure PCTCN2020097362-appb-100013
    Figure PCTCN2020097362-appb-100013
    其中：among them:
    R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    R选自氢、卤素或C 1-6烷基； R is selected from hydrogen, halogen or C 1-6 alkyl;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
    R 3选自氢或卤素； R 3 is selected from hydrogen or halogen;
    R 5各自独立地选自氢、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基、卤素、氰基或-(CH 2) nOR aa，或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , Or, two R 5 are connected to form a C 3-8 cycloalkyl or 3-12 membered heterocyclic group;
    R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基或氧代基； R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo;
    R 9选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基、氧代基、羟烷基、C 3-8环烷基、3-12元杂环基、-(CH 2) nC(O)R aa、-(CH 2) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb；n为0-2的整数； R 9 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano, oxo, hydroxyalkyl, C 3 -8 cycloalkyl, 3-12 membered heterocyclic group, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ; n is an integer of 0-2;
    R aa和R bb各自独立地选自氢、氘、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基或取代或未取代的C 3-8环烷基； R aa and R bb are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or substituted or unsubstituted C 3-8 ring alkyl;
    q为0-2的整数；q is an integer of 0-2;
    y为0-4的整数；y is an integer from 0-4;
    z为0-4的整数；z is an integer of 0-4;
    u为0-4的整数；且u is an integer from 0-4; and
    i为0-2的整数。i is an integer of 0-2.
  8. 根据权利要求2或7所述的化合物，其立体异构体或其药学上可接受盐，其特征在于，所述通式进一步为通式(VII)所示：The compound of claim 2 or 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula is further represented by general formula (VII):
    Figure PCTCN2020097362-appb-100014
    Figure PCTCN2020097362-appb-100014
  9. 根据权利要求2所述的化合物，其立体异构体或其药学上可接受盐，其特征在于，所述通式(I)进一步为通式((VIII-B)所示：The compound of claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula ((VIII-B):
    Figure PCTCN2020097362-appb-100015
    Figure PCTCN2020097362-appb-100015
    其中：among them:
    环F选自取代或未取代的环烷基或取代或未取代的杂环基，优选取代或未取代的C 4-7环烷基或取代或未取代的5-7元杂环基，进一步优选哌啶基、四氢吡咯基、环丁基、环戊基、环己基、四氢呋喃基或四氢吡喃基； Ring F is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group, preferably substituted or unsubstituted C 4-7 cycloalkyl or substituted or unsubstituted 5-7 membered heterocyclic group, further Preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
    R 12选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) nR aa、-(CH 2) nNR aaR bb或-(CH 2) nC(O)R aa，优选氢、C 1-6烷基、取代或未取代的杂环基、-(CH 2) nR aa、-(CH 2) nNR aaR bb或-(CH 2) nC(O)R aa； R 12 is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n C(O)R aa , preferably hydrogen, C 1-6 alkyl, substituted or unsubstituted heterocyclic group, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n C(O)R aa ;
    s为0-4的整数。s is an integer from 0-4.
  10. 根据权利要求1-2中任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-2, characterized in that:
    环A选自如下基团：Ring A is selected from the following groups:
    Figure PCTCN2020097362-appb-100016
    Figure PCTCN2020097362-appb-100016
  11. 根据权利要求2、3、6～8中任一项所述的化合物，其立体异构体或其药学上可接受盐，其特征在于，环B选自含有一个或两个选自氮原子或氧原子的4-6元单环杂环基或含有一个或两个选自氮原子或氧原子的7-9元稠环杂环基，优选如下基团：The compound according to any one of claims 2, 3, 6 to 8, its stereoisomers or pharmaceutically acceptable salts thereof, wherein the ring B is selected from containing one or two nitrogen atoms or The 4-6 membered monocyclic heterocyclic group of oxygen atom or the 7-9 membered fused ring heterocyclic group containing one or two selected from nitrogen atom or oxygen atom, preferably the following groups:
    Figure PCTCN2020097362-appb-100017
    Figure PCTCN2020097362-appb-100017
  12. 根据权利要求3、6～8中任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 3, 6 to 8, characterized in that:
    环B选自如下基团：Ring B is selected from the following groups:
    Figure PCTCN2020097362-appb-100018
    Figure PCTCN2020097362-appb-100018
  13. 根据权利要求1或3所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1 or 3, characterized in that:
    环D选自3-8元杂环基；优选5-6元杂环基，更优选含有2-3个选自氮或氧 原子的5-6元杂环基。Ring D is selected from 3-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups, more preferably 5-6 membered heterocyclic groups containing 2-3 selected from nitrogen or oxygen atoms.
