WO2020253862A1 - Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof - Google Patents

Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof Download PDF

Info

Publication number
WO2020253862A1
WO2020253862A1 PCT/CN2020/097369 CN2020097369W WO2020253862A1 WO 2020253862 A1 WO2020253862 A1 WO 2020253862A1 CN 2020097369 W CN2020097369 W CN 2020097369W WO 2020253862 A1 WO2020253862 A1 WO 2020253862A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
cycloalkyl
group
amino
Prior art date
Application number
PCT/CN2020/097369
Other languages
French (fr)
Chinese (zh)
Inventor
高鹏
王少宝
孙广俊
修文华
谭松良
蔡家强
包如迪
Original Assignee
上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海翰森生物医药科技有限公司, 江苏豪森药业集团有限公司 filed Critical 上海翰森生物医药科技有限公司
Priority to CN202080004109.6A priority Critical patent/CN112513029B/en
Publication of WO2020253862A1 publication Critical patent/WO2020253862A1/en

Links

Classifications

    • 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 a nitrogen-containing 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 is an integer of 0-2;
  • n is an integer of 0-2.
  • 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 is an integer of 0-2;
  • y is an integer from 0-4;
  • q is an integer of 0-2;
  • n is an integer of 0-2.
  • 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 is an integer of 0-2;
  • y is an integer from 0-4;
  • q is an integer of 0-2;
  • n is an integer of 0-2;
  • n is an integer of 0-2.
  • 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, 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.
  • a preferred embodiment of the present invention is to provide a compound represented by general formula (IC-A) or general formula (IC-B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
  • the presence or absence of M, when present, is selected from O, S, NR aa , CR aa R bb , NR aa (CR bb R cc ) n , O(CR aa R bb ) n or NR aa C(O)(CR bb R cc ) n , preferably O, S, NH, NCH 3 , CH 2 , CH 3 CH, NHC(O)CH 2 , NHC(O)CH 2 CH 2 , NHC(O)CH 2 CH 2 CH 2 , OC (F 2 )CH 2 , NHCH 2 CH 2 or N(CH 3 )CH 2 CH 2 ;
  • M 6 or M 7 is independently selected from N or CR aa when present ;
  • ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl when present, 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 condensed heterocyclic group, more preferably
  • ring C when present, 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 C 3-6 cycloalkyl, containing 1 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group with -2 N or O atoms, more preferably
  • ring B and ring C are linked to form a spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spiroheterocyclic group, fused heterocyclic group or bridged heterocyclic group; preferably containing 1-2 N or O atoms [3-6,3-6] Spiro heterocyclyl, more preferably
  • 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 ,
  • 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, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group, 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, tetrahydrofuranyl or tetrahydropyranyl;
  • ring C 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, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl,
  • the heterocyclic group, aryl group and heteroaryl group are substituted by one or more substituents, preferably C 3-8 cycloalkyl, 3-8 membered heterocyclic group, more preferably C 4-7 cycloalkyl, 5- 7-membered heterocyclic group, more preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohex
  • R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl, oxo Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocycly
  • R 10 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, -(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 , preferably hydrogen, C 1-6 alkyl, 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 ,
  • 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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl,
  • t is selected from an integer of 0-4;
  • z is selected from an integer of 0-4;
  • r is selected from an integer of 0-4.
  • ring B when ring B is present, it is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, Condensed ring alkyl, 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 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group of O atom, more preferably
  • ring C When ring C exists, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused cycloalkyl, 3-8 Member monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, containing 1-2 N or 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group of O atom, more preferably
  • 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
  • ring C 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, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa are substituted by one or more C 3-8 cycloalkyl group, 3-8 membered heterocyclic group are preferred, C 4-7 cycloalkyl group, 5-7
  • R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl, oxo Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n NR aa C(O)R bb , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1- 6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxy, C
  • 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, 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 C 3 -6 cycloalkyl, more preferably hydrogen, methyl, ethyl
  • a more preferred embodiment of the present invention is to provide a compound represented by general formula (ID-A) or general formula (ID-B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
  • M is selected from bond, O, S, NR aa or CR aa R bb;
  • M 8 or M 9 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;
  • 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 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 aa or R bb are independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen, C 1-3 alkyl or C 1-3 alkoxy;
  • p is an integer from 0-4.
  • a further preferred embodiment of the present invention is to provide a compound represented by general formula (IE-A) or general formula (IE-B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
  • 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 (III), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • 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 groups, aryl groups and heteroaryl groups are optionally further selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, Haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl,
  • R 6 and R 7 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, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in 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;
  • 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 , Deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in aryl and heteroaryl;
  • p is an integer from 0-4.
  • the present invention also provides a preferred solution, and the general formula (I) is further represented by the general formula (I-1):
  • 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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, 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 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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, 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
  • R 8 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo Group, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
  • R 9 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl , Oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocycly
  • 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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl,
  • q is an integer of 0-2;
  • y is an integer from 0-4;
  • z is an integer from 0-4;
  • p is an integer of 0-8.
  • the present invention also provides a preferred solution, which is a compound represented by general formula (V), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • M is O, S, NR aa or CR aa R bb .
  • the present invention also provides a preferred solution, which is a compound represented by general formula (III-A), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • Ring B is a heterocyclic 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, -(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 ;
  • z is an integer from 0-4.
  • 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, -(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 or -(CH 2 ) n NR aa C(O)R bb .
  • the present invention also provides a preferred solution, which is a compound represented by general formula (III-B), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (III-C1) or general formula (III-C2), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • M 10 is selected from N or CR aa , preferably N or CH;
  • R 11 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl; 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.
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (IF-1), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • P and Q are different, and each is independently selected from C or N;
  • 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:
  • Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
  • R is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, 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 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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, 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
  • R 8 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo Group, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
  • R 9 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl , Oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocycly
  • 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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl,
  • q is an integer of 0-4;
  • y is an integer from 0-4;
  • z is an integer from 0-4;
  • p is an integer of 0-8.
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (IF), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • P and Q are different, and each is independently selected from C or N;
  • Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (VI), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (I-1a), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
  • the present invention also provides another preferred embodiment, which is a compound represented by general formula (VIII-A), its stereoisomers or pharmaceutically acceptable salts thereof, 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 is an integer from 0-4.
  • the present invention also provides a preferred solution.
  • Ring A is selected from the following groups:
  • Ring B is selected from the following groups:
  • Ring C is selected from the following groups:
  • 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.
  • 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 relates to a compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof:
  • P and Q are different, and each is independently selected from C or N;
  • Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
  • 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;
  • n is an integer from 0-4;
  • n1 is an integer of 0-2;
  • q is an integer of 0-2.
  • 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;
  • P and Q are different, and each is independently selected from C or N;
  • Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
  • 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;
  • n is an integer from 0-4;
  • n1 is an integer of 0-2;
  • q is an integer of 0-2.
  • the present invention also relates to a method for preparing a compound represented by the general formula (A-1), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
  • the compound represented by general formula (A) reacts with the compound represented by general formula (A-2) 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 a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
  • the compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-3) to obtain the target compound represented by the general formula (III);
  • R 3 is bromine
  • R 4 is hydrogen
  • 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 a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
  • the compound represented by the general formula (III) reacts with the compound containing ring B to obtain the target compound represented by the general formula (I-1);
  • R 3 is bromine
  • R 4 is hydrogen
  • Ring B is selected from cycloalkyl, heterocyclic, 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 fused heterocyclic group; further preferred are the following groups:
  • the present invention also relates to a method for preparing a compound represented by the general formula (IF-1), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
  • the compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-4) to obtain the target compound represented by the general formula (IF-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 treating 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, 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, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , 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 with 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.
  • 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 may 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
  • DIPEA diisopropylethylamine
  • 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 2 Preparation of (6-aminoquinoxalin-5-yl) dimethyl phosphine oxidation
  • the third step Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
  • the seventh step (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5- ((Trimethylsilyl)ethynyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
  • the eighth step (6-((5-bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
  • reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((5-bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (21 mg, yield: 50%).
  • the eighth step (6-((5-bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3 -Dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
  • the first step (6-aminoquinoxalin-5-yl) dimethyl phosphine vulcanization preparation
  • the second step (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation
  • Step 1 Preparation of 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane
  • the third 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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
  • the fourth step 1-(4-((5-bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl (Oxy-2-methylphenyl) piperidin-4-one
  • the fifth step ((6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-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
  • the sixth step (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl -2-Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
  • Step 1 Preparation of (6-((6-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
  • the third step Preparation of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline
  • the fourth step (6-((6-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation

Abstract

Disclosed are a nitrogen-containing aryl phosphorus oxide derivative inhibitor, a preparation method therefor, and the use thereof. 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 thereof as an EGFR inhibitor in the treatment of cancer-related diseases.

Description

含氮芳基磷氧化物类衍生物、其制备方法和应用Nitrogen-containing aryl phosphorus oxide derivatives, preparation method and application thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及一种含氮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 a nitrogen-containing 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 PCTCN2020097369-appb-000001
Figure PCTCN2020097369-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0-2的整数；且m is an integer of 0-2; and
n为0-2的整数。n is an integer of 0-2.
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 PCTCN2020097369-appb-000002
Figure PCTCN2020097369-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 PCTCN2020097369-appb-000003
Figure PCTCN2020097369-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 PCTCN2020097369-appb-000003
Figure PCTCN2020097369-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 PCTCN2020097369-appb-000005
Figure PCTCN2020097369-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 PCTCN2020097369-appb-000005
Figure PCTCN2020097369-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 PCTCN2020097369-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 PCTCN2020097369-appb-000007
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.
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 PCTCN2020097369-appb-000008
Figure PCTCN2020097369-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0-2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.
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，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.
本发明优选的实施方案为提供一种通式(IC-A)或通式(IC-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：A preferred embodiment of the present invention is to provide a compound represented by general formula (IC-A) or general formula (IC-B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
Figure PCTCN2020097369-appb-000009
Figure PCTCN2020097369-appb-000009
M存在或不存在，存在时选自O、S、NR aa、CR aaR bb、NR aa(CR bbR cc) n、O(CR aaR bb) n或NR aaC(O)(CR bbR cc) n，优选O、S、NH、NCH 3、CH 2、CH 3CH、NHC(O)CH 2、NHC(O)CH 2CH 2、NHC(O)CH 2CH 2CH 2、OC(F 2)CH 2、NHCH 2CH 2或N(CH 3)CH 2CH 2； The presence or absence of M, when present, is selected from O, S, NR aa , CR aa R bb , NR aa (CR bb R cc ) n , O(CR aa R bb ) n or NR aa C(O)(CR bb R cc ) n , preferably O, S, NH, NCH 3 , CH 2 , CH 3 CH, NHC(O)CH 2 , NHC(O)CH 2 CH 2 , NHC(O)CH 2 CH 2 CH 2 , OC (F 2 )CH 2 , NHCH 2 CH 2 or N(CH 3 )CH 2 CH 2 ;
M 6或M 7存在或不存在，存在时各自独立的选自N或CR aa； The presence or absence of M 6 or M 7 is independently selected from N or CR aa when present ;
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
Figure PCTCN2020097369-appb-000010
Figure PCTCN2020097369-appb-000011
The presence or absence of ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl when present, 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 condensed heterocyclic group, more preferably
Figure PCTCN2020097369-appb-000010
Figure PCTCN2020097369-appb-000011
环C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C 3-6环烷基、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
Figure PCTCN2020097369-appb-000012
Figure PCTCN2020097369-appb-000013
The presence or absence of ring C, when present, 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 C 3-6 cycloalkyl, containing 1 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group with -2 N or O atoms, more preferably
Figure PCTCN2020097369-appb-000012
Figure PCTCN2020097369-appb-000013
或者，环B与环C链接形成螺环烷基、稠环烷基、桥环烷基、螺杂环基、稠杂环基或桥杂环基；优选含有1-2个N或O原子的[3-6,3-6]螺杂环基，更优选
Figure PCTCN2020097369-appb-000014
Alternatively, ring B and ring C are linked to form a spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spiroheterocyclic group, fused heterocyclic group or bridged heterocyclic group; preferably containing 1-2 N or O atoms [3-6,3-6] Spiro heterocyclyl, more preferably
Figure PCTCN2020097369-appb-000014
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，优选氢、烷基、烷氧基、卤代烷基、-NR aaC(O)R bb，更优选氢、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、-NR aaC(O)R bb，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、氟、氯、溴、卤代甲基或卤代乙基、-NR aaC(O)R 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 , preferably hydrogen, alkyl, alkoxy Group, haloalkyl group, -NR aa C(O)R bb , more preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -NR aa C(O)R bb , More preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyano, fluorine, chlorine, bromine, halomethyl or haloethyl, -NR aa C(O)R bb ;
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、芳基和杂芳基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、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 Selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group, 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, tetrahydrofuranyl or tetrahydropyranyl;
或者，环C与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，优选C 3-8环烷基、3-8元杂环基，更优选C 4-7环烷基、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； Alternatively, ring C 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, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, The heterocyclic group, aryl group and heteroaryl group are substituted by one or more substituents, preferably C 3-8 cycloalkyl, 3-8 membered heterocyclic group, more preferably C 4-7 cycloalkyl, 5- 7-membered heterocyclic group, more preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
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、腈基、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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaR bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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)C 3-6环烷基或-(CH 2) nN(C 1-3烷基) 2，更优选氢、甲基、乙基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、环丙基、甲酰基、
Figure PCTCN2020097369-appb-000015
Figure PCTCN2020097369-appb-000016
R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl, oxo Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, C 1-3 haloalkyl, C 1-3 alkane Oxy, halogenated 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)C 3-6 cycloalkyl or -(CH 2 ) n N(C 1- 3 alkyl) 2 , more preferably hydrogen, methyl, ethyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, cyclopropyl, formyl,
Figure PCTCN2020097369-appb-000015
Figure PCTCN2020097369-appb-000016
R 10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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、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、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或-(CH 2) nNR aaR bb，进一步优选氢、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、卤素、羟基、C 1-3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或-(CH 2) nNR aaR bb； R 10 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, -(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 , preferably hydrogen, C 1-6 alkyl, 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 or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, hydroxyl, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb ;
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、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、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、氟、氯、溴、
Figure PCTCN2020097369-appb-000017
Figure PCTCN2020097369-appb-000018
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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, fluorine, chlorine, bromine,
Figure PCTCN2020097369-appb-000017
Figure PCTCN2020097369-appb-000018
t选自0-4的整数；t is selected from an integer of 0-4;
z选自0-4的整数；z is selected from an integer of 0-4;
r选自0-4的整数。r is selected from an integer of 0-4.
本发明的进一步优选方案中，环B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
Figure PCTCN2020097369-appb-000019
Figure PCTCN2020097369-appb-000020
In a further preferred embodiment of the present invention, when ring B is present, it is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, Condensed ring alkyl, 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 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group of O atom, more preferably
Figure PCTCN2020097369-appb-000019
Figure PCTCN2020097369-appb-000020
环C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C 3-6环烷基、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
Figure PCTCN2020097369-appb-000021
Figure PCTCN2020097369-appb-000022
When ring C exists, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused cycloalkyl, 3-8 Member monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, containing 1-2 N or 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group of O atom, more preferably
Figure PCTCN2020097369-appb-000021
Figure PCTCN2020097369-appb-000022
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, further preferably cyclobutyl, cyclopentyl Group, piperidinyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydropyranyl;
或者，环C与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 3-8环烷基、3-8元杂环基，更优选C 4-7环烷基、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； Alternatively, ring C 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, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa are substituted by one or more C 3-8 cycloalkyl group, 3-8 membered heterocyclic group are preferred, C 4-7 cycloalkyl group, 5-7 membered heterocyclic group are more preferred, and piperidinyl, tetrahydropyrrolyl, Cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
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、腈基、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) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb或-(CH 2) nNR aaC(O)R bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaC(O)R bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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(O)C 1-3烷基、-(CH 2) nNHC(O)C 1-3烷基，更优选氢、甲基、乙基、羧基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、CH 3CH 2HN-、CH 3(O)C(CH 3)N-、CH 3(O)CHN-、(CH 3CH 2)(CH 3)N-、CH 3(O)C-、CH 3O(O)C-、环丙基、甲酰基、
Figure PCTCN2020097369-appb-000023
R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl, oxo Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n NR aa C(O)R bb , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1- 6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxy, 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 or -(CH 2 ) n NR aa C(O)R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, 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(O)C 1-3 alkyl, -(CH 2 ) n NHC(O)C 1-3 alkyl, more Preferably hydrogen, methyl, ethyl, carboxyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, CH 3 CH 2 HN-, CH 3 (O)C(CH 3 )N-, CH 3 (O)CHN-, ( CH 3 CH 2 )(CH 3 )N-, CH 3 (O)C-, CH 3 O(O)C-, cyclopropyl, formyl,
Figure PCTCN2020097369-appb-000023
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、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 PCTCN2020097369-appb-000024
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, 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 C 3 -6 cycloalkyl, more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,
Figure PCTCN2020097369-appb-000024
本发明更优选的实施方案为提供一种通式(ID-A)或通式(ID-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：A more preferred embodiment of the present invention is to provide a compound represented by general formula (ID-A) or general formula (ID-B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
Figure PCTCN2020097369-appb-000025
Figure PCTCN2020097369-appb-000025
其中：among them:
M选自键、O、S、NR aa或CR aaR bb； M is selected from bond, O, S, NR aa or CR aa R bb;
M 8或M 9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 8 or M 9 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;
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;
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 aa或R bb独立地选自氢、C 1-6烷基或C 1-6烷氧基，优选氢、C 1-3烷基或C 1-3烷氧基； R aa or R bb are independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen, C 1-3 alkyl or C 1-3 alkoxy;
p为0-4的整数。p is an integer from 0-4.
本发明进一步优选的实施方案在于提供一种通式(IE-A)或通式(IE-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：A further preferred embodiment of the present invention is to provide a compound represented by general formula (IE-A) or general formula (IE-B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:
Figure PCTCN2020097369-appb-000026
Figure PCTCN2020097369-appb-000026
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 PCTCN2020097369-appb-000027
Figure PCTCN2020097369-appb-000027
本发明还提供了一种优选方案，其为通式(III)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 (III), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000028
Figure PCTCN2020097369-appb-000028
其中：among them:
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、-(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和-(CH 2) nNR aaS(O) mR bb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 groups, aryl groups and heteroaryl groups are optionally further selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, Haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and 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 and -(CH 2 ) n NR aa S(O ) substituted by one or more substituents in m R bb ;
或者，R 6和R 7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 6 and R 7 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, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in 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； 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;
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、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 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 , Deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in aryl and heteroaryl;
p为0-4的整数。p is an integer from 0-4.
本发明还提供了一种优选方案，通式(I)进一步为通式(I-1)所示：The present invention also provides a preferred solution, and the general formula (I) is further represented by the general formula (I-1):
Figure PCTCN2020097369-appb-000029
Figure PCTCN2020097369-appb-000029
其中：among them:
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 PCTCN2020097369-appb-000030
Figure PCTCN2020097369-appb-000030
R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，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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, 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 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、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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, 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 ;
R 8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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo Group, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
R 9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、腈基、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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaR bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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)C 3-6环烷基或-(CH 2) nN(C 1-3烷基) 2，更优选氢、甲基、乙基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、环丙基、甲酰基、
Figure PCTCN2020097369-appb-000031
R 9 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl , Oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, C 1-3 haloalkyl, C 1 -3 alkoxy, halogenated 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)C 3-6 cycloalkyl or -(CH 2 ) n N( C 1-3 alkyl) 2 , more preferably hydrogen, methyl, ethyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, cyclopropyl, formyl,
Figure PCTCN2020097369-appb-000031
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、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、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、氟、氯、溴、
Figure PCTCN2020097369-appb-000032
Figure PCTCN2020097369-appb-000033
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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, fluorine, chlorine, bromine,
Figure PCTCN2020097369-appb-000032
Figure PCTCN2020097369-appb-000033
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；且z is an integer from 0-4; and
p为0-8的整数。p is an integer of 0-8.
本发明还提供了一种优选方案，其为通式(V)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 (V), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000034
Figure PCTCN2020097369-appb-000034
其中：among them:
M为O、S、NR aa或CR aaR bb。 M is O, S, NR aa or CR aa R bb .
本发明还提供了一种优选方案，其为通式(III-A)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 (III-A), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000035
Figure PCTCN2020097369-appb-000035
其中：among them:
环B为杂环基；Ring B is a heterocyclic 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、-(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, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 ;
z为0-4的整数。z is an integer from 0-4.
本发明的进一步优选方案中，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或-(CH 2) nNR aaC(O)R bb。 In a further preferred embodiment of the present invention, 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, -(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 or -(CH 2 ) n NR aa C(O)R bb .
本发明还提供了一种优选方案，其为通式(III-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 a preferred solution, which is a compound represented by general formula (III-B), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000036
Figure PCTCN2020097369-appb-000036
本发明还提供另一优选的实施方案，其为通式(III-C1)或通式(III-C2)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 (III-C1) or general formula (III-C2), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000037
Figure PCTCN2020097369-appb-000037
M 10选自N或CR aa，优选N或CH； M 10 is selected from N or CR aa , preferably N or CH;
R 11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 11 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl; 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.
本发明还提供另一优选的实施方案，其为通式(IF-1)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 (IF-1), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000038
Figure PCTCN2020097369-appb-000038
其中：among them:
P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
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 PCTCN2020097369-appb-000039
Figure PCTCN2020097369-appb-000039
环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
Figure PCTCN2020097369-appb-000040
Figure PCTCN2020097369-appb-000041
Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
Figure PCTCN2020097369-appb-000040
Figure PCTCN2020097369-appb-000041
R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，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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, 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 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、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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, 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 ;
R 8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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo Group, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
R 9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、腈基、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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaR bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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)C 3-6环烷基或-(CH 2) nN(C 1-3烷基) 2，更优选氢、甲基、乙基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、环丙基、甲酰基、
Figure PCTCN2020097369-appb-000042
R 9 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl , Oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, C 1-3 haloalkyl, C 1 -3 alkoxy, halogenated 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)C 3-6 cycloalkyl or -(CH 2 ) n N( C 1-3 alkyl) 2 , more preferably hydrogen, methyl, ethyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, cyclopropyl, formyl,
Figure PCTCN2020097369-appb-000042
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、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、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、氟、氯、溴、
Figure PCTCN2020097369-appb-000043
Figure PCTCN2020097369-appb-000044
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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, fluorine, chlorine, bromine,
Figure PCTCN2020097369-appb-000043
Figure PCTCN2020097369-appb-000044
q为0-4的整数；q is an integer of 0-4;
y为0-4的整数；y is an integer from 0-4;
z为0-4的整数；且z is an integer from 0-4; and
p为0-8的整数。p is an integer of 0-8.
本发明还提供另一优选的实施方案，其为通式(IF)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 (IF), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000045
Figure PCTCN2020097369-appb-000045
其中：among them:
P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
Figure PCTCN2020097369-appb-000046
Figure PCTCN2020097369-appb-000047
Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
Figure PCTCN2020097369-appb-000046
Figure PCTCN2020097369-appb-000047
本发明还提供另一优选的实施方案，其为通式(VI)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 (VI), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000048
Figure PCTCN2020097369-appb-000048
本发明还提供另一优选的实施方案，其为通式(I-1a)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 (I-1a), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000049
Figure PCTCN2020097369-appb-000049
本发明还提供另一优选的实施方案，其为通式(VIII-A)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 (VIII-A), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:
Figure PCTCN2020097369-appb-000050
Figure PCTCN2020097369-appb-000050
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.
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：The present invention also provides a preferred solution. The compounds represented by the general formulae, their stereoisomers or their pharmaceutically acceptable salts, wherein:
环A选自如下基团：Ring A is selected from the following groups:
Figure PCTCN2020097369-appb-000051
Figure PCTCN2020097369-appb-000051
环B选自如下基团：Ring B is selected from the following groups:
Figure PCTCN2020097369-appb-000052
Figure PCTCN2020097369-appb-000052
环C选自如下基团：Ring C is selected from the following groups:
Figure PCTCN2020097369-appb-000053
Figure PCTCN2020097369-appb-000053
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 PCTCN2020097369-appb-000054
Figure PCTCN2020097369-appb-000054
其中：among them:
P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
Figure PCTCN2020097369-appb-000055
Figure PCTCN2020097369-appb-000056
Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
Figure PCTCN2020097369-appb-000055
Figure PCTCN2020097369-appb-000056
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 ;
n为0-4的整数；n is an integer from 0-4;
m1为0-2的整数；且m1 is an integer of 0-2; and
q为0-2的整数。q is an integer of 0-2.
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 PCTCN2020097369-appb-000057
Figure PCTCN2020097369-appb-000057
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;
P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
Figure PCTCN2020097369-appb-000058
Figure PCTCN2020097369-appb-000059
Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
Figure PCTCN2020097369-appb-000058
Figure PCTCN2020097369-appb-000059
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;
n为0-4的整数；n is an integer from 0-4;
m1为0-2的整数；且m1 is an integer of 0-2; and
q为0-2的整数。q is an integer of 0-2.
本发明还涉及一种制备通式(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 a compound represented by the general formula (A-1), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
Figure PCTCN2020097369-appb-000060
Figure PCTCN2020097369-appb-000060
通式(A)所示的化合物与通式(A-2)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-2) 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通式(III)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 a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
Figure PCTCN2020097369-appb-000061
Figure PCTCN2020097369-appb-000061
通式(A-1)所示的化合物与通式(A-3)所示的化合物反应，得到通式(III)所示的目标化合物；The compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-3) to obtain the target compound represented by the general formula (III);
其中：among them:
R 3为溴； R 3 is bromine;
R 4为氢； R 4 is hydrogen;
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通式(III)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 a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
Figure PCTCN2020097369-appb-000062
Figure PCTCN2020097369-appb-000062
通式(III)所示的化合物与含环B的化合物反应，得到通式(I-1)所示的目标化合物；The compound represented by the general formula (III) reacts with the compound containing ring B to obtain the target compound represented by the general formula (I-1);
其中：among them:
R 3为溴； R 3 is bromine;
R 4为氢； R 4 is hydrogen;
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, heterocyclic, 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 fused heterocyclic group; further preferred are the following groups:
Figure PCTCN2020097369-appb-000063
Figure PCTCN2020097369-appb-000063
本发明还涉及一种制备通式(IF-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 a compound represented by the general formula (IF-1), its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
Figure PCTCN2020097369-appb-000064
Figure PCTCN2020097369-appb-000064
通式(A-1)所示的化合物与通式(A-4)所示的的化合物反应，得到通式(IF-1)所示的目标化合物；The compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-4) to obtain the target compound represented by the general formula (IF-1);
其中：among them:
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 PCTCN2020097369-appb-000065
Figure PCTCN2020097369-appb-000065
Figure PCTCN2020097369-appb-000066
Figure PCTCN2020097369-appb-000066
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 treating 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、宫颈癌、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, 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, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , 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电子系统。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 shared spiro atoms 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 PCTCN2020097369-appb-000067
Figure PCTCN2020097369-appb-000067
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 PCTCN2020097369-appb-000068
Figure PCTCN2020097369-appb-000068
术语“稠环烷基”指5至20元，系统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电子系统。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 PCTCN2020097369-appb-000069
Figure PCTCN2020097369-appb-000069
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电子系统。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 PCTCN2020097369-appb-000070
Figure PCTCN2020097369-appb-000070
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；最优选包含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，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、含氮螺杂环基或含氮稠杂环基。 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; most preferably contains 3 to 8 ring atoms; further preferably contains 1-3 nitrogen atoms, 3-8 The membered heterocyclic group is optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.
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电子系统。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 PCTCN2020097369-appb-000071
Figure PCTCN2020097369-appb-000071
术语“稠杂环基”指5至20元，系统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电子系统，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 PCTCN2020097369-appb-000072
Figure PCTCN2020097369-appb-000072
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电子系统，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 PCTCN2020097369-appb-000073
Figure PCTCN2020097369-appb-000073
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 PCTCN2020097369-appb-000074
等。
Figure PCTCN2020097369-appb-000074
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 may 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 PCTCN2020097369-appb-000075
Figure PCTCN2020097369-appb-000075
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、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为三唑基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有选三唑基、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 PCTCN2020097369-appb-000076
Figure PCTCN2020097369-appb-000076
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.
“DIPEA”指二异丙基乙胺。"DIPEA" refers to diisopropylethylamine.
“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”指乙醚。 "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 occasions 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 1200Infinity 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.
实施例1Example 1
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000077
Figure PCTCN2020097369-appb-000077
第一步：5-碘喹喔啉-6-胺的制备Step 1: Preparation of 5-iodoquinoxaline-6-amine
Figure PCTCN2020097369-appb-000078
Figure PCTCN2020097369-appb-000078
往喹喔啉-6-胺(2.9g,20mmol)的乙酸溶液(20mL)中滴加I 2(5g,20mmol)的乙酸溶液(15mL)，室温下反应1h，减压浓缩有机溶剂，残留物用乙酸乙酯和石油醚打浆，过滤出的固体干燥后得到标题化合物5-碘喹喔啉-6-胺(4.9g，收率:91％)。 Add I 2 (5g, 20mmol) in acetic acid solution (15mL) dropwise to quinoxaline-6-amine (2.9g, 20mmol) in acetic acid solution (20mL), react at room temperature for 1 hour, concentrate the organic solvent under reduced pressure, and leave the residue It was slurried with ethyl acetate and petroleum ether, and the filtered solid was dried to obtain the title compound 5-iodoquinoxaline-6-amine (4.9 g, yield: 91%).
MS m/z(ESI):272.2[M+H] +. MS m/z(ESI): 272.2[M+H] + .
第二步：(6-氨基喹喔啉-5-基)二甲基膦氧化的制备Step 2: Preparation of (6-aminoquinoxalin-5-yl) dimethyl phosphine oxidation
Figure PCTCN2020097369-appb-000079
Figure PCTCN2020097369-appb-000079
5-碘喹喔啉-6-胺(2.71g,10mmol)，二甲基氧化磷(1.17g,15mmol)，磷酸钾(4.24g,20mmol)混合于N,N-二甲基甲酰胺(20mL)中，加入醋酸钯(224mg,1mmol)和Xantphos(578mg,1.0mmol)，N 2保护下110℃反应过夜。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-氨基喹喔啉-5-基)二甲基膦氧化(1.81g,收率:81％)。 5-Iodoquinoxaline-6-amine (2.71g, 10mmol), dimethyl phosphorus oxide (1.17g, 15mmol), potassium phosphate (4.24g, 20mmol) mixed in N, N-dimethylformamide (20mL ), add palladium acetate (224 mg, 1 mmol) and Xantphos (578 mg, 1.0 mmol), and react overnight at 110°C under N 2 protection. After cooling to room temperature, the organic solvent was concentrated under reduced pressure and the column chromatography was separated to obtain the title compound (6-aminoquinoxalin-5-yl) dimethylphosphine oxide (1.81 g, yield: 81%).
MS m/z(ESI):222.2[M+H] +. MS m/z(ESI): 222.2[M+H] + .
第三步：(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备The third step: Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000080
Figure PCTCN2020097369-appb-000080
往(6-氨基喹喔啉-5-基)二甲基膦氧化(884mg,4mmol)和5-溴-2,4-二氯嘧啶(957.0mg,4.2mmol)的DMF溶液(10mL)中加入DIPEA(1.0g,8mmol)，70℃搅拌过夜。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)喹喔啉-5-基)二甲基膦氧化(1.1g,收率:67％)。To (6-aminoquinoxalin-5-yl) dimethylphosphine oxide (884mg, 4mmol) and 5-bromo-2,4-dichloropyrimidine (957.0mg, 4.2mmol) in DMF solution (10mL) DIPEA (1.0 g, 8 mmol) was stirred at 70°C overnight. After cooling 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)quinoxalin-5-yl)dimethylphosphine oxide (1.1g, yield: 67%).
MS m/z(ESI):412.1[M+H] +. MS m/z(ESI): 412.1[M+H] + .
第四步：1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪的制备Step 4: Preparation of 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine
Figure PCTCN2020097369-appb-000081
Figure PCTCN2020097369-appb-000081
往1-溴-2-氟-4-甲氧基-5-硝基苯(2.5g,10mmol)和1-甲基-4-(哌啶-4-基)哌嗪(2.0g,11mmol)的DMF溶液(15mL)中加入K 2CO 3(2.8g,20.0mmol)，70℃搅拌过夜。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1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(3.3g,收率:80％)。 To 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (2.5g, 10mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (2.0g, 11mmol) K 2 CO 3 (2.8 g, 20.0 mmol) was added to the DMF solution (15 mL), and the mixture was stirred at 70°C overnight. After cooling to room temperature, 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-nitrophenyl)piperidin-4-yl)-4- Methylpiperazine (3.3g, yield: 80%).
MS m/z(ESI):413.2[M+H] +. MS m/z(ESI): 413.2[M+H] + .
第五步：1-(1-(5-甲氧基-4-硝基-2-((三甲基甲硅烷基)乙炔基)苯基)哌啶-4-基)-4-甲基哌嗪的制备The fifth step: 1-(1-(5-methoxy-4-nitro-2-((trimethylsilyl)ethynyl)phenyl)piperidin-4-yl)-4-methyl Preparation of piperazine
Figure PCTCN2020097369-appb-000082
Figure PCTCN2020097369-appb-000082
往1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(1.24g,3mmol)和三甲基乙炔基硅(589mg,6mmol)的甲苯溶液(30mL)中，加入双三苯基磷二氯化钯(211mg,0.3mmol)，碘化亚铜(57mg,0.3mmol)和DBU(1.37g,9mmol)，加热至110℃反应过夜。冷却至室温，反应液减压浓缩后柱层析分离得到标题化合物1-(1-(5-甲氧基-4-硝基-2-((三甲基甲硅烷基)乙炔基)苯基)哌啶-4-基)-4-甲基哌嗪(929mg,收率:72％)。To 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1.24g, 3mmol) and trimethylethynyl To the toluene solution (30mL) of silicon (589mg, 6mmol), add bistriphenylphosphorus palladium dichloride (211mg, 0.3mmol), cuprous iodide (57mg, 0.3mmol) and DBU (1.37g, 9mmol), Heat to 110°C and react overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 1-(1-(5-methoxy-4-nitro-2-((trimethylsilyl)ethynyl)phenyl ) Piperidin-4-yl)-4-methylpiperazine (929 mg, yield: 72%).
MS m/z(ESI):431.2[M+H] +。 MS m/z (ESI): 431.2 [M+H] + .
第六步：2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯胺的制备The sixth step: 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((trimethylsilyl)ethynyl)aniline Preparation
Figure PCTCN2020097369-appb-000083
Figure PCTCN2020097369-appb-000083
1-(1-(5-甲氧基-4-硝基-2-((三甲基甲硅烷基)乙炔基)苯基)哌啶-4-基)-4-甲基哌嗪(860mg,2.0mmol)溶于乙醇(9mL)和水(3mL)，加入还原铁粉(672mg，12mmol)和氯化铵(1.07g,20mmol)，回流反应2h。反应液过滤，滤液减压浓缩后得到标题化合物2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯胺(640mg,收率:80％)。1-(1-(5-Methoxy-4-nitro-2-((trimethylsilyl)ethynyl)phenyl)piperidin-4-yl)-4-methylpiperazine (860mg , 2.0mmol) was dissolved in ethanol (9mL) and water (3mL), reduced iron powder (672mg, 12mmol) and ammonium chloride (1.07g, 20mmol) were added, and the reaction was refluxed for 2h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((trimethyl (Silyl)ethynyl)aniline (640mg, yield: 80%).
MS m/z(ESI):401.2[M+H] +. MS m/z(ESI): 401.2[M+H] + .
第七步：(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备The seventh step: (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5- ((Trimethylsilyl)ethynyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000084
Figure PCTCN2020097369-appb-000084
往2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯胺(40mg,0.1mmol)和(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(41mg,0.1mmol)的叔丁醇(2mL)混合溶液中，加入甲磺酸(48mg,0.5mmol)，90℃反应过夜。冷却至室温，反应液减压浓缩后柱层析分离得到标题化合物(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(47mg,收率:60％)。To 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((trimethylsilyl)ethynyl)aniline (40mg, 0.1mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (41mg, 0.1mmol) tert-butanol (2mL) To the mixed solution, methanesulfonic acid (48mg, 0.5mmol) was added and reacted at 90°C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazine-1) -Yl)piperidin-1-yl)-5-((trimethylsilyl)ethynyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine Oxidation (47mg, yield: 60%).
