WO2020253860A1 - Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation 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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English (en)
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/zh
Publication of WO2020253860A1 publication Critical patent/WO2020253860A1/fr

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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:

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Abstract

La présente invention concerne un inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation. En particulier, la présente invention concerne un composé représenté par la formule générale (IA), un procédé de préparation correspondant, et une composition pharmaceutique contenant le composé, ainsi que l'utilisation de celui-ci en tant qu'inhibiteur d'EGFR dans le traitement de maladies associées à une tumeur.
PCT/CN2020/097362 2019-06-21 2020-06-22 Inhibiteur de dérivé d'oxyde de phosphore aryle, son procédé de préparation et son utilisation WO2020253860A1 (fr)

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WO2022127807A1 (fr) * 2020-12-18 2022-06-23 江苏豪森药业集团有限公司 Forme cristalline d'un dérivé d'oxyde de phosphore aryle sous forme de base libre, son procédé de préparation et son utilisation
WO2023011610A1 (fr) * 2021-08-06 2023-02-09 南京红云生物科技有限公司 Composé de benzodioxane, son procédé de préparation et son application
WO2023093859A1 (fr) * 2021-11-26 2023-06-01 南京正大天晴制药有限公司 Sel d'inhibiteur de kinase axl, son procédé de préparation et son utilisation
WO2023093861A1 (fr) * 2021-11-26 2023-06-01 南京正大天晴制药有限公司 Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci
US11878968B2 (en) 2021-07-09 2024-01-23 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate IKZF2

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