  14. 根据权利要求3、6～8中任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于：R 9选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nC(O)R aa、-(CH 2) nC(O)OR aa、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-(CH 2) nNR aaC(O)R bb或-(CH 2) nS(O) mR aa； The compound according to any one of claims 3, 6 to 8, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, Haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Radical, -(CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n NR aa C(O)R bb or -(CH 2 ) n S(O) m R aa ;
    优选氢、氘、C 1-6烷基、C 1-6烷基氰基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、卤素、羟基、C 1-6羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nOR aa、-(CH 2) nC(O)R aa、-(CH 2) nNR aaR bb、-(CH 2) nC(O)OR aa、-(CH 2) nNR aaC(O)R bb或-(CH 2) nS(O) mR aa； Preferably hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl cyano, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n NR aa C(O)R bb or -(CH 2 ) n S(O) m R aa ;
    进一步优选氢、氘、C 1-3烷基、C 1-3烷基氰基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、羟基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nOC 1-3烷基、-(CH 2) nC(O)C 1-3烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nC(O)C 3-6环烷基、-(CH 2) nC(O)OR aa、-(CH 2) nNHC 3-6环烷基、-(CH 2) nN(C 1-3烷基) 2、-(CH 2) nNHC 1-3烷基、-(CH 2) nN(C 1-3烷基)(C 3-6环烷基)、-(CH 2) nN(C 1-3烷基)(C 3-6杂环基)、-(CH 2) nN(C 1-3烷基)C(O)C 1-3烷基、-(CH 2) nNHC(O)C 1-3烷基、-(CH 2) nSC 1-3烷基、-(CH 2) nS(O)C 1-3烷基或-(CH 2) nS(O) 2C 1-3烷基。 More preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkyl cyano, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, hydroxy , C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OC 1-3 alkyl, -(CH 2 ) n C(O)C 1 -3 alkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n C(O)C 3-6 cycloalkyl, -(CH 2 ) n C(O) OR aa , -(CH 2 ) n NHC 3-6 cycloalkyl, -(CH 2 ) n N(C 1-3 alkyl) 2 , -(CH 2 ) n NHC 1-3 alkyl, -(CH 2 ) n N(C 1-3 alkyl)(C 3-6 cycloalkyl), -(CH 2 ) n N(C 1-3 alkyl)(C 3-6 heterocyclyl), -(CH 2 ) n N(C 1-3 alkyl) C(O)C 1-3 alkyl, -(CH 2 ) n NHC(O)C 1-3 alkyl, -(CH 2 ) n SC 1-3 Alkyl group, -(CH 2 ) n S(O)C 1-3 alkyl group or -(CH 2 ) n S(O) 2 C 1-3 alkyl group.