MS m/z(ESI):776.2[M+H] +. MS m/z(ESI): 776.2[M+H] + .
第八步：(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)喹喔啉-5-基)二甲基膦氧化的制备The eighth step: (6-((5-bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000085
Figure PCTCN2020097369-appb-000085
往(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(46.6mg,0.06mmol)的THF(1mL)混合溶液中，加入四丁基氟化胺的THF溶液(1.0M,0.3mL,0.3mmol)，室温反应1h。反应液减压浓缩后柱层析分离得到标题化合物(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)喹喔啉-5-基)二甲基膦氧化(21mg,收率:50％)。To (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((三(Methylsilyl)ethynyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (46.6mg, 0.06mmol) in a mixed solution of THF (1mL) THF solution (1.0M, 0.3mL, 0.3mmol) of tetrabutylamine fluoride was added and reacted at room temperature for 1h. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((5-bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (21 mg, yield: 50%).
MS m/z(ESI):704.2[M+H] +. MS m/z(ESI): 704.2[M+H] + .
实施例2Example 2
(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-乙烯基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-vinylphenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000086
Figure PCTCN2020097369-appb-000086
(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-乙烯基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-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-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-vinylphenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1.
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例3Example 3
5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯甲腈的制备5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4 -(4-Methylpiperazin-1-yl)piperidin-1-yl) benzonitrile preparation
Figure PCTCN2020097369-appb-000087
Figure PCTCN2020097369-appb-000087
5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯甲腈的制备方法参照实施例1。5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4 The preparation method of -(4-methylpiperazin-1-yl)piperidin-1-yl)benzonitrile refers to Example 1.
1H NMR(400MHz,CD 3OD)δ1.75-1.85(m,2H),2.00-2.05(m,2H),2.13(s,3H),2.17(s,3H),2.72(s,3H),2.83-3.14(m,11H),3.55-3.65(m,2H),3.96(s,3H),6.73(s,1H),8.12-8.19(m,2H),8.28(s,1H),8.79-8.87(m,3H)； 1 H NMR(400MHz, CD 3 OD)δ1.75-1.85(m,2H), 2.00-2.05(m,2H), 2.13(s,3H), 2.17(s,3H), 2.72(s,3H) ,2.83-3.14(m,11H),3.55-3.65(m,2H),3.96(s,3H),6.73(s,1H),8.12-8.19(m,2H),8.28(s,1H),8.79 -8.87(m,3H);
MS m/z(ESI):705.2[M+H] +. MS m/z(ESI):705.2[M+H] + .
实施例4Example 4
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000088
Figure PCTCN2020097369-appb-000088
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(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) quinoxalin-5-yl) dimethyl phosphine oxidation preparation method refer to Example 1.
1H NMR(400MHz,CD 3OD)δ1.06(t,J＝7.4Hz,3H),1.72-1.82(m,2H),2.03-2.07(m,1H),2.09(s,3H),2.13(s,3H),2.48(s,3H),2.54-2.62(m,1H),2.63-2.71(m,2H),2.73-2.97(m,9H),3.15-3.23(m,2H),3.79(s,3H),4.55-4.65(m,2H),6.68(s,1H),7.72-7.78(m,1H),8.16(s,1H),8.73-8.77(m,1H),8.78-8.86(m,2H)； 1 H NMR(400MHz,CD 3 OD)δ1.06(t,J=7.4Hz,3H),1.72-1.82(m,2H),2.03-2.07(m,1H),2.09(s,3H),2.13 (s,3H),2.48(s,3H),2.54-2.62(m,1H),2.63-2.71(m,2H),2.73-2.97(m,9H),3.15-3.23(m,2H),3.79 (s,3H),4.55-4.65(m,2H),6.68(s,1H),7.72-7.78(m,1H),8.16(s,1H),8.73-8.77(m,1H),8.78-8.86 (m,2H);
MS m/z(ESI):726.2[M+H] +. MS m/z(ESI): 726.2[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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000089
Figure PCTCN2020097369-appb-000089
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(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) quinoxalin-5-yl) dimethyl phosphine oxidation preparation method refer to Example 1.
1H NMR(400MHz,CDCl 3)δ0.91(t,J＝7.5,3H),1.67-1.78(m,2H),1.95-2.02(m,2H),2.12(s,3H),2.16(s,3H),2.45-2.52(m,3H),2.60(s,3H),2.72-2.81(m,2H),2.97-3.03(m,2H),3.05-3.13(s,5H),3.15-3.23(m,3H),3.93(s,3H),7.49(s,1H),7.82(s,1H),8.13(d,J＝9.5,1H),8.27-8.31(m,2H),8.73-8.81(m,2H),8.90-8.95(m,1H)； 1 H NMR(400MHz,CDCl 3 )δ0.91(t,J=7.5,3H),1.67-1.78(m,2H),1.95-2.02(m,2H),2.12(s,3H),2.16(s ,3H),2.45-2.52(m,3H),2.60(s,3H),2.72-2.81(m,2H),2.97-3.03(m,2H),3.05-3.13(s,5H),3.15-3.23 (m,3H),3.93(s,3H),7.49(s,1H),7.82(s,1H),8.13(d,J=9.5,1H),8.27-8.31(m,2H),8.73-8.81 (m,2H),8.90-8.95(m,1H);
MS m/z(ESI):726.2[M+H] +. MS m/z(ESI): 726.2[M+H] + .
实施例6Example 6
(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)喹喔啉-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 oxafuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine
Figure PCTCN2020097369-appb-000090
Figure PCTCN2020097369-appb-000090
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 PCTCN2020097369-appb-000091
Figure PCTCN2020097369-appb-000091
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 PCTCN2020097369-appb-000092
Figure PCTCN2020097369-appb-000092
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 PCTCN2020097369-appb-000093
Figure PCTCN2020097369-appb-000093
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 PCTCN2020097369-appb-000094
Figure PCTCN2020097369-appb-000094
-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 PCTCN2020097369-appb-000095
Figure PCTCN2020097369-appb-000095
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 PCTCN2020097369-appb-000096
Figure PCTCN2020097369-appb-000096
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 PCTCN2020097369-appb-000097
Figure PCTCN2020097369-appb-000097
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] + .
第八步：(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)喹喔啉-5-基)二甲基膦氧化的制备The eighth step: (6-((5-bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3 -Dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000098
Figure PCTCN2020097369-appb-000098
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(20mg,0.061mmol)，(6-((2-氨基-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(25mg,0.061mmol)和TsOH(42mg,0.242mmol)混合于特戊醇(3mL)里，95℃下搅拌4天，冷却，用DCM稀释反应液，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后制备薄层析纯化得到标题化合物(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)喹喔啉-5-基)二甲基膦氧化(20mg,收率:47％)。5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-amine (20mg, 0.061mmol), (6-((2-Amino-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (25mg, 0.061mmol) and TsOH (42mg, 0.242mmol) were mixed in special Stir at 95°C for 4 days in pentanol (3mL), cool, dilute the reaction solution with DCM, wash with saturated aqueous sodium bicarbonate solution and saturated brine successively, separate the organic phase, dry with anhydrous sodium sulfate, and concentrate the organic solvent under reduced pressure After preparative thin chromatography purification to obtain the title compound (6-((5-bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl )-2,3-Dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (20mg, yield: 47%).
1H NMR(400MHz,CD 3OD)δ1.73(d,J＝12.1Hz,2H),2.02(d,J＝11.4Hz,2H),2.08-2.29(m,9H),2.61(s,3H),2.63-2.72(m,1H),2.83-3.22(m,12H),3.30-3.37(m,2H),4.48(t,J＝8.5Hz,2H),7.24(s,1H),7.92(d,J＝9.5Hz,1H),8.19(s,1H),8.78(s,1H),8.83(s,1H),8.97-9.09(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.73(d,J=12.1Hz,2H), 2.02(d,J=11.4Hz,2H), 2.08-2.29(m,9H), 2.61(s,3H ), 2.63-2.72(m, 1H), 2.83-3.22(m, 12H), 3.30-3.37(m, 2H), 4.48(t, J=8.5Hz, 2H), 7.24(s, 1H), 7.92( d,J=9.5Hz,1H), 8.19(s,1H), 8.78(s,1H), 8.83(s,1H), 8.97-9.09(m,1H);
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例7Example 7
(6-((5-溴-2-((6-乙基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)色烷-8-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-ethyl-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)chroman-8-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000099
Figure PCTCN2020097369-appb-000099
(6-((5-溴-2-((6-乙基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)色烷-8-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例6。(6-((5-Bromo-2-((6-ethyl-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)chroman-8-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 6.
MS m/z(ESI):734.2[M+H] +. MS m/z(ESI): 734.2[M+H] + .
实施例8Example 8
(6-((5-溴-2-((3-甲氧基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)二环[4.2.0]辛-1(6),2,4-三烯-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((3-methoxy-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)bicyclo[4.2.0] Octyl-1(6), 2,4-trien-2-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000100
Figure PCTCN2020097369-appb-000100
(6-((5-溴-2-((3-甲氧基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)二环[4.2.0]辛-1(6),2,4-三烯-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((3-methoxy-5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)bicyclo[4.2.0] The preparation method of octyl-1(6),2,4-trien-2-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxidation refers to Example 1.
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例9Example 9
(6-((5-溴-2-((5-甲氧基-7-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢-1H-茚-4-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-methoxy-7-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydro -1H-Inden-4-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000101
Figure PCTCN2020097369-appb-000101
(6-((5-溴-2-((5-甲氧基-7-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氢-1H-茚-4-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-methoxy-7-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydro The preparation method of -1H-inden-4-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation refers to Example 1.
MS m/z(ESI):720.2[M+H] +. MS m/z(ESI): 720.2[M+H] + .
实施例10Example 10
(6-((5-溴-2-(((4aS)-9-甲氧基-3-(4-甲基哌嗪-1-基)-2,3,4,4a,5,6-六氢-1H-吡啶并[1,2-a]喹啉-8-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-(((4aS)-9-methoxy-3-(4-methylpiperazin-1-yl)-2,3,4,4a,5,6- Preparation of hexahydro-1H-pyrido[1,2-a]quinolin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000102
Figure PCTCN2020097369-appb-000102
(6-((5-溴-2-(((4aS)-9-甲氧基-3-(4-甲基哌嗪-1-基)-2,3,4,4a,5,6-六氢-1H-吡啶并[1,2-a]喹啉-8-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-(((4aS)-9-methoxy-3-(4-methylpiperazin-1-yl)-2,3,4,4a,5,6- The preparation method of hexahydro-1H-pyrido[1,2-a]quinolin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation reference example 1.
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例11Example 11
(6-((5-溴-2-(((4aR)-9-甲氧基-3-(4-甲基哌嗪-1-基)-2,3,4,4a,5,6-六氢-1H-吡啶并[1,2-a]喹啉-8-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-(((4aR)-9-methoxy-3-(4-methylpiperazin-1-yl)-2,3,4,4a,5,6- Preparation of hexahydro-1H-pyrido[1,2-a]quinolin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000103
Figure PCTCN2020097369-appb-000103
(6-((5-溴-2-(((4aR)-9-甲氧基-3-(4-甲基哌嗪-1-基)-2,3,4,4a,5,6-六氢-1H-吡啶并[1,2-a]喹啉-8-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-(((4aR)-9-methoxy-3-(4-methylpiperazin-1-yl)-2,3,4,4a,5,6- The preparation method of hexahydro-1H-pyrido[1,2-a]quinolin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation reference example 1.
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例12Example 12
(6-((5-溴-2-((3-(4-(4-甲基哌嗪-1-基)哌啶-1-基)二环[1.1.1]戊烷-1-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((3-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)bicyclo[1.1.1]pentane-1-yl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000104
Figure PCTCN2020097369-appb-000104
(6-((5-溴-2-((3-(4-(4-甲基哌嗪-1-基)哌啶-1-基)二环[1.1.1]戊烷-1-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((3-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)bicyclo[1.1.1]pentane-1-yl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1.
MS m/z(ESI):640.2[M+H] +. MS m/z(ESI): 640.2[M+H] + .
实施例13Example 13
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000105
Figure PCTCN2020097369-appb-000105
第一步：(6-氨基喹喔啉-5-基)二甲基膦硫化的制备The first step: (6-aminoquinoxalin-5-yl) dimethyl phosphine vulcanization preparation
Figure PCTCN2020097369-appb-000106
Figure PCTCN2020097369-appb-000106
往(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(884mg,4mmol)的甲苯(40mL)溶液中，加入劳森试剂(3.2g,8mmol)，110℃反应4h。反应液冷却至室温，过滤后滤液减压浓缩有机溶剂，柱层析分离得到标题化合物(6-氨基喹喔啉-5-基)二甲基膦硫化(569mg,收率:60％)。To (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (884mg, 4mmol) in toluene (40mL) solution, add Lawson Reagent (3.2g, 8mmol), react at 110°C for 4h. The reaction solution was cooled to room temperature. After filtration, the filtrate was concentrated to an organic solvent under reduced pressure, and the title compound (6-aminoquinoxalin-5-yl)dimethylphosphine sulfide (569 mg, yield: 60%) was obtained by column chromatography.
MS m/z(ESI):238.2[M+H] +. MS m/z(ESI): 238.2[M+H] + .
第二步：(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)喹喔啉-5-基)二甲基膦硫化的制备The second step: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000107
Figure PCTCN2020097369-appb-000107
(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)喹喔啉-5-基)二甲基膦硫化的制备参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl ) Amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine sulfide preparation refer to Example 1.
MS m/z(ESI):724.2[M+H] +. MS m/z(ESI): 724.2[M+H] + .
实施例14Example 14
1-(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)喹喔啉-5-基)磷杂丁环1-氧化的制备1-(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) (Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)phosphabutane 1-oxidation preparation
Figure PCTCN2020097369-appb-000108
Figure PCTCN2020097369-appb-000108
1-(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)喹喔啉-5-基)磷杂丁环1-氧化的制备方法参照实施例1。1-(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Refer to Example 1 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)phosphabutane 1-oxidation.
MS m/z(ESI):720.2[M+H] +. MS m/z(ESI): 720.2[M+H] + .
实施例15Example 15
(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-氟喹喔啉-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-fluoroquinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000109
Figure PCTCN2020097369-appb-000109
(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-氟喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-8-fluoroquinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):726.2[M+H] +. MS m/z(ESI): 726.2[M+H] + .
实施例16Example 16
(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-氟喹喔啉-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-fluoroquinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000110
Figure PCTCN2020097369-appb-000110
(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-氟喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-7-fluoroquinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):726.2[M+H] +. MS m/z(ESI): 726.2[M+H] + .
实施例17Example 17
(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)噻吩并[2,3-b]吡嗪-7-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)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000111
Figure PCTCN2020097369-appb-000111
(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)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
1H NMR(400MHz,CD 3OD)δ1.18(t,J＝7.5Hz,3H),1.80-1.86(m,2H),1.96(s,3H),2.00(s,3H),2.05-2.12(m,2H),2.64-2.87(m,10H),3.00-3.14(m,8H),3.81(s,3H),6.83(s,1H),7.47(s,1H),8.23(s,1H),8.29(d,J＝2.6Hz,1H),8.48(d,J＝2.6Hz,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.18(t,J=7.5Hz,3H),1.80-1.86(m,2H),1.96(s,3H),2.00(s,3H),2.05-2.12 (m,2H),2.64-2.87(m,10H),3.00-3.14(m,8H),3.81(s,3H),6.83(s,1H),7.47(s,1H),8.23(s,1H) ), 8.29(d,J=2.6Hz,1H), 8.48(d,J=2.6Hz,1H);
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例18Example 18
5-溴-N2-(5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(5-(甲磺酰)喹喔啉-6-基)嘧啶-2,4-二胺的制备5-bromo-N2-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(5 -(Methanesulfonyl)quinoxalin-6-yl)pyrimidine-2,4-diamine
Figure PCTCN2020097369-appb-000112
Figure PCTCN2020097369-appb-000112
5-溴-N2-(5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(5-(甲磺酰)喹喔啉-6-基)嘧啶-2,4-二胺的制备方法参照实施例1。5-bromo-N2-(5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N4-(5 Refer to Example 1 for the preparation method of -(methylsulfonyl)quinoxalin-6-yl)pyrimidine-2,4-diamine.
MS m/z(ESI):710.2[M+H] +. MS m/z(ESI): 710.2[M+H] + .
实施例19Example 19
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000113
Figure PCTCN2020097369-appb-000113
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 PCTCN2020097369-appb-000114
Figure PCTCN2020097369-appb-000114
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 PCTCN2020097369-appb-000115
Figure PCTCN2020097369-appb-000115
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] + .
第三步：(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)喹喔啉-5-基)二甲基膦氧化的制备The third 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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000116
Figure PCTCN2020097369-appb-000116
往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(300mg,1.1mmol)和(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(444mg,1.1mmol)的特戊醇(3mL)溶液中加入DIPEA(250mg,4.0mmol)，180℃下微波反应6h。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-((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)喹喔啉-5-基)二甲基膦氧化(260mg，收率:37％)。To 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (300mg, 1.1mmol) and (6-( (5-Bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (444mg, 1.1mmol) in popentanol (3mL) was added DIPEA (250mg, 4.0 mmol), microwave reaction at 180°C for 6h. After cooling to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound Hetero-8-azaspiro[4.5]decane-8-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (260mg, yield: 37 %).
MS m/z(ESI):654.1[M+H] +. MS m/z(ESI): 654.1[M+H] + .
第四步：1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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 fourth step: 1-(4-((5-bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl (Oxy-2-methylphenyl) piperidin-4-one
Figure PCTCN2020097369-appb-000117
Figure PCTCN2020097369-appb-000117
(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)喹喔啉-5-基)二甲基膦氧化(260mg,0.4mmol)的醋酸(2mL)溶液中，加入水(2mL)，70℃下反应6小时。冷却至室温，乙酸乙酯稀释。饱和碳酸氢钠水溶液中和醋酸，分离有机相用无水硫酸钠干燥，过滤后浓缩有机溶剂得到标题化合物1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(230mg，收率:95％)。(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)quinoxalin-5-yl)dimethylphosphine oxide (260mg, 0.4mmol) in acetic acid (2mL) solution, add water (2mL), and react at 70℃ 6 hours. Cool to room temperature and dilute with ethyl acetate. Saturated aqueous sodium bicarbonate solution neutralized acetic acid, separated the organic phase and dried over anhydrous sodium sulfate, filtered and concentrated the organic solvent to obtain the title compound 1-(4-((5-bromo-4-((5-(dimethylphosphorus group) ) Quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (230 mg, yield: 95%).
MS m/z(ESI):610.1[M+H] +. MS m/z(ESI): 610.1[M+H] + .
第五步：((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)喹喔啉-5-基)二甲基膦氧化的制备The fifth step: ((6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000118
Figure PCTCN2020097369-appb-000118
往1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(30mg,0.05mmol)和3-(二甲氨基)氮杂环丁烷二盐酸盐(25mg,0.15mmol)的DCE(2mL)溶液中，加入3滴醋酸，搅拌一小时后加入三乙酰氧基硼氢化钠(21mg,0.1mol)，室温搅拌过夜，加入二氯甲烷稀释反应液，饱和碳酸氢钠水溶液调节pH至碱性，分离有机相用无水硫酸钠干燥，过滤干燥剂后浓缩有机溶剂，柱层析分离得到标题化合物(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)喹喔啉-5-基)二甲基膦氧化(13mg,收率:38％)。To 1-(4-((5-bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy- 2-methylphenyl)piperidin-4-one (30mg, 0.05mmol) and 3-(dimethylamino)azetidine dihydrochloride (25mg, 0.15mmol) in DCE (2mL) solution, Add 3 drops of acetic acid, stir for one hour, add sodium triacetoxyborohydride (21mg, 0.1mol), stir overnight at room temperature, add dichloromethane to dilute the reaction solution, adjust the pH to alkaline with saturated aqueous sodium bicarbonate, separate the organic phase Dry over anhydrous sodium sulfate, filter the desiccant, concentrate the organic solvent, and separate by column chromatography to obtain the title compound (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetin (Pyridine-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (13mg, yield: 38%).
1H NMR(400MHz，CD 3OD)δ1.45-1.57(m,2H),1.93-2.01(m,2H),2.05(s,3H),2.11(s,3H),2.15(s,3H),2.22(s,6H),2.55-2.65(m,1H),2.66-2.73(m,2H),3.07-3.18(m,3H),3.30-3.37(m,2H),3.78-3.87(m,5H),6.73(s,1H),7.60(s,1H),7.96(d,J＝9.5Hz,1H),8.20(s,1H),8.76-8.84(m,2H),8.91-8.96(m,1H)； 1 H NMR(400MHz, CD 3 OD)δ1.45-1.57(m,2H),1.93-2.01(m,2H),2.05(s,3H),2.11(s,3H),2.15(s,3H) ,2.22(s,6H),2.55-2.65(m,1H),2.66-2.73(m,2H),3.07-3.18(m,3H),3.30-3.37(m,2H),3.78-3.87(m, 5H), 6.73 (s, 1H), 7.60 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 8.20 (s, 1H), 8.76-8.84 (m, 2H), 8.91-8.96 (m ,1H);
MS m/z(ESI):694.1[M+H] +. MS m/z(ESI): 694.1[M+H] + .
实施例20Example 20
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000119
Figure PCTCN2020097369-appb-000119
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照(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)quinoxalin-5-yl)dimethylphosphine oxidation preparation method reference
实施例19。Example 19.
1H NMR(400MHz,CD 3OD)δ1.13-1.25(s,6H),1.57-1.63(m,2H),1.94-2.34(m,11H),2.73(t,J＝11.4Hz,2H),2.80-2.90(m,1H),3.17(d,J＝11.7Hz,2H),3.79-3.98(m,5H),4.17(dd,J＝21.2,11.0Hz,2H),6.75(s,1H),7.62(s,1H),7.98(d,J＝9.6Hz,1H),8.22(s,1H),8.79(d,J＝1.9Hz,1H),8.84(d,J＝1.9Hz,1H),8.95(dd,J＝9.7,4.0Hz,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.13-1.25(s,6H),1.57-1.63(m,2H),1.94-2.34(m,11H),2.73(t,J=11.4Hz,2H) ,2.80-2.90(m,1H),3.17(d,J=11.7Hz,2H),3.79-3.98(m,5H), 4.17(dd,J=21.2,11.0Hz,2H), 6.75(s,1H) ), 7.62(s,1H),7.98(d,J=9.6Hz,1H),8.22(s,1H),8.79(d,J=1.9Hz,1H),8.84(d,J=1.9Hz,1H ),8.95(dd,J=9.7,4.0Hz,1H);
MS m/z(ESI):727.2[M+H] +. MS m/z(ESI): 727.2[M+H] + .
实施例21Example 21
(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)喹喔啉-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)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000120
Figure PCTCN2020097369-appb-000120
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(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)quinoxalin-5-yl)dimethylphosphine oxidation preparation method reference Example 1.
1H NMR(400MHz,CD 3OD)δ0.84(t,J＝7.7Hz,3H),1.84(d,J＝12.1Hz,2H),2.10-2.21(m,8H),2.49(q,J＝7.5Hz,2H),2.79(t,J＝11.5Hz,2H),2.91-2.95(m,6H),3.07-3.15(m,4H),3.30-3.37(m,4H),3.65(d,J＝9.1Hz,2H),3.85(s,3H),6.79(s,1H),7.66(s,1H),7.98(d,J＝9.5Hz,1H),8.24(s,1H),8.80-8.93(m,3H)； 1 H NMR (400MHz, CD 3 OD) δ 0.84 (t, J = 7.7 Hz, 3H), 1.84 (d, J = 12.1Hz, 2H), 2.10-2.21 (m, 8H), 2.49 (q, J =7.5Hz,2H),2.79(t,J=11.5Hz,2H),2.91-2.95(m,6H),3.07-3.15(m,4H),3.30-3.37(m,4H),3.65(d, J = 9.1Hz, 2H), 3.85 (s, 3H), 6.79 (s, 1H), 7.66 (s, 1H), 7.98 (d, J = 9.5 Hz, 1H), 8.24 (s, 1H), 8.80- 8.93(m,3H);
MS m/z(ESI):798.2[M+H] + MS m/z(ESI): 798.2[M+H] +
实施例22Example 22
(6-((5-溴-2-((5-乙基-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzene Preparation of oxafuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine
Figure PCTCN2020097369-appb-000121
Figure PCTCN2020097369-appb-000121
(6-((5-溴-2-((5-乙基-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例6。(6-((5-Bromo-2-((5-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzene Refer to Example 6 for the preparation method of nitrofuran-7-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):720.2[M+H] +. MS m/z(ESI): 720.2[M+H] + .
实施例23Example 23
(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)喹喔啉-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 (Oxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000122
Figure PCTCN2020097369-appb-000122
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 PCTCN2020097369-appb-000123
Figure PCTCN2020097369-appb-000123
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 PCTCN2020097369-appb-000124
Figure PCTCN2020097369-appb-000124
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 PCTCN2020097369-appb-000125
Figure PCTCN2020097369-appb-000125
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 PCTCN2020097369-appb-000126
Figure PCTCN2020097369-appb-000126
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 PCTCN2020097369-appb-000127
Figure PCTCN2020097369-appb-000127
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] + .
第六步：(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)喹喔啉-5-基)二甲基膦氧化的制备The sixth step: (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl -2-Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000128
Figure PCTCN2020097369-appb-000128
往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(20mg,0.06mmol)和(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(25mg,0.06mmol)的特戊醇(2mL)混合溶液中，加入对甲苯磺酸(24mg,0.24mmol)，90℃反应过夜。冷却至室温，反应液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-((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)喹喔啉-5-基)二甲基膦氧化(7.7mg,收率:18％)。To 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (20mg, 0.06mmol ) And (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (25mg, 0.06mmol) in pivalol (2mL) mixed solution In, p-toluenesulfonic acid (24mg, 0.24mmol) was added and reacted at 90°C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the organic solvent was separated by column chromatography to obtain the title compound (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1) -Yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (7.7mg, Yield: 18%).
1H NMR(400MHz，CD 3OD)δ0.83(t,J＝7.5Hz,3H),1.49-1.60(m,2H),1.99-2.06(m,2H),2.12(s,3H),2.15(s,3H),2.26(s,6H),2.44-2.51(m,2H),2.73-2.85(m,3H),3.05-3.12(m,2H),3.15-3.23(m,1H),3.56-3.62(m,2H),3.85(s,3H),3.95-4.02(m,2H),6.80(s,1H),7.65(s,1H),7.98(d,J＝9.5Hz,1H),8.24(s,1H),8.79-8.82(m,1H),8.83-8.89(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.83 (t, J = 7.5 Hz, 3H), 1.49-1.60 (m, 2H), 1.99-2.06 (m, 2H), 2.12 (s, 3H), 2.15 (s,3H),2.26(s,6H),2.44-2.51(m,2H),2.73-2.85(m,3H),3.05-3.12(m,2H),3.15-3.23(m,1H),3.56 -3.62(m,2H),3.85(s,3H),3.95-4.02(m,2H),6.80(s,1H),7.65(s,1H),7.98(d,J=9.5Hz,1H), 8.24(s,1H),8.79-8.82(m,1H),8.83-8.89(m,2H)
MS m/z(ESI):708.2[M+H] +. MS m/z(ESI): 708.2[M+H] + .
实施例24Example 24
N-(2-((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)苯基)环丙磺酰胺的制备N-(2-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2- Preparation of methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide
Figure PCTCN2020097369-appb-000129
Figure PCTCN2020097369-appb-000129
N-(2-((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)苯基)环丙磺酰胺的制备方法参照实施例19。N-(2-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2- Refer to Example 19 for the preparation method of methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide.
MS m/z(ESI):690.2[M+H] +. MS m/z(ESI): 690.2[M+H] + .
实施例25Example 25
1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)-4-(4-甲基哌嗪-1-基)哌啶-2-酮的制备1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5- Preparation of methoxyphenyl)-4-(4-methylpiperazin-1-yl)piperidin-2-one
Figure PCTCN2020097369-appb-000130
Figure PCTCN2020097369-appb-000130
1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)-4-(4-甲基哌嗪-1-基)哌啶-2-酮的制备方法参照实施例1。1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5- Refer to Example 1 for the preparation method of methoxyphenyl)-4-(4-methylpiperazin-1-yl)piperidin-2-one.
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例26Example 26
1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)-4-甲基哌嗪-2-酮的制备1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl -5-Methoxyphenyl)piperidin-4-yl)-4-methylpiperazin-2-one
Figure PCTCN2020097369-appb-000131
Figure PCTCN2020097369-appb-000131
1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)-4-甲基哌嗪-2-酮的制备方法参照实施例1。1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl The preparation method of -5-methoxyphenyl)piperidin-4-yl)-4-methylpiperazin-2-one refers to Example 1.
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例27Example 27
4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)-1-甲基哌嗪-2-酮的制备4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl -5-Methoxyphenyl)piperidin-4-yl)-1-methylpiperazin-2-one
Figure PCTCN2020097369-appb-000132
Figure PCTCN2020097369-appb-000132
4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)-1-甲基哌嗪-2-酮的制备方法参照实施例1。4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl The preparation method of -5-methoxyphenyl)piperidin-4-yl)-1-methylpiperazin-2-one refers to Example 1.
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例28Example 28
(6-((5-溴-2-((4-(4-(4-环丙基哌嗪-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000133
Figure PCTCN2020097369-appb-000133
(6-((5-溴-2-((4-(4-(4-环丙基哌嗪-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-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-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1.
MS m/z(ESI):734.2[M+H] +. MS m/z(ESI): 734.2[M+H] + .
实施例29Example 29
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-(噁丁环-3-基)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-(oxbutan-3-yl)piperazin-1-yl)piperidine -1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000134
Figure PCTCN2020097369-appb-000134
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-(噁丁环-3-基)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-(oxbutan-3-yl)piperazin-1-yl)piperidine -1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 1.
MS m/z(ESI):750.2[M+H] +. MS m/z(ESI): 750.2[M+H] + .
实施例30Example 30
1-(4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)哌嗪-1-基)乙烷-1-酮的制备1-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2 -Ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethane-1-one
Figure PCTCN2020097369-appb-000135
Figure PCTCN2020097369-appb-000135
1-(4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)哌嗪-1-基)乙烷-1-酮的制备方法参照实施例1。1-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2 -Ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethane-1-one is prepared according to Example 1.
1H NMR(400MHz,CD 3OD)δ0.84(t,J＝7.5,3H),1.67-1.78(m,2H),1.96-2.03(m,2H),2.09-2.21(m,9H),2.43-2.53(m,3H),2.64-2.80(m,6H),3.07-3.13(m,2H),3.57-3.66(m,4H),3.84(s,3H),4.60(s,2H),6.79(s,1H),7.62(s,1H),7.98(d,J＝9.5,1H),8.23(s,1H),8.78-8.81(m,1H),8.83-8.90(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.84 (t, J = 7.5, 3H), 1.67-1.78 (m, 2H), 1.96-2.03 (m, 2H), 2.09-2.21 (m, 9H), 2.43-2.53(m,3H),2.64-2.80(m,6H),3.07-3.13(m,2H),3.57-3.66(m,4H), 3.84(s,3H), 4.60(s,2H), 6.79(s,1H), 7.62(s,1H), 7.98(d,J=9.5,1H), 8.23(s,1H), 8.78-8.81(m,1H), 8.83-8.90(m,2H);
MS m/z(ESI):736.2[M+H] +. MS m/z(ESI): 736.2[M+H] + .
实施例31Example 31
(6-((5-溴-2-((5-乙基-4-(4-(4-(2-羟基乙基)哌嗪-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-4-(4-(4-(2-hydroxyethyl)piperazin-1-yl)piperidin-1-yl)-2- (Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000136
Figure PCTCN2020097369-appb-000136
(6-((5-溴-2-((5-乙基-4-(4-(4-(2-羟基乙基)哌嗪-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-4-(4-(4-(2-hydroxyethyl)piperazin-1-yl)piperidin-1-yl)-2- Refer to Example 1 for the preparation method of methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):738.2[M+H] +. MS m/z(ESI): 738.2[M+H] + .
实施例32Example 32
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-(2-甲氧基乙基)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-(2-methoxyethyl)piperazin-1-yl)piperidine -1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000137
Figure PCTCN2020097369-appb-000137
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-(2-甲氧基乙基)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-(2-methoxyethyl)piperazin-1-yl)piperidine -1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 1.
MS m/z(ESI):752.2[M+H] +. MS m/z(ESI): 752.2[M+H] + .
实施例33Example 33
(6-((5-溴-2-((5-乙基-4-(4-(4-(2-氟乙基)哌嗪-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-4-(4-(4-(2-fluoroethyl)piperazin-1-yl)piperidin-1-yl)-2- (Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000138
Figure PCTCN2020097369-appb-000138
(6-((5-溴-2-((5-乙基-4-(4-(4-(2-氟乙基)哌嗪-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-4-(4-(4-(2-fluoroethyl)piperazin-1-yl)piperidin-1-yl)-2- Refer to Example 1 for the preparation method of methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):740.2[M+H] +. MS m/z(ESI): 740.2[M+H] + .
实施例34Example 34
2-(4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)哌嗪-1-基)乙酰腈的制备2-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2 -Ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)acetonitrile
Figure PCTCN2020097369-appb-000139
Figure PCTCN2020097369-appb-000139
2-(4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)哌嗪-1-基)乙酰腈的制备方法参照实施例1。2-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2 -Ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)acetonitrile The preparation method refers to Example 1.
MS m/z(ESI):733.2[M+H] +. MS m/z(ESI): 733.2[M+H] + .
实施例35Example 35
(6-((5-溴-2-((5-乙基-2-甲氧基-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000140
Figure PCTCN2020097369-appb-000140
(6-((5-溴-2-((5-乙基-2-甲氧基-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper (Pyridin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 1.
1H NMR(400MHz，CD 3OD)δ0.84(t,J＝7.5Hz,3H),1.73-1.82(m,2H),1.90-1.98(m,2H),2.02-2.09(m,2H),2.12(s,3H),2.15(s,3H),2.45-2.52(m,2H),2.73-2.89(m,6H),3.03-3.15(m,6H),3.20-3.24(m,2H),3.26-3.31(m,2H),3.84(s,3H),6.79(s,1H),7.63(s,1H),7.97(d,J＝9.5Hz,1H),8.23(s,1H),8.78-8.81(m,1H),8.82-8.90(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.84 (t, J = 7.5 Hz, 3H), 1.73-1.82 (m, 2H), 1.90-1.98 (m, 2H), 2.02-2.09 (m, 2H) ,2.12(s,3H),2.15(s,3H),2.45-2.52(m,2H),2.73-2.89(m,6H),3.03-3.15(m,6H),3.20-3.24(m,2H) ,3.26-3.31(m,2H),3.84(s,3H),6.79(s,1H),7.63(s,1H),7.97(d,J=9.5Hz,1H),8.23(s,1H), 8.78-8.81(m,1H),8.82-8.90(m,2H);
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例36Example 36
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((1S,4S)-5-甲基-2,5-二氮杂二环[2.2.1]庚烷-2-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]Heptan-2-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide
Figure PCTCN2020097369-appb-000141
Figure PCTCN2020097369-appb-000141
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((1S,4S)-5-甲基-2,5-二氮杂二环[2.2.1]庚烷-2-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((1S,4S)-5-methyl-2,5-diazabicyclo [2.2.1]Heptan-2-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation method refer to implementation example 1.
MS m/z(ESI):736.2[M+H] +. MS m/z(ESI): 736.2[M+H] + .
实施例37Example 37
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((1R,4R)-5-甲基-2,5-二氮杂二环[2.2.1]庚烷-2-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((1R,4R)-5-methyl-2,5-diazabicyclo [2.2.1]Heptan-2-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000142
Figure PCTCN2020097369-appb-000142
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((1R,4R)-5-甲基-2,5-二氮杂二环[2.2.1]庚烷-2-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((1R,4R)-5-methyl-2,5-diazabicyclo [2.2.1]Heptan-2-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation method refer to implementation example 1.
MS m/z(ESI):736.2[M+H] +. MS m/z(ESI): 736.2[M+H] + .
实施例38Example 38
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(3-甲基-3,6-二氮杂二环[3.1.1]庚烷-6-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-methyl-3,6-diazabicyclo[3.1.1]hept (Alk-6-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000143
Figure PCTCN2020097369-appb-000143
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(3-甲基-3,6-二氮杂二环[3.1.1]庚烷-6-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-methyl-3,6-diazabicyclo[3.1.1]hept The preparation method of alkyl-6-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide refers to Example 1.
MS m/z(ESI):736.2[M+H] +. MS m/z(ESI): 736.2[M+H] + .
实施例39Example 39
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(6-甲基-3,6-二氮杂二环[3.1.1]庚烷-3-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(6-methyl-3,6-diazabicyclo[3.1.1]hept (Alk-3-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000144
Figure PCTCN2020097369-appb-000144
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(6-甲基-3,6-二氮杂二环[3.1.1]庚烷-3-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(6-methyl-3,6-diazabicyclo[3.1.1]hept The preparation method of alkyl-3-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide is referred to Example 1.
MS m/z(ESI):736.2[M+H] +. MS m/z(ESI): 736.2[M+H] + .
实施例40Example 40
(6-((2-((4-(4-((1R,5S)-8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((2-((4-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)piperidin-1-yl )-5-Ethyl-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000145
Figure PCTCN2020097369-appb-000145
(6-((2-((4-(4-((1R,5S)-8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((2-((4-(4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)piperidin-1-yl )-5-Ethyl-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation method refer to Example 1.
MS m/z(ESI):737.2[M+H] +. MS m/z(ESI): 737.2[M+H] + .
实施例41Example 41
(6-((2-((4-(4-((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((2-((4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-yl)piperidin-1-yl )-5-Ethyl-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000146
Figure PCTCN2020097369-appb-000146
(6-((2-((4-(4-((1R,5S)-3-氧杂-8-氮杂二环[3.2.1]辛烷-8-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((2-((4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-yl)piperidin-1-yl )-5-Ethyl-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation method refer to Example 1.
MS m/z(ESI):737.2[M+H] +. MS m/z(ESI): 737.2[M+H] + .
实施例42Example 42
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(2-甲基-2,7-二氮杂螺[3.5]壬烷-7-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(2-methyl-2,7-diazaspiro[3.5]nonane-7-yl) (Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine sulfide preparation
Figure PCTCN2020097369-appb-000147
Figure PCTCN2020097369-appb-000147
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(2-甲基-2,7-二氮杂螺[3.5]壬烷-7-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(2-methyl-2,7-diazaspiro[3.5]nonane-7-yl) Refer to Example 1 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide.
MS m/z(ESI):681.2[M+H] +. MS m/z(ESI): 681.2[M+H] + .
实施例43Example 43
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl )Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide preparation
Figure PCTCN2020097369-appb-000148
Figure PCTCN2020097369-appb-000148
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦硫化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl ) Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine sulfide preparation method refer to Example 1.
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例44Example 44
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(((1s,3s)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(((1s,3s)-3-(4-methylpiperazin-1-yl)cyclobutane (Yl)amino)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000149
Figure PCTCN2020097369-appb-000149
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(((1s,3s)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(((1s,3s)-3-(4-methylpiperazin-1-yl)cyclobutane (Phenyl)amino)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例45Example 45
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(((1r,3r)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutane (Yl)amino)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000150
Figure PCTCN2020097369-appb-000150
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(((1r,3r)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutane (Phenyl)amino)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例46Example 46
(6-((5-溴-2-((5-乙基-2-甲氧基-4-((1s,3s)-3-(4-甲基哌嗪-1-基)环丁氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-((1s,3s)-3-(4-methylpiperazin-1-yl)cyclobutoxy (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000151
Figure PCTCN2020097369-appb-000151
(6-((5-溴-2-((5-乙基-2-甲氧基-4-((1s,3s)-3-(4-甲基哌嗪-1-基)环丁氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-((1s,3s)-3-(4-methylpiperazin-1-yl)cyclobutoxy (Phenyl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxidation preparation method refer to Example 1.
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例47Example 47
(6-((5-溴-2-((5-乙基-2-甲氧基-4-((1r,3r)-3-(4-甲基哌嗪-1-基)环丁氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutoxy (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000152
Figure PCTCN2020097369-appb-000152
(6-((5-溴-2-((5-乙基-2-甲氧基-4-((1r,3r)-3-(4-甲基哌嗪-1-基)环丁氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutoxy (Phenyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例48Example 48
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(甲基((1s,3s)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(methyl((1s,3s)-3-(4-methylpiperazin-1-yl) Cyclobutyl) amino) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000153
Figure PCTCN2020097369-appb-000153
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(甲基((1s,3s)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(methyl((1s,3s)-3-(4-methylpiperazin-1-yl) Cyclobutyl) amino) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 1.
MS m/z(ESI):708.2[M+H] +. MS m/z(ESI): 708.2[M+H] + .
实施例49Example 49
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(甲基((1r,3r)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(methyl((1r,3r)-3-(4-methylpiperazin-1-yl) Cyclobutyl) amino) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000154
Figure PCTCN2020097369-appb-000154
(6-((5-溴-2-((5-乙基-2-甲氧基-4-(甲基((1r,3r)-3-(4-甲基哌嗪-1-基)环丁基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(methyl((1r,3r)-3-(4-methylpiperazin-1-yl) Cyclobutyl) amino) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 1.
MS m/z(ESI):708.2[M+H] +. MS m/z(ESI): 708.2[M+H] + .
实施例50Example 50
(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)喹喔啉-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] Preparation of pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000155
Figure PCTCN2020097369-appb-000155
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Refer to Example 23 for the preparation method of pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ0.84(t,J＝7.5Hz,3H),1.75-1.90(m,2H),2.12(s,3H),2.14-2.21(m,5H),2.50(t,J＝7.6Hz,2H),2.71-2.90(m,5H),2.97-3.17(m,4H),3.50-3.58(m,2H),3.62-3.72(m,2H),3.78-3.87(m,5H),6.79(s,1H),7.66(s,1H),7.98(d,J＝9.5Hz,1H),8.24(s,1H),8.80-8.91(m,3H)； 1 H NMR(400MHz,CD 3 OD)δ0.84(t,J=7.5Hz,3H),1.75-1.90(m,2H),2.12(s,3H),2.14-2.21(m,5H), 2.50 (t,J=7.6Hz,2H),2.71-2.90(m,5H),2.97-3.17(m,4H),3.50-3.58(m,2H),3.62-3.72(m,2H),3.78-3.87 (m, 5H), 6.79 (s, 1H), 7.66 (s, 1H), 7.98 (d, J = 9.5 Hz, 1H), 8.24 (s, 1H), 8.80-8.91 (m, 3H);
MS m/z(ESI):721.2[M+H] +. MS m/z(ESI): 721.2[M+H] + .
实施例51Example 51
(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxybenzene (Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000156
Figure PCTCN2020097369-appb-000156
(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxybenzene (Yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 23.
1H NMR(400MHz,CD 3OD)δ0.82(t,J＝7.5Hz,3H),1.21(t,J＝7.0Hz,3H),1.46-1.56(m,2H),1.93-2.01(m,2H),2.12(s,3H),2.15(s,3H),2.42-2.50(m,2H),2.60-2.67(m,1H),2.70-2.79(m,2H),3.04-3.11(m,2H),3.40-3.45(m,2H),3.48-3.55(m,2H),3.84(s,3H),3.93-3.97(m,2H),4.21-4.28(m,1H),6.79(s,1H),7.64(s,1H),7.97(d,J＝9.5Hz,1H),8.23(s，1H),8.78-8.82(m,1H),8.83-8.90(m,2H)； 1 H NMR(400MHz,CD 3 OD)δ0.82(t,J=7.5Hz,3H),1.21(t,J=7.0Hz,3H),1.46-1.56(m,2H),1.93-2.01(m , 2H), 2.12 (s, 3H), 2.15 (s, 3H), 2.42-2.50 (m, 2H), 2.60-2.67 (m, 1H), 2.70-2.79 (m, 2H), 3.04-3.11 (m , 2H), 3.40-3.45 (m, 2H), 3.48-3.55 (m, 2H), 3.84 (s, 3H), 3.93-3.97 (m, 2H), 4.21-4.28 (m, 1H), 6.79 (s ,1H),7.64(s,1H),7.97(d,J=9.5Hz,1H),8.23(s,1H),8.78-8.82(m,1H),8.83-8.90(m,2H);
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例52Example 52
(6-((5-氯-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-乙烯基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-vinylphenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000157
Figure PCTCN2020097369-appb-000157
(6-((5-氯-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-乙烯基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-vinylphenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 23.
1H NMR(400MHz,CD 3OD)δ1.74-1.85(m,2H),2.00-2.08(m,2H),2.12(s,3H),2.16(s,3H),2.62(s,3H),2.68-3.09(m,13H),3.88(s,3H),5.15-5.25(m,2H),6.75(s,1H),6.95-7.05(m,1H),7.87-7.95(m,2H),8.15(s,1H),8.80(d,J＝22.4Hz,2H),9.04-9.11(m,1H)； 1 H NMR(400MHz, CD 3 OD)δ1.74-1.85(m,2H), 2.00-2.08(m,2H), 2.12(s,3H), 2.16(s,3H), 2.62(s,3H) ,2.68-3.09(m,13H),3.88(s,3H),5.15-5.25(m,2H),6.75(s,1H),6.95-7.05(m,1H),7.87-7.95(m,2H) ,8.15(s,1H),8.80(d,J=22.4Hz,2H),9.04-9.11(m,1H);
MS m/z(ESI):662.2[M+H] +. MS m/z(ESI): 662.2[M+H] + .
实施例53Example 53
(6-((5-氯-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000158
Figure PCTCN2020097369-appb-000158
(6-((5-氯-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Chloro-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1.
1H NMR(400MHz,CD 3OD)δ1.68-1.80(m,2H),1.96-2.06(m,2H),2.11(s,3H),2.15(s,3H),2.39-2.48(m,4H),2.60-2.90(m,12H),3.35(s,1H),3.89(s,3H),6.63(s,1H),7.95(s,1H),8.10-8.22(m,2H),8.80(m,2H),9.03-9.10(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.68-1.80 (m, 2H), 1.96-2.06 (m, 2H), 2.11 (s, 3H), 2.15 (s, 3H), 2.39-2.48 (m, 4H), 2.60-2.90 (m, 12H), 3.35 (s, 1H), 3.89 (s, 3H), 6.63 (s, 1H), 7.95 (s, 1H), 8.10-8.22 (m, 2H), 8.80 (m,2H),9.03-9.10(m,1H);
MS m/z(ESI):660.2[M+H] +. MS m/z(ESI): 660.2[M+H] + .
实施例54Example 54
(6-((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)噻吩并[3,2-d]嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)thiophene Preparation of and [3,2-d]pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000159
Figure PCTCN2020097369-appb-000159
(6-((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)噻吩并[3,2-d]嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)thiophene And [3,2-d]pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 23.
1H NMR(400MHz,CD 3OD)δ1.07(t,J＝7.5Hz,3H),1.77-1.85(m,2H),2.03-2.10(m,2H),2.16(s,3H),2.19(s,3H),2.59-2.71(m,7H),2.78-2.87(m,3H),2.90-3.09(m,6H),3.15-3.22(m,2H),3.87(s,3H),6.84(s,1H),7.20(d,J＝5.4Hz,1H),7.81(s,1H),7.98-8.05(m,2H),8.77-8.79(m,1H),8.81-8.85(m,1H),9.39-9.45(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.07(t,J=7.5Hz,3H),1.77-1.85(m,2H),2.03-2.10(m,2H),2.16(s,3H),2.19 (s, 3H), 2.59-2.71 (m, 7H), 2.78-2.87 (m, 3H), 2.90-3.09 (m, 6H), 3.15-3.22 (m, 2H), 3.87 (s, 3H), 6.84 (s, 1H), 7.20 (d, J = 5.4 Hz, 1H), 7.81 (s, 1H), 7.98-8.05 (m, 2H), 8.77-8.79 (m, 1H), 8.81-8.85 (m, 1H) ),9.39-9.45(m,1H);
MS m/z(ESI):686.2[M+H] +. MS m/z(ESI): 686.2[M+H] + .
实施例55Example 55
(6-((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)-5-(甲硫基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 5-(methylthio)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000160
Figure PCTCN2020097369-appb-000160
(6-((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)-5-(甲硫基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 23 for the preparation method of 5-(methylthio)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):676.2[M+H] +. MS m/z(ESI): 676.2[M+H] + .
实施例56Example 56
(6-((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)-5-乙炔基嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 5-ethynylpyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000161
Figure PCTCN2020097369-appb-000161
(6-((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)-5-乙炔基嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 23 for the preparation method of 5-ethynylpyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):654.2[M+H] +. MS m/z(ESI): 654.2[M+H] + .
实施例57Example 57
(6-((5-(环丙基乙炔基)-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-(Cyclopropylethynyl)-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine- Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000162
Figure PCTCN2020097369-appb-000162
(6-((5-(环丙基乙炔基)-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-(Cyclopropylethynyl)-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine- 1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 23.
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例58Example 58
(6-((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)-5-(丙-1-炔 -1-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000163
Figure PCTCN2020097369-appb-000163
(6-((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)-5-(丙-1-炔-1-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 23 for the preparation method of 5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CDCl 3)δ0.89-0.95(m,3H),1.25(s,3H),1.67-1.80(m,3H),1.95-2.02(m,2H),2.08(s,3H),2.12(s,3H),2.21(s,3H),2.42(s,3H),2.50-2.56(m,2H),2.63-2.71(m,4H),2.78-2.88(m,3H),3.06-3.12(m,2H),3.85(s,3H),6.65(s,1H),7.42(s,1H),8.03-8.1(m,2H),8.24(s,1H),8.69-8.74(m,2H),9.08-9.12(m,1H),12.50-12.55(m,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.89-0.95 (m, 3H), 1.25 (s, 3H), 1.67-1.80 (m, 3H), 1.95-2.02 (m, 2H), 2.08 (s, 3H) ), 2.12 (s, 3H), 2.21 (s, 3H), 2.42 (s, 3H), 2.50-2.56 (m, 2H), 2.63-2.71 (m, 4H), 2.78-2.88 (m, 3H), 3.06-3.12 (m, 2H), 3.85 (s, 3H), 6.65 (s, 1H), 7.42 (s, 1H), 8.03-8.1 (m, 2H), 8.24 (s, 1H), 8.69-8.74 ( m,2H),9.08-9.12(m,1H),12.50-12.55(m,1H);
MS m/z(ESI):668.2[M+H] +. MS m/z(ESI): 668.2[M+H] + .
实施例59Example 59
(6-((5-环丙基-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)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备(6-((5-Cyclopropyl-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) (Phenyl)amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000164
Figure PCTCN2020097369-appb-000164
(6-((5-环丙基-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)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Cyclopropyl-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Refer to Example 23 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation.
MS m/z(ESI):676.2[M+H] +. MS m/z(ESI): 676.2[M+H] + .
实施例60Example 60
(6-((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)-5-(三氟甲基)嘧啶-4-基)氨基)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 5-(trifluoromethyl)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000165
Figure PCTCN2020097369-appb-000165
(6-((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)-5-(三氟甲基)嘧啶-4-基)氨基)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 23 for the preparation method of 5-(trifluoromethyl)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation.
MS m/z(ESI):704.2[M+H] +. MS m/z(ESI): 704.2[M+H] + .
实施例61Example 61
(7-((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)吡啶并[3,4-b]吡嗪-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrido[3,4-b]pyrazine-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000166
Figure PCTCN2020097369-appb-000166
(7-((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)吡啶并[3,4-b]吡嗪-8-基)二甲基膦氧化的制备方法参照实施例23。(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrido[3,4-b]pyrazine-8-yl)dimethylphosphine oxidized preparation method refer to Example 23.
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例62Example 62
(7-((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)吡啶并[2,3-b]吡嗪-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrido[2,3-b]pyrazine-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000167
Figure PCTCN2020097369-appb-000167
(7-((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)吡啶并[2,3-b]吡嗪-8-基)二甲基膦氧化的制备方法参照实施例23。(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrido[2,3-b]pyrazin-8-yl)dimethylphosphine oxidation method refer to Example 23.
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例63Example 63
N-(2-((2-((4-(4-((3aR,6aS)-5-乙酰基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)苯基)环丙磺酰胺的制备N-(2-((2-((4-(4-((3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)piperidine- Preparation of 1-yl)-5-ethyl-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide
Figure PCTCN2020097369-appb-000168
Figure PCTCN2020097369-appb-000168
N-(2-((2-((4-(4-((3aR,6aS)-5-乙酰基六氢吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)苯基)环丙磺酰胺的制备方法参照实施例19。N-(2-((2-((4-(4-((3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)piperidine- The preparation method of 1-yl)-5-ethyl-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide refers to Example 19.
MS m/z(ESI):753.2[M+H] +. MS m/z(ESI):753.2[M+H] + .
实施例64Example 64
N-(2-((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)苯基)环丙磺酰胺的制备N-(2-((5-Bromo-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide
Figure PCTCN2020097369-appb-000169
Figure PCTCN2020097369-appb-000169
N-(2-((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)苯基)环丙磺酰胺的制备方法参照实施例19。N-(2-((5-Bromo-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxy-5- Refer to Example 19 for the preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide.
MS m/z(ESI):686.2[M+H] +. MS m/z(ESI): 686.2[M+H] + .
实施例65Example 65
(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)氧代)喹喔啉-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)oxo)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000170
Figure PCTCN2020097369-appb-000170
(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)氧代)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl ) Amino) pyrimidin-4-yl) oxo) quinoxalin-5-yl) dimethyl phosphine oxidation method refer to Example 23.
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例66Example 66
(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)硫代)喹喔啉-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)thio)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000171
Figure PCTCN2020097369-appb-000171
(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)硫代)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)thio)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 23.
MS m/z(ESI):725.2[M+H] +. MS m/z(ESI): 725.2[M+H] + .
实施例67Example 67
(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)(甲基)氨基)喹喔啉-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)(methyl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000172
Figure PCTCN2020097369-appb-000172
(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)(甲基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)(methyl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 23.
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例68Example 68
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)甲基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)methyl)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000173
Figure PCTCN2020097369-appb-000173
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)甲基)喹喔啉-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-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)methyl)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 1.
MS m/z(ESI):693.2[M+H] +. MS m/z(ESI): 693.2[M+H] + .
实施例69Example 69
(6-(2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)喹喔啉-5-基)二甲基膦氧化的制备(6-(2-((2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-7H -Pyrrolo[2,3-d]pyrimidin-7-yl)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000174
Figure PCTCN2020097369-appb-000174
(6-(2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)喹喔啉-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-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-7H -Pyrrolo[2,3-d]pyrimidin-7-yl)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):640.2[M+H] +. MS m/z(ESI): 640.2[M+H] + .
实施例70Example 70
(6-(5-氯-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)喹喔啉-5-基)二甲基膦氧化的制备(6-(5-Chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) (Amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000175
Figure PCTCN2020097369-appb-000175
(6-(5-氯-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)喹喔啉-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-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)quinoxalin-5-yl)dimethylphosphine oxidation is prepared according to Example 1.
MS m/z(ESI):674.2[M+H] +. MS m/z(ESI): 674.2[M+H] + .
实施例71Example 71
(6-((5-溴-2-((5-乙基-2-甲氧基-4-((1-(1-甲基吖丁啶-3-基)哌啶-4-基)氧代)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-((1-(1-methylazetidine-3-yl)piperidin-4-yl) Oxo) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxidation preparation
Figure PCTCN2020097369-appb-000176
Figure PCTCN2020097369-appb-000176
(6-((5-溴-2-((5-乙基-2-甲氧基-4-((1-(1-甲基吖丁啶-3-基)哌啶-4-基)氧代)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-((1-(1-methylazetidine-3-yl)piperidin-4-yl) (Oxo) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 23.
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例72Example 72
1-(3-(4-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧基苯氧基)哌啶-1-基)吖丁啶-1-基)乙烷-1-酮的制备1-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2 -Ethyl-5-methoxyphenoxy)piperidin-1-yl)azetidine-1-yl)ethane-1-one
Figure PCTCN2020097369-appb-000177
Figure PCTCN2020097369-appb-000177
1-(3-(4-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-乙基-5-甲氧基苯氧基)哌啶-1-基)吖丁啶-1-基)乙烷-1-酮的制备方法参照实施例23。1-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2 -Ethyl-5-methoxyphenoxy)piperidin-1-yl)azetidin-1-yl)ethane-1-one The preparation method refers to Example 23.
MS m/z(ESI):723.2[M+H] +. MS m/z(ESI): 723.2[M+H] + .
实施例73Example 73
(6-((5-溴-2-((2-甲氧基-4-((1-(1-(2-甲氧基乙基)吖丁啶-3-基)哌啶-4-基)氧代)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-((1-(1-(2-methoxyethyl)azetidine-3-yl)piperidine-4- (Yl)oxo)-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000178
Figure PCTCN2020097369-appb-000178
(6-((5-溴-2-((2-甲氧基-4-((1-(1-(2-甲氧基乙基)吖丁啶-3-基)哌啶-4-基)氧代)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((2-methoxy-4-((1-(1-(2-methoxyethyl)azetidine-3-yl)piperidine-4- (Yl)oxo)-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 23.
MS m/z(ESI):725.2[M+H] +. MS m/z(ESI): 725.2[M+H] + .
实施例74Example 74
(6-((5-溴-2-((4-((1-(1-(2-氟乙基)吖丁啶-3-基)哌啶-4-基)氧代)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-((1-(1-(2-fluoroethyl)azetidine-3-yl)piperidin-4-yl)oxo)-2- (Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000179
Figure PCTCN2020097369-appb-000179
(6-((5-溴-2-((4-((1-(1-(2-氟乙基)吖丁啶-3-基)哌啶-4-基)氧代)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((4-((1-(1-(2-fluoroethyl)azetidine-3-yl)piperidin-4-yl)oxo)-2- Refer to Example 23 for the preparation method of methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):713.2[M+H] +. MS m/z(ESI): 713.2[M+H] + .
实施例75Example 75
(6-((5-溴-2-((4-((1-(1-乙基吖丁啶-3-基)哌啶-4-基)(甲基)氨基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-((1-(1-ethylazetidine-3-yl)piperidin-4-yl)(methyl)amino)-2-methoxy (5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000180
Figure PCTCN2020097369-appb-000180
(6-((5-溴-2-((4-((1-(1-乙基吖丁啶-3-基)哌啶-4-基)(甲基)氨基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((4-((1-(1-ethylazetidine-3-yl)piperidin-4-yl)(methyl)amino)-2-methoxy For the preparation method of oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine, refer to Example 23.
MS m/z(ESI):708.2[M+H] +. MS m/z(ESI): 708.2[M+H] + .
实施例76Example 76
1-(3-(4-((4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)(甲基)氨基)哌啶-1-基)吖丁啶-1-基)乙烷-1-酮的制备1-(3-(4-((4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- Preparation of 5-methoxy-2-methylphenyl)(methyl)amino)piperidin-1-yl)azetidine-1-yl)ethane-1-one
Figure PCTCN2020097369-appb-000181
Figure PCTCN2020097369-appb-000181
1-(3-(4-((4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)(甲基)氨基)哌啶-1-基)吖丁啶-1-基)乙烷-1-酮的制备方法参照实施例23。1-(3-(4-((4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- Refer to Example 23 for the preparation method of 5-methoxy-2-methylphenyl)(methyl)amino)piperidin-1-yl)azetidine-1-yl)ethane-1-one.
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例77Example 77
(6-((5-溴-2-((2-甲氧基-4-((1-(1-(2-甲氧基乙基)吖丁啶-3-基)哌啶-4-基)(甲基)氨基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-((1-(1-(2-methoxyethyl)azetidine-3-yl)piperidine-4- (Methyl)(methyl)amino)-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000182
Figure PCTCN2020097369-appb-000182
(6-((5-溴-2-((2-甲氧基-4-((1-(1-(2-甲氧基乙基)吖丁啶-3-基)哌啶-4-基)(甲基)氨基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((2-methoxy-4-((1-(1-(2-methoxyethyl)azetidine-3-yl)piperidine-4- (Methyl)(methyl)amino)-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 23.
MS m/z(ESI):738.2[M+H] +. MS m/z(ESI): 738.2[M+H] + .
实施例78Example 78
(6-((5-溴-2-((4-((1-(1-(2-氟乙基)吖丁啶-3-基)哌啶-4-基)(甲基)氨基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-((1-(1-(2-fluoroethyl)azetidine-3-yl)piperidin-4-yl)(methyl)amino) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000183
Figure PCTCN2020097369-appb-000183
(6-((5-溴-2-((4-((1-(1-(2-氟乙基)吖丁啶-3-基)哌啶-4-基)(甲基)氨基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((4-((1-(1-(2-fluoroethyl)azetidine-3-yl)piperidin-4-yl)(methyl)amino) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 23.
MS m/z(ESI):726.2[M+H] +. MS m/z(ESI): 726.2[M+H] + .
实施例79Example 79
(6-((5-溴-2-((2-甲氧基-4-(1-甲氧基-4-(4-甲基哌嗪-1-基)环己基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(1-methoxy-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-methyl (Phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000184
Figure PCTCN2020097369-appb-000184
(6-((5-溴-2-((2-甲氧基-4-(1-甲氧基-4-(4-甲基哌嗪-1-基)环己基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-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-(1-methoxy-4-(4-methylpiperazin-1-yl)cyclohexyl)-5-methyl Refer to Example 1 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):723.2[M+H] +. MS m/z(ESI): 723.2[M+H] + .
实施例80Example 80
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-2,2-二氟环丙烷-1-甲酰胺的制备N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2,2-difluorocyclopropane-1-carboxamide
Figure PCTCN2020097369-appb-000185
Figure PCTCN2020097369-appb-000185
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-2,2-二氟环丙烷-1-甲酰胺的制备方法参照实施例1。N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2,2-difluorocyclopropane-1-carboxamide The preparation method refers to Example 1.
1H NMR(400MHz,CD 3OD)δ1.45-1.65(m,2H),1.80-1.92(m,2H),1.98-2.06(m,2H),2.12(d,J＝5.1Hz,3H),2.16(d,J＝5.2Hz,3H),2.58-2.88(m,7H),2.97-3.20(m,10H),3.88(s,3H),6.86(s,1H),7.96(d,J＝9.5Hz,1H),8.25(s,1H),8.41(s,1H),8.77-8.81(m,1H),8.81-8.85(m,1H),8.88-8.95(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.45-1.65(m,2H),1.80-1.92(m,2H),1.98-2.06(m,2H), 2.12(d,J=5.1Hz,3H) , 2.16(d,J=5.2Hz,3H),2.58-2.88(m,7H),2.97-3.20(m,10H),3.88(s,3H),6.86(s,1H),7.96(d,J ＝9.5Hz, 1H), 8.25 (s, 1H), 8.41 (s, 1H), 8.77-8.81 (m, 1H), 8.81-8.85 (m, 1H), 8.88-8.95 (m, 1H);
MS m/z(ESI):799.2[M+H] +. MS m/z(ESI): 799.2[M+H] + .
实施例81Example 81
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-3,3-二氟丙酰胺的制备N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)-3,3-difluoropropionamide
Figure PCTCN2020097369-appb-000186
Figure PCTCN2020097369-appb-000186
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-3,3-二氟丙酰胺的制备方法参照实施例1。N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)-3,3-difluoropropionamide The preparation method refers to Example 1.
MS m/z(ESI):787.2[M+H] +. MS m/z(ESI): 787.2[M+H] + .
实施例82Example 82
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)噁丁环-2-甲酰胺的制备N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)oxbutane-2-carboxamide
Figure PCTCN2020097369-appb-000187
Figure PCTCN2020097369-appb-000187
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)噁丁环-2-甲酰胺的制备方法参照实施例1。N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 Refer to Example 1 for the preparation method of (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)oxetane-2-carboxamide.
1H NMR(400MHz,CD 3OD)δ1.70-1.82(m,2H),2.03-2.17(m,8H),2.68-3.18(m,18H),3.87(s,3H),4.62-4.70(m,1H),4.72-4.79(m,2H),6.94(s,1H),7.85(d,J＝9.5Hz,1H),8.24(s,1H),8.75-8.79(m,2H),8.80-8.84(m,1H),8.92-8.98(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.70-1.82 (m, 2H), 2.03-2.17 (m, 8H), 2.68-3.18 (m, 18H), 3.87 (s, 3H), 4.62-4.70 ( m,1H),4.72-4.79(m,2H),6.94(s,1H),7.85(d,J=9.5Hz,1H),8.24(s,1H),8.75-8.79(m,2H),8.80 -8.84(m,1H),8.92-8.98(m,1H);
MS m/z(ESI):779.2[M+H] +. MS m/z(ESI): 779.2[M+H] + .
实施例83Example 83
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)噁丁环-3-甲酰胺的制备N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 -(4-(4-Methylpiperazin-1-yl)piperidin-1-yl)phenyl)oxbutane-3-carboxamide
Figure PCTCN2020097369-appb-000188
Figure PCTCN2020097369-appb-000188
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)噁丁环-3-甲酰胺的制备方法参照实施例1。N-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2 Refer to Example 1 for the preparation method of (4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)oxbutane-3-carboxamide.
MS m/z(ESI):779.2[M+H] +. MS m/z(ESI): 779.2[M+H] + .
实施例84Example 84
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)-3,3-二氟丙酰胺的制备N-(5-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-( (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3,3-difluoropropionamide
Figure PCTCN2020097369-appb-000189
Figure PCTCN2020097369-appb-000189
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)-3,3-二氟丙酰胺的制备方法参照实施例1。N-(5-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-( Refer to Example 1 for the preparation method of dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-3,3-difluoropropionamide.
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例85Example 85
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)-2,2-二氟环丙烷-1-甲酰胺的制备N-(5-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-( (Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-2,2-difluorocyclopropane-1-carboxamide
Figure PCTCN2020097369-appb-000190
Figure PCTCN2020097369-appb-000190
N-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧苯基)-2,2-二氟环丙烷-1-甲酰胺的制备方法参照实施例1。N-(5-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-((2-( Refer to Example 1 for the preparation method of dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-2,2-difluorocyclopropane-1-carboxamide.
MS m/z(ESI):718.2[M+H] +. MS m/z(ESI): 718.2[M+H] + .
实施例86Example 86
(6-((5-溴-2-((5-(2,2-二氟乙基)-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-(2,2-difluoroethyl)-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl (Oxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000191
Figure PCTCN2020097369-appb-000191
(6-((5-溴-2-((5-(2,2-二氟乙基)-4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-(2,2-difluoroethyl)-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl The preparation method of oxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation refers to Example 1.
MS m/z(ESI):663.2[M+H] +. MS m/z(ESI): 663.2[M+H] + .
实施例87Example 87
2-(5-((5-溴-4-((7-(二甲基磷基)噻吩并[2,3-b]吡嗪-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)乙酰腈的制备2-(5-((5-Bromo-4-((7-(dimethylphosphoryl)thieno[2,3-b]pyrazin-6-yl)amino)pyrimidin-2-yl)amino) Preparation of -4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acetonitrile
Figure PCTCN2020097369-appb-000192
Figure PCTCN2020097369-appb-000192
2-(5-((5-溴-4-((7-(二甲基磷基)噻吩并[2,3-b]吡嗪-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)乙酰腈的制备方法参照实施例1。2-(5-((5-Bromo-4-((7-(dimethylphosphoryl)thieno[2,3-b]pyrazin-6-yl)amino)pyrimidin-2-yl)amino) Refer to Example 1 for the preparation method of -4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acetonitrile.
MS m/z(ESI):725.2[M+H] +. MS m/z(ESI): 725.2[M+H] + .
实施例88Example 88
(6-((5-溴-2-((5-(2,2-二氟乙基)-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)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-(2,2-difluoroethyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000193
Figure PCTCN2020097369-appb-000193
(6-((5-溴-2-((5-(2,2-二氟乙基)-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)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备方法参照实施例1。(6-((5-Bromo-2-((5-(2,2-difluoroethyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidation preparation method refers to Example 1.
MS m/z(ESI):750.2[M+H] +. MS m/z(ESI): 750.2[M+H] + .
实施例89Example 89
(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-(三氟甲基)苯基)氨基)嘧啶-4-基)氨基)噻吩并[2,3-b]吡嗪-7-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(trifluoromethyl (Yl)phenyl)amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000194
Figure PCTCN2020097369-appb-000194
(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-(三氟甲基)苯基)氨基)嘧啶-4-基)氨基)噻吩并[2,3-b]吡嗪-7-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-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(trifluoromethyl (Yl)phenyl)amino)pyrimidin-4-yl)amino)thieno[2,3-b]pyrazin-7-yl)dimethylphosphine oxidized preparation method refer to Example 1.
MS m/z(ESI):754.2[M+H] +. MS m/z(ESI): 754.2[M+H] + .
实施例90Example 90
(6-((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)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrrole And [2,1-f][1,2,4]triazin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000195
Figure PCTCN2020097369-appb-000195
(6-((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)吡咯并[2,1-f][1,2,4]三嗪-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrrole And the preparation method of [2,1-f][1,2,4]triazin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized according to Example 1.
MS m/z(ESI):669.2[M+H] +. MS m/z(ESI): 669.2[M+H] + .
实施例91Example 91
(6-((3-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,2,4-噻二唑-5-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((3-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 1,2,4-thiadiazol-5-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000196
Figure PCTCN2020097369-appb-000196
(6-((3-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,2,4-噻二唑-5-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((3-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 1 for the preparation method of 1,2,4-thiadiazol-5-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):636.2[M+H] +. MS m/z(ESI): 636.2[M+H] + .
实施例92Example 92
(6-((6-溴-3-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,2,4-三嗪-5-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((6-Bromo-3-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)-1,2,4-triazin-5-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000197
Figure PCTCN2020097369-appb-000197
(6-((6-溴-3-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,2,4-三嗪-5-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((6-Bromo-3-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)-1,2,4-triazin-5-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1.
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例93Example 93
(6-((6-((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)喹喔啉-5-基)二甲基膦氧化的制备(6-((6-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000198
Figure PCTCN2020097369-appb-000198
第一步：(6-((6-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备Step 1: Preparation of (6-((6-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000199
Figure PCTCN2020097369-appb-000199
往(6-氨基喹喔啉-5-基)二甲基膦氧化(221mg,1.0mmol)和4,6-二氯嘧啶(162.8mg,1.1mmol)的叔丁醇溶液(2.0mL)中加入DIPEA(250mg,4.0mmol)，180℃微波反应2h。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-((6-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(200mg,收率:60％)。Add (6-aminoquinoxalin-5-yl) dimethylphosphine oxide (221mg, 1.0mmol) and 4,6-dichloropyrimidine (162.8mg, 1.1mmol) in tert-butanol solution (2.0mL) DIPEA (250mg, 4.0mmol), microwave reaction at 180°C for 2h. After cooling to room temperature, the organic solvent was concentrated under reduced pressure and the column chromatography was separated to obtain the title compound (6-((6-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (200mg, yield Rate: 60%).
MS m/z(ESI):334.1[M+H] +. MS m/z(ESI): 334.1[M+H] + .
第二步：1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-4-甲基哌嗪的制备Step 2: Preparation of 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine
Figure PCTCN2020097369-appb-000200
Figure PCTCN2020097369-appb-000200
往1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(412mg,1.0mmol)和乙烯基三氟硼酸钾(201mg,1.5mmol)的二氧六环溶液(5mL)和水(1mL)混合液中，加入Pd(dppf) 2Cl 2(82mg,0.1mmol)和Cs 2CO 3(1.14g,3mmol)，加热至100℃反应过夜。冷却至室温，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1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-4-甲基哌嗪(270mg,收率:75％)。 To 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (412mg, 1.0mmol) and vinyl trifluoroboric acid To a mixture of potassium (201mg, 1.5mmol) in dioxane solution (5mL) and water (1mL), add Pd(dppf) 2 Cl 2 (82mg, 0.1mmol) and Cs 2 CO 3 (1.14g, 3mmol) , Heat to 100°C and react overnight. After cooling to room temperature, CH 2 Cl 2 and water were added to the reaction. The organic phase was concentrated under reduced pressure and then separated by column chromatography to obtain the title compound 1-(1-(5-methoxy-4-nitro-2-vinyl Phenyl)piperidin-4-yl)-4-methylpiperazine (270 mg, yield: 75%).