  15. 根据权利要求3、6～8中任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R 9选自氢、卤素、羟基、C 1-3烷基、氰基取代的C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、-(CH 2) nOC 1-3烷基、-(CH 2) nC(O)C 1-3烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nC(O)C 3-6环烷基、-(CH 2) nC(O)OC 1-3烷基、-(CH 2) nNC 1-3-3-6元杂环基、-(CH 2) nN(C 1-3烷基) 2、-(CH 2) nNHC 1-3烷基、-(CH 2) nN(C 1-3烷基)、-(CH 2) nNHC(O)C 1-3烷基或-(CH 2) nS(O) 2C 1-3烷基； The compound according to any one of claims 3, 6 to 8, its stereoisomers or pharmaceutically acceptable salts thereof, wherein R 9 is selected from hydrogen, halogen, hydroxy, C 1-3 alkyl , Cyano substituted C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 ring Alkyl, C 3-6 heterocyclyl, -(CH 2 ) n OC 1-3 alkyl, -(CH 2 ) n C(O)C 1-3 alkyl, -(CH 2 ) n C(O )OC 1-3 alkyl, -(CH 2 ) n C(O)C 3-6 cycloalkyl, -(CH 2 ) n C(O)OC 1-3 alkyl, -(CH 2 ) n NC 1-3 -3-6-membered heterocyclic group, -(CH 2 ) n N(C 1-3 alkyl) 2 , -(CH 2 ) n NHC 1-3 alkyl, -(CH 2 ) n N( C 1-3 alkyl), -(CH 2 ) n NHC(O)C 1-3 alkyl or -(CH 2 ) n S(O) 2 C 1-3 alkyl;
    优选氢、甲基、乙基、羧基、-CH 2OH、HOCH 2CH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、(CH 3) 2SO 2-、CH 3CH 2O-、CH 3CH 2NH-、CH 3(O)C(CH 3)N-、CH 3(O)CNH-、(CH 3CH 2)(CH 3)N-、CH 3(O)C-、CH 3O(O)C-、环丙基或甲酰基。 Preferably hydrogen, methyl, ethyl, carboxyl, -CH 2 OH, HOCH 2 CH 2 -, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 2 FCH 2 -, CNCH 2 -, (CH 3 ) 2 N-, (CH 3 CH 2 ) 2 N-, (CH 3 ) 2 SO 2 -, CH 3 CH 2 O-, CH 3 CH 2 NH-, CH 3 (O)C(CH 3 )N-, CH 3 (O)CNH-, (CH 3 CH 2 )(CH 3 )N-, CH 3 (O)C-, CH 3 O(O)C-, cyclopropyl or formyl.
  16. 根据权利要求3、6～8中任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R aa、R bb或R cc各自独立的选自氢、C 1-6烷基、取代或未取代的C 1-6烷氧基、一个或多个卤原子取代的C 1-6烷基、取代或未取代的3-6元杂环基或取代或未取代的C 3-6环烷基；更优选氢、甲基、乙基、环丙基、 环丁基、甲氧基、乙氧基、三甲基硅基、氟、氯、溴、
    Figure PCTCN2020097362-appb-100019
    Figure PCTCN2020097362-appb-100020
    The compound according to any one of claims 3, 6 to 8, its stereoisomers or pharmaceutically acceptable salts thereof, wherein R aa , R bb or R cc are each independently selected from hydrogen, C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, substituted with one or more halogen atoms, a C 1-6 alkyl group, a substituted or unsubstituted 3-6 membered heterocyclyl group or a substituted or unsubstituted Substituted C 3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,
    Figure PCTCN2020097362-appb-100019
    Figure PCTCN2020097362-appb-100020
  17. 根据权利要求1～16中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，The compound, its stereoisomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 16, characterized in that:
    R选自氢、卤素或C 1-6烷基； R is selected from hydrogen, halogen or C 1-6 alkyl;
    R 1选自取代的或未取代的3-12元杂环基、-(CH 2) nOR aa或-(CH 2) nNR aaR bb； R 1 is selected from a substituted or unsubstituted 3-12 membered heterocyclic group, -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
    R 3选自氢或卤素； R 3 is selected from hydrogen or halogen;
    R 4选自氢； R 4 is selected from hydrogen;
    R 5选自氢、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基、卤素、氰基或-(CH 2) nOR aa，或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
    R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基或氧代基； R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo;
    或者，R 5和R 8链接形成一个C 3-8环烷基，任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、氨基、氧代基、氰基和羟基中的一个或多个取代基所取代； Alternatively, R 5 and R 8 are linked to form a C 3-8 cycloalkyl group, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, amino, oxo, Substituted by one or more substituents in the cyano group and the hydroxyl group;
    R 9选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基、氧代基、羟烷基、C 3-8环烷基、3-12元杂环基、-(CH 2) nC(O)R aa、-(CH 2) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb； R 9 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano, oxo, hydroxyalkyl, C 3 -8 cycloalkyl, 3-12 membered heterocyclic group, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb ;
    R aa和R bb各自独立地选自氢、氘、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基或取代或未取代的C 3-8环烷基。 R aa and R bb are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl or substituted or unsubstituted C 3-8 ring alkyl.
  18. 根据权利要求1～17中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 17, characterized in that:
    环D为5-6元含氧杂环基；优选5-6元含双氧杂环基；更优选
    Figure PCTCN2020097362-appb-100021
    Ring D is a 5-6 membered oxygen-containing heterocyclic group; preferably a 5-6 membered dioxyheterocyclic group; more preferably
    Figure PCTCN2020097362-appb-100021
    环B为3-8元杂环基；优选3-8元单环杂环基或3-8元并环杂环基；更优选
    Figure PCTCN2020097362-appb-100022
    Ring B is a 3-8 membered heterocyclic group; preferably a 3-8 membered monocyclic heterocyclic group or a 3-8 membered bicyclic heterocyclic group; more preferably
    Figure PCTCN2020097362-appb-100022
    R选自氢、卤素或C 1-6烷基； R is selected from hydrogen, halogen or C 1-6 alkyl;
    R 2选自-(CH 2) nP(＝O)R aaR bb； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb ;
    R 3选自氢、卤素、-SR aa或C 1-6卤代烷基；更优选溴； R 3 is selected from hydrogen, halogen, -SR aa or C 1-6 haloalkyl; more preferably bromine;
    R 4选自氢； R 4 is selected from hydrogen;
    R 5选自氢、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-4炔基、卤素、氰基或-(CH 2) nOR aa，或者，两个R 5相连形成一个C 3-8环烷基或5-6元杂环基； R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-4 alkynyl, halogen, cyano or -(CH 2 ) n OR aa , or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 5-6 membered heterocyclic group;
    R 8选自氢； R 8 is selected from hydrogen;
    R 9选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6羟基取代烷基、C 1-6氰基取代烷基、C 1-6卤代烷基、-(CH 2) nR aa、-(CH 2) nOR aa、-(CH 2) nC(O)R aa、-(CH 2) nS(O) mR aa或-(CH 2) nNR aaR bb； R 9 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 hydroxy substituted alkyl, C 1-6 cyano substituted alkyl, C 1 -6 haloalkyl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n S(O) m R aa or -(CH 2 ) n NR aa R bb ;
    R aa和R bb各自独立地选自氢、氘、卤素、氰基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基或3-6元杂环基。 R aa and R bb are each independently selected from hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, or 3-6 membered heterocyclic group.
  19. 根据根据权利要求2、3、6～8中任一项所述的化合物，其立体异构体或其药学上可接受盐，其特征在于，The compound according to any one of claims 2, 3, 6 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:
    R 2选自-P(＝O)(CH 3) 2或-P(＝S)(CH 3) 2； R 2 is selected from -P(=O)(CH 3 ) 2 or -P(=S)(CH 3 ) 2 ;
    R 3选自氢或卤素； R 3 is selected from hydrogen or halogen;
    R 5选自氢、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 2-6烯基、或C 2-4炔基，或者，两个R 5相连形成一个C 3-8环烷基或3-12元杂环基； R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-4 alkynyl, or, Two R 5 are connected to form a C 3-8 cycloalkyl group or a 3-12 membered heterocyclic group;
    R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、卤素、氨基、羟基、氰基或氧代基。 R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, amino, hydroxyl, cyano or oxo.