MS m/z(ESI):361.2[M+H] +. MS m/z(ESI): 361.2[M+H] + .
第三步：5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺的制备The third step: Preparation of 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline
Figure PCTCN2020097369-appb-000201
Figure PCTCN2020097369-appb-000201
1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-4-甲基哌嗪(270mg,0.75mmol)溶于甲醇(5mL)中，加入Pd/C(30mg)，氢气氛围下室温搅拌2h。反应液过滤，滤液减压浓缩后得到标题化合物5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(235mg,收率:94％)。1-(1-(5-Methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-4-methylpiperazine (270mg, 0.75mmol) dissolved in methanol (5mL) Pd/C (30mg) was added to the mixture, and the mixture was stirred at room temperature for 2h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (235mg , Yield: 94%).
MS m/z(ESI):333.2[M+H] +. MS m/z(ESI): 333.2[M+H] + .
第四步：(6-((6-((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)喹喔啉-5-基)二甲基膦氧化的制备The fourth step: (6-((6-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000202
Figure PCTCN2020097369-appb-000202
往5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(33.2mg,0.1mmol)和(6-((6-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(33.3mg,0.1mmol)的叔丁醇(2mL)混合液中，加入TsOH(68.8mg,0.4mmol)，100℃反应过夜。冷却至室温，反应液减压浓缩后柱层析分离得到标题化合物(6-((6-((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)喹喔啉-5-基)二甲基膦氧化(35mg,收率:56％)。To 5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (33.2mg, 0.1mmol) and (6-(( 6-Chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (33.3mg, 0.1mmol) in tert-butanol (2mL) mixed solution, add TsOH (68.8mg, 0.4mmol) ), react at 100°C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((6-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (35 mg, yield: 56%).
1H NMR(400MHz,CD 3OD)δ1.22(t,J＝7.5Hz,3H),1.68-1.77(m,2H),1.98-2.06(m,2H),2.08(s,3H),2.12(s,3H),2.42(s,3H),2.47-2.54(m,1H),2.90-2.63(m,12H),3.10-3.18(m,2H),3.83(s,3H),5.97(s,1H),6.81(s,1H),7.35(s,1H),8.11(d,J＝9.6Hz,1H),8.28(s,1H),8.69-8.73(m,1H),8.76-8.80(m,1H),9.15-9.21(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.22 (t, J = 7.5Hz, 3H), 1.68-1.77 (m, 2H), 1.98-2.06 (m, 2H), 2.08 (s, 3H), 2.12 (s, 3H), 2.42 (s, 3H), 2.47-2.54 (m, 1H), 2.90-2.63 (m, 12H), 3.10-3.18 (m, 2H), 3.83 (s, 3H), 5.97 (s ,1H),6.81(s,1H),7.35(s,1H),8.11(d,J=9.6Hz,1H),8.28(s,1H),8.69-8.73(m,1H),8.76-8.80( m,1H),9.15-9.21(m,1H);
MS m/z(ESI):630.2[M+H] +. MS m/z(ESI): 630.2[M+H] + .
实施例94Example 94
(6-((4-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000203
Figure PCTCN2020097369-appb-000203
(6-((4-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 93 for the preparation method of 1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz，CD 3OD)δ1.17(t,J＝8.2Hz,3H),1.76-1.86(m,2H),2.03-2.19(m,8H),2.64-2.73(m,5H),2.75-2.84(m,3H),3.01-3.12(m,7H),3.15-3.22(m,3H),3.85(s,3H),6.83(s,1H),7.66(s,1H),7.91-8.05(m,1H),8.31(s,1H),8.77(s,1H),8.82(s,1H),9.11-9.27(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.17 (t, J = 8.2 Hz, 3H), 1.76-1.86 (m, 2H), 2.03-2.19 (m, 8H), 2.64-2.73 (m, 5H) ,2.75-2.84(m,3H),3.01-3.12(m,7H),3.15-3.22(m,3H),3.85(s,3H),6.83(s,1H),7.66(s,1H),7.91 -8.05(m,1H),8.31(s,1H),8.77(s,1H),8.82(s,1H),9.11-9.27(m,1H);
MS m/z(ESI):631.2[M+H] +. MS m/z(ESI): 631.2[M+H] + .
实施例95Example 95
(6-((4-((5-乙基-2-甲氧基-4-(4-(吡咯烷-1-基)哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)-1,3, Preparation of 5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000204
Figure PCTCN2020097369-appb-000204
(6-((4-((5-乙基-2-甲氧基-4-(4-(吡咯烷-1-基)哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)-1,3, Refer to Example 93 for the preparation method of 5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.17(t,J＝7.4Hz,3H),1.87-1.98(m,2H),2.08-2.15(m,9H),2.24-2.32(m,2H),2.64-2.73(m,4H),2.81-2.90(m,2H),3.18-3.27(m,3H),3.39-3.45(m,3H),3.86(s,3H),6.84(s,1H),7.70(s,1H),7.88-8.11(m,1H),8.32(s,1H),8.75-8.79(m,1H),8.81-8.85(m,1H),9.11-9.33(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.17(t,J=7.4Hz,3H),1.87-1.98(m,2H),2.08-2.15(m,9H),2.24-2.32(m,2H) ,2.64-2.73(m,4H),2.81-2.90(m,2H),3.18-3.27(m,3H), 3.39-3.45(m,3H), 3.86(s,3H), 6.84(s,1H) ,7.70(s,1H),7.88-8.11(m,1H),8.32(s,1H),8.75-8.79(m,1H),8.81-8.85(m,1H),9.11-9.33(m,1H) ；
MS m/z(ESI):602.2[M+H] +. MS m/z(ESI): 602.2[M+H] + .
实施例96Example 96
(6-((4-((4-(4-(二乙胺基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((4-(4-(Diethylamino)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-1,3,5-tri Oxidation of azin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine
Figure PCTCN2020097369-appb-000205
Figure PCTCN2020097369-appb-000205
(6-((4-((4-(4-(二乙胺基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((4-(4-(Diethylamino)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-1,3,5-tri Refer to Example 93 for the preparation method of azin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):604.2[M+H] +. MS m/z(ESI): 604.2[M+H] + .
实施例97Example 97
(6-((4-((5-乙基-2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-1,3,5-triazine- Preparation of 2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000206
Figure PCTCN2020097369-appb-000206
(6-((4-((5-乙基-2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-1,3,5-triazine- Refer to Example 93 for the preparation method of 2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):618.2[M+H] +. MS m/z(ESI): 618.2[M+H] + .
实施例98Example 98
环丙基(4-(1-(4-((4-((5-(二甲基磷基)喹喔啉-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)哌嗪-1-基)甲酮的制备Cyclopropyl (4-(1-(4-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)-1,3,5-triazin-2-yl )Amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methanone
Figure PCTCN2020097369-appb-000207
Figure PCTCN2020097369-appb-000207
环丙基(4-(1-(4-((4-((5-(二甲基磷基)喹喔啉-6-基)氨基)-1,3,5-三嗪-2-基)氨基)-2-乙基-5-甲氧苯基)哌啶-4-基)哌嗪-1-基)甲酮的制备方法参照实施例93。Cyclopropyl (4-(1-(4-((4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)-1,3,5-triazin-2-yl )Amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methanone. Refer to Example 93 for the preparation method.
1H NMR(400MHz,CD 3OD)δ0.81-0.92(m,4H),1.16(m,3H),1.76-1.87(m,2H),1.95-2.02(m,1H),2.05-2.18(m,8H),2.65-2.74(m,3H),2.78-2.95(m,6H),3.16-3.24(m,2H),3.67-3.76(m,2H),3.84-3.93(m,5H),6.85(s,1H),7.66(s,1H),7.91-8.11(m,H),8.32(s,1H),8.76-8.80(m,1H),8.81-8.85(m,1H),9.15-9.29(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.81-0.92 (m, 4H), 1.16 (m, 3H), 1.76-1.87 (m, 2H), 1.95-2.02 (m, 1H), 2.05-2.18 ( m,8H),2.65-2.74(m,3H),2.78-2.95(m,6H),3.16-3.24(m,2H), 3.67-3.76(m,2H),3.84-3.93(m,5H), 6.85(s,1H),7.66(s,1H),7.91-8.11(m,H),8.32(s,1H),8.76-8.80(m,1H),8.81-8.85(m,1H),9.15- 9.29(m,1H);
MS m/z(ESI):685.2[M+H] +. MS m/z(ESI): 685.2[M+H] + .
实施例99Example 99
(6-((4-((4-(4-(4-环丁基哌嗪-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((4-(4-(4-cyclobutylpiperazin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)- Preparation of 1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000208
Figure PCTCN2020097369-appb-000208
(6-((4-((4-(4-(4-环丁基哌嗪-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((4-(4-(4-cyclobutylpiperazin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)- Refer to Example 93 for the preparation method of 1,3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):671.2[M+H] +. MS m/z(ESI): 671.2[M+H] + .
实施例100Example 100
(6-((4-((5-乙基-2-甲氧基-4-((1-甲基哌啶-4-基)氧代)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-((1-methylpiperidin-4-yl)oxo)phenyl)amino)-1,3,5- Preparation of triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000209
Figure PCTCN2020097369-appb-000209
(6-((4-((5-乙基-2-甲氧基-4-((1-甲基哌啶-4-基)氧代)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-((1-methylpiperidin-4-yl)oxo)phenyl)amino)-1,3,5- Refer to Example 93 for the preparation method of triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):563.2[M+H] +. MS m/z(ESI): 563.2[M+H] + .
实施例101Example 101
(6-((4-((5-乙基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,3,5-triazine-2 -Yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000210
Figure PCTCN2020097369-appb-000210
(6-((4-((5-乙基-2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,3,5-triazine-2 Refer to Example 93 for the preparation method of -yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):548.2[M+H] +. MS m/z(ESI): 548.2[M+H] + .
实施例102Example 102
(6-((4-((5-乙基-2-甲氧基-4-(4-甲氧基哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(4-methoxypiperidin-1-yl)phenyl)amino)-1,3,5-triazine- Preparation of 2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000211
Figure PCTCN2020097369-appb-000211
(6-((4-((5-乙基-2-甲氧基-4-(4-甲氧基哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(4-methoxypiperidin-1-yl)phenyl)amino)-1,3,5-triazine- Refer to Example 93 for the preparation method of 2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):563.2[M+H] +. MS m/z(ESI): 563.2[M+H] + .
实施例103Example 103
(6-((4-((4-(4-(吖丁啶-1-基甲基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((4-(4-(azetidin-1-ylmethyl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-1, 3,5-Triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000212
Figure PCTCN2020097369-appb-000212
(6-((4-((4-(4-(吖丁啶-1-基甲基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((4-(4-(azetidin-1-ylmethyl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-1, Refer to Example 93 for the preparation method of 3,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):602.2[M+H] +. MS m/z(ESI): 602.2[M+H] + .
实施例104Example 104
(6-((4-((5-乙基-2-甲氧基-4-(4-(2-甲基吗啉代)哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(4-(2-methylmorpholino)piperidin-1-yl)phenyl)amino)-1,3 ,5-Triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000213
Figure PCTCN2020097369-appb-000213
(6-((4-((5-乙基-2-甲氧基-4-(4-(2-甲基吗啉代)哌啶-1-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(4-(2-methylmorpholino)piperidin-1-yl)phenyl)amino)-1,3 Refer to Example 93 for the preparation method of ,5-triazin-2-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):632.2[M+H] +. MS m/z(ESI): 632.2[M+H] + .
实施例105Example 105
(6-((4-((5-乙基-2-甲氧基-4-(1-甲基哌啶-4-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((4-((5-ethyl-2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-1,3,5-triazine-2 -Yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000214
Figure PCTCN2020097369-appb-000214
(6-((4-((5-乙基-2-甲氧基-4-(1-甲基哌啶-4-基)苯基)氨基)-1,3,5-三嗪-2-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例93。(6-((4-((5-ethyl-2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-1,3,5-triazine-2 Refer to Example 93 for the preparation method of -yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):547.2[M+H] +. MS m/z(ESI): 547.2[M+H] + .
实施例106Example 106
(6-((5-溴-2-((7-甲氧基-1-(3-(4-甲基哌嗪-1-基)丙基)-1,2,3,4-四氢喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-1-(3-(4-methylpiperazin-1-yl)propyl)-1,2,3,4-tetrahydro (Quinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000215
Figure PCTCN2020097369-appb-000215
(6-((5-溴-2-((7-甲氧基-1-(3-(4-甲基哌嗪-1-基)丙基)-1,2,3,4-四氢喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-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-(3-(4-methylpiperazin-1-yl)propyl)-1,2,3,4-tetrahydro For the preparation method of quinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 1.
1H NMR(400MHz,CDCl 3)δ1.75-1.85(m,2H),1.86-1.96(m,2H),2.10(s,3H),2.14(s,3H),2.32(s,3H),2.39-2.79(m,12H),3.21-3.34(m,4H),3.83(s,3H),6.22(s,1H),7.12(s,1H),7.59(s,1H),8.06(d,J＝9.5Hz,1H),8.22(s,1H),8.72(dd,J＝13.8,1.7Hz,2H),9.10(dd,J＝9.5,4.2Hz,1H),12.51(s,1H)； 1 H NMR(400MHz, CDCl 3 )δ1.75-1.85(m,2H),1.86-1.96(m,2H), 2.10(s,3H), 2.14(s,3H), 2.32(s,3H), 2.39-2.79(m,12H), 3.21-3.34(m,4H), 3.83(s,3H), 6.22(s,1H), 7.12(s,1H), 7.59(s,1H), 8.06(d, J = 9.5Hz, 1H), 8.22 (s, 1H), 8.72 (dd, J = 13.8, 1.7 Hz, 2H), 9.10 (dd, J = 9.5, 4.2 Hz, 1H), 12.51 (s, 1H);
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例107Example 107
(6-((5-溴-2-((7-甲氧基-2-(2-(4-甲基哌嗪-1-基)乙基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2-(2-(4-methylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydro Preparation of isoquinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000216
Figure PCTCN2020097369-appb-000216
(6-((5-溴-2-((7-甲氧基-2-(2-(4-甲基哌嗪-1-基)乙基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-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-(2-(4-methylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydro Refer to Example 1 for the preparation method of isoquinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):680.2[M+H] +. MS m/z(ESI): 680.2[M+H] + .
实施例108Example 108
N-(3-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧苯 基)-2-(4-甲基哌嗪-1-基)乙酰胺的制备N-(3-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl) Preparation of -2-(4-methylpiperazin-1-yl)acetamide
Figure PCTCN2020097369-appb-000217
Figure PCTCN2020097369-appb-000217
第一步：(6-((5-溴-2-((2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备The first step: (6-((5-bromo-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097369-appb-000218
Figure PCTCN2020097369-appb-000218
往2-甲氧基-5-硝基苯胺(33mg,1.2mmol)和(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(411mg,1.0mmol)的叔丁醇(5mL)混合液中，加入TsOH(344mg,2.0mmol)，100℃反应过夜。冷却至室温，反应液减压浓缩后柱层析分离得到标题化合物(6-((5-溴-2-((2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(358mg,收率:66％)。To 2-methoxy-5-nitroaniline (33mg, 1.2mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl TsOH (344 mg, 2.0 mmol) was added to the mixture of phosphine oxidation (411 mg, 1.0 mmol) and tert-butanol (5 mL) and reacted at 100°C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((5-bromo-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl )Amino)quinoxalin-5-yl)dimethylphosphine oxide (358mg, yield: 66%).
MS m/z(ESI):544.1[M+H] +. MS m/z(ESI): 544.1[M+H] + .
第二步：(6-((2-((5-氨基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备The second step: (6-((2-((5-amino-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine Oxidation preparation
Figure PCTCN2020097369-appb-000219
Figure PCTCN2020097369-appb-000219
(6-((5-溴-2-((2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(358mg,0.66mmol)溶于乙醇(10mL)溶液中，加入氯化亚锡水合物(903mg,4.0mmol)，80℃反应过夜。冷却至室温，浓缩掉乙醇，DCM与饱和碳酸钠水溶液分液，有机相减压浓缩后柱层析分离得到标题化合物(6-((2-((5-氨基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(270mg,收率:80％)。(6-((5-Bromo-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide ( 358mg, 0.66mmol) was dissolved in ethanol (10mL) solution, stannous chloride hydrate (903mg, 4.0mmol) was added and reacted at 80°C overnight. After cooling to room temperature, ethanol was concentrated, DCM was separated from saturated aqueous sodium carbonate solution, and the organic phase was concentrated under reduced pressure and column chromatography was separated to obtain the title compound (6-((2-((5-amino-2-methoxyphenyl) Amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (270 mg, yield: 80%).
MS m/z(ESI):514.1[M+H] +. MS m/z(ESI): 514.1[M+H] + .
第三步：N-(3-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧苯基)-2-(4-甲基哌嗪-1-基)乙酰胺的制备The third step: N-(3-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methyl Preparation of oxyphenyl)-2-(4-methylpiperazin-1-yl)acetamide
Figure PCTCN2020097369-appb-000220
Figure PCTCN2020097369-appb-000220
往(6-((2-((5-氨基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(51mg,0.1mmol)，2-(4-甲基哌嗪-1-基)乙酸(24mg,0.15mmol)和DIPEA(0.1mL)的DMF(2mL)混合液中，加入HATU(76mg,0.2mmol)，室温反应过夜。DCM与饱和碳酸氢钠水溶液分液，有机相减压浓缩后柱层析分离得到标题化合物N-(3-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧苯基)-2-(4-甲基哌嗪-1-基)乙酰胺(33mg,收率:50％)。To (6-((2-((5-amino-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (51mg , 0.1mmol), 2-(4-methylpiperazin-1-yl)acetic acid (24mg, 0.15mmol) and DIPEA (0.1mL) in DMF (2mL) mixture, add HATU (76mg, 0.2mmol), React overnight at room temperature. DCM was separated with saturated aqueous sodium bicarbonate solution, and the organic phase was concentrated under reduced pressure and separated by column chromatography to obtain the title compound N-(3-((5-bromo-4-((5-(dimethylphosphoryl)quinoxaline) -6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)acetamide (33 mg, yield: 50%).
1H NMR(400MHz,CD 3OD)δ2.12(s,3H),2.16(s,3H),2.70-2.82(m,7H),3.08-3.20(m,6H),3.89(s,3H),6.99(d,J＝8.8Hz,1H),7.24-7.30(m,1H),8.01(d,J＝9.5Hz,1H),8.20-8.30(m,2H),8.80-8.86(m,2H),9.01-9.07(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 2.12 (s, 3H), 2.16 (s, 3H), 2.70-2.82 (m, 7H), 3.08-3.20 (m, 6H), 3.89 (s, 3H) ,6.99(d,J=8.8Hz,1H),7.24-7.30(m,1H),8.01(d,J=9.5Hz,1H),8.20-8.30(m,2H),8.80-8.86(m,2H ),9.01-9.07(m,1H);
MS m/z(ESI):654.1[M+H] +. MS m/z(ESI): 654.1[M+H] + .
实施例109Example 109
N-(3-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧苯基)-4-(二甲氨基)丁酰胺的制备N-(3-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl) Preparation of -4-(dimethylamino)butanamide
Figure PCTCN2020097369-appb-000221
Figure PCTCN2020097369-appb-000221
N-(3-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-4-甲氧苯基)-4-(二甲氨基)丁酰胺的制备方法参照实施例108。N-(3-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl) Refer to Example 108 for the preparation method of -4-(dimethylamino)butanamide.
1H NMR(400MHz,CD 3OD)δ1.90-1.98(m,2H),2.12(s,3H),2.16(s,3H),2.35-2.43(m,2H),2.85(s,6H),3.06-3.16(m,2H),3.89(s,3H),6.98(d,J＝8.8Hz,1H),7.28-7.34(m,1H),8.01(d,J＝9.5Hz,1H),8.13-8.17(m,1H),8.28(s,1H), 8.79-8.88(m,2H),9.00-9.07(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.90-1.98(m,2H), 2.12(s,3H), 2.16(s,3H), 2.35-2.43(m,2H), 2.85(s,6H) ,3.06-3.16(m,2H),3.89(s,3H),6.98(d,J=8.8Hz,1H),7.28-7.34(m,1H),8.01(d,J=9.5Hz,1H), 8.13-8.17(m,1H), 8.28(s,1H), 8.79-8.88(m,2H), 9.00-9.07(m,1H);
MS m/z(ESI):627.2[M+H] +. MS m/z(ESI): 627.2[M+H] + .
实施例110Example 110
(6-((5-溴-2-((5-(1,1-二氟-2-吗啉代乙氧基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-(1,1-difluoro-2-morpholinoethoxy)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino) Preparation of quinoxalin-5-yl) dimethyl phosphine oxidation
Figure PCTCN2020097369-appb-000222
Figure PCTCN2020097369-appb-000222
(6-((5-溴-2-((5-(1,1-二氟-2-吗啉代乙氧基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例108。(6-((5-Bromo-2-((5-(1,1-difluoro-2-morpholinoethoxy)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino) Refer to Example 108 for the preparation method of quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):664.2[M+H] +. MS m/z(ESI): 664.2[M+H] + .
实施例111Example 111
(6-((5-溴-2-((2-甲氧基-5-((2-吗啉代乙基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-((2-morpholinoethyl)amino)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline- Preparation of 5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000223
Figure PCTCN2020097369-appb-000223
(6-((5-溴-2-((2-甲氧基-5-((2-吗啉代乙基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例108。(6-((5-Bromo-2-((2-methoxy-5-((2-morpholinoethyl)amino)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline- Refer to Example 108 for the preparation method of 5-yl)dimethylphosphine oxidation.
MS m/z(ESI):627.2[M+H] +. MS m/z(ESI): 627.2[M+H] + .
实施例112Example 112
(6-((5-溴-2-((2-甲氧基-5-((1-甲基哌啶-3-基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-((1-methylpiperidin-3-yl)amino)phenyl)amino)pyrimidin-4-yl)amino)quine Oxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000224
Figure PCTCN2020097369-appb-000224
(6-((5-溴-2-((2-甲氧基-5-((1-甲基哌啶-3-基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例108。(6-((5-Bromo-2-((2-methoxy-5-((1-methylpiperidin-3-yl)amino)phenyl)amino)pyrimidin-4-yl)amino)quine Refer to Example 108 for the preparation method of oxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):611.2[M+H] +. MS m/z(ESI): 611.2[M+H] + .
实施例113Example 113
(6-((5-溴-2-((2-甲氧基-5-((1-甲基哌啶-4-基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrimidin-4-yl)amino)quine Oxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000225
Figure PCTCN2020097369-appb-000225
(6-((5-溴-2-((2-甲氧基-5-((1-甲基哌啶-4-基)氨基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例108。(6-((5-Bromo-2-((2-methoxy-5-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrimidin-4-yl)amino)quine Refer to Example 108 for the preparation method of oxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):611.2[M+H] +. MS m/z(ESI): 611.2[M+H] + .
实施例114Example 114
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000226
Figure PCTCN2020097369-appb-000226
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper Refer to Example 23 for the preparation method of pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):708.2[M+H] +. MS m/z(ESI): 708.2[M+H] + .
实施例115Example 115
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000227
Figure PCTCN2020097369-appb-000227
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino )-5-Bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 23.
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例116Example 116
(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000228
Figure PCTCN2020097369-appb-000228
(6-((5-溴-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-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-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 1.
1H NMR(400MHz，CD 3OD)δ1.72-1.82(m,2H),1.96-2.05(m,2H),2.13(s,3H),2.17(s,3H),2.62-2.71(m,4H),2.87-3.05(m,8H),3.38-3.55(m,4H),3.99(s,3H),6.79(s,1H),7.98(d,J＝9.4Hz,1H),8.31(s,1H),8.53(s,1H),8.75-8.82(m,2H),8.84-8.86(m,1H)； 1 H NMR(400MHz, CD 3 OD)δ1.72-1.82(m,2H),1.96-2.05(m,2H),2.13(s,3H),2.17(s,3H),2.62-2.71(m, 4H), 2.87-3.05(m, 8H), 3.38-3.55(m, 4H), 3.99(s, 3H), 6.79(s, 1H), 7.98(d, J=9.4Hz, 1H), 8.31(s ,1H),8.53(s,1H),8.75-8.82(m,2H),8.84-8.86(m,1H);
MS m/z(ESI):725.2[M+H] +. MS m/z(ESI): 725.2[M+H] + .
实施例117Example 117
(6-((2-((5-氨基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 -Bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000229
Figure PCTCN2020097369-appb-000229
(6-((2-((5-氨基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 -Bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例118Example 118
(6-((5-氯-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((trimethyl (Methylsilyl)ethynyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000230
Figure PCTCN2020097369-appb-000230
(6-((5-氯-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-((三甲基甲硅烷基)乙炔基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-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-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-((trimethyl For the preparation method of oxyalkylsilyl)ethynyl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine, refer to Example 1.
MS m/z(ESI):732.3[M+H] +. MS m/z(ESI): 732.3[M+H] + .
实施例119Example 119
(6-((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)-5-(三氟甲基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(6-((2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- 5-(Trifluoromethyl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
Figure PCTCN2020097369-appb-000231
Figure PCTCN2020097369-appb-000231
(6-((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)-5-(三氟甲基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 1 for the preparation method of 5-(trifluoromethyl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):694.3[M+H] +. MS m/z(ESI): 694.3[M+H] + .
实施例120Example 120
(6-((2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(丙-1-炔-1-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000232
Figure PCTCN2020097369-appb-000232
(6-((2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-(丙-1-炔-1-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 23 for the preparation method of 5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):654.3[M+H] +. MS m/z(ESI): 654.3[M+H] + .
实施例121Example 121
(6-((3-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,2,4-噻二唑-5-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Preparation of 1,2,4-thiadiazol-5-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000233
Figure PCTCN2020097369-appb-000233
(6-((3-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-1,2,4-噻二唑-5-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)- Refer to Example 23 for the preparation method of 1,2,4-thiadiazol-5-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):622.3[M+H] +. MS m/z(ESI): 622.3[M+H] + .
实施例122Example 122
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000234
Figure PCTCN2020097369-appb-000234
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(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)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 19.
1H NMR(400MHz,CD 3OD)δ0.83(t,J＝7.4Hz,3H),1.22(s,6H),1.60-1.68(m,2H),2.03-2.19(m,8H),2.48(q,J＝7.5Hz,2H),2.78(t,J＝11.5Hz,2H),3.01-3.15(m,3H),3.85(s,3H),3.99-4.14(m,2H),4.30-4.42(m,2H),6.81(s,1H),7.65(s,1H),7.98(d,J＝9.3Hz,1H),8.38(s,1H),8.80-8.90(m,3H)； 1 H NMR (400MHz, CD 3 OD) δ 0.83 (t, J = 7.4Hz, 3H), 1.22 (s, 6H), 1.60-1.68 (m, 2H), 2.03-2.19 (m, 8H), 2.48 (q,J=7.5Hz,2H),2.78(t,J=11.5Hz,2H),3.01-3.15(m,3H),3.85(s,3H),3.99-4.14(m,2H),4.30- 4.42(m,2H), 6.81(s,1H), 7.65(s,1H), 7.98(d,J=9.3Hz,1H), 8.38(s,1H), 8.80-8.90(m,3H);
MS m/z(ESI):741.2[M+H] +. MS m/z(ESI): 741.2[M+H] + .
实施例123Example 123
(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)喹喔啉-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) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000235
Figure PCTCN2020097369-appb-000235
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl Refer to Example 19 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz，CD 3OD)δ1.21(t,J＝7.0Hz,3H),1.44-1.57(m,2H), 1.91-1.99(m,2H),2.06(s,3H),2.12(s,3H),2.16(s,3H),2.48-2.60(m,1H),2.66-2.75(m,3H),3.08-3.17(m,2H),3.46-3.54(m,3H),3.81-3.93(m,5H),4.17-4.25(m,1H),6.75(s,1H),7.61(s,1H),7.98(d,J＝9.5Hz,1H),8.22(s,1H),8.78-8.85(m,2H),8.92-8.98(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.21 (t, J = 7.0 Hz, 3H), 1.44-1.57 (m, 2H), 1.91-1.99 (m, 2H), 2.06 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.48-2.60 (m, 1H), 2.66-2.75 (m, 3H), 3.08-3.17 (m, 2H), 3.46-3.54 (m, 3H), 3.81 -3.93(m,5H),4.17-4.25(m,1H),6.75(s,1H),7.61(s,1H),7.98(d,J=9.5Hz,1H),8.22(s,1H), 8.78-8.85(m,2H),8.92-8.98(m,1H);
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例124Example 124
1-(4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)哌嗪-1-基)乙烷-1-酮的制备1-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethane-1-one
Figure PCTCN2020097369-appb-000236
Figure PCTCN2020097369-appb-000236
1-(4-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)哌嗪-1-基)乙烷-1-酮的制备方法参照实施例19。1-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethane-1-one The preparation method refers to Example 19.
1H NMR(400MHz，CD 3OD)δ1.71-1.82(m,2H),2.00-2.59(m,5H),2.12(d,J＝3.5Hz，6H),2.15(s，3H),2.61-2.76(m,3H),2.77-2.90(m,4H),3.14-3.22(m,2H),3.61-3.73(m,4H),3.83(s,3H),6.73(s,1H),7.60(s,1H),7.96(d,J＝9.5Hz,1H),8.20(s,1H),8.76-8.87(m,2H),8.90-8.98(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.71-1.82 (m, 2H), 2.00-2.59 (m, 5H), 2.12 (d, J = 3.5 Hz, 6H), 2.15 (s, 3H), 2.61 -2.76(m,3H),2.77-2.90(m,4H),3.14-3.22(m,2H),3.61-3.73(m,4H),3.83(s,3H),6.73(s,1H),7.60 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 8.20 (s, 1H), 8.76-8.87 (m, 2H), 8.90-8.98 (m, 1H);
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例125Example 125
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000237
Figure PCTCN2020097369-appb-000237
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Trifluoromethyl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 19.
1H NMR(400MHz，CD 3OD)δ1.47-1.60(m,3H),1.95-2.03(m,2H),2.13(s,3H),2.16(s,3H),2.25(s,6H),2.77-2.91(m,3H),3.06-3.18(m,3H),3.51-3.61(m,2H),3.91-4.00(m,4H),7.09(m,1H),8.00(d,J＝9.5Hz,1H),8.17(s,1H),8.31(s,1H),8.78-8.89(m,3H)； 1 H NMR(400MHz, CD 3 OD)δ1.47-1.60(m,3H),1.95-2.03(m,2H),2.13(s,3H),2.16(s,3H),2.25(s,6H) ,2.77-2.91(m,3H),3.06-3.18(m,3H),3.51-3.61(m,2H),3.91-4.00(m,4H),7.09(m,1H),8.00(d,J= 9.5Hz, 1H), 8.17 (s, 1H), 8.31 (s, 1H), 8.78-8.89 (m, 3H);
MS m/z(ESI):748.2[M+H] +. MS m/z(ESI): 748.2[M+H] + .
实施例126Example 126
(6-((5-溴-2-((5-(二氟甲基)-4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-(difluoromethyl)-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl) -2-Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000238
Figure PCTCN2020097369-appb-000238
(6-((5-溴-2-((5-(二氟甲基)-4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((5-(difluoromethyl)-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl) -2-Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 19.
MS m/z(ESI):730.2[M+H] +. MS m/z(ESI): 730.2[M+H] + .
实施例127Example 127
2-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-4-甲氧苯基)乙酰腈的制备2-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(3 -(Dimethylamino)azetidine-1-yl)piperidin-1-yl)-4-methoxyphenyl)acetonitrile
Figure PCTCN2020097369-appb-000239
Figure PCTCN2020097369-appb-000239
2-(5-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-4-甲氧苯基)乙酰腈的制备方法参照实施例19。2-(5-((5-Bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(3 -(Dimethylamino)azetidin-1-yl)piperidin-1-yl)-4-methoxyphenyl)acetonitrile Refer to Example 19 for the preparation method.
MS m/z(ESI):719.2[M+H] +. MS m/z(ESI): 719.2[M+H] + .
实施例128Example 128
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000240
Figure PCTCN2020097369-appb-000240
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 23.
1H NMR(400MHz，CD 3OD)δ1.45-1.58(m,3H),1.96-2.04(m,2H),2.09(s,3H),2.13(s,3H),2.25(s,6H),2.29-2.43(m,2H),2.67-2.85(m,4H),3.01-3.10(m,2H),3.12-3.21(m,1H),3.46-3.58(m,3H),3.85(s,3H),3.90-3.99(m,2H),6.79(s, 1H),7.60(s,1H),7.90-8.04(m,1H),8.41(s,1H),8.52-8.65(m,1H),8.79-8.90(m,2H)； 1 H NMR(400MHz, CD 3 OD)δ1.45-1.58(m,3H),1.96-2.04(m,2H),2.09(s,3H),2.13(s,3H),2.25(s,6H) ,2.29-2.43(m,2H),2.67-2.85(m,4H),3.01-3.10(m,2H),3.12-3.21(m,1H),3.46-3.58(m,3H),3.85(s, 3H), 3.90-3.99 (m, 2H), 6.79 (s, 1H), 7.60 (s, 1H), 7.90-8.04 (m, 1H), 8.41 (s, 1H), 8.52-8.65 (m, 1H) ,8.79-8.90(m,2H);
MS m/z(ESI):698.3[M+H] +. MS m/z(ESI): 698.3[M+H] + .
实施例129Example 129
(6-((5-氯-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Chloro-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxybenzene (Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000241
Figure PCTCN2020097369-appb-000241
(6-((5-氯-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Chloro-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxybenzene (Yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 23.
1H NMR(400MHz,CD 3OD)δ0.91(t,J＝7.4Hz,3H),1.23(t,J＝7.0Hz,3H),1.54-1.69(m,2H),2.01-2.24(m,8H),2.53(q,J＝7.5Hz,2H),2.73-2.87(m,2H),3.01-3.14(m,3H),3.54(q,J＝7.0Hz,2H),3.85-3.88(m,5H),4.26(t,J＝8.4Hz,2H),4.31-4.42(m,1H),6.81(s,1H),7.67(s,1H),7.98(d,J＝9.5Hz,1H),8.14(s,1H),8.79(d,J＝2.0Hz,1H),8.84(d,J＝1.9Hz,1H),9.04(dd,J＝9.5,4.3Hz,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.91 (t, J = 7.4 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H), 1.54-1.69 (m, 2H), 2.01-2.24 (m ,8H),2.53(q,J=7.5Hz,2H),2.73-2.87(m,2H),3.01-3.14(m,3H),3.54(q,J=7.0Hz,2H),3.85-3.88( m,5H), 4.26(t,J=8.4Hz,2H),4.31-4.42(m,1H),6.81(s,1H),7.67(s,1H),7.98(d,J=9.5Hz,1H ), 8.14 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 1.9 Hz, 1H), 9.04 (dd, J = 9.5, 4.3 Hz, 1H);
MS m/z(ESI):665.3[M+H] +. MS m/z(ESI): 665.3[M+H] + .
实施例130Example 130
(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-(甲硫基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(methylthio)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000242
Figure PCTCN2020097369-appb-000242
(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-(甲硫基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(methylthio)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 19.
1H NMR(400MHz，CD 3OD)δ1.45-1.63(m,2H),1.94-2.03(m,2H),2.06(s,3H),2.12(s,3H),2.15(s,3H),2.23(s,6H),2.35(s,3H),2.63-2.77(m,3H),3.08-3.19(m,3H),3.37-3.45(m,2H),3.82-3.91(m,5H),6.75(s,1H),7.64(s,1H),7.96(d,J＝9.5Hz,1H),8.26(s,1H),8.74-8.87(m,2H),9.00-9.10(m,1H)； 1 H NMR(400MHz, CD 3 OD)δ1.45-1.63(m,2H),1.94-2.03(m,2H),2.06(s,3H),2.12(s,3H),2.15(s,3H) ,2.23(s,6H),2.35(s,3H),2.63-2.77(m,3H),3.08-3.19(m,3H),3.37-3.45(m,2H),3.82-3.91(m,5H) ,6.75(s,1H),7.64(s,1H),7.96(d,J=9.5Hz,1H),8.26(s,1H),8.74-8.87(m,2H),9.00-9.10(m,1H) );
MS m/z(ESI):662.3[M+H] +. MS m/z(ESI): 662.3[M+H] + .