  20. 根据权利要求1～19中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于所述化合物具体结构如下：The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-19, characterized in that the specific structure of the compound is as follows:
    Figure PCTCN2020097362-appb-100023
    Figure PCTCN2020097362-appb-100023
    Figure PCTCN2020097362-appb-100024
    Figure PCTCN2020097362-appb-100024
    Figure PCTCN2020097362-appb-100025
    Figure PCTCN2020097362-appb-100025
    Figure PCTCN2020097362-appb-100026
    Figure PCTCN2020097362-appb-100026
    Figure PCTCN2020097362-appb-100027
    Figure PCTCN2020097362-appb-100027
    Figure PCTCN2020097362-appb-100028
    Figure PCTCN2020097362-appb-100028
    Figure PCTCN2020097362-appb-100029
    Figure PCTCN2020097362-appb-100029
  21. 一种通式(A)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020097362-appb-100030
    Figure PCTCN2020097362-appb-100030
    其中：among them:
    R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、 氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
    R aa或R bb各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基； R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Oxo group, trimethylsilyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group;
    R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    i为0-4的整数；i is an integer from 0-4;
    u为0-4的整数；且u is an integer from 0-4; and
    q为0-2的整数。q is an integer of 0-2.
  22. 一种通式(A-1)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by general formula (A-1), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020097362-appb-100031
    Figure PCTCN2020097362-appb-100031
    其中：among them:
    X1为卤素、氨基、硼酸或硼酸酯；优选氯或溴；X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
    R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
    R aa或R bb各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基； R aa or R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Oxo group, trimethylsilyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group;
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 4选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 13选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、羟烷基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 13 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    i为0-4的整数；i is an integer from 0-4;
    u为0-4的整数；且u is an integer from 0-4; and
    q为0-2的整数。q is an integer of 0-2.
  23. 一种通式(A-2)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by general formula (A-2), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020097362-appb-100032
    Figure PCTCN2020097362-appb-100032
    其中：among them:
    R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；优选氢、卤素或C 1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycle Group, aryl or heteroaryl; preferably hydrogen, halogen or C 1-6 alkyl;
    R 2选自-(CH 2) nP(＝O)R aaR bb、(CH 2) nP(＝S)R aaR bb或-(CH 2) nS(O) m1R aa； R 2 is selected from -(CH 2 ) n P(=O)R aa R bb , (CH 2 ) n P(=S)R aa R bb or -(CH 2 ) n S(O) m1 R aa ;
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基、C 1-6卤代烷基或-SR aa； R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl or -SR aa ;
    R 4选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、取代或未取代的炔基、环烷基、杂环基、芳基、杂芳基或-SR aa；优选氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, substituted or unsubstituted alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR aa ; preferably hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 5选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、氰基取代的烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR aa、-(CH 2) nNR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) mR bb、-(CH 2) nS(O) mNR aaR bb、-(CH 2) nC(O)R aa、-NR aaC(O)OR bb、-(CH 2) nS(O) mR aa、-(CH 2) nNR aaS(O) mR bb或-(CH 2) nC≡CR aa，优选氢、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、氰基、氰基取代的烷基、烯基、炔基、-NR aaC(O)R bb或-(CH 2) nC≡CR aa，更优选氢、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、卤素、氨基、硝基、氰基、氰基取代的烷基、C 2-4烯基、C 2-4炔基、-NR aaC(O)R bb或-(CH 2) nC≡CR aa，进一步优选氢、甲基、乙基、丙基、甲氧基、乙氧基、乙烯基、乙炔基、氰基、氨基、硝基、氟、氯、溴、卤代甲基、卤 代乙基、-CH 2CN、-NR aaC(O)R bb或-(CH 2) nC≡CR aa； R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, cyano substituted alkyl, alkenyl, alkyne Group, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m R bb , -(CH 2 ) n S(O) m NR aa R bb , -(CH 2 ) n C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa S(O) m R bb or- (CH 2 ) n C≡CR aa , preferably hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, cyano, cyano substituted alkyl, alkenyl, alkynyl, -NR aa C (O)R bb or -(CH 2 ) n C≡CR aa , more preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, amino, nitro, Cyano, cyano-substituted alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -NR aa C(O)R bb or -(CH 2 ) n C≡CR aa , more preferably hydrogen, methyl Group, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyano, amino, nitro, fluorine, chlorine, bromine, halomethyl, haloethyl, -CH 2 CN , -NR aa C(O)R bb or -(CH 2 ) n C≡CR aa ;
    或者，两个相同或者不同的R 5链接形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nR aa、-(CH 2) nNR aaR bb和-(CH 2) nC(O)R aa中的一个或多个取代基所取代；优选C 3-6环烷基、3-6元杂环基；更优选C 4-6环烷基、5-6元杂环基；进一步优选环丁基、环戊基、哌啶基、四氢吡咯基、四氢呋喃基或四氢吡喃基； Alternatively, two identical or different R 5 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further Is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, one of -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa or Multiple substituents are substituted; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group; more preferably C 4-6 cycloalkyl, 5-6 membered heterocyclic group; more preferably cyclobutyl, cyclopentyl , Piperidinyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydropyranyl;
    R 6和R 7各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 6 and R 7 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy Substituted by one or more substituents in the group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，R 6和R 7链接形成一个氧代基、环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 6 and R 7 are linked to form an oxo group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group optionally further Is selected from hydrogen atom, deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
    R 8选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、环烷基、杂环基、芳基或杂芳基；优选氢、C 1-6烷基、C 1-6烷氧基、卤素、羟基、氰基或氧代基； R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo, ring Alkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
    R aa、R bb或R cc各自独立的选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、氧代基、三甲基硅基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基，优选氢、C 1-6烷基、取代或未取代的C 1-6烷氧基、一个或多个卤原子取代的C 1-6烷基、取代或未取代的3-6元杂环基或取代或未取代的C 3-6环烷基，更优选氢、甲基、乙基、环丙基、环丁基、甲氧基、乙氧基、三甲基硅基、氟、氯、溴、
    Figure PCTCN2020097362-appb-100033
    R aa , R bb or R cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl , Alkynyl, oxo, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, substituted with one or more halogen atoms, a C 1-6 alkyl group, a substituted or unsubstituted 3-6 membered heterocyclyl or A substituted or unsubstituted C 3-6 cycloalkyl group, more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine ,
    Figure PCTCN2020097362-appb-100033
    i为0-4的整数；i is an integer from 0-4;
    u为0-4的整数；u is an integer from 0-4;
    q为0-2的整数；q is an integer of 0-2;
    n为0-4的整数；n is an integer from 0-4;
    m为0-2的整数；m is an integer of 0-2;
    m1为0-2的整数；m1 is an integer of 0-2;
    y为0-4的整数；且y is an integer from 0-4; and
    p为0-2的整数。p is an integer of 0-2.
  24. 一种制备根据权利要求22所述的通式(A-1)所示的化合物、其立体异构体或其药学上可接受盐的方法，其特征在于包含如下步骤：A method for preparing the compound represented by the general formula (A-1) according to claim 22, its stereoisomer or its pharmaceutically acceptable salt, characterized by comprising the following steps:
    Figure PCTCN2020097362-appb-100034
    Figure PCTCN2020097362-appb-100034
    通式(A)所示的化合物与通式(A-3)所示的化合物反应，得到通式(A-1)所示的目标化合物；The compound represented by general formula (A) reacts with the compound represented by general formula (A-3) to obtain the target compound represented by general formula (A-1);
    其中：among them:
    X1为卤素、氨基、硼酸或硼酸酯；优选氯或溴；X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
    X2为卤素、氨基、硼酸或硼酸酯；优选氯或溴。X2 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine.