实施例131Example 131
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000243
Figure PCTCN2020097369-appb-000243
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- Refer to Example 19 for the preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.52-1.62(m,2H),1.99-2.06(m,2H),2.09-2.14(m,6H),2.16(s,3H),2.26(s,6H),2.68-2.82(m,3H),3.12-3.23(m,3H),3.50-3.59 (m,2H),3.85(s,3H),3.91-3.98(m,2H),6.76(s,1H),7.63(s,1H),7.98(d,J＝9.6Hz,1H),8.12(s,1H),8.77-8.85(m,2H),9.08-9.14(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.52-1.62 (m, 2H), 1.99-2.06 (m, 2H), 2.09-2.14 (m, 6H), 2.16 (s, 3H), 2.26 (s, 6H), 2.68-2.82 (m, 3H), 3.12-3.23 (m, 3H), 3.50-3.59 (m, 2H), 3.85 (s, 3H), 3.91-3.98 (m, 2H), 6.76 (s, 1H), 7.63(s,1H), 7.98(d,J=9.6Hz,1H), 8.12(s,1H), 8.77-8.85(m,2H), 9.08-9.14(m,1H);
MS m/z(ESI):650.3[M+H] +. MS m/z(ESI): 650.3[M+H] + .
实施例132Example 132
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000244
Figure PCTCN2020097369-appb-000244
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 19.
1H NMR(400MHz，CD 3OD)δ1.49-1.63(m,3H),1.93-1.99(m,2H),2.01-2.06(m,2H),2.10(s,3H),2.13(s,3H),2.27(s,6H),2.67-2.76(m,2H),2.81-2.90(m,1H),3.11-3.25(m,3H),3.57-3.66(m,2H),3.84(s,3H),3.95-4.04(m,2H),6.74(s,1H),7.55(s,1H),7.90-8.02(m,1H),8.40(s,1H),8.61-8.73(m,1H),8.79-8.89(m,2H)； 1 H NMR(400MHz, CD 3 OD)δ1.49-1.63(m,3H),1.93-1.99(m,2H),2.01-2.06(m,2H),2.10(s,3H),2.13(s, 3H), 2.27 (s, 6H), 2.67-2.76 (m, 2H), 2.81-2.90 (m, 1H), 3.11-3.25 (m, 3H), 3.57-3.66 (m, 2H), 3.84 (s, 3H), 3.95-4.04(m, 2H), 6.74(s, 1H), 7.55(s, 1H), 7.90-8.02(m, 1H), 8.40(s, 1H), 8.61-8.73(m, 1H) ,8.79-8.89(m,2H);
MS m/z(ESI):684.3[M+H] +. MS m/z(ESI): 684.3[M+H] + .
实施例133Example 133
(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-(丙-1-炔-1-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000245
Figure PCTCN2020097369-appb-000245
(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-(丙-1-炔-1-基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl )Amino)-5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 19.
MS m/z(ESI):654.3[M+H] +. MS m/z(ESI): 654.3[M+H] + .
实施例134Example 134
(6-((5-溴-2-((4-(4-(3-(环丙基氨基)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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(cyclopropylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000246
Figure PCTCN2020097369-appb-000246
(6-((5-溴-2-((4-(4-(3-(环丙基氨基)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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(cyclopropylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 19.
1H NMR(400MHz,CD 3OD)δ0.34-0.43(m,2H),0.49-0.56(m,2H),1.59-1.70(m,2H),2.06-2.20(m,12H),2.70-2.80(m,2H),3.14-3.24(m,3H),3.83-3.93(m,6H),4.26-4.36(m,2H),6.75(s,1H),7.64(s,1H),7.98(d,J＝9.6Hz,1H),8.23(s,1H),8.78-8.86(m,2H),8.92-8.98(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.34-0.43 (m, 2H), 0.49-0.56 (m, 2H), 1.59-1.70 (m, 2H), 2.06-2.20 (m, 12H), 2.70- 2.80(m,2H),3.14-3.24(m,3H),3.83-3.93(m,6H),4.26-4.36(m,2H),6.75(s,1H),7.64(s,1H),7.98( d, J=9.6Hz, 1H), 8.23 (s, 1H), 8.78-8.86 (m, 2H), 8.92-8.98 (m, 1H);
MS m/z(ESI):706.2[M+H] +. MS m/z(ESI):706.2[M+H] + .
实施例135Example 135
(6-((5-溴-2-((4-(4-(3-(乙胺基)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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(ethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000247
Figure PCTCN2020097369-appb-000247
(6-((5-溴-2-((4-(4-(3-(乙胺基)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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(ethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- Refer to Example 19 for the preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz，CD 3OD)δ1.39(t,J＝7.1Hz,3H),1.90-2.04(m,2H),2.15(s,3H),2.19(d,J＝6.6Hz,6H),2.27-2.37(m,2H),3.07-3.19(m,4H),3.49-3.71(m,5H),3.91(s,3H),4.41-4.52(m,1H),4.65-4.76(m,3H),7.10(s,1H),7.36(s,1H),8.11-8.18(m,1H),8.30(s,1H),8.73-8.88(m,1H),8.91-9.02(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 1.39 (t, J = 7.1Hz, 3H), 1.90-2.04 (m, 2H), 2.15 (s, 3H), 2.19 (d, J = 6.6Hz, 6H ), 2.27-2.37 (m, 2H), 3.07-3.19 (m, 4H), 3.49-3.71 (m, 5H), 3.91 (s, 3H), 4.41-4.52 (m, 1H), 4.65-4.76 (m ,3H),7.10(s,1H),7.36(s,1H),8.11-8.18(m,1H),8.30(s,1H),8.73-8.88(m,1H),8.91-9.02(m,2H) );
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例136Example 136
N-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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)-N-甲基乙酰胺的制备N-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)-N-methylacetamide
Figure PCTCN2020097369-appb-000248
Figure PCTCN2020097369-appb-000248
N-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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)-N-甲基乙酰胺的制备方法参照实施例19。N-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)-N-methylacetamide The preparation method refers to Example 19.
MS m/z(ESI):722.2[M+H] +. MS m/z(ESI): 722.2[M+H] + .
实施例137Example 137
N-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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)乙酰胺的制备N-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetamide
Figure PCTCN2020097369-appb-000249
Figure PCTCN2020097369-appb-000249
N-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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)乙酰胺的制备方法参照实施例19。N-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetamide The preparation method refers to Example 19.
MS m/z(ESI):708.2[M+H] +. MS m/z(ESI): 708.2[M+H] + .
实施例138Example 138
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000250
Figure PCTCN2020097369-appb-000250
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methoxy For the preparation method of oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine, refer to Example 19.
1H NMR(400MHz，CD 3OD)δ1.14(t,J＝7.2Hz,3H),1.51-1.63(m,2H),2.01-2.08(m,5H),2.12(s,3H),2.16(s,3H),2.28(s,3H),2.47-2.56(m,2H), 2.69-2.77(m,2H),2.81-2.90(m,1H),3.11-3.20(m,2H),3.36-3.43(m,1H),3.58-3.67(m,2H),3.84(s,3H),3.97-4.06(m,2H),6.75(s,1H),7.62(s,1H),7.98(d,J＝9.5Hz,1H),8.22(s,1H),8.76-8.87(m,2H),8.91-8.99(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.14 (t, J = 7.2Hz, 3H), 1.51-1.63 (m, 2H), 2.01-2.08 (m, 5H), 2.12 (s, 3H), 2.16 (s,3H),2.28(s,3H),2.47-2.56(m,2H), 2.69-2.77(m,2H),2.81-2.90(m,1H),3.11-3.20(m,2H),3.36 -3.43(m,1H),3.58-3.67(m,2H),3.84(s,3H),3.97-4.06(m,2H),6.75(s,1H),7.62(s,1H),7.98(d ,J=9.5Hz,1H),8.22(s,1H),8.76-8.87(m,2H),8.91-8.99(m,1H);
MS m/z(ESI):708.3[M+H] +. MS m/z(ESI): 708.3[M+H] + .
实施例139Example 139
(6-((5-溴-2-((4-(4-(3-(二乙胺基)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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(diethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000251
Figure PCTCN2020097369-appb-000251
(6-((5-溴-2-((4-(4-(3-(二乙胺基)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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(diethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 19.
1H NMR(400MHz,CD 3OD)δ1.12(t,J＝7.2Hz,6H),1.50-1.64(m,3H),1.99-2.08(m,5H),2.12(s,3H),2.16(s,3H),2.69-2.86(m,6H),3.11-3.21(m,2H),3.58-3.64(m,2H),3.67-3.74(m,1H),3.85(s,3H),3.96-4.05(m,2H),6.75(s,1H),7.62(s,1H),7.98(d,J＝9.5Hz,1H),8.22(s,1H),8.77-8.86(m,2H),8.93-9.00(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.12 (t, J = 7.2Hz, 6H), 1.50-1.64 (m, 3H), 1.99-2.08 (m, 5H), 2.12 (s, 3H), 2.16 (s, 3H), 2.69-2.86 (m, 6H), 3.11-3.21 (m, 2H), 3.58-3.64 (m, 2H), 3.67-3.74 (m, 1H), 3.85 (s, 3H), 3.96 -4.05 (m, 2H), 6.75 (s, 1H), 7.62 (s, 1H), 7.98 (d, J = 9.5 Hz, 1H), 8.22 (s, 1H), 8.77-8.86 (m, 2H), 8.93-9.00(m,1H);
MS m/z(ESI):722.3[M+H] +. MS m/z(ESI): 722.3[M+H] + .
实施例140Example 140
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000252
Figure PCTCN2020097369-appb-000252
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(S)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy The preparation method of -5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide refers to Example 19.
1H NMR(400MHz,CD 3OD)δ1.76-1.78(m,2H),1.93-2.04(m,1H),2.07(s,3H),2.11-2.13(m,8H),2.27-2.29(m,1H),2.57(s,6H),2.72-2.73(m,3H),3.06-3.08(m,2H),3.12-3.25(m,3H),3.35-3.66(m,1H),3.84(s,3H),6.73(s,1H),7.61(s,1H),7.96-7.97(m,1H),8.21(s,1H),8.49(s,1H),8.81-8.82(m,2H),8.89-9.01(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.76-1.78 (m, 2H), 1.93-2.04 (m, 1H), 2.07 (s, 3H), 2.11-2.13 (m, 8H), 2.27-2.29 ( m, 1H), 2.57 (s, 6H), 2.72-2.73 (m, 3H), 3.06-3.08 (m, 2H), 3.12-3.25 (m, 3H), 3.35-3.66 (m, 1H), 3.84 ( s, 3H), 6.73 (s, 1H), 7.61 (s, 1H), 7.96-7.97 (m, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 8.81-8.82 (m, 2H) ,8.89-9.01(m,1H);
MS m/z(ESI):708.3[M+H] +. MS m/z(ESI): 708.3[M+H] + .
实施例141Example 141
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000253
Figure PCTCN2020097369-appb-000253
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(S)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy The preparation method of -5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide refers to Example 19.
1H NMR(400MHz,CD 3OD)δ1.76-1.78(m,2H),1.93-2.04(m,1H),2.07(s,3H),2.11-2.13(m,8H),2.27-2.29(m,1H),2.57(s,6H),2.72-2.73(m,3H),3.06-3.08(m,2H),3.12-3.25(m,3H),3.35-3.66(m,1H),3.84(s,3H),6.73(s,1H),7.61(s,1H),7.96-7.97(m,1H),8.21(s,1H),8.49(s,1H),8.81-8.82(m,2H),8.89-9.01(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.76-1.78 (m, 2H), 1.93-2.04 (m, 1H), 2.07 (s, 3H), 2.11-2.13 (m, 8H), 2.27-2.29 ( m, 1H), 2.57 (s, 6H), 2.72-2.73 (m, 3H), 3.06-3.08 (m, 2H), 3.12-3.25 (m, 3H), 3.35-3.66 (m, 1H), 3.84 ( s, 3H), 6.73 (s, 1H), 7.61 (s, 1H), 7.96-7.97 (m, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 8.81-8.82 (m, 2H) ,8.89-9.01(m,1H);
MS m/z(ESI):708.3[M+H] +. MS m/z(ESI): 708.3[M+H] + .
实施例142Example 142
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000254
Figure PCTCN2020097369-appb-000254
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(S)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 19.
1H NMR(400MHz,CDCl 3)δ1.19-1.21(m,4H),1.23-1.26(m,5H),2.10-2.11(m,6H),2.15(s,3H),2.65-2.67(m,2H),2.79-2.82(m,1H),2.91-2.92(m,1H),3.01-3.02(m,1H),3.17-3.19(m,2H),3.28-3.29(m,1H),3.41-3.63(m,3H),3.86(s,3H),4.17(s,1H),6.61(s,1H),7.40(s,1H),7.99(s,1H),8.10-8.13(m,1H),8.27(s,1H),8.75-8.76(m,2H),9.03-9.06(m,1H),12.54(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.19-1.21 (m, 4H), 1.23-1.26 (m, 5H), 2.10-2.11 (m, 6H), 2.15 (s, 3H), 2.65-2.67 (m ,2H),2.79-2.82(m,1H),2.91-2.92(m,1H),3.01-3.02(m,1H),3.17-3.19(m,2H),3.28-3.29(m,1H),3.41 -3.63 (m, 3H), 3.86 (s, 3H), 4.17 (s, 1H), 6.61 (s, 1H), 7.40 (s, 1H), 7.99 (s, 1H), 8.10-8.13 (m, 1H) ), 8.27(s,1H),8.75-8.76(m,2H),9.03-9.06(m,1H),12.54(s,1H);
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例143Example 143
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000255
Figure PCTCN2020097369-appb-000255
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(R)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 19.
1H NMR(400MHz,CDCl 3)δ1.19-1.21(m,4H),1.23-1.26(m,5H),2.10-2.11(m,6H),2.15(s,3H),2.65-2.67(m,2H),2.79-2.82(m,1H),2.91-2.92(m,1H),3.01-3.02(m,1H),3.17-3.19(m,2H),3.28-3.29(m,1H),3.41-3.63(m,3H),3.86(s,3H),4.17(s,1H),6.61(s,1H),7.40(s,1H),7.99(s,1H),8.10-8.13(m,1H),8.27(s,1H),8.75-8.76(m,2H),9.03-9.06(m,1H),12.54(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.19-1.21 (m, 4H), 1.23-1.26 (m, 5H), 2.10-2.11 (m, 6H), 2.15 (s, 3H), 2.65-2.67 (m ,2H),2.79-2.82(m,1H),2.91-2.92(m,1H),3.01-3.02(m,1H),3.17-3.19(m,2H),3.28-3.29(m,1H),3.41 -3.63 (m, 3H), 3.86 (s, 3H), 4.17 (s, 1H), 6.61 (s, 1H), 7.40 (s, 1H), 7.99 (s, 1H), 8.10-8.13 (m, 1H) ), 8.27(s,1H),8.75-8.76(m,2H),9.03-9.06(m,1H),12.54(s,1H);
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例144Example 144
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((1-(1-甲基吖丁啶-3-基)哌啶-4-基)氧代)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((1-(1-methylazetidine-3-yl)piperidin-4-yl) Oxo) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxidation preparation
Figure PCTCN2020097369-appb-000256
Figure PCTCN2020097369-appb-000256
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((1-(1-甲基吖丁啶-3-基)哌啶-4-基)氧代)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((1-(1-methylazetidine-3-yl)piperidin-4-yl) (Oxo) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 19.
MS m/z(ESI):681.2[M+H] +. MS m/z(ESI): 681.2[M+H] + .
实施例145Example 145
1-(3-(4-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯氧基)哌啶-1-基)吖丁啶-1-基)乙烷-1-酮的制备1-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenoxy) piperidin-1-yl) azetidine-1-yl) ethane-1-one
Figure PCTCN2020097369-appb-000257
Figure PCTCN2020097369-appb-000257
1-(3-(4-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯氧基)哌啶-1-基)吖丁啶-1-基)乙烷-1-酮的制备方法参照实施例19。1-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenoxy)piperidin-1-yl)azetidin-1-yl)ethane-1-one The preparation method refers to Example 19.
1H NMR(400MHz,CD 3OD)δ1.84-1.95(m,5H),1.98-2.06(m,5H),2.08-2.16(m,7H),2.40-2.54(m,2H),2.63-2.75(m,2H),3.79-3.90(m,4H),4.03-4.13(m,2H),4.25-4.32(m,1H),4.43-4.53(m,1H),6.64(s,1H),7.48(s,1H),7.90(d,J＝9.5Hz,1H),8.15(s,1H),8.76-8.82(m,2H),8.88-8.96(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.84-1.95 (m, 5H), 1.98-2.06 (m, 5H), 2.08-2.16 (m, 7H), 2.40-2.54 (m, 2H), 2.63 2.75(m,2H),3.79-3.90(m,4H),4.03-4.13(m,2H),4.25-4.32(m,1H),4.43-4.53(m,1H),6.64(s,1H), 7.48(s,1H),7.90(d,J=9.5Hz,1H), 8.15(s,1H), 8.76-8.82(m,2H), 8.88-8.96(m,1H);
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例146Example 146
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000258
Figure PCTCN2020097369-appb-000258
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施19。(6-((2-((5-Bromo-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino )-5-Chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 19.
MS m/z(ESI):714.2[M+H] +. MS m/z(ESI): 714.2[M+H] + .
实施例147Example 147
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000259
Figure PCTCN2020097369-appb-000259
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((2-((5-Bromo-4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)- Refer to Example 19 for the preparation method of 5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.23(t,J＝7.0Hz,3H),1.56-1.68(m,2H),2.00-2.08(m,2H),2.13(s,3H),2.17(s,3H),2.66-2.78(m,2H),2.93-3.05(m,1H),3.33-3.39(m,2H),3.49-3.58(m,2H),3.74-3.82(m,2H),3.89(s,3H),4.16-4.26(m,2H),4.28-4.38(m,1H),6.78(s,1H),8.11-8.19(m,3H),8.76-8.86(m,2H),8.97-9.06(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.23 (t, J = 7.0Hz, 3H), 1.56-1.68 (m, 2H), 2.00-2.08 (m, 2H), 2.13 (s, 3H), 2.17 (s,3H),2.66-2.78(m,2H),2.93-3.05(m,1H),3.33-3.39(m,2H),3.49-3.58(m,2H),3.74-3.82(m,2H) ,3.89(s,3H),4.16-4.26(m,2H),4.28-4.38(m,1H),6.78(s,1H),8.11-8.19(m,3H),8.76-8.86(m,2H) ,8.97-9.06(m,1H);
MS m/z(ESI):715.2[M+H] +. MS m/z(ESI): 715.2[M+H] + .
实施例148Example 148
甲基1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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-羧酸酯的制备Methyl 1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5- Preparation of methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-carboxylate
Figure PCTCN2020097369-appb-000260
Figure PCTCN2020097369-appb-000260
甲基1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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-羧酸酯的制备方法参照实施例19。Methyl 1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5- Refer to Example 19 for the preparation method of methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-carboxylate.
1H NMR(400MHz,CD 3OD)δ1.51-1.53(m,2H),2.00-2.02(m,2H),2.05(s,3H),2.12-2.14(m,6H),2.71-2.73(m,2H),2.85-2.87(m,1H),3.11-3.14(m,2H),3.51-3.62(m,1H),3.78(s,3H),3.84(s,3H),3.88-4.01(m,2H),4.03-4.06(m,2H),6.74(s,1H),7.23-7.26(m,1H),7.62(s,1H),7.71-7.73(m,1H),7.97-7.99(m,1H),8.81-8.85(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ1.51-1.53 (m, 2H), 2.00-2.02 (m, 2H), 2.05 (s, 3H), 2.12-2.14 (m, 6H), 2.71-2.73 ( m, 2H), 2.85-2.87 (m, 1H), 3.11-3.14 (m, 2H), 3.51-3.62 (m, 1H), 3.78 (s, 3H), 3.84 (s, 3H), 3.88-4.01 ( m,2H),4.03-4.06(m,2H),6.74(s,1H),7.23-7.26(m,1H),7.62(s,1H),7.71-7.73(m,1H),7.97-7.99( m,1H),8.81-8.85(m,2H);
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例149Example 149
(6-((5-溴-2-((4-(4-(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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000261
Figure PCTCN2020097369-appb-000261
(6-((5-溴-2-((4-(4-(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(hydroxymethyl)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- Refer to Example 19 for the preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CDCl 3)δ1.96-2.04(m,2H),2.08(s,3H),2.12(s,3H),2.15(s,3H),2.60-2.69(m,2H),2.96-3.08(m,2H),3.15-3.20(m,2H),3.76-3.80(m,2H),3.85(s,3H),3.91-4.02(m,2H),4.06-4.10(m,2H),6.62(s,1H),7.41(s,1H),7.98(s,1H),8.01-8.09(m,1H),8.26(s,1H),8.75-8.79(m,2H),9.01-9.05(m,1H),12.52(s,1H)； 1 H NMR(400MHz, CDCl 3 )δ1.96-2.04(m,2H), 2.08(s,3H), 2.12(s,3H), 2.15(s,3H), 2.60-2.69(m,2H), 2.96-3.08(m,2H),3.15-3.20(m,2H),3.76-3.80(m,2H),3.85(s,3H),3.91-4.02(m,2H),4.06-4.10(m,2H) ), 6.62 (s, 1H), 7.41 (s, 1H), 7.98 (s, 1H), 8.01-8.09 (m, 1H), 8.26 (s, 1H), 8.75-8.79 (m, 2H), 9.01 9.05(m,1H),12.52(s,1H);
MS m/z(ESI):681.2[M+H] +. MS m/z(ESI): 681.2[M+H] + .
实施例150Example 150
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000262
Figure PCTCN2020097369-appb-000262
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- Refer to Example 19 for the preparation method of 5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.51-1.52(m,2H),1.96-1.99(m,2H),2.06(s,3H),2.14-2.18(m,7H),2.71-2.76(m,3H),2.90-2.92(m,1H),3.15-3.18(m,2H),3.41-3.43(m,4H),3.81-3.83(m,5H),4.59-4.61(m,2H),6.75(s,1H),7.61(s,1H),7.96-7.99(m,1H),8.22(s,1H),8.82-8.84(m,2H),8.95-8.97(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.51-1.52 (m, 2H), 1.96-1.99 (m, 2H), 2.06 (s, 3H), 2.14-2.18 (m, 7H), 2.71-2.76 ( m,3H),2.90-2.92(m,1H),3.15-3.18(m,2H),3.41-3.43(m,4H),3.81-3.83(m,5H),4.59-4.61(m,2H), 6.75(s,1H),7.61(s,1H),7.96-7.99(m,1H),8.22(s,1H),8.82-8.84(m,2H),8.95-8.97(m,1H);
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例151Example 151
1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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-羧酸的制备1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy 2-methylphenyl)piperidin-4-yl)azetidine-3-carboxylic acid
Figure PCTCN2020097369-appb-000263
Figure PCTCN2020097369-appb-000263
1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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-羧酸的制备方法参照实施例19。1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy For the preparation method of 2-methylphenyl)piperidin-4-yl)azetidine-3-carboxylic acid, refer to Example 19.
1H NMR(400MHz,CD 3OD)δ1.60-1.62(m,2H),2.05-2.07(m,3H),2.14-2.16(m,9H),2.76-2.78(m,3H),3.07-3.18(m,3H),3.85(s,3H),4.24-4.28(m,3H),6.77(s,1H),7.63(s,1H),7.99-8.01(m,1H),8.23(s,1H),8.82-8.86(m,2H),8.95-8.99(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.60-1.62 (m, 2H), 2.05-2.07 (m, 3H), 2.14-2.16 (m, 9H), 2.76-2.78 (m, 3H), 3.07- 3.18(m,3H),3.85(s,3H),4.24-4.28(m,3H),6.77(s,1H),7.63(s,1H),7.99-8.01(m,1H),8.23(s, 1H), 8.82-8.86 (m, 2H), 8.95-8.99 (m, 1H);
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例152Example 152
1-(3-((3aR,6aS)-5-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吖丁啶-1-基)乙烷-1-酮的制备1-(3-((3aR,6aS)-5-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- (Yl)amino)-5-methoxy-2-methylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)azetidine-1-yl)ethane-1 -Preparation of ketones
Figure PCTCN2020097369-appb-000264
Figure PCTCN2020097369-appb-000264
1-(3-((3aR,6aS)-5-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)吖丁啶-1-基)乙烷-1-酮的制备方法参照实施例19。1-(3-((3aR,6aS)-5-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- (Yl)amino)-5-methoxy-2-methylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)azetidine-1-yl)ethane-1 -Refer to Example 19 for the preparation method of the ketone.
1H NMR(400MHz,CD 3OD)δ1.88(s,3H),2.10(s,3H),2.12(s,3H),2.15(s,3H),2.47(d,J＝7.1Hz,2H),2.95(s,2H),2.99-3.08(m,4H),3.17(s,2H),3.49(d,J＝8.8Hz,1H),3.84(s,3H),3.91(dd,J＝10.5,4.8Hz,1H),4.06-4.23(m,2H),4.34(t,J＝8.3Hz,1H),6.74(s,1H),7.56(s,1H),7.96(d,J＝9.6Hz,1H),8.21(s,1H),8.79(d,J＝1.9Hz,1H),8.83(d,J＝2.0Hz,1H),8.94(dd,J＝9.6,4.3Hz,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.88(s,3H), 2.10(s,3H), 2.12(s,3H), 2.15(s,3H), 2.47(d,J=7.1Hz,2H ), 2.95 (s, 2H), 2.99-3.08 (m, 4H), 3.17 (s, 2H), 3.49 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.91 (dd, J = 10.5,4.8Hz,1H),4.06-4.23(m,2H), 4.34(t,J=8.3Hz,1H),6.74(s,1H),7.56(s,1H),7.96(d,J=9.6 Hz, 1H), 8.21 (s, 1H), 8.79 (d, J = 1.9 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.94 (dd, J = 9.6, 4.3 Hz, 1H);
MS m/z(ESI):720.2[M+H] +. MS m/z(ESI): 720.2[M+H] + .
实施例153Example 153
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole- 2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000265
Figure PCTCN2020097369-appb-000265
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole- 2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation is prepared according to Example 19.
MS m/z(ESI):637.2[M+H] +. MS m/z(ESI): 637.2[M+H] + .
实施例154Example 154
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((3aR,6aS)-5-(噁丁环-3-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((3aR,6aS)-5-(oxbutan-3-yl)hexahydropyrrolo[3 ,4-c)pyrrole-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000266
Figure PCTCN2020097369-appb-000266
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((3aR,6aS)-5-(噁丁环-3-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((3aR,6aS)-5-(oxbutan-3-yl)hexahydropyrrolo[3 ,4-c]pyrrole-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation method refer to Example 19.
MS m/z(ESI):679.2[M+H] +. MS m/z(ESI): 679.2[M+H] + .
实施例155Example 155
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((1r,3r)-3-(4-甲基哌嗪-1-基)环丁氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutoxy (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000267
Figure PCTCN2020097369-appb-000267
(6-((5-溴-2-((2-甲氧基-5-甲基-4-((1r,3r)-3-(4-甲基哌嗪-1-基)环丁氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutoxy (Yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 19.
MS m/z(ESI):681.2[M+H] +. MS m/z(ESI): 681.2[M+H] + .
实施例156Example 156
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000268
Figure PCTCN2020097369-appb-000268
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(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)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 19 .
1H NMR(400MHz,CD 3OD)δ1.81(d,J＝11.3Hz,2H),2.08(s,3H),2.12(s,3H),2.16(s,3H),2.59-2.79(m,6H),2.89-3.45(m,14H),3.84(s,3H),6.74(s,1H),7.62(s,1H),7.98(d,J＝9.5Hz,1H),8.22(s,1H),8.79(d,J＝1.9Hz,1H),8.84(d,J＝1.9Hz,1H),8.95(dd,J＝9.8,4.2Hz,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.81 (d, J = 11.3Hz, 2H), 2.08 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.59-2.79 (m ,6H),2.89-3.45(m,14H),3.84(s,3H),6.74(s,1H),7.62(s,1H),7.98(d,J=9.5Hz,1H),8.22(s, 1H), 8.79 (d, J = 1.9 Hz, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.95 (dd, J = 9.8, 4.2 Hz, 1H);
MS m/z(ESI):720.3[M+H] +. MS m/z(ESI): 720.3[M+H] + .
实施例157Example 157
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000269
Figure PCTCN2020097369-appb-000269
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(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)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 19 .
MS m/z(ESI):676.3[M+H] +. MS m/z(ESI): 676.3[M+H] + .
实施例158Example 158
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000270
Figure PCTCN2020097369-appb-000270
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(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)quinoxalin-5-yl)dimethylphosphine oxidation preparation Refer to Example 19 for the method.
MS m/z(ESI):710.3[M+H] +. MS m/z(ESI): 710.3[M+H] + .
实施例159Example 159
N-(2-((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)苯基)环丙磺酰胺的制备N-(2-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide
Figure PCTCN2020097369-appb-000271
Figure PCTCN2020097369-appb-000271
N-(2-((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)苯基)环丙磺酰胺的制备方法参照实施例19。N-(2-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy- Refer to Example 19 for the preparation method of 5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide.
MS m/z(ESI):685.2[M+H] +. MS m/z(ESI): 685.2[M+H] + .
实施例160Example 160
N-(2-((5-溴-2-((4-(4-(3-(氰基甲基)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)苯基)环丙磺酰胺的制备N-(2-((5-Bromo-2-((4-(4-(3-(cyanomethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy -5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide
Figure PCTCN2020097369-appb-000272
Figure PCTCN2020097369-appb-000272
N-(2-((5-溴-2-((4-(4-(3-(氰基甲基)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)苯基)环丙磺酰胺的制备方法参照实施例19。N-(2-((5-Bromo-2-((4-(4-(3-(cyanomethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy Refer to Example 19 for the preparation method of -5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide.
MS m/z(ESI):681.2[M+H] +. MS m/z(ESI): 681.2[M+H] + .
实施例161Example 161
N-(2-((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)苯基)环丙磺酰胺的制备N-(2-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl )-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide
Figure PCTCN2020097369-appb-000273
Figure PCTCN2020097369-appb-000273
N-(2-((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)苯基)环丙磺酰胺的制备方法参照实施例19。N-(2-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl )-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)cyclopropanesulfonamide. Refer to Example 19 for the preparation method.
MS m/z(ESI):686.2[M+H] +. MS m/z(ESI): 686.2[M+H] + .
实施例162Example 162
(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)喹喔啉-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] Preparation of pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000274
Figure PCTCN2020097369-appb-000274
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Refer to Example 19 for the preparation method of pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.76-1.91(m,2H),2.08(s,3H),2.12(s,3H),2.14-2.19(m,5H),2.74(t,J＝11.7Hz,2H),2.85(s,3H),3.06(s,2H),3.19(d,J＝12.0Hz,2H),3.58(s,2H),3.67(dd,J＝9.4,5.3Hz,2H),3.73-3.87(m,5H),6.74(s,1H),7.63(s,1H),7.98(d,J＝9.5Hz,1H),8.23(s,1H),8.79(d,J＝1.9Hz,1H),8.84(d,J＝2.0Hz,1H),8.96(dd,J＝9.6,4.2Hz,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.76-1.91(m,2H), 2.08(s,3H), 2.12(s,3H), 2.14-2.19(m,5H), 2.74(t,J= 11.7Hz, 2H), 2.85 (s, 3H), 3.06 (s, 2H), 3.19 (d, J = 12.0 Hz, 2H), 3.58 (s, 2H), 3.67 (dd, J = 9.4, 5.3 Hz, 2H), 3.73-3.87 (m, 5H), 6.74 (s, 1H), 7.63 (s, 1H), 7.98 (d, J = 9.5 Hz, 1H), 8.23 (s, 1H), 8.79 (d, J =1.9Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.96 (dd, J = 9.6, 4.2 Hz, 1H);
MS m/z(ESI):707.2[M+H] +. MS m/z(ESI): 707.2[M+H] + .
实施例163Example 163
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000275
Figure PCTCN2020097369-appb-000275
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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19。2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile for the preparation method refer to Example 19.
1H NMR(400MHz,CDCl 3)δ1.50-1.52(m,2H),1.72-1.88(m,2H),2.05-2.19(m,9H),2.30-2.31(m,2H),2.60-2.68(m,3H),2.92-2.95(m,1H),2.99-3.22(m,4H),3.47-3.70(m,2H),3.86(s,3H),6.63(s,1H),7.39(s,1H),7.98(s,1H),8.10-8.11(m,1H),8.27(s,1H),8.74-8.76(m,2H),9.01-9.05(m,1H),12.55(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.50-1.52 (m, 2H), 1.72-1.88 (m, 2H), 2.05-2.19 (m, 9H), 2.30-2.31 (m, 2H), 2.60-2.68 (m, 3H), 2.92-2.95 (m, 1H), 2.99-3.22 (m, 4H), 3.47-3.70 (m, 2H), 3.86 (s, 3H), 6.63 (s, 1H), 7.39 (s ,1H),7.98(s,1H),8.10-8.11(m,1H),8.27(s,1H),8.74-8.76(m,2H),9.01-9.05(m,1H),12.55(s,1H) );
MS m/z(ESI):690.2[M+H] +. MS m/z(ESI): 690.2[M+H] + .
实施例164Example 164
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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)quinoxalin-6-yl)amino)pyrimidine-2- (Yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)ethane-1- Preparation of ketones
Figure PCTCN2020097369-appb-000276
Figure PCTCN2020097369-appb-000276
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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19。1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidine-2- (Yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)ethane-1- Refer to Example 19 for the preparation method of the ketone.
1H NMR(400MHz,CDCl 3)δ1.85-1.92(m,4H),2.00(s,3H),2.05(s,6H),2.08(s,3H),2.11-2.33(m,1H),2.40-2.48(m,2H),2.58(t,J＝11.8Hz,2H),2.79-3.09(m,6H),3.33(d,J＝11.0Hz,1H),3.44(dd,J＝12.6,4.1Hz,1H),3.61(dd,J＝12.8,8.3Hz,2H),3.79(s,3H),6.54(s,1H),7.32(s,1H),7.91(s,1H),8.03(d,J＝9.5Hz,1H),8.20(s,1H),8.66(d,J＝1.9Hz,1H),8.70(d,J＝1.9Hz,1H),8.98(dd,J＝9.5,4.1Hz,1H),12.47(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ1.85-1.92 (m, 4H), 2.00 (s, 3H), 2.05 (s, 6H), 2.08 (s, 3H), 2.11-2.33 (m, 1H), 2.40-2.48(m,2H), 2.58(t,J=11.8Hz,2H), 2.79-3.09(m,6H), 3.33(d,J=11.0Hz,1H), 3.44(dd,J=12.6, 4.1Hz, 1H), 3.61 (dd, J = 12.8, 8.3 Hz, 2H), 3.79 (s, 3H), 6.54 (s, 1H), 7.32 (s, 1H), 7.91 (s, 1H), 8.03 ( d,J=9.5Hz,1H), 8.20(s,1H), 8.66(d,J=1.9Hz,1H), 8.70(d,J=1.9Hz,1H), 8.98(dd,J=9.5,4.1 Hz,1H),12.47(s,1H);
MS m/z(ESI):748.2[M+H] +. MS m/z(ESI): 748.2[M+H] + .
实施例165Example 165
2-(1-(1-(4-((5-氯-4-((5-(二甲基磷基)喹喔啉-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)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000277
Figure PCTCN2020097369-appb-000277
2-(1-(1-(4-((5-氯-4-((5-(二甲基磷基)喹喔啉-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19。2-(1-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile for the preparation method refer to Example 19.
MS m/z(ESI):646.3[M+H] +. MS m/z(ESI):646.3[M+H] + .
实施例166Example 166
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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)quinoxalin-6-yl)amino)pyrimidine-2- (Yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)ethane-1-one Preparation
Figure PCTCN2020097369-appb-000278
Figure PCTCN2020097369-appb-000278
1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-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23。1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)pyrimidine-2- (Yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)ethane-1-one Refer to Example 23 for the preparation method.
1H NMR(400MHz,CD 3OD)δ0.83(t,J＝7.6Hz,3H),1.89(dd,J＝17.7,7.4Hz,2H),1.95-2.27(m,11H),2.48(q,J＝7.6Hz,2H),2.78(t,J＝11.7Hz,2H),2.99-3.25(m,7H),3.53-3.67(m,5H),3.78(t,J＝9.8Hz,1H),3.84(s,3H),6.77(s,1H),7.66(s,1H),7.95(d,J＝9.5Hz,1H),8.22(s,1H),8.79-8.86(m,3H)； 1 H NMR (400MHz, CD 3 OD) δ 0.83 (t, J = 7.6 Hz, 3H), 1.89 (dd, J = 17.7, 7.4 Hz, 2H), 1.95-2.27 (m, 11H), 2.48 (q ,J=7.6Hz,2H),2.78(t,J=11.7Hz,2H),2.99-3.25(m,7H),3.53-3.67(m,5H),3.78(t,J=9.8Hz,1H) ,3.84(s,3H),6.77(s,1H),7.66(s,1H),7.95(d,J=9.5Hz,1H),8.22(s,1H),8.79-8.86(m,3H);
MS m/z(ESI):762.3[M+H] +. MS m/z(ESI): 762.3[M+H] + .
实施例167Example 167
2-(1-(1-(4-((4-((5-(二甲基磷基)喹喔啉-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)quinoxalin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )Amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000279
Figure PCTCN2020097369-appb-000279
2-(1-(1-(4-((4-((5-(二甲基磷基)喹喔啉-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19。2-(1-(1-(4-((4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl ) Amino)-5-methoxy-2-methylphenyl) piperidin-4-yl) azetidine-3-yl) acetonitrile for the preparation method referring to Example 19.
MS m/z(ESI):680.3[M+H] +. MS m/z(ESI): 680.3[M+H] + .
实施例168Example 168
(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)喹喔啉-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)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000280
Figure PCTCN2020097369-appb-000280
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(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)quinoxalin-5-yl)dimethylphosphine oxidation preparation method reference Example 19.
MS m/z(ESI):784.2[M+H] +. MS m/z(ESI): 784.2[M+H] + .
实施例169Example 169
(6-((5-氯-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Preparation of pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000281
Figure PCTCN2020097369-appb-000281
(6-((5-氯-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Refer to Example 19 for the preparation method of pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):663.2[M+H] +. MS m/z(ESI): 663.2[M+H] + .
实施例170Example 170
(6-((5-溴-2-((4-(4-(二乙胺基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(diethylamino)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4 -Yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000282
Figure PCTCN2020097369-appb-000282
(6-((5-溴-2-((4-(4-(二乙胺基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(diethylamino)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4 Refer to Example 19 for the preparation method of -yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.21-1.26(m,6H),1.77-1.88(m,2H),1.99-2.06(m,2H),2.07-2.17(m,9H),2.70-2.80(m,2H),2.93-3.06(m,5H),3.16-3.24(m,2H),3.85(s,3H),6.76(s,1H),7.61(s,1H),7.95-8.05(m,1H),8.22(s,1H),8.77-8.87(m,2H),8.92-9.00(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.21-1.26 (m, 6H), 1.77-1.88 (m, 2H), 1.99-2.06 (m, 2H), 2.07-2.17 (m, 9H), 2.70- 2.80(m,2H),2.93-3.06(m,5H),3.16-3.24(m,2H),3.85(s,3H),6.76(s,1H),7.61(s,1H),7.95-8.05( m,1H),8.22(s,1H),8.77-8.87(m,2H),8.92-9.00(m,1H);
MS m/z(ESI):667.2[M+H] +. MS m/z(ESI): 667.2[M+H] + .
实施例171Example 171
(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)喹喔啉-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- Preparation of 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000283
Figure PCTCN2020097369-appb-000283
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照 实施例19。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxbutan-3-yl)amino)azetidine- The preparation method of 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide refers to Example 19.
1H NMR(400MHz,CD 3OD)δ1.43-1.50(m,2H),1.88-1.97(m,2H),2.06(s,3H),2.11-2.17(m,9H),2.65-2.75(m,2H),3.08-3.18(m,5H),3.58-3.66(m,2H),3.70-3.75(m,1H),3.85(s,3H),4.58-4.68(m,5H),6.75(s,1H),7.60(s,1H),7.96-8.04(m,1H),8.22(s,1H),8.78-8.86(m,2H),8.91-9.00(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.43-1.50 (m, 2H), 1.88-1.97 (m, 2H), 2.06 (s, 3H), 2.11-2.17 (m, 9H), 2.65-2.75 ( m, 2H), 3.08-3.18 (m, 5H), 3.58-3.66 (m, 2H), 3.70-3.75 (m, 1H), 3.85 (s, 3H), 4.58-4.68 (m, 5H), 6.75 ( s,1H),7.60(s,1H),7.96-8.04(m,1H),8.22(s,1H),8.78-8.86(m,2H),8.91-9.00(m,1H);
MS m/z(ESI):736.2[M+H] +. MS m/z(ESI): 736.2[M+H] + .
实施例172Example 172
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)-3-甲基哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)-3-methylpiperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000284
Figure PCTCN2020097369-appb-000284
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)-3-甲基哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)-3-methylpiperidin-1-yl)-2-methyl For the preparation method of oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 19.
MS m/z(ESI):708.3[M+H] +. MS m/z(ESI): 708.3[M+H] + .
实施例173Example 173
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)-3-(三氟甲基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)-3-(trifluoromethyl)piperidin-1-yl) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000285
Figure PCTCN2020097369-appb-000285
(6-((5-溴-2-((4-(4-(3-(二甲氨基)吖丁啶-1-基)-3-(三氟甲基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)-3-(trifluoromethyl)piperidin-1-yl) The preparation method of -2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation refers to Example 19.
MS m/z(ESI):762.2[M+H] +. MS m/z(ESI): 762.2[M+H] + .
实施例174Example 174
(6-((2-((5-溴-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((5-Bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 -Chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000286
Figure PCTCN2020097369-appb-000286
(6-((2-((5-溴-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例1。(6-((2-((5-Bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 -Chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 1.
MS m/z(ESI):714.1[M+H] +. MS m/z(ESI): 714.1[M+H] + .
实施例175Example 175
(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)喹喔啉-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 (Oxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000287
Figure PCTCN2020097369-appb-000287
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methyl The preparation method of oxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation refers to Example 23.
1H NMR(400MHz,CD 3OD)δ0.91(t,J＝7.5Hz,3H),1.44-1.55(m,2H),1.90-2.00(m,2H)，2.12(s,3H),2.16(s,3H),2.20(s,6H),2.47-2.57(m,3H),2.75(t,J＝11.5Hz，2H),3.01-3.12(m,3H),3.17-3.26(m,2H),3.76(t,J＝7.5Hz，2H),3.85(s,3H),6.82(s,1H),7.64(s,1H),7.98(d,J＝9.5Hz,1H),8.14(s,1H),8.78-8.87(m,2H),9.00-9.07(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ0.91(t,J=7.5Hz,3H),1.44-1.55(m,2H),1.90-2.00(m,2H), 2.12(s,3H), 2.16 (s, 3H), 2.20 (s, 6H), 2.47-2.57 (m, 3H), 2.75 (t, J = 11.5 Hz, 2H), 3.01-3.12 (m, 3H), 3.17-3.26 (m, 2H) ), 3.76(t,J=7.5Hz,2H),3.85(s,3H),6.82(s,1H),7.64(s,1H),7.98(d,J=9.5Hz,1H),8.14(s ,1H), 8.78-8.87(m,2H),9.00-9.07(m,1H);
MS m/z(ESI):664.1[M+H] +. MS m/z(ESI): 664.1[M+H] + .
实施例176Example 176
2-(1-(1-(4-((4-((5-(二甲基磷基)喹喔啉-6-基)氨基)-5-(三氟甲基)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-((4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )Amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000288
Figure PCTCN2020097369-appb-000288
2-(1-(1-(4-((4-((5-(二甲基磷基)喹喔啉-6-基)氨基)-5-(三氟甲基)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23。2-(1-(1-(4-((4-((5-(dimethylphosphorus)quinoxalin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )Amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile for the preparation method according to Example 23.
1H NMR(400MHz,CD 3OD)δ1.41-1.54(m,3H),1.91-1.9(m,2H),2.09(s,3H),2.13(s,3H),2.29-2.42(m,2H),2.60-2.85(m,6H),2.94-3.08(m,3H),3.38-3.47(m,3H),3.79-3.90(m,5H),6.78(s,1H),7.59(s,1H),7.96(d,J＝8.4Hz1H),8.41(s,1H),8.56-8.67(m,1H),8.80-8.87(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ1.41-1.54 (m, 3H), 1.91-1.9 (m, 2H), 2.09 (s, 3H), 2.13 (s, 3H), 2.29-2.42 (m, 2H), 2.60-2.85(m, 6H), 2.94-3.08(m, 3H), 3.38-3.47(m, 3H), 3.79-3.90(m, 5H), 6.78(s, 1H), 7.59(s, 1H),7.96(d,J=8.4Hz1H),8.41(s,1H),8.56-8.67(m,1H),8.80-8.87(m,2H);
MS m/z(ESI):694.1[M+H] +. MS m/z(ESI): 694.1[M+H] + .
实施例177Example 177
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000289
Figure PCTCN2020097369-appb-000289
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(methylthio)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidized preparation method refer to Example 23.
1H NMR(400MHz,CD 3OD)δ0.81(t,J＝7.5Hz,3H),1.43-1.53(m,2H),1.89-1.97(m,2H),2.12(s,3H),2.15(s,3H),2.19(s,6H),2.36(s,3H),2.43-2.51(m,3H),2.74(t,J＝11.1Hz,2H),3.01-3.09(m,3H),3.12-3.21(m,2H),3.73(t,J＝7.4Hz,2H),3.85(s,3H),6.80(s,1H),7.67(s,1H),7.97(d,J＝9.6Hz，1H),8.27(s,1H),8.76-8.87(m,2H),8.93-9.00(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.81 (t, J = 7.5 Hz, 3H), 1.43-1.53 (m, 2H), 1.89-1.97 (m, 2H), 2.12 (s, 3H), 2.15 (s, 3H), 2.19 (s, 6H), 2.36 (s, 3H), 2.43-2.51 (m, 3H), 2.74 (t, J = 11.1Hz, 2H), 3.01-3.09 (m, 3H), 3.12-3.21(m,2H),3.73(t,J=7.4Hz,2H),3.85(s,3H),6.80(s,1H),7.67(s,1H),7.97(d,J=9.6Hz ,1H),8.27(s,1H),8.76-8.87(m,2H),8.93-9.00(m,1H);
MS m/z(ESI):676.1[M+H] +. MS m/z(ESI): 676.1[M+H] + .
实施例178Example 178
(6-((5-环丙基-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Cyclopropyl-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000290
Figure PCTCN2020097369-appb-000290
(6-((5-环丙基-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Cyclopropyl-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy- Refer to Example 23 for the preparation method of 5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ0.61-0.66(m,2H),1.02-1.07(m,2H),1.54-1.66 (m,2H),1.76-1.83(m,1H),1.99-2.08(m,2H),2.11(s,3H),2.13(s,3H),2.17(s,3H),2.29(s,6H),2.75(t,J＝11.5Hz,2H),2.96-3.07(m,1H),3.12-3.28(m,3H),3.73-3.81(m,2H),3.86(s,3H),4.09(t,J＝8.5Hz,2H),6.76(s,1H),7.73(s,1H),7.90(s,1H),7.99(d,J＝9.6Hz,1H),7.74-8.86(m,2H),9.17-9.26(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.61-0.66 (m, 2H), 1.02-1.07 (m, 2H), 1.54-1.66 (m, 2H), 1.76-1.83 (m, 1H), 1.99- 2.08 (m, 2H), 2.11 (s, 3H), 2.13 (s, 3H), 2.17 (s, 3H), 2.29 (s, 6H), 2.75 (t, J = 11.5 Hz, 2H), 2.96-3.07 (m,1H),3.12-3.28(m,3H),3.73-3.81(m,2H),3.86(s,3H),4.09(t,J=8.5Hz,2H),6.76(s,1H), 7.73(s,1H),7.90(s,1H),7.99(d,J=9.6Hz,1H),7.74-8.86(m,2H),9.17-9.26(m,1H);
MS m/z(ESI):656.1[M+H] +. MS m/z(ESI): 656.1[M+H] + .
实施例179Example 179
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)-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-5-甲腈的制备2-((4-(4-(3-(Dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-4 -((5-(Dimethylphosphoryl)quinoxaline-6-yl)amino)pyrimidine-5-carbonitrile preparation
Figure PCTCN2020097369-appb-000291
Figure PCTCN2020097369-appb-000291
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)-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-5-甲腈的制备方法参照实施例19。2-((4-(4-(3-(Dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)-4 Refer to Example 19 for the preparation method of ((5-(dimethylphosphorus)quinoxaline-6-yl)amino)pyrimidine-5-carbonitrile.
1H NMR(400MHz,CD 3OD)δ1.50-1.62(m,2H),2.01-2.10(m,3H),2.11(s,3H),2.15(s,3H),2.26(s,6H),2.70-2.83(m,4H),3.15-3.24(m,3H),3.48-3.57(m,3H),3.84(s,3H),3.95(t,J＝8.2Hz,2H),6.78(s,1H),7.51(s,1H),7.93(d,J＝8.2Hz,1H),8.44(s,1H),8.79-8.87(m,2H),8.89-8.97(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.50-1.62 (m, 2H), 2.01-2.10 (m, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.26 (s, 6H) ,2.70-2.83(m,4H),3.15-3.24(m,3H),3.48-3.57(m,3H),3.84(s,3H),3.95(t,J=8.2Hz,2H),6.78(s ,1H),7.51(s,1H),7.93(d,J=8.2Hz,1H),8.44(s,1H),8.79-8.87(m,2H),8.89-8.97(m,1H);
MS m/z(ESI):641.1[M+H] +. MS m/z(ESI):641.1[M+H] + .
实施例180Example 180
(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-氟嘧啶-4-基)氨基)喹喔啉-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-fluoropyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000292
Figure PCTCN2020097369-appb-000292
(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-氟嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) Amino)-5-fluoropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 23.
1H NMR(400MHz,CD 3OD)δ1.06(t,J＝7.5Hz,3H),1.53-1.62(m,2H),2.01-2.08(m,2H),2.13(s,3H),2.16(s,3H),2.26(s,6H),2.58-2.67(m,2H),2.76-2.87(m,3H),3.09-3.23(m,3H),3.53-3.61(m,2H),3.86(s,3H),3.97(t,J＝8.1Hz,2H),6.83(s,1H),7.72(s,1H),8.01-8.09(m,2H),8.76-8.87(m,2H),9.29-9.35(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.06 (t, J = 7.5Hz, 3H), 1.53-1.62 (m, 2H), 2.01-2.08 (m, 2H), 2.13 (s, 3H), 2.16 (s, 3H), 2.26 (s, 6H), 2.58-2.67 (m, 2H), 2.76-2.87 (m, 3H), 3.09-3.23 (m, 3H), 3.53-3.61 (m, 2H), 3.86 (s,3H),3.97(t,J=8.1Hz,2H),6.83(s,1H),7.72(s,1H),8.01-8.09(m,2H),8.76-8.87(m,2H), 9.29-9.35(m,1H);
MS m/z(ESI):648.1[M+H] +. MS m/z(ESI):648.1[M+H] + .
实施例181Example 181
(6-((5-溴-2-((5-环丙基-4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((5-cyclopropyl-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2- (Methoxyphenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000293
Figure PCTCN2020097369-appb-000293
(6-((5-溴-2-((5-环丙基-4-(4-(3-(二甲氨基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((5-Bromo-2-((5-cyclopropyl-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2- Refer to Example 23 for the preparation method of methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):720.1[M+H] +. MS m/z(ESI): 720.1[M+H] + .
实施例182Example 182
(6-((2-((4-(4-(1,4-噁吖庚环-4-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino) Preparation of 5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000294
Figure PCTCN2020097369-appb-000294
(6-((2-((4-(4-(1,4-噁吖庚环-4-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)-5-溴嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino) For the preparation method of -5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 23.
1H NMR(400MHz,CD 3OD)δ0.84(t,J＝7.5Hz,3H),1.92-2.01(m,2H),2.10-2.19(m,9H),2.46-2.54(m,2H),2.84(t,J＝11.5Hz,2H),3.13-3.20(m,2H),3.36-3.49(m,6H),3.81-3.88(m,5H),3.89-3.94(m,2H),6.80(s,1H),7.67(s,1H),7.98(d,J＝9.5Hz,1H),8.24(s,1H),8.80(d,J＝1.9Hz,1H),8.84-8.90(m,2H)； 1 H NMR(400MHz,CD 3 OD)δ0.84(t,J=7.5Hz,3H),1.92-2.01(m,2H),2.10-2.19(m,9H),2.46-2.54(m,2H) ,2.84(t,J=11.5Hz,2H),3.13-3.20(m,2H),3.36-3.49(m,6H),3.81-3.88(m,5H),3.89-3.94(m,2H),6.80 (s,1H),7.67(s,1H),7.98(d,J=9.5Hz,1H),8.24(s,1H),8.80(d,J=1.9Hz,1H),8.84-8.90(m, 2H);
MS m/z(ESI):709.1[M+H] +. MS m/z(ESI):709.1[M+H] + .
实施例183Example 183
(6-((5-溴-2-((4-(4-(3-(羟甲基)-3-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(hydroxymethyl)-3-methylazetidine-1-yl)piperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000295
Figure PCTCN2020097369-appb-000295
(6-((5-溴-2-((4-(4-(3-(羟甲基)-3-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-(hydroxymethyl)-3-methylazetidine-1-yl)piperidin-1-yl)-2-methyl For the preparation method of oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 19.
1H NMR(400MHz,CD 3OD)δ1.29(s,3H),1.63(dd,J＝13.2,9.2Hz,3H),1.98-2.22(m,11H),2.76(t,J＝11.7Hz,2H),3.11-3.27(m,2H),3.50(s,2H),3.80-3.91(m,5H),4.14(d,J＝10.2Hz,2H),6.76(s,1H),7.64(s,1H),7.99(d,J＝9.6Hz,1H),8.24(s,1H),8.79(d,J＝2.0Hz,1H),8.85(d,J＝1.9Hz,1H),8.97(dd,J＝9.7,4.2Hz,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.29 (s, 3H), 1.63 (dd, J = 13.2, 9.2 Hz, 3H), 1.98-2.22 (m, 11H), 2.76 (t, J = 11.7 Hz ,2H),3.11-3.27(m,2H),3.50(s,2H),3.80-3.91(m,5H),4.14(d,J=10.2Hz,2H),6.76(s,1H),7.64( s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 8.24 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.97 ( dd,J=9.7,4.2Hz,1H);
MS m/z(ESI):695.1[M+H] +. MS m/z(ESI): 695.1[M+H] + .
实施例184Example 184
(6-((5-溴-2-((4-(4-((2-(二甲氨基)乙基)(甲基)氨基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidin-1-yl)-2-methoxy- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000296
Figure PCTCN2020097369-appb-000296
(6-((5-溴-2-((4-(4-((2-(二甲氨基)乙基)(甲基)氨基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidin-1-yl)-2-methoxy- Refer to Example 19 for the preparation method of 5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.79-1.92(m,2H),1.92-2.02(m,2H),2.05-2.24(m,12H),2.52-2.56(m,2H),2.68-2.78(m,7H),2.95-3.03(m,2H),3.05-3.11(m,2H),3.17-3.25(m,2H),3.84(s,3H),6.75(s,1H),7.61(s,1H),7.94-8.02(m,1H),8.22(s,1H),8.76-8.82(m,2H),8.92-9.00(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.79-1.92 (m, 2H), 1.92-2.02 (m, 2H), 2.05-2.24 (m, 12H), 2.52-2.56 (m, 2H), 2.68- 2.78(m,7H),2.95-3.03(m,2H),3.05-3.11(m,2H),3.17-3.25(m,2H), 3.84(s,3H), 6.75(s,1H), 7.61( s,1H),7.94-8.02(m,1H),8.22(s,1H),8.76-8.82(m,2H),8.92-9.00(m,1H);
MS m/z(ESI):696.1[M+H] +. MS m/z(ESI): 696.1[M+H] + .
实施例185Example 185
(6-((5-溴-2-((4-(4-(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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000297
Figure PCTCN2020097369-appb-000297
(6-((5-溴-2-((4-(4-(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施 例19。(6-((5-Bromo-2-((4-(4-(3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidin-1-yl)-2-methyl For the preparation method of oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 19.
1H NMR(400MHz,CD 3OD)δ1.16(s,6H),1.57-1.67(m,2H),2.05-2.19(m,12H),2.73-2.83(m,2H),3.16-3.25(m,3H),3.86(s,3H),4.07-4.20(m,4H),6.76(s,1H),7.64(s,1H),7.96-8.01(m,1H),8.24(s,1H),8.78-8.87(m,2H),8.94-9.00(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.16 (s, 6H), 1.57-1.67 (m, 2H), 2.05-2.19 (m, 12H), 2.73-2.83 (m, 2H), 3.16-3.25 ( m, 3H), 3.86 (s, 3H), 4.07-4.20 (m, 4H), 6.76 (s, 1H), 7.64 (s, 1H), 7.96-8.01 (m, 1H), 8.24 (s, 1H) ,8.78-8.87(m,2H),8.94-9.00(m,1H);
MS m/z(ESI):709.1[M+H] +. MS m/z(ESI):709.1[M+H] + .
实施例186Example 186
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000298
Figure PCTCN2020097369-appb-000298
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy For the preparation method of oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine, refer to Example 19.
1H NMR(400MHz,CD 3OD)δ1.60(q,J＝12.4,11.9Hz,2H),1.97-2.30(m,11H),2.73(t,J＝11.7Hz,2H),2.84-3.02(m,1H),3.16(d,J＝11.8Hz,2H),3.69-4.21(m,9H),6.74(s,1H),7.62(s,1H),7.97(d,J＝9.5Hz,1H),8.21(s,1H),8.79(s,1H),8.83(s,1H),8.92-8.95(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.60 (q, J = 12.4, 11.9 Hz, 2H), 1.97-2.30 (m, 11H), 2.73 (t, J = 11.7 Hz, 2H), 2.84-3.02 (m, 1H), 3.16 (d, J = 11.8 Hz, 2H), 3.69-4.21 (m, 9H), 6.74 (s, 1H), 7.62 (s, 1H), 7.97 (d, J = 9.5 Hz, 1H), 8.21(s,1H), 8.79(s,1H), 8.83(s,1H), 8.92-8.95(m,1H);
MS m/z(ESI):699.1[M+H] +. MS m/z(ESI): 699.1[M+H] + .
实施例187Example 187
(7-((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)喹唑啉-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)quinazolin-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000299
Figure PCTCN2020097369-appb-000299
(7-((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)喹唑啉-8-基)二甲基膦氧化的制备方法参照实施例19。(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- Refer to Example 19 for the preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)quinazolin-8-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.41-1.55(m,3H),1.89-1.96(m,2H),2.00-2.06(m,1H),2.09(s,3H),2.15(s,3H),2.17-2.23(m,8H),2.65-2.75(m,2H),2.99-3.06(m,1H),3.08-3.15(m,4H),3.66-3.74(m,2H),3.85(s,3H),6.75(s,1H),7.64(s,1H),8.02(d,J＝9.3Hz,1H),8.25(s,1H),8.84-8.93(m,1H),9.17(s,1H),9.33(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.41-1.55 (m, 3H), 1.89-1.96 (m, 2H), 2.00-2.06 (m, 1H), 2.09 (s, 3H), 2.15 (s, 3H), 2.17-2.23 (m, 8H), 2.65-2.75 (m, 2H), 2.99-3.06 (m, 1H), 3.08-3.15 (m, 4H), 3.66-3.74 (m, 2H), 3.85 ( s, 3H), 6.75 (s, 1H), 7.64 (s, 1H), 8.02 (d, J = 9.3 Hz, 1H), 8.25 (s, 1H), 8.84-8.93 (m, 1H), 9.17 (s ,1H),9.33(s,1H);
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例188Example 188
(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)喹唑啉-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) quinazolin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000300
Figure PCTCN2020097369-appb-000300
(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)喹唑啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl Refer to Example 19 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.20(t,J＝7.0Hz,3H),1.39-1.50(m,2H),1.88-1.95(m,2H),2.06(s,3H),2.10(s,3H),2.54-2.67(m,3H),2.94-3.03(m,2H),3.36-3.44(m,3H),3.47-3.53(m,4H),3.81(s,3H),3.89-3.97(m,2H),4.20-4.28(m,1H),6.64(s,1H),7.34(s,1H),8.11(d,J＝9.2Hz,1H),8.21(s,1H),8.41-8.48(m, 1H),9.29(s,1H),10.28(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.20 (t, J = 7.0 Hz, 3H), 1.39-1.50 (m, 2H), 1.88-1.95 (m, 2H), 2.06 (s, 3H), 2.10 (s, 3H), 2.54-2.67(m, 3H), 2.94-3.03(m, 2H), 3.36-3.44(m, 3H), 3.47-3.53(m, 4H), 3.81(s, 3H), 3.89 -3.97(m,2H),4.20-4.28(m,1H),6.64(s,1H),7.34(s,1H),8.11(d,J=9.2Hz,1H),8.21(s,1H), 8.41-8.48(m, 1H), 9.29(s, 1H), 10.28(s, 1H);
MS m/z(ESI):695.2[M+H] +. MS m/z(ESI): 695.2[M+H] + .
实施例189Example 189
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-6-基)二甲基膦氧化的制备(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)quinoxalin-6-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000301
Figure PCTCN2020097369-appb-000301
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-6-基)二甲基膦氧化的制备方法参照实施例19。(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl ) Amino) pyrimidin-4-yl) amino) quinoxalin-6-yl) dimethyl phosphine oxidation preparation method refer to Example 19.
MS m/z(ESI):694.2[M+H] +. MS m/z(ESI): 694.2[M+H] + .
实施例190Example 190
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000302
Figure PCTCN2020097369-appb-000302
第一步：叔-丁基[1,2,4]三唑并[1,5-a]吡啶-6-基氨基甲酸酯的制备Step 1: Preparation of tert-butyl[1,2,4]triazolo[1,5-a]pyridin-6-yl carbamate
Figure PCTCN2020097369-appb-000303
Figure PCTCN2020097369-appb-000303
往6-溴-[1,2,4]三唑并[1,5-a]吡啶(1.0g,5.0mmol)和叔-丁基氨基甲酸酯 (1.18g,10.1mmol)，碳酸铯(3.6g,11mmol)的二氧六环溶液(15mL)，加入三(二亚苄基丙酮)二钯(101mg,0.11mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(127mg,0.22mmol)，氮气除氧5分钟，110℃反应过夜。用二氯甲烷稀释反应液，有机相用饱和食盐水洗涤多次，然后分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物标题化合物叔-丁基[1,2,4]三唑并[1,5-a]吡啶-6-基氨基甲酸酯(600mg，收率:51％)。To 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (1.0g, 5.0mmol) and tert-butyl carbamate (1.18g, 10.1mmol), cesium carbonate ( 3.6g, 11mmol) in dioxane solution (15mL), add tris(dibenzylideneacetone)dipalladium (101mg, 0.11mmol) and 4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene (127 mg, 0.22 mmol), deoxygenated with nitrogen for 5 minutes, reacted at 110°C overnight. The reaction solution was diluted with dichloromethane, the organic phase was washed with saturated brine several times, and then the organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and the column chromatography was separated to obtain the title compound, tert-butyl [1 ,2,4]triazolo[1,5-a]pyridin-6-yl carbamate (600 mg, yield: 51%).
MS m/z(ESI):235.1[M+H] +. MS m/z(ESI): 235.1[M+H] + .
第二步：[1,2,4]三唑并[1,5-a]吡啶-6-胺的制备Step 2: Preparation of [1,2,4]triazolo[1,5-a]pyridine-6-amine
Figure PCTCN2020097369-appb-000304
Figure PCTCN2020097369-appb-000304
室温条件下，将叔-丁基[1,2,4]三唑并[1,5-a]吡啶-6-基氨基甲酸酯(600mg，2.56mmol)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[1,2,4]三唑并[1,5-a]吡啶-6-胺粗品(340mg)直接用于下一步反应。At room temperature, dissolve tert-butyl[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamate (600mg, 2.56mmol) in dioxane hydrochloride (10mL After stirring at room temperature overnight, the organic solvent was concentrated under reduced pressure to obtain the title compound [1,2,4]triazolo[1,5-a]pyridine-6-amine (340mg), which was directly used in the next reaction.
MS m/z(ESI):135.1[M+H] +. MS m/z(ESI): 135.1[M+H] + .
第三步：5-碘-[1,2,4]三唑并[1,5-a]吡啶-6-胺的制备The third step: Preparation of 5-iodo-[1,2,4]triazolo[1,5-a]pyridine-6-amine
Figure PCTCN2020097369-appb-000305
Figure PCTCN2020097369-appb-000305
往[1,2,4]三唑并[1,5-a]吡啶-6-胺(0.3g,2.24mmol)的DMF溶液(5mL)中滴加高碘酸钠(0.62g,2.91mmol)，I 2(0.73g,2.91mmol)，室温下反应1h，减压浓缩有机溶剂后柱层析分离得到标题化合物5-碘-[1,2,4]三唑并[1,5-a]吡啶-6-胺(0.35g，收率:60％)。 To [1,2,4]triazolo[1,5-a]pyridine-6-amine (0.3g, 2.24mmol) in DMF solution (5mL) add dropwise sodium periodate (0.62g, 2.91mmol) , I 2 (0.73g, 2.91mmol), react at room temperature for 1h, concentrate the organic solvent under reduced pressure and separate by column chromatography to obtain the title compound 5-iodo-[1,2,4]triazolo[1,5-a] Pyridine-6-amine (0.35 g, yield: 60%).
MS m/z(ESI):261.1[M+H] +. MS m/z(ESI): 261.1[M+H] + .
第四步：(6-氨基-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备Step 4: Preparation of (6-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000306
Figure PCTCN2020097369-appb-000306
5-碘-[1,2,4]三唑并[1,5-a]吡啶-6-胺(0.35g,1.35mmol)，二甲基氧化磷(0.21g,2.7mmol)，磷酸钾(0.57g,2.7mmol)混合于N,N-二甲基甲酰胺(5mL)中，加入醋酸钯(112mg,0.5mmol)和Xantphos(578mg,1.0mmol)，N 2保护下150℃反应过夜。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(6-氨基-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化(0.15g,收率:53％)。 5-iodo-[1,2,4]triazolo[1,5-a]pyridine-6-amine (0.35g, 1.35mmol), dimethylphosphorus oxide (0.21g, 2.7mmol), potassium phosphate ( 0.57g, 2.7mmol) was mixed in N,N-dimethylformamide (5mL), palladium acetate (112mg, 0.5mmol) and Xantphos (578mg, 1.0mmol) were added, and reacted at 150°C overnight under N 2 protection. 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 (6-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethyl Phosphine oxidation (0.15g, yield: 53%).
MS m/z(ESI):211.2[M+H] +. MS m/z(ESI): 211.2[M+H] + .
第五步：(6-((5-溴-2-氯嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备Step 5: (6-((5-Bromo-2-chloropyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097369-appb-000307
Figure PCTCN2020097369-appb-000307
往(6-氨基喹喔啉-5-基)二甲基膦氧化(150mg,0.71mmol)和5-溴-2,4-二氯嘧啶(244mg,1.1mmol)的叔丁醇溶液(2.0mL)中加入DIPEA(185mg,1.43mmol)，180℃微波反应2h。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(6-((5-溴-2-氯嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化(120mg，收率:42％)。To (6-aminoquinoxalin-5-yl) dimethylphosphine oxide (150mg, 0.71mmol) and 5-bromo-2,4-dichloropyrimidine (244mg, 1.1mmol) in tert-butanol solution (2.0mL ) Was added DIPEA (185mg, 1.43mmol) and reacted in microwave at 180°C for 2h. 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 (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-[1,2,4]triazolo [1,5-a]pyridin-5-yl)dimethylphosphine oxidation (120 mg, yield: 42%).
MS m/z(ESI):401.1[M+H] +. MS m/z(ESI): 401.1[M+H] + .
第六步：(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备The sixth step: (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy (5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000308
Figure PCTCN2020097369-appb-000308
往1-(1-(4-氨基-5-甲氧基-2-甲基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(27mg,0.09mmol)和(6-((5-溴-2-氯嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化(35mg,0.09mmol)的叔丁醇(2mL)混合液中，加入TsOH(66.3mg,0.35mmol)，100℃反应过夜。反应体系冷却至室温，反应液减压浓缩后柱层析分离得到标题化合物(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化(18mg,收率:30％)。To 1-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (27mg, 0.09 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethyl TsOH (66.3mg, 0.35mmol) was added to the mixture of phosphine oxidation (35mg, 0.09mmol) in tert-butanol (2mL) and reacted at 100°C overnight. The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1) -Yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5- a] Pyridin-5-yl)dimethylphosphine oxidation (18 mg, yield: 30%).
1H NMR(400MHz,CD 3OD)δ1.45-1.57(m,2H),1.99-2.01(m,2H),2.04(s,3H),2.15-2.18(m,6H),2.23(s,6H),2.70-2.76(m,2H),3.06-3.19(m,3H),3.37-3.46(m,3H),3.81(s,3H),3.85-3.88(m,2H),6.74(s,1H),7.52(s,1H),7.73-7.81(m,1H), 8.17(s,1H),8.44(s,1H),8.72-8.76(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.45-1.57 (m, 2H), 1.99-2.01 (m, 2H), 2.04 (s, 3H), 2.15-2.18 (m, 6H), 2.23 (s, 6H), 2.70-2.76 (m, 2H), 3.06-3.19 (m, 3H), 3.37-3.46 (m, 3H), 3.81 (s, 3H), 3.85-3.88 (m, 2H), 6.74 (s, 1H),7.52(s,1H),7.73-7.81(m,1H), 8.17(s,1H),8.44(s,1H),8.72-8.76(m,1H);
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例191Example 191
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000309
Figure PCTCN2020097369-appb-000309
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl Refer to Example 190 for the preparation method of phenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):684.2[M+H] +. MS m/z(ESI): 684.2[M+H] + .
实施例192Example 192
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000310
Figure PCTCN2020097369-appb-000310
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method reference Example 190.
MS m/z(ESI):684.2[M+H] +. MS m/z(ESI): 684.2[M+H] + .
实施例193Example 193
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000311
Figure PCTCN2020097369-appb-000311
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-[1,2,4]三唑并[1,5-a]吡啶-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190。2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphorus)-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Example 190.
1H NMR(400MHz,CD 3OD)δ1.44-1.51(m,2H),1.88-1.93(m,2H),2.04(s,3H),2.16-2.18(m,7H),2.33(s,1H),2.68-2.70(m,2H),2.74-2.79(m,2H),2.81-2.89(m,1H),3.09-3.16(m,4H),3.59-3.63(m,2H),3.83(s,3H),6.74(s,1H),7.50(s,1H),7.74-7.81(m,1H),8.17(s,1H),8.44(s,1H),8.73-8.79(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.44-1.51(m,2H),1.88-1.93(m,2H),2.04(s,3H),2.16-2.18(m,7H),2.33(s, 1H), 2.68-2.70 (m, 2H), 2.74-2.79 (m, 2H), 2.81-2.89 (m, 1H), 3.09-3.16 (m, 4H), 3.59-3.63 (m, 2H), 3.83 ( s, 3H), 6.74 (s, 1H), 7.50 (s, 1H), 7.74-7.81 (m, 1H), 8.17 (s, 1H), 8.44 (s, 1H), 8.73-8.79 (m, 1H) ；
MS m/z(ESI):679.2[M+H] +. MS m/z(ESI): 679.2[M+H] + .