  25. 一种制备根据权利要求23所述的通式(A-2)所示的化合物、其立体异构体或其药学上可接受盐的方法，其特征在于包含如下步骤：A method for preparing the compound represented by the general formula (A-2), its stereoisomer or its pharmaceutically acceptable salt according to claim 23, characterized by comprising the following steps:
    Figure PCTCN2020097362-appb-100035
    Figure PCTCN2020097362-appb-100035
    通式(A-1)所示的化合物与通式(A-4)所示的化合物反应，得到通式(A-2)所示的目标化合物；The compound represented by general formula (A-1) reacts with the compound represented by general formula (A-4) to obtain the target compound represented by general formula (A-2);
    其中：among them:
    X1为卤素、氨基、硼酸或硼酸酯；优选氯或溴；X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;
    X3为卤素、氨基、硼酸或硼酸酯；优选氯、溴或氨基。X3 is halogen, amino, boric acid or boric acid ester; preferably chlorine, bromine or amino.
  26. 一种制备根据权利要求6所述的通式(G-1)所示的化合物、其立体异构体或其药学上可接受盐的方法，其特征在于包含如下步骤：A method for preparing the compound represented by the general formula (G-1), its stereoisomer or its pharmaceutically acceptable salt according to claim 6, characterized by comprising the following steps:
    Figure PCTCN2020097362-appb-100036
    Figure PCTCN2020097362-appb-100036
    通式(A-2)所示的化合物与含环B的化合物反应，得到通式(G-1)所示的目标化合物；The compound represented by general formula (A-2) reacts with the compound containing ring B to obtain the target compound represented by general formula (G-1);
    环B选自环烷基、杂环基、芳基或杂芳基；优选C3-8单环环烷基、桥环烷基、螺环烷基、稠环烷基、3-8元单环杂环基、桥杂环基、螺杂环基、稠杂环基、芳基或3-8元杂芳基；更优选含1-2个N或O原子的5-7元杂环基、桥杂环基、螺杂环基或稠杂环基；进一步优选以下基团：Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably C3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, condensed cycloalkyl, 3-8 membered monocyclic ring Heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably 5-7 membered heterocyclic group containing 1-2 N or O atoms, Bridge heterocyclic group, spiro heterocyclic group or condensed heterocyclic group; the following groups are further preferred:
    Figure PCTCN2020097362-appb-100037
    Figure PCTCN2020097362-appb-100037
  27. 一种药用组合物，其包括治疗有效剂量的权利要求1～20中所述的化合物及其立体异构体或其药学上可接受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。A pharmaceutical composition, which comprises a therapeutically effective dose of the compound described in claims 1-20, and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, Diluent or excipient.
  28. 根据权利要求1～20中任一项所述的化合物、及其立体异构体或其药学上可接受的盐，或权利要求27所述的药物组合物在制备MEK抑制剂、EGFR抑制剂和EGFR单抗及其联用相关药物中的应用。The compound according to any one of claims 1-20, and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 27 when preparing MEK inhibitors, EGFR inhibitors and Application of EGFR monoclonal antibody and related drugs in combination.
  29. 根据权利要求1～20中任一项所述的化合物及其立体异构体或其药学上可接受的盐，或权利要求27所述的药物组合物在制备治癌症相关疾病中的应用；其中所述癌症为肺癌。The use of the compound according to any one of claims 1-20 and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 27 in the preparation and treatment of cancer-related diseases; wherein The cancer is lung cancer.
  30. 根据权利要求1～20中任一项所述的化合物及其立体异构体或其药学上可接受的盐，或权利要求27所述的药物组合物在制备治癌症相关疾病中的应用；其中所述的癌症选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、 脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤或骨髓瘤；优选非小细胞肺癌。The use of the compound according to any one of claims 1-20 and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 27 in the preparation and treatment of cancer-related diseases; wherein The cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma or bone marrow Tumor; preferably non-small cell lung cancer.
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