实施例194Example 194
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridine- Preparation of 5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000312
Figure PCTCN2020097369-appb-000312
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(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)-[1,2,4]triazolo[1,5-a]pyridine- Refer to Example 190 for the preparation method of 5-yl)dimethylphosphine oxidation.
MS m/z(ESI):709.2[M+H] +. MS m/z(ESI): 709.2[M+H] + .
实施例195Example 195
(R)-(6-((5-溴-2-((4-(4-(3-异丙基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((4-(4-(3-isopropylpyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000313
Figure PCTCN2020097369-appb-000313
(R)-(6-((5-溴-2-((4-(4-(3-异丙基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(R)-(6-((5-Bromo-2-((4-(4-(3-isopropylpyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refer to implementation Example 190.
MS m/z(ESI):696.2[M+H] +. MS m/z(ESI): 696.2[M+H] + .
实施例196Example 196
(S)-(6-((5-溴-2-((4-(4-(3-异丙基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((4-(4-(3-isopropylpyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000314
Figure PCTCN2020097369-appb-000314
(S)-(6-((5-溴-2-((4-(4-(3-异丙基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参 照实施例190。(S)-(6-((5-Bromo-2-((4-(4-(3-isopropylpyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refer to implementation Example 190.
MS m/z(ESI):696.2[M+H] +. MS m/z(ESI): 696.2[M+H] + .
实施例197Example 197
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000315
Figure PCTCN2020097369-appb-000315
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(S)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refer to implementation Example 190.
MS m/z(ESI):698.2[M+H] +. MS m/z(ESI): 698.2[M+H] + .
实施例198Example 198
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000316
Figure PCTCN2020097369-appb-000316
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(R)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refer to implementation Example 190.
MS m/z(ESI):698.2[M+H] +. MS m/z(ESI): 698.2[M+H] + .
实施例199Example 199
(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)-[1,2,4]三唑并[4,3-a]吡啶-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)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000317
Figure PCTCN2020097369-appb-000317
(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)-[1,2,4]三唑并[4,3-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refer to Examples 190.
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例200Example 200
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[4,3-a]吡啶-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000318
Figure PCTCN2020097369-appb-000318
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[4,3-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)dimethylphosphine oxidation method refers to Example 190.
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例201Example 201
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基) 嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000319
Figure PCTCN2020097369-appb-000319
第一步：叔-丁基[1,2,4]三唑并[1,5-a]吡啶-7-基氨基甲酸酯的制备The first step: Preparation of tert-butyl[1,2,4]triazolo[1,5-a]pyridin-7-yl carbamate
Figure PCTCN2020097369-appb-000320
Figure PCTCN2020097369-appb-000320
往7-溴-[1,2,4]三唑并[1,5-a]吡啶(1.0g,5.0mmol)和叔-丁基氨基甲酸酯(1.18g,10.1mmol)，碳酸铯(3.6g,11mmol)的二氧六环溶液(15mL)，加入三(二亚苄基丙酮)二钯(101mg,0.11mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(127mg,0.22mmol)，氮气除氧5分钟，110℃反应过夜。用二氯甲烷稀释反应液，有机相用饱和食盐水洗涤多次，然后分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物标题化合物叔-丁基[1,2,4]三唑并[1,5-a]吡啶-7-基氨基甲酸酯(575mg，收率:49％)。To 7-bromo-[1,2,4]triazolo[1,5-a]pyridine (1.0g, 5.0mmol) and tert-butyl carbamate (1.18g, 10.1mmol), cesium carbonate ( 3.6g, 11mmol) in dioxane solution (15mL), add tris(dibenzylideneacetone)dipalladium (101mg, 0.11mmol) and 4,5-bisdiphenylphosphine-9,9-dimethyl Xanthene (127 mg, 0.22 mmol), deoxygenated with nitrogen for 5 minutes, reacted at 110°C overnight. The reaction solution was diluted with dichloromethane, the organic phase was washed with saturated brine several times, and then the organic phase was separated and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and the column chromatography was separated to obtain the title compound, tert-butyl [1 ,2,4]triazolo[1,5-a]pyridin-7-yl carbamate (575 mg, yield: 49%).
MS m/z(ESI):235.1[M+H] +. MS m/z(ESI): 235.1[M+H] + .
第二步：[1,2,4]三唑并[1,5-a]吡啶-7-胺的制备Step 2: Preparation of [1,2,4]triazolo[1,5-a]pyridine-7-amine
Figure PCTCN2020097369-appb-000321
Figure PCTCN2020097369-appb-000321
室温条件下，将叔-丁基[1,2,4]三唑并[1,5-a]吡啶-6-基氨基甲酸酯(575mg，2.45mmol)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[1,2,4]三唑并[1,5-a]吡啶-7-胺粗品(320mg)直接用于下一步反应。At room temperature, dissolve tert-butyl[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamate (575mg, 2.45mmol) in dioxane hydrochloride (10mL After stirring at room temperature overnight, the organic solvent was concentrated under reduced pressure to obtain the title compound [1,2,4]triazolo[1,5-a]pyridine-7-amine (320mg), which was directly used in the next reaction.
MS m/z(ESI):135.1[M+H] +. MS m/z(ESI): 135.1[M+H] + .
第三步：8-碘-[1,2,4]三唑并[1,5-a]吡啶-7-胺的制备The third step: Preparation of 8-iodo-[1,2,4]triazolo[1,5-a]pyridine-7-amine
Figure PCTCN2020097369-appb-000322
Figure PCTCN2020097369-appb-000322
往[1,2,4]三唑并[1,5-a]吡啶-7-胺(0.3g,2.24mmol)的DMF溶液(5mL)中 滴加高碘酸钠(0.62g,2.91mmol)，I 2(0.73g,2.91mmol)，室温下反应1h，减压浓缩有机溶剂后柱层析分离得到标题化合物8-碘-[1,2,4]三唑并[1,5-a]吡啶-7-胺(0.35g，收率:60％)。 To [1,2,4]triazolo[1,5-a]pyridine-7-amine (0.3g, 2.24mmol) in DMF solution (5mL) was added dropwise sodium periodate (0.62g, 2.91mmol) , I 2 (0.73g, 2.91mmol), react for 1h at room temperature, concentrate the organic solvent under reduced pressure and separate by column chromatography to obtain the title compound 8-iodo-[1,2,4]triazolo[1,5-a] Pyridine-7-amine (0.35 g, yield: 60%).
MS m/z(ESI):261.1[M+H] +. MS m/z(ESI): 261.1[M+H] + .
第四步：(7-氨基-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备Step 4: Preparation of (7-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000323
Figure PCTCN2020097369-appb-000323
8-碘-[1,2,4]三唑并[1,5-a]吡啶-7-胺(0.35g,1.35mmol)，二甲基氧化磷(0.21g,2.7mmol)，磷酸钾(0.57g,2.7mmol)混合于N,N-二甲基甲酰胺(5mL)中，加入醋酸钯(112mg,0.5mmol)和Xantphos(578mg,1.0mmol)，N 2保护下150℃反应过夜。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(7-氨基-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化(0.12g,收率:42％)。 8-iodo-[1,2,4]triazolo[1,5-a]pyridine-7-amine (0.35g, 1.35mmol), dimethyl phosphorous oxide (0.21g, 2.7mmol), potassium phosphate ( 0.57g, 2.7mmol) was mixed in N,N-dimethylformamide (5mL), palladium acetate (112mg, 0.5mmol) and Xantphos (578mg, 1.0mmol) were added, and reacted at 150°C overnight under N 2 protection. 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 (7-amino-[1,2,4]triazolo[1,5-a]pyridine-8-yl)dimethyl Phosphine oxidation (0.12g, yield: 42%).
MS m/z(ESI):211.2[M+H] +. MS m/z(ESI): 211.2[M+H] + .
第五步：(7-((5-溴-2-氯嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备Step 5: (7-((5-Bromo-2-chloropyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethyl Preparation of phosphine oxidation
Figure PCTCN2020097369-appb-000324
Figure PCTCN2020097369-appb-000324
往(7-氨基-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化(120mg,0.56mmol)和5-溴-2,4-二氯嘧啶(244mg,1.1mmol)的叔丁醇溶液(2.0mL)中加入DIPEA(185mg,1.43mmol)，180℃微波反应2h。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(7-((5-溴-2-氯嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化(105mg，收率:46％)。To (7-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxide (120mg, 0.56mmol) and 5-bromo-2,4-bis DIPEA (185mg, 1.43mmol) was added to the tert-butanol solution (2.0mL) of chloropyrimidine (244mg, 1.1mmol), and the reaction was carried out in microwave at 180°C for 2h. 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 (7-((5-bromo-2-chloropyrimidin-4-yl)amino)-[1,2,4]triazolo [1,5-a]pyridin-8-yl)dimethylphosphine oxide (105 mg, yield: 46%).
MS m/z(ESI):401.1[M+H] +. MS m/z(ESI): 401.1[M+H] + .
第六步：(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备The sixth step: (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy (5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000325
Figure PCTCN2020097369-appb-000325
往2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(35mg,0.09mmol)和(7-((5-溴-2-氯嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化(35mg,0.09mmol)的叔丁醇(2mL)混合液中，加入TsOH(66.3mg,0.35mmol)，100℃反应过夜。反应体系冷却至室温，反应液减压浓缩后柱层析分离得到标题化合物(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化(16mg,收率:27％)。To 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (35mg, 0.09mmol) and (7-((5 -Bromo-2-chloropyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxide (35mg, 0.09mmol) TsOH (66.3 mg, 0.35 mmol) was added to the tert-butanol (2 mL) mixed solution and reacted at 100°C overnight. The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound (6-((5-bromo-2-((4-(4-(3-(dimethylamino)azetidine-1) -Yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5- a] Pyridin-5-yl)dimethylphosphine oxidation (16 mg, yield: 27%).
1H NMR(400MHz,CD 3OD)δ1.69-1.83(m,2H),2.06-2.09(m,5H),2.12(s,3H),2.17(s,3H),2.51-2.60(m,5H),2.77-2.79(m,9H),3.21-3.33(m,2H),3.84(s,3H),6.77(s,1H),7.57(s,1H),8.26-8.28(m,2H),8.52-8.53(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 1.69-1.83 (m, 2H), 2.06-2.09 (m, 5H), 2.12 (s, 3H), 2.17 (s, 3H), 2.51-2.60 (m, 5H), 2.77-2.79(m, 9H), 3.21-3.33(m, 2H), 3.84(s, 3H), 6.77(s, 1H), 7.57(s, 1H), 8.26-8.28(m, 2H) ,8.52-8.53(m,2H);
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例202Example 202
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000326
Figure PCTCN2020097369-appb-000326
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方 法参照实施例201。(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation preparation method refer to Examples 201.
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例203Example 203
(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)咪唑并[1,2-a]吡啶-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)imidazo[1,2-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000327
Figure PCTCN2020097369-appb-000327
(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)咪唑并[1,2-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- The preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-5-yl)dimethylphosphine oxidation refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例204Example 204
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,2-a]吡啶-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000328
Figure PCTCN2020097369-appb-000328
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,2-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例205Example 205
(7-((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)咪唑并[1,2-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000329
Figure PCTCN2020097369-appb-000329
(7-((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)咪唑并[1,2-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例190。(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- The preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-8-yl)dimethylphosphine oxidation refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例206Example 206
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,2-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000330
Figure PCTCN2020097369-appb-000330
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,2-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例190。(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-8-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例207Example 207
(7-((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)-[1,2,4]三唑并[4,3-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000331
Figure PCTCN2020097369-appb-000331
(7-((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)-[1,2,4]三唑并[4,3-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例190。(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)dimethylphosphine oxidation preparation method refer to Examples 190.
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例208Example 208
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[4,3-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000332
Figure PCTCN2020097369-appb-000332
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[4,3-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例190。(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)dimethylphosphine oxidation method refers to Example 190.
MS m/z(ESI):683.2[M+H] +. MS m/z(ESI): 683.2[M+H] + .
实施例209Example 209
(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)吡唑并[1,5-a]吡啶-7-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)pyrazolo[1,5-a]pyridin-7-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000333
Figure PCTCN2020097369-appb-000333
(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)吡唑并[1,5-a]吡啶-7-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)pyrazolo[1,5-a]pyridin-7-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例210Example 210
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)吡唑并[1,5-a]吡啶-7-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrazolo[1,5-a]pyridin-7-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000334
Figure PCTCN2020097369-appb-000334
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)吡唑并[1,5-a]吡啶-7-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrazolo[1,5-a]pyridin-7-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例211Example 211
(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)咪唑并[1,5-a]吡啶-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)imidazo[1,5-a]pyridin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000335
Figure PCTCN2020097369-appb-000335
(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)咪唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-2-methoxy-5- The preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例212Example 212
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000336
Figure PCTCN2020097369-appb-000336
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例213Example 213
(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)吡唑并[1,5-a]吡啶-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)pyrazolo[1,5-a]pyridin-4-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000337
Figure PCTCN2020097369-appb-000337
(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)吡唑并[1,5-a]吡啶-4-基)二甲基膦氧化的制备方法参照实施例190。(5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)pyrazolo[1,5-a]pyridin-4-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例214Example 214
(5-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)吡唑并[1,5-a]吡啶-4-基)二甲基膦氧化的制备(5-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrazolo[1,5-a]pyridin-4-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000338
Figure PCTCN2020097369-appb-000338
(5-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)吡唑并[1,5-a]吡啶-4-基)二甲基膦氧化的制备方法参照实施例190。(5-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)pyrazolo[1,5-a]pyridin-4-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例215Example 215
(7-((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)咪唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000339
Figure PCTCN2020097369-appb-000339
(7-((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)咪唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例190。(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5- The preparation method of methylphenyl)amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例216Example 216
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000340
Figure PCTCN2020097369-appb-000340
(7-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)咪唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例190。(7-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)imidazo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation The preparation method refers to Example 190.
MS m/z(ESI):682.2[M+H] +. MS m/z(ESI): 682.2[M+H] + .
实施例217Example 217
(6-((5-溴-2-((7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) (Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000341
Figure PCTCN2020097369-appb-000341
第一步：7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉的制备Step 1: Preparation of 7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
Figure PCTCN2020097369-appb-000342
Figure PCTCN2020097369-appb-000342
7-甲氧基-1,2,3,4-四氢异喹啉(1.96g,12mmol)和DIPEA(3.9g,30mmol)混合于DCM(30mL)中，滴加碘甲烷(2.55g,18.0mmol)的DCM(10mL)混合溶液，室温反应4h。减压浓缩反应液，残留物DCM与饱和NaHCO3水溶液分液，分离并干燥有机相，减压浓缩有机溶剂后柱层析分离得到标题化合物7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉(1.77g,收率:83％)。7-Methoxy-1,2,3,4-tetrahydroisoquinoline (1.96g, 12mmol) and DIPEA (3.9g, 30mmol) were mixed in DCM (30mL), and methyl iodide (2.55g, 18.0 A mixed solution of mmol) in DCM (10 mL) was reacted at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, the residue DCM was separated with saturated NaHCO3 aqueous solution, the organic phase was separated and dried, the organic solvent was concentrated under reduced pressure and column chromatography was separated to obtain the title compound 7-methoxy-2-methyl-1,2 3,4-Tetrahydroisoquinoline (1.77 g, yield: 83%).
MS m/z(ESI):178.2[M+H] +. MS m/z(ESI): 178.2[M+H] + .
第二步：7-甲氧基-2-甲基-6-硝基-1,2,3,4-四氢异喹啉的制备Step 2: Preparation of 7-methoxy-2-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline
Figure PCTCN2020097369-appb-000343
Figure PCTCN2020097369-appb-000343
7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉(1.77g,10mmol)溶于TFA(20mL)中，冷却至0℃，滴加HNO 3(693mg,11.0mmol)的TFA(5mL)混合溶液，滴完后自然升温至室温反应4h。减压浓缩反应液，残留物DCM与饱和NaHCO 3水溶液分液，分离并干燥有机相，减压浓缩有机溶剂后柱层析分离得到标题化合物7-甲氧基-2-甲基-6-硝基-1,2,3,4-四氢异喹啉(800mg,收率:36％)。 7-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.77g, 10mmol) was dissolved in TFA (20mL), cooled to 0℃, and HNO 3 (693mg, 11.0mmol) TFA (5mL) mixed solution, after dripping, the temperature was naturally raised to room temperature to react for 4h. The reaction solution was concentrated under reduced pressure, the residue DCM was separated with saturated aqueous NaHCO 3 solution, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure and then separated by column chromatography to obtain the title compound 7-methoxy-2-methyl-6-nitro -1,2,3,4-tetrahydroisoquinoline (800mg, yield: 36%).
MS m/z(ESI):223.2[M+H] +。 MS m/z (ESI): 223.2 [M+H] + .
第三步：7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-6-胺的制备The third step: Preparation of 7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine
Figure PCTCN2020097369-appb-000344
Figure PCTCN2020097369-appb-000344
7-甲氧基-2-甲基-6-硝基-1,2,3,4-四氢异喹啉(800mg,3.6mmol)溶于甲醇(16mL)，加入钯碳(160mg)，氢气氛围下室温反应2h。反应液过滤，滤液减压浓缩后得到标题化合物7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-6-胺(692mg,收率:100％)。7-Methoxy-2-methyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (800mg, 3.6mmol) was dissolved in methanol (16mL), palladium on carbon (160mg), hydrogen React at room temperature for 2h under atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine (692 mg, yield: 100%).
MS m/z(ESI):193.2[M+H] +. MS m/z(ESI): 193.2[M+H] + .
第四步：(6-((5-溴-2-((7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备The fourth step: (6-((5-bromo-2-((7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine- Preparation of 4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000345
Figure PCTCN2020097369-appb-000345
往7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-6-胺(19.3mg,0.1mmol)和(6-((5-溴-2-氯嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(41.1mg,0.1mmol)的叔丁醇(2mL)混合溶液中，加入对甲苯磺酸(51.6mg,0.3mmol)，90℃反应过夜。冷却至室温，反应液用DCM与饱和NaHCO 3水溶液分液，分离并干燥有机相，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-((7-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化(28.4mg,收率:50％)。 To 7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine (19.3mg, 0.1mmol) and (6-((5-bromo-2-chloropyrimidine) -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (41.1mg, 0.1mmol) in tert-butanol (2mL) mixed solution, add p-toluenesulfonic acid (51.6mg, 0.3mmol) , React at 90°C overnight. After cooling to room temperature, the reaction solution was partitioned with DCM and saturated aqueous NaHCO 3 solution. The organic phase was separated and dried. The organic solvent was concentrated under reduced pressure and the column chromatography was separated to obtain the title compound (6-((5-bromo-2-((7- Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (28.4mg, yield: 50%).
MS m/z(ESI):568.2[M+H] +. MS m/z(ESI): 568.2[M+H] + .
实施例218Example 218
(6-((5-溴-2-((7-甲氧基-2-(噁丁环-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2-(oxbutan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000346
Figure PCTCN2020097369-appb-000346
(6-((5-溴-2-((7-甲氧基-2-(噁丁环-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-2-(oxbutan-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino ) Pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 217.
MS m/z(ESI):610.2[M+H] +. MS m/z(ESI): 610.2[M+H] + .
实施例219Example 219
(6-((5-溴-2-((7-甲氧基-2-(1-甲基吖丁啶-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2-(1-methylazetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6 -Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000347
Figure PCTCN2020097369-appb-000347
(6-((5-溴-2-((7-甲氧基-2-(1-甲基吖丁啶-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-2-(1-methylazetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6 -Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
1H NMR(400MHz,CD 3OD)δ2.13(s,3H),2.17(s,3H),2.56-2.68(m,4H),2.84(s,3H),3.34-3.45(m,3H),3.55(s,2H),3.85(s,3H),4.10-4.21(m,2H),6.72(s,1H),7.70(s,1H),8.09(d,J＝9.5Hz,1H),8.26(s,1H),8.79-8.87(m,2H),8.89-8.96(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 2.13 (s, 3H), 2.17 (s, 3H), 2.56-2.68 (m, 4H), 2.84 (s, 3H), 3.34-3.45 (m, 3H) ,3.55(s,2H),3.85(s,3H),4.10-4.21(m,2H),6.72(s,1H),7.70(s,1H),8.09(d,J=9.5Hz,1H), 8.26(s,1H), 8.79-8.87(m,2H), 8.89-8.96(m,1H);
MS m/z(ESI):623.2[M+H] +. MS m/z(ESI): 623.2[M+H] + .
实施例220Example 220
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000348
Figure PCTCN2020097369-appb-000348
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-2-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):624.2[M+H] +. MS m/z(ESI): 624.2[M+H] + .
实施例221Example 221
(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)喹喔啉-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)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000349
Figure PCTCN2020097369-appb-000349
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6- (Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refer to Example 217.
1H NMR(400MHz,CD 3OD)δ2.13(s,3H),2.17(s,3H),,2.32-2.39(m,2H),2.60-2.67(m,2H),2.71-2.84(m,3H),2.88(s,3H),3.33-3.42(m,3H),3.47-3.54(m,1H),3.66-3.79(m,2H),3.85(s,3H),6.71(s,1H),7.71(s,1H),8.06(d,J＝9.6Hz,1H),8.23(s,1H),8.79-8.86(m,2H),8.88-8.94(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 2.13 (s, 3H), 2.17 (s, 3H), 2.32-2.39 (m, 2H), 2.60-2.67 (m, 2H), 2.71-2.84 (m ,3H), 2.88 (s, 3H), 3.33-3.42 (m, 3H), 3.47-3.54 (m, 1H), 3.66-3.79 (m, 2H), 3.85 (s, 3H), 6.71 (s, 1H) ), 7.71 (s, 1H), 8.06 (d, J = 9.6 Hz, 1H), 8.23 (s, 1H), 8.79-8.86 (m, 2H), 8.88-8.94 (m, 1H);
MS m/z(ESI):637.2[M+H] +. MS m/z(ESI): 637.2[M+H] + .
实施例222Example 222
1-(6-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-7-甲氧基-3,4-二氢异喹啉-2(1H)-基)乙烷-1-酮的制备1-(6-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-7-methoxy-3 Preparation of 1,4-Dihydroisoquinoline-2(1H)-yl)ethane-1-one
Figure PCTCN2020097369-appb-000350
Figure PCTCN2020097369-appb-000350
1-(6-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-7-甲氧基-3,4-二氢异喹啉-2(1H)-基)乙烷-1-酮的制备方法参照实施例217。1-(6-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-7-methoxy-3 Refer to Example 217 for the preparation method of 4-dihydroisoquinoline-2(1H)-yl)ethane-1-one.
MS m/z(ESI):596.2[M+H] +. MS m/z(ESI): 596.2[M+H] + .
实施例223Example 223
(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)喹喔啉-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)quinoxaline -5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000351
Figure PCTCN2020097369-appb-000351
(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)喹喔啉-5-基)二甲的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxaline For the preparation method of -5-yl)dimethyl, refer to Example 217.
MS m/z(ESI):554.2[M+H] +. MS m/z(ESI): 554.2[M+H] + .
实施例224Example 224
(6-((5-溴-2-((6-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl )Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000352
Figure PCTCN2020097369-appb-000352
(6-((5-溴-2-((6-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl ) Amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):596.2[M+H] +. MS m/z(ESI): 596.2[M+H] + .
实施例225Example 225
(6-((5-溴-2-((7-甲氧基-1-甲基-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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-1-methyl-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroiso (Quinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000353
Figure PCTCN2020097369-appb-000353
(6-((5-溴-2-((7-甲氧基-1-甲基-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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-1-methyl-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroiso For the preparation method of quinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 217.
MS m/z(ESI):651.2[M+H] +. MS m/z(ESI): 651.2[M+H] + .
实施例226Example 226
(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)喹喔啉-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)quinoxaline -5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000354
Figure PCTCN2020097369-appb-000354
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)quinoxaline Refer to Example 217 for the preparation method of -5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ2.14(s,3H),2.17(s,3H),3.10(t,J＝6.4Hz,2H),3.48(t,J＝6.4Hz,2H),3.92(s,3H),4.07(s,2H),6.90(s,1H),7.92(s,1H),8.18(d,J＝9.4Hz,1H),8.31(s,1H),8.84(d,J＝1.9Hz,1H),8.88(d,J＝2.0Hz,1H),8.94(dd,J＝9.5,4.1Hz,1H)； 1 H NMR (400MHz, CD 3 OD) δ 2.14 (s, 3H), 2.17 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.92(s,3H),4.07(s,2H),6.90(s,1H),7.92(s,1H),8.18(d,J=9.4Hz,1H),8.31(s,1H),8.84(d ,J=1.9Hz,1H), 8.88(d,J=2.0Hz,1H), 8.94(dd,J=9.5,4.1Hz,1H);
MS m/z(ESI):554.2[M+H] +. MS m/z(ESI): 554.2[M+H] + .
实施例227Example 227
(6-((5-溴-2-((6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl) (Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000355
Figure PCTCN2020097369-appb-000355
(6-((5-溴-2-((6-甲氧基-2-甲基-1,2,3,4-四氢异喹啉-7-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl) Refer to Example 217 for the preparation method of amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):568.2[M+H] +. MS m/z(ESI): 568.2[M+H] + .
实施例228Example 228
(6-((5-溴-2-((6-甲氧基-1-(1-甲基吡咯烷-3-基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-methoxy-1-(1-methylpyrrolidin-3-yl)indol-5-yl)amino)pyrimidin-4-yl) (Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000356
Figure PCTCN2020097369-appb-000356
(6-((5-溴-2-((6-甲氧基-1-(1-甲基吡咯烷-3-基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-methoxy-1-(1-methylpyrrolidin-3-yl)indol-5-yl)amino)pyrimidin-4-yl) Refer to Example 217 for the preparation method of amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):623.2[M+H] +. MS m/z(ESI): 623.2[M+H] + .
实施例229Example 229
(6-((5-溴-2-((6-甲氧基-1-((1-甲基吖丁啶-3-基)甲基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-methoxy-1-((1-methylazetidine-3-yl)methyl)indol-5-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000357
Figure PCTCN2020097369-appb-000357
(6-((5-溴-2-((6-甲氧基-1-((1-甲基吖丁啶-3-基)甲基)二氢吲哚-5-基)氨基)嘧 啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-methoxy-1-((1-methylazetidine-3-yl)methyl)indol-5-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):623.2[M+H] +. MS m/z(ESI): 623.2[M+H] + .
实施例230Example 230
(6-((5-溴-2-((6-甲氧基-1-(1-甲基吖丁啶-3-基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-methoxy-1-(1-methylazetidine-3-yl)indol-5-yl)amino)pyrimidin-4-yl )Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000358
Figure PCTCN2020097369-appb-000358
(6-((5-溴-2-((6-甲氧基-1-(1-甲基吖丁啶-3-基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-methoxy-1-(1-methylazetidine-3-yl)indol-5-yl)amino)pyrimidin-4-yl ) Amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):609.2[M+H] +. MS m/z(ESI): 609.2[M+H] + .
实施例231Example 231
(6-((5-溴-2-((6-甲氧基-1-(1-甲基哌啶-4-基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((6-methoxy-1-(1-methylpiperidin-4-yl)indol-5-yl)amino)pyrimidin-4-yl) (Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000359
Figure PCTCN2020097369-appb-000359
(6-((5-溴-2-((6-甲氧基-1-(1-甲基哌啶-4-基)二氢吲哚-5-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((6-methoxy-1-(1-methylpiperidin-4-yl)indol-5-yl)amino)pyrimidin-4-yl) Refer to Example 217 for the preparation method of amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):637.2[M+H] +. MS m/z(ESI): 637.2[M+H] + .
实施例232Example 232
(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)喹喔啉-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) quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000360
Figure PCTCN2020097369-appb-000360
(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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例23。(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) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refers to Example 23.
1H NMR(400MHz,CD 3OD)δ0.83(t,J＝7.6Hz,3H),1.51-1.62(m,2H),1.96-2.06(m,2H),2.13(s,3H),2.17(s,3H),2.43-2.52(m,2H),2.72-2.85(m,3H),3.05-3.14(m,2H),3.76-3.88(m,7H),3.94-4.05(m,2H),6.80(s,1H),7.65(s,1H),7.95-8.01(m,1H),8.24(s,1H),8.78-8.90(m,3H)； 1 H NMR (400MHz, CD 3 OD) δ 0.83 (t, J = 7.6 Hz, 3H), 1.51-1.62 (m, 2H), 1.96-2.06 (m, 2H), 2.13 (s, 3H), 2.17 (s,3H),2.43-2.52(m,2H),2.72-2.85(m,3H),3.05-3.14(m,2H),3.76-3.88(m,7H),3.94-4.05(m,2H) ,6.80(s,1H),7.65(s,1H),7.95-8.01(m,1H),8.24(s,1H),8.78-8.90(m,3H);
MS m/z(ESI):713.1[M+H] +. MS m/z(ESI): 713.1[M+H] + .
实施例233Example 233
(6-((5-溴-2-((4-(4-(3-氟-3-(甲氧基甲基)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)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-2- (Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000361
Figure PCTCN2020097369-appb-000361
(6-((5-溴-2-((4-(4-(3-氟-3-(甲氧基甲基)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)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((4-(4-(3-fluoro-3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-2- Refer to Example 19 for the preparation method of methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.45-1.57(m,2H),1.90-1.98(m,2H),2.06(s,3H),2.12(s,3H),2.16(s,3H),2.66-2.76(m,2H),3.09-3.17(m,2H),3.45(s,3H),3.47-3.59(m,3H),3.66-3.79(m,4H),3.84(s,3H),6.75(s,1H),7.60(s,1H),7.98(d,J＝9.5Hz,1H),8.23(s,1H),8.78-8.86(m,2H),8.92-8.96(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.45-1.57(m,2H),1.90-1.98(m,2H),2.06(s,3H), 2.12(s,3H), 2.16(s,3H) ,2.66-2.76(m,2H),3.09-3.17(m,2H),3.45(s,3H),3.47-3.59(m,3H),3.66-3.79(m,4H),3.84(s,3H) ,6.75(s,1H),7.60(s,1H),7.98(d,J=9.5Hz,1H),8.23(s,1H),8.78-8.86(m,2H),8.92-8.96(m,1H );
MS m/z(ESI):713.1[M+H] +. MS m/z(ESI): 713.1[M+H] + .
实施例234Example 234
(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)-3-甲基吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)-3-methylazetidine-1-yl)piperidine- Preparation of 1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000362
Figure PCTCN2020097369-appb-000362
(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)-3-甲基吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例19。(6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)-3-methylazetidine-1-yl)piperidine- The preparation method of 1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation refers to Example 19.
MS m/z(ESI):709.1[M+H] +. MS m/z(ESI):709.1[M+H] + .
实施例235Example 235
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)-3-甲基吖丁啶-3-基)乙酰腈的制备2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)-3-methylazetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000363
Figure PCTCN2020097369-appb-000363
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-5-甲氧基-2-甲基苯基)哌啶-4-基)-3-甲基吖丁啶-3-基)乙酰腈的制备方法参照实施例19。2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-methylphenyl)piperidin-4-yl)-3-methylazetidine-3-yl)acetonitrile for the preparation method refer to Example 19.
1H NMR(400MHz,CD 3OD)δ1.48-1.68(m,5H),1.92-2.27(m,11H),2.64-2.81(m,3H),2.85(s,2H),3.16(d,J＝11.9Hz,2H),3.56(d,J＝9.4Hz,2H),3.66(d,J＝9.3Hz,2H),3.85(s,3H),6.76(s,1H),7.62(s,1H),7.99(d,J＝9.5Hz,1H),8.23(s,1H),8.80(s,1H),8.84(s,1H),8.94-8.98(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.48-1.68 (m, 5H), 1.92-2.27 (m, 11H), 2.64-2.81 (m, 3H), 2.85 (s, 2H), 3.16 (d, J = 11.9Hz, 2H), 3.56 (d, J = 9.4Hz, 2H), 3.66 (d, J = 9.3Hz, 2H), 3.85 (s, 3H), 6.76 (s, 1H), 7.62 (s, 1H),7.99(d,J=9.5Hz,1H), 8.23(s,1H),8.80(s,1H),8.84(s,1H),8.94-8.98(m,1H);
MS m/z(ESI):704.1[M+H] +. MS m/z(ESI):704.1[M+H] + .
实施例236Example 236
(6-((5-溴-2-((2-乙基-7-甲氧基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-ethyl-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) (Amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000364
Figure PCTCN2020097369-appb-000364
(6-((5-溴-2-((2-乙基-7-甲氧基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((2-ethyl-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) Refer to Example 217 for the preparation method of amino)quinoxalin-5-yl)dimethylphosphine oxidation.
1H NMR(400MHz,CD 3OD)δ1.27(t,J＝7.2Hz,3H),2.13(s,3H),2.17(s,3H),2.68-2.75(m,2H),2.79-2.87(m,2H),2.92-2.99(m,2H),3.82-3.90(m,5H),6.77(s,1H),7.81(s,1H),8.12(d,J＝9.5Hz,1H),8.27(s,1H),8.80-8.88(m,2H),8.90-8.97(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.27 (t, J = 7.2Hz, 3H), 2.13 (s, 3H), 2.17 (s, 3H), 2.68-2.75 (m, 2H), 2.79-2.87 (m,2H),2.92-2.99(m,2H),3.82-3.90(m,5H),6.77(s,1H),7.81(s,1H),8.12(d,J=9.5Hz,1H), 8.27(s,1H), 8.80-8.88(m,2H), 8.90-8.97(m,1H);
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
实施例237Example 237
(S)-(6-((5-溴-2-((7-甲氧基-1,2-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((7-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000365
Figure PCTCN2020097369-appb-000365
(S)-(6-((5-溴-2-((7-甲氧基-1,2-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(S)-(6-((5-Bromo-2-((7-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino ) Pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 217.
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
实施例238Example 238
(R)-(6-((5-溴-2-((7-甲氧基-1,2-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((7-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000366
Figure PCTCN2020097369-appb-000366
(R)-(6-((5-溴-2-((7-甲氧基-1,2-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(R)-(6-((5-Bromo-2-((7-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino ) Pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 217.
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
实施例239Example 239
(6-((5-溴-2-((7-甲氧基-1,1,2-三甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000367
Figure PCTCN2020097369-appb-000367
(6-((5-溴-2-((7-甲氧基-1,1,2-三甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI): 596.1[M+H] + .
实施例240Example 240
(R)-(6-((5-溴-2-((7-甲氧基-2,4-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((7-methoxy-2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000368
Figure PCTCN2020097369-appb-000368
(R)-(6-((5-溴-2-((7-甲氧基-2,4-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(R)-(6-((5-Bromo-2-((7-methoxy-2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino ) Pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 217.
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
实施例241Example 241
(S)-(6-((5-溴-2-((7-甲氧基-2,4-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((7-methoxy-2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )Pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000369
Figure PCTCN2020097369-appb-000369
(S)-(6-((5-溴-2-((7-甲氧基-2,4-二甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(S)-(6-((5-Bromo-2-((7-methoxy-2,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino ) Pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxidation preparation method refer to Example 217.
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
实施例242Example 242
(6-((5-溴-2-((7-甲氧基-2,4,4-三甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000370
Figure PCTCN2020097369-appb-000370
(6-((5-溴-2-((7-甲氧基-2,4,4-三甲基-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI): 596.1[M+H] + .
实施例243Example 243
(6-((5-溴-2-((7-甲氧基-1,1-二甲基-2-(1-甲基吖丁啶-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-1,1-dimethyl-2-(1-methylazetidine-3-yl)-1,2,3,4 -Tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000371
Figure PCTCN2020097369-appb-000371
(6-((5-溴-2-((7-甲氧基-1,1-二甲基-2-(1-甲基吖丁啶-3-基)-1,2,3,4-四氢异喹啉 -6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-1,1-dimethyl-2-(1-methylazetidine-3-yl)-1,2,3,4 -Tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation The preparation method refers to Example 217.
MS m/z(ESI):651.1[M+H] +. MS m/z(ESI): 651.1[M+H] + .
实施例244Example 244
(6-((5-溴-2-((7-甲氧基-1,1-二甲基-2-(噁丁环-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((7-methoxy-1,1-dimethyl-2-(oxbutan-3-yl)-1,2,3,4-tetrahydroiso (Quinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000372
Figure PCTCN2020097369-appb-000372
(6-((5-溴-2-((7-甲氧基-1,1-二甲基-2-(噁丁环-3-基)-1,2,3,4-四氢异喹啉-6-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(6-((5-Bromo-2-((7-methoxy-1,1-dimethyl-2-(oxbutan-3-yl)-1,2,3,4-tetrahydroiso For the preparation method of quinolin-6-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation, refer to Example 217.
MS m/z(ESI):638.1[M+H] +. MS m/z(ESI):638.1[M+H] + .
实施例245Example 245
(R)-(6-((5-溴-2-((6-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((6-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000373
Figure PCTCN2020097369-appb-000373
(R)-(6-((5-溴-2-((6-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(R)-(6-((5-Bromo-2-((6-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
1H NMR(400MHz,CD 3OD)δ1.71-1.84(m,1H),2.10-2.20(m,7H),2.57-2.70(m,2H),2.77-2.86(m,5H),2.92-3.01(m,1H),3.08-3.18(m,1H),3.19-3.26(m,1H),3.35-3.47(m,1H),3.87(s,3H),6.78(s,1H),7.68-7.76(m,1H),8.02-8.11(m,1H),8.25(s,1H),8.79-8.88(m,2H),8.89-8.96(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.71-1.84 (m, 1H), 2.10-2.20 (m, 7H), 2.57-2.70 (m, 2H), 2.77-2.86 (m, 5H), 2.92 3.01(m,1H),3.08-3.18(m,1H),3.19-3.26(m,1H),3.35-3.47(m,1H),3.87(s,3H),6.78(s,1H),7.68- 7.76(m,1H), 8.02-8.11(m,1H), 8.25(s,1H), 8.79-8.88(m,2H), 8.89-8.96(m,1H);
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI): 596.1[M+H] + .
实施例246Example 246
(S)-(6-((5-溴-2-((6-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((6-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000374
Figure PCTCN2020097369-appb-000374
(S)-(6-((5-溴-2-((6-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(S)-(6-((5-Bromo-2-((6-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
1H NMR(400MHz,CD 3OD)δ1.71-1.84(m,1H),2.10-2.20(m,7H),2.57-2.70(m,2H),2.77-2.86(m,5H),2.92-3.01(m,1H),3.08-3.18(m,1H),3.19-3.26(m,1H),3.35-3.47(m,1H),3.87(s,3H),6.78(s,1H),7.68-7.76(m,1H),8.02-8.11(m,1H),8.25(s,1H),8.79-8.88(m,2H),8.89-8.96(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.71-1.84 (m, 1H), 2.10-2.20 (m, 7H), 2.57-2.70 (m, 2H), 2.77-2.86 (m, 5H), 2.92 3.01(m,1H),3.08-3.18(m,1H),3.19-3.26(m,1H),3.35-3.47(m,1H),3.87(s,3H),6.78(s,1H),7.68- 7.76(m,1H), 8.02-8.11(m,1H), 8.25(s,1H), 8.79-8.88(m,2H), 8.89-8.96(m,1H);
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI): 596.1[M+H] + .
实施例247Example 247
(R)-(6-((5-溴-2-((5-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(R)-(6-((5-Bromo-2-((5-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000375
Figure PCTCN2020097369-appb-000375
(R)-(6-((5-溴-2-((5-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(R)-(6-((5-Bromo-2-((5-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI): 596.1[M+H] + .
实施例248Example 248
(S)-(6-((5-溴-2-((5-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(S)-(6-((5-Bromo-2-((5-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000376
Figure PCTCN2020097369-appb-000376
(S)-(6-((5-溴-2-((5-(二甲氨基)-3-甲氧基-5,6,7,8-四氢萘-2-基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例217。(S)-(6-((5-Bromo-2-((5-(dimethylamino)-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation method refers to Example 217.
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI): 596.1[M+H] + .
实施例249Example 249
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine
Figure PCTCN2020097369-appb-000377
Figure PCTCN2020097369-appb-000377
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methyl (Oxyphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method refer to Example 190 .
1H NMR(400MHz,CD 3OD)δ0.85(t,J＝7.6Hz,3H),1.53-1.58(m,2H),2.02-2.09(m,2H),2.16-2.18(m,6H),2.25(s,6H),2.41-2.48(m,2H),2.75-2.79(m,3H),3.07-3.11(m,2H),3.16-3.22(m,1H),3.57-3.61(m,2H),3.84(s,3H),3.96-4.01(m,2H),6.79(s,1H),7.57(s,1H),7.73-7.79(m,1H),8.19(s,1H),8.45-8.51(m,1H),8.63-8.65(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ0.85(t,J=7.6Hz,3H),1.53-1.58(m,2H),2.02-2.09(m,2H),2.16-2.18(m,6H) ,2.25(s,6H),2.41-2.48(m,2H),2.75-2.79(m,3H),3.07-3.11(m,2H),3.16-3.22(m,1H),3.57-3.61(m, 2H), 3.84 (s, 3H), 3.96-4.01 (m, 2H), 6.79 (s, 1H), 7.57 (s, 1H), 7.73-7.79 (m, 1H), 8.19 (s, 1H), 8.45 -8.51(m,1H),8.63-8.65(m,1H);
MS m/z(ESI):697.1[M+H] +. MS m/z(ESI): 697.1[M+H] + .
实施例250Example 250
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000378
Figure PCTCN2020097369-appb-000378
2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-[1,2,4]三唑并[1,5-a]吡啶-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190。2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphorus)-[1,2,4]triazolo[1,5-a]pyridine- 6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile preparation method Reference Example 190.
1H NMR(400MHz,CD 3OD)δ1.26-1.32(m,3H),1.47-1.57(m,2H),1.95-2.04(m,2H),2.13(s,3H),2.17(s,3H),2.40-2.50(m,2H),2.71-2.86(m,5H),3.01-3.10(m,3H),3.54-3.62(m,2H),3.84(s,3H),3.93-4.01(m,2H),6.79(s,1H),7.57(s,1H),7.73(d,J＝9.8Hz,1H),8.19(s,1H),8.42-8.48(m,1H),8.58-8.68(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.26-1.32(m,3H),1.47-1.57(m,2H),1.95-2.04(m,2H),2.13(s,3H),2.17(s, 3H), 2.40-2.50 (m, 2H), 2.71-2.86 (m, 5H), 3.01-3.10 (m, 3H), 3.54-3.62 (m, 2H), 3.84 (s, 3H), 3.93-4.01 ( m,2H),6.79(s,1H),7.57(s,1H),7.73(d,J=9.8Hz,1H), 8.19(s,1H),8.42-8.48(m,1H),8.58-8.68 (m,1H);
MS m/z(ESI):693.1[M+H] +. MS m/z(ESI): 693.1[M+H] + .
实施例251Example 251
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000379
Figure PCTCN2020097369-appb-000379
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation preparation method reference Example 190.
1H NMR(400MHz,CD 3OD)δ0.85(t,J＝7.6Hz,3H),1.53-1.59(m,2H),2.00-2.03(m,2H),2.16-2.19(m,6H),2.44-2.52(m,2H),2.75-2.79(m,2H),2.90-2.93(m,2H),3.07-3.13(m,2H),3.42(s,3H),3.52-3.55(m,2H),3.69-3.72(m,2H),3.84(s,3H),3.91-3.95(m,2H),6.78(s,1H),7.57(s,1H),7.73-7.79(m,1H),8.19(s, 1H),8.45(s,1H),8.62-8.68(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.85 (t, J = 7.6 Hz, 3H), 1.53-1.59 (m, 2H), 2.00-2.03 (m, 2H), 2.16-2.19 (m, 6H) ,2.44-2.52(m,2H),2.75-2.79(m,2H),2.90-2.93(m,2H),3.07-3.13(m,2H),3.42(s,3H),3.52-3.55(m, 2H), 3.69-3.72 (m, 2H), 3.84 (s, 3H), 3.91-3.95 (m, 2H), 6.78 (s, 1H), 7.57 (s, 1H), 7.73-7.79 (m, 1H) ,8.19(s, 1H),8.45(s,1H),8.62-8.68(m,1H);
MS m/z(ESI):698.1[M+H] +. MS m/z(ESI): 698.1[M+H] + .
实施例252Example 252
(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxybenzene (Yl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000380
Figure PCTCN2020097369-appb-000380
(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methoxybenzene (Yl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)dimethylphosphine oxidation method refer to Example 190.
1H NMR(400MHz,CD 3OD)δ0.85(t,J＝7.6Hz,3H),1.22(t,J＝7.0Hz,3H),1.56-1.58(m,2H),2.04-2.06(m,2H),2.16-2.18(m,6H),2.44-2.51(m,2H),2.76-2.78(m,2H),2.95-2.97(m,1H),3.08-3.12(m,2H),3.49-3.60(m,2H),3.75-3.79(m,2H),3.84(s,3H),4.12-4.23(m,2H),4.27-4.39(m,1H),6.78(s,1H),7.57(s,1H),7.72-7.78(m,1H),8.19(s,1H),8.45(s,1H),8.62-8.65(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.85 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.56-1.58 (m, 2H), 2.04-2.06 (m ,2H),2.16-2.18(m,6H),2.44-2.51(m,2H),2.76-2.78(m,2H),2.95-2.97(m,1H),3.08-3.12(m,2H),3.49 -3.60(m,2H),3.75-3.79(m,2H),3.84(s,3H),4.12-4.23(m,2H),4.27-4.39(m,1H),6.78(s,1H),7.57 (s,1H),7.72-7.78(m,1H),8.19(s,1H),8.45(s,1H),8.62-8.65(m,1H);
MS m/z(ESI):698.1[M+H] +. MS m/z(ESI): 698.1[M+H] + .
实施例253Example 253
(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)-[1,2,4]三唑并[1,5-a]吡啶-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)-[1,2,4]triazolo[1,5-a]pyridin-5-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000381
Figure PCTCN2020097369-appb-000381
(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)-[1,2,4]三唑并[1,5-a]吡啶-5-基)二甲基膦氧化的制备方法参照实施例190。(6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl) dimethylphosphine oxidation preparation Refer to Example 190 for the method.
1H NMR(400MHz,CD 3OD)δ1.47-1.54(m,2H),1.95-2.02(m,3H),2.11(s,3H),2.15(s,3H),2.24(s,6H),2.68-2.76(m,3H),3.01-3.06(m,2H),3.11-3.17(m,2H),3.42-3.50(m,4H),3.84(s,3H),3.87-3.93(m,3H),6.77(s,1H),7.23(d,J＝8.0Hz,1H),7.51(s,1H),7.68-7.74(m,1H),8.36(s,1H),8.46(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.47-1.54 (m, 2H), 1.95-2.02 (m, 3H), 2.11 (s, 3H), 2.15 (s, 3H), 2.24 (s, 6H) , 2.68-2.76 (m, 3H), 3.01-3.06 (m, 2H), 3.11-3.17 (m, 2H), 3.42-3.50 (m, 4H), 3.84 (s, 3H), 3.87-3.93 (m, 3H), 6.77(s,1H), 7.23(d,J=8.0Hz,1H), 7.51(s,1H), 7.68-7.74(m,1H), 8.36(s,1H), 8.46(s,1H) );
MS m/z(ESI):687.1[M+H] +. MS m/z(ESI): 687.1[M+H] + .
实施例254Example 254
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000382
Figure PCTCN2020097369-appb-000382
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidized preparation method refer to Example 201.
1H NMR(400MHz,CD 3OD)δ1.02(t,J＝7.6Hz,3H),1.70-1.76(m,2H),2.03(s,1H),2.10-2.12(m,6H),2.55-2.63(m,5H),2.67-2.69(s,1H),2.78-2.81(m,3H), 2.95-2.99(m,6H),3.14-3.16(m,3H),3.82-3.88(m,3H),6.81(s,1H),7.62(s,1H),8.27-8.29(m,2H),8.48-8.51(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 1.02 (t, J = 7.6 Hz, 3H), 1.70 to 1.76 (m, 2H), 2.03 (s, 1H), 2.10-2.12 (m, 6H), 2.55 -2.63(m,5H),2.67-2.69(s,1H),2.78-2.81(m,3H), 2.95-2.99(m,6H),3.14-3.16(m,3H),3.82-3.88(m, 3H), 6.81(s,1H), 7.62(s,1H), 8.27-8.29(m,2H), 8.48-8.51(m,2H);
MS m/z(ESI):697.2[M+H] +. MS m/z(ESI): 697.2[M+H] + .
实施例255Example 255
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methyl Oxidation of oxyphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine
Figure PCTCN2020097369-appb-000383
Figure PCTCN2020097369-appb-000383
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidin-1-yl)piperidin-1-yl)-5-ethyl-2-methyl Oxyphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation preparation method refer to Example 201 .
1H NMR(400MHz,CD 3OD)δ0.99(t,J＝7.6Hz,3H),1.43-1.57(m,2H),1.98-2.03(m,2H),2.10-2.13(m,7H),2.22-2.26(m,7H),2.56-2.62(m,3H),2.76-2.81(m,2H),3.03-3.15(m,3H),3.76-3.90(m,5H),6.82(s,1H),7.62(s,1H),8.27-8.31(m,2H),8.50-8.52(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.99 (t, J = 7.6 Hz, 3H), 1.43-1.57 (m, 2H), 1.98-2.03 (m, 2H), 2.10-2.13 (m, 7H) ,2.22-2.26(m,7H),2.56-2.62(m,3H),2.76-2.81(m,2H),3.03-3.15(m,3H),3.76-3.90(m,5H),6.82(s, 1H), 7.62(s,1H), 8.27-8.31(m,2H), 8.50-8.52(m,2H);
MS m/z(ESI):697.2[M+H] +. MS m/z(ESI): 697.2[M+H] + .
实施例256Example 256
2-(1-(1-(4-((5-溴-4-((8-(二甲基磷基)-[1,2,4]三唑并[1,5-a]吡啶-7-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-((8-(dimethylphosphorus)-[1,2,4]triazolo[1,5-a]pyridine- 7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile
Figure PCTCN2020097369-appb-000384
Figure PCTCN2020097369-appb-000384
2-(1-(1-(4-((5-溴-4-((8-(二甲基磷基)-[1,2,4]三唑并[1,5-a]吡啶-7-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201。2-(1-(1-(4-((5-Bromo-4-((8-(dimethylphosphorus)-[1,2,4]triazolo[1,5-a]pyridine- 7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Example 201.
1H NMR(400MHz,CD 3OD)δ1.53-1.55(m,2H),1.99-2.01(m,2H),2.10-2.13(m,6H),2.16(s,3H),2.73-2.76(m,3H),2.80-2.83(m,2H),2.99-3.01(m,1H),3.17-3.19(m,2H),3.45-3.49(m,2H),3.85-3.88(m,5H),6.77(s,1H),7.58(s,1H),8.27-8.29(m,2H),8.52-8.56(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 1.53-1.55 (m, 2H), 1.99-2.01 (m, 2H), 2.10-2.13 (m, 6H), 2.16 (s, 3H), 2.73-2.76 ( m,3H),2.80-2.83(m,2H),2.99-3.01(m,1H),3.17-3.19(m,2H),3.45-3.49(m,2H),3.85-3.88(m,5H), 6.77(s,1H),7.58(s,1H),8.27-8.29(m,2H),8.52-8.56(m,2H);
MS m/z(ESI):679.2[M+H] +. MS m/z(ESI): 679.2[M+H] + .
实施例257Example 257
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl)- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000385
Figure PCTCN2020097369-appb-000385
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridine-8-yl)dimethylphosphine oxidation preparation method reference Example 201.
1H NMR(400MHz,CD 3OD)δ1.58-1.68(m,2H),2.07-2.17(m,11H),2.72-2.81(m,2H),3.02-3.14(m,2H),3.18-3.26(m,2H),3.44-3.48(m,3H),3.51-3.55(m,2H),3.84(s,3H),4.05-4.14(m,2H),4.20-4.28(m,2H),6.76(s,1H),7.62(s,1H),8.23(s,1H),8.34-8.41(m,1H),8.49-8.59(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 1.58-1.68 (m, 2H), 2.07-2.17 (m, 11H), 2.72-2.81 (m, 2H), 3.02-3.14 (m, 2H), 3.18- 3.26(m,2H),3.44-3.48(m,3H),3.51-3.55(m,2H),3.84(s,3H),4.05-4.14(m,2H),4.20-4.28(m,2H), 6.76(s,1H),7.62(s,1H),8.23(s,1H),8.34-8.41(m,1H),8.49-8.59(m,2H);
MS m/z(ESI):684.2[M+H] +. MS m/z(ESI): 684.2[M+H] + .
实施例258Example 258
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((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)-[1,2,4]triazolo[1,5-a]pyridine-8-yl)dimethylphosphine oxidation
Figure PCTCN2020097369-appb-000386
Figure PCTCN2020097369-appb-000386
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridine-8-yl)dimethylphosphine oxidation preparation method reference Example 201.
1H NMR(400MHz,CD 3OD)δ0.99(t,J＝7.5Hz,3H),1.57-1.68(m,2H),2.02-2.16(m,8H),2.52-2.60(m,2H),2.75-2.85(m,2H),3.02-3.20(m,4H),3.44-3.50(m,3H),3.50-3.55(m,2H),3.85(s,3H),4.06-4.14(m,2H),4.19-4.29(m,2H),6.81(s,1H),7.66(s,1H),8.25(s,1H),8.30(s,1H),8.44-8.56(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.99 (t, J = 7.5 Hz, 3H), 1.57-1.68 (m, 2H), 2.02-2.16 (m, 8H), 2.52-2.60 (m, 2H) ,2.75-2.85(m,2H),3.02-3.20(m,4H),3.44-3.50(m,3H), 3.50-3.55(m,2H), 3.85(s,3H),4.06-4.14(m, 2H), 4.19-4.29 (m, 2H), 6.81 (s, 1H), 7.66 (s, 1H), 8.25 (s, 1H), 8.30 (s, 1H), 8.44-8.56 (m, 2H);
MS m/z(ESI):698.2[M+H] +. MS m/z(ESI): 698.2[M+H] + .
实施例259Example 259
(7-((5-溴-2-((5-乙基-2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl) (Amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000387
Figure PCTCN2020097369-appb-000387
(7-((5-溴-2-((5-乙基-2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl) Amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation preparation method refers to Example 201.
1H NMR(400MHz,CD 3OD)δ1.01(t,J＝7.6Hz,3H),1.75-1.79(m,2H),2.10-2.15(m,9H),2.59-2.63(m,3H),2.78-2.81(m,3H),2.85-2.87(m,4H),3.80-3.82(m,4H),3.84(s,3H),6.82(s,1H),7.62(s,1H),8.26-8.28(m,2H),8.46-8.49(m,2H)； 1 H NMR(400MHz,CD 3 OD)δ1.01(t,J=7.6Hz,3H),1.75-1.79(m,2H),2.10-2.15(m,9H),2.59-2.63(m,3H) , 2.78-2.81(m,3H), 2.85-2.87(m,4H), 3.80-3.82(m,4H), 3.84(s,3H), 6.82(s,1H), 7.62(s,1H), 8.26 -8.28(m,2H),8.46-8.49(m,2H);
MS m/z(ESI):684.2[M+H] +. MS m/z(ESI): 684.2[M+H] + .
实施例260Example 260
(7-((5-溴-2-((5-乙基-4-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((5-Bromo-2-((5-ethyl-4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl) (Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000388
Figure PCTCN2020097369-appb-000388
(7-((5-溴-2-((5-乙基-4-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-2-甲氧苯基)氨基)嘧啶-4-基)氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((5-Bromo-2-((5-ethyl-4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl) Amino)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)dimethylphosphine oxidation preparation method refers to Example 201.
1H NMR(400MHz,CD 3OD)δ1.01(t,J＝7.6Hz,3H),1.17-1.19(m,3H),1.73-1.76(m,2H),2.04-2.06(m,3H),2.10-2.13(m,6H),2.48(s,2H),2.58-2.61(m,4H),2.73-2.88(m,7H),3.09-3.17(m,3H),3.84(s,3H),6.82(s,1H),7.60(s,1H),8.27-8.29(m,2H),8.48-8.51(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ1.01 (t, J = 7.6Hz, 3H), 1.17-1.19 (m, 3H), 1.73-1.76 (m, 2H), 2.04-2.06 (m, 3H) , 2.10-2.13 (m, 6H), 2.48 (s, 2H), 2.58-2.61 (m, 4H), 2.73-2.88 (m, 7H), 3.09-3.17 (m, 3H), 3.84 (s, 3H) ,6.82(s,1H),7.60(s,1H),8.27-8.29(m,2H),8.48-8.51(m,2H);
MS m/z(ESI):711.3[M+H] +. MS m/z(ESI): 711.3[M+H] + .
实施例261Example 261
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(methylthio)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000389
Figure PCTCN2020097369-appb-000389
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(methylthio)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation method Refer to Example 201.
1H NMR(400MHz,CD 3OD)δ0.99(t,J＝7.5Hz,3H),1.56-1.68(m,2H),2.05-2.15(m,8H),2.28-2.36(m,9H),2.54-2.61(m,2H),2.75-2.84(m,2H),3.06-3.18(m,3H),3.33-3.36(m,1H),3.82-3.90(m,5H),4.12-4.19(m,2H),6.82(s,1H),7.66(s,1H),8.27-8.31(m,2H),8.46-8.62(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 0.99 (t, J = 7.5 Hz, 3H), 1.56-1.68 (m, 2H), 2.05-2.15 (m, 8H), 2.28-2.36 (m, 9H) ,2.54-2.61(m,2H),2.75-2.84(m,2H),3.06-3.18(m,3H),3.33-3.36(m,1H),3.82-3.90(m,5H),4.12-4.19( m,2H),6.82(s,1H),7.66(s,1H),8.27-8.31(m,2H),8.46-8.62(m,2H);
MS m/z(ESI):665.3[M+H] +. MS m/z(ESI): 665.3[M+H] + .
实施例262Example 262
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备(7-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000390
Figure PCTCN2020097369-appb-000390
(7-((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)-[1,2,4]三唑并[1,5-a]吡啶-8-基)二甲基膦氧化的制备方法参照实施例201。(7-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl) (Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl) dimethylphosphine oxidation preparation Refer to Example 201 for the method.
1H NMR(400MHz,CD 3OD)δ0.75-1.00(m,3H),1.48-1.62(m,2H),2.00-2.12(m,8H),2.26(s,6H),2.44-2.53(m,2H),2.72-2.85(m,2H),3.06-3.14(m,2H),3.16-3.22(m,1H),3.52-3.62(m,3H),3.85(s,3H),3.93-4.01(m,2H),6.82(s,1H),7.60(s,1H),8.31(s,1H),8.45(d,J＝22.7Hz,3H)； 1 H NMR (400MHz, CD 3 OD) δ0.75-1.00 (m, 3H), 1.48-1.62 (m, 2H), 2.00-2.12 (m, 8H), 2.26 (s, 6H), 2.44-2.53 ( m, 2H), 2.72-2.85 (m, 2H), 3.06-3.14 (m, 2H), 3.16-3.22 (m, 1H), 3.52-3.62 (m, 3H), 3.85 (s, 3H), 3.93 4.01(m,2H), 6.82(s,1H), 7.60(s,1H), 8.31(s,1H), 8.45(d,J=22.7Hz,3H);
MS m/z(ESI):687.3[M+H] +. MS m/z(ESI): 687.3[M+H] + .
实施例263Example 263
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基六氢吡咯并[3,2-b]吡咯-1(2H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylhexahydropyrrolo[3,2-b]pyrrole-1(2H )-Yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000391
Figure PCTCN2020097369-appb-000391
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基六氢吡咯并[3,2-b]吡咯-1(2H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例122。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylhexahydropyrrolo[3,2-b]pyrrole-1(2H )-Yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation method refer to Example 122.
MS m/z(ESI):720.1[M+H] +. MS m/z(ESI): 720.1[M+H] + .
实施例264Example 264
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(1-甲基六氢吡咯并[3,4-b]吡咯-5(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H )-Yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000392
Figure PCTCN2020097369-appb-000392
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(1-甲基六氢吡咯并[3,4-b]吡咯-5(1H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例122。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H )-Yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation method refer to Example 122.
1H NMR(400MHz,CD 3OD)δ1.80-1.83(m,3H),2.00-2.25(m,12H),2.33(s,1H),2.73-2.81(m,9H),3.06(s,1H),3.17-3.19(m,3H),3.46-3.49(m,2H),3.85(s,3H),6.75(s,1H),7.62(s,1H),7.99-8.01(m,1H),8.23(s,1H),8.82-8.85(m,2H),8.97-8.99(m,1H)； 1 H NMR (400MHz, CD 3 OD) δ1.80-1.83 (m, 3H), 2.00-2.25 (m, 12H), 2.33 (s, 1H), 2.73-2.81 (m, 9H), 3.06 (s, 1H), 3.17-3.19 (m, 3H), 3.46-3.49 (m, 2H), 3.85 (s, 3H), 6.75 (s, 1H), 7.62 (s, 1H), 7.99-8.01 (m, 1H) ,8.23(s,1H),8.82-8.85(m,2H),8.97-8.99(m,1H);
MS m/z(ESI):720.1[M+H] +. MS m/z(ESI): 720.1[M+H] + .
实施例265Example 265
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基)哌啶 -1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(5-methylhexahydropyrrolo[3,4-b]pyrrole-1(2H )-Yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000393
Figure PCTCN2020097369-appb-000393
(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例122。(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(5-methylhexahydropyrrolo[3,4-b]pyrrole-1(2H )-Yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation method refer to Example 122.
1H NMR(400MHz,CD 3OD)δ1.70-1.91(m,4H),2.01-2.08(m,1H),2.09(s,3H),2.13(s,3H),2.16(s,3H),2.23-2.32(m,1H),2.68(s,3H),2.73-2.88(m,6H),3.04-3.22(m,4H),3.35-3.44(m,2H),3.76-3.81(m,1H),3.85(s,3H),6.75(s,1H),7.62(s,1H),7.99(d,J＝9.5Hz,1H),8.23(s,1H),8.77-8.88(m,2H),8.94-9.01(m,1H)； 1 H NMR(400MHz,CD 3 OD)δ1.70-1.91(m,4H), 2.01-2.08(m,1H), 2.09(s,3H), 2.13(s,3H), 2.16(s,3H) ,2.23-2.32(m,1H),2.68(s,3H),2.73-2.88(m,6H),3.04-3.22(m,4H),3.35-3.44(m,2H),3.76-3.81(m, 1H), 3.85 (s, 3H), 6.75 (s, 1H), 7.62 (s, 1H), 7.99 (d, J = 9.5Hz, 1H), 8.23 (s, 1H), 8.77-8.88 (m, 2H) ),8.94-9.01(m,1H);
MS m/z(ESI):720.1[M+H] +. MS m/z(ESI): 720.1[M+H] + .
实施例266Example 266
(6-((5-溴-2-((4-(4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备(6-((5-Bromo-2-((4-(4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)piperidin-1-yl)-2- (Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation preparation
Figure PCTCN2020097369-appb-000394
Figure PCTCN2020097369-appb-000394
(6-((5-溴-2-((4-(4-(六氢吡咯并[1,2-a]吡嗪-2(1H)-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基膦氧化的制备方法参照实施例122。(6-((5-Bromo-2-((4-(4-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)piperidin-1-yl)-2- Refer to Example 122 for the preparation method of methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxidation.
MS m/z(ESI):720.1[M+H] +. MS m/z(ESI): 720.1[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 in Dilution buffer. After reacting at room temperature for 120 minutes, add 10μL of detection solution (TK antibody 16nM, XL665 0.5μM) to each well after 20 minutes at room temperature and avoid light, 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 PCTCN2020097369-appb-000395
Figure PCTCN2020097369-appb-000395
Figure PCTCN2020097369-appb-000396
Figure PCTCN2020097369-appb-000396
Figure PCTCN2020097369-appb-000397
Figure PCTCN2020097369-appb-000397
Figure PCTCN2020097369-appb-000398
Figure PCTCN2020097369-appb-000398
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 Start the reaction with 24μM 4×ATP solution. 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 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 PCTCN2020097369-appb-000399
Figure PCTCN2020097369-appb-000399
Figure PCTCN2020097369-appb-000400
Figure PCTCN2020097369-appb-000400
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。It can be concluded from the above scheme that the compound of the embodiment 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 PCTCN2020097369-appb-000401
Figure PCTCN2020097369-appb-000401
Figure PCTCN2020097369-appb-000402
Figure PCTCN2020097369-appb-000402
Figure PCTCN2020097369-appb-000403
Figure PCTCN2020097369-appb-000403
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19Example 19 5.765.76
实施例21Example 21 2.842.84
实施例124Example 124 2.242.24
实施例128Example 128 1.431.43
实施例139Example 139 8.008.00
实施例150Example 150 0.210.21
实施例156Example 156 2.892.89
实施例163Example 163 0.580.58
实施例164Example 164 0.270.27
实施例166Example 166 0.510.51
实施例177Example 177 1.401.40
实施例188Example 188 0.610.61
实施例190Example 190 3.653.65
实施例201Example 201 2.762.76
实施例232Example 232 2.682.68
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)2013-0006 N0.311620400001794)。Balb/C Mouse (6 mice/example), male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No 0.311620400001794).
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 PCTCN2020097369-appb-000404
Figure PCTCN2020097369-appb-000404
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30-FAExample 30-FA 1.01.0 40774077 3778337783 3788337883 4.64.6 5.35.3
实施例51-FAExample 51-FA 1.01.0 17431743 1949519495 1971319713 3.73.7 6.26.2
实施例118-FAExample 118-FA 2.02.0 17931793 1997319973 2006920069 3.03.0 5.95.9
实施例122-FAExample 122-FA 0.50.5 35503550 3240532405 3281832818 4.24.2 5.65.6
实施例163-FAExample 163-FA 2.02.0 12701270 1116311163 1117711177 3.13.1 5.15.1
实施例254-FAExample 254-FA 4.04.0 699699 1001710017 1016210162 3.73.7 6.86.8
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:
1、生物安全柜(BSC-1300II A2，上海博讯实业有限公司医疗设备厂)1. Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)
2、超净工作台(CJ-2F，苏州市冯氏实验动物设备有限公司)2. Ultra-clean workbench (CJ-2F, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.)
3、CO 2培养箱(Thermo-311，Thermo) 3. CO 2 incubator (Thermo-311, Thermo)
4、离心机(Centrifuge 5720R，Eppendorf)4. Centrifuge (Centrifuge 5720R, Eppendorf)
5、全自动细胞计数仪(Countess II，Life Technologies)5. Automatic cell counter (Countess II, Life Technologies)
6、游标卡尺(CD-6”AX，日本三丰)6. Vernier calipers (CD-6"AX, Mitutoyo, Japan)
7、细胞培养瓶(T75/T225，Corning)7. Cell culture flask (T75/T225, Corning)
8、电子天平(CPA2202S，赛多利斯)8. Electronic balance (CPA2202S, Sartorius)
9、电子天平(BSA2202S-CW，赛多利斯)9. Electronic balance (BSA2202S-CW, Sartorius)
6.2.2试剂：6.2.2 Reagents:
1、RPMI-1640培养基(22400-089，Gibco)1. RPMI-1640 medium (22400-089, Gibco)
2、胎牛血清(FBS)(10099-141C，Gibco)2. Fetal Bovine Serum (FBS) (10099-141C, Gibco)
3、磷酸盐缓冲液(PBS)(10010-023，Gibco)3. Phosphate buffered saline (PBS) (10010-023, Gibco)
4、羟丙基甲基纤维素(138425，上海卡乐康包衣技术有限公司)4. Hydroxypropyl methylcellulose (138425, Shanghai Colorcon Coating Technology Co., Ltd.)
6.2.3动物：6.2.3 Animals:
BALB/c裸小鼠，6-8周，♀，购自上海市计划生育科学研究所。BALB/c nude mice, 6-8 weeks, ♀, purchased from Shanghai Family Planning Research Institute.
6.3实验步骤6.3 Experimental procedure
6.3.1细胞培养6.3.1 Cell culture
a)从细胞库中取出一株BaF3(EGFR 19del/T790M/C797S)细胞，用RPMI-1640培养基(RPMI-1640+10％FBS)复苏细胞，复苏后的细胞置细胞培养瓶中(在瓶壁标记好细胞种类、日期、培养人名字等)置于CO 2培养箱中培养(培养箱温度为37℃，CO 2浓度为5％)； a) Take out a BaF3 (EGFR 19del/T790M/C797S) cell from the cell bank, use RPMI-1640 medium (RPMI-1640+10% FBS) to recover the cells, and place the recovered cells in a cell culture flask (in the flask). The wall is marked with cell type, date, culture name, etc.) and placed in a CO 2 incubator (the temperature of the incubator is 37°C, and the CO 2 concentration is 5%);
b)每三天传代一次，传代后细胞继续置于CO 2培养箱中培养。重复该过程直到细胞数满足体内药效需求； b) Passage once every three days. After passaging, the cells continue to be cultured in a CO 2 incubator. Repeat the process until the number of cells meets the requirements for the efficacy in the body;
c)收集培养好的细胞，用全自动细胞计数仪计数，根据计数结果用PBS重悬细胞，制成细胞悬液(密度2×10 7/mL)，置于冰盒中待用。 c) Collect the cultured cells, count them with an automatic cell counter, and resuspend the cells with PBS according to the counting results to make a cell suspension (density 2×10 7 /mL), and place in an ice box for later use.
6.3.2细胞接种6.3.2 Cell seeding
a)接种前用一次性大小鼠通用耳标标记裸鼠；a) Mark nude mice with disposable universal ear tags for rats and mice before inoculation;
b)接种时混匀细胞悬液，用1mL注射器抽取0.1-1mL细胞悬液、排除气泡，然后将注射器置于冰袋上待用；b) Mix the cell suspension during inoculation, use a 1 mL syringe to draw 0.1-1 mL of the cell suspension, remove air bubbles, and then place the syringe on an ice bag for later use;
c)左手保定好裸鼠，用75％酒精消毒裸鼠右侧背部靠右肩位置(接种部位)，30秒后开始接种；c) Set the nude mouse with the left hand, disinfect the right shoulder of the right back of the nude mouse with 75% alcohol (the inoculation site), and start the inoculation after 30 seconds;
d)依次给试验裸鼠接种(每只小鼠接种0.1mL细胞悬液)。d) Sequentially inoculate the test nude mice (each mouse is inoculated with 0.1 mL cell suspension).
6.3.3荷瘤鼠量瘤、分组、给药6.3.3 Tumor measurement, grouping and administration of tumor-bearing mice
a)根据肿瘤生长情况，在接种后第8-14天量瘤、并计算肿瘤大小。a) According to the growth of the tumor, measure the tumor and calculate the tumor size from 8 to 14 days after inoculation.
肿瘤体积计算：肿瘤体积(mm 3)＝长(mm)×宽(mm)×宽(mm)/2。 Tumor volume calculation: tumor volume (mm 3 ) = length (mm) x width (mm) x width (mm)/2.
b)根据荷瘤鼠体重和肿瘤大小，采用随机分组的方法进行分组。b) According to the body weight and tumor size of the tumor-bearing mice, the random grouping method is used for grouping.
c)根据分组结果，开始给予测试药物(给药方式：口服给药；给药剂量：30mg/kg；给药体积：10mL/kg；给药频率：1次/天；给药周期：14天；溶媒：0.5％HPMC)。c) According to the grouping results, start to administer the test drug (administration method: oral administration; dose: 30 mg/kg; dose volume: 10 mL/kg; dosing frequency: 1 time/day; dosing cycle: 14 days ; Solvent: 0.5% HPMC).
d)开始给予测试药物后每周两次量瘤、称重。d) Tumors were measured and weighed twice a week after the test drug was started.
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：当肿瘤无消退时，TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。当肿瘤有消退时，TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/该处理组开始给药时平均瘤体积]×100％。f) Use Excel and other software to process the data. Calculation of compound tumor inhibition rate TGI (%): When the tumor does not regress, TGI (%) = [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group)) /(Average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group)]×100% When the tumor is regressed, TGI(%)=[1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the start of the treatment group)/Average tumor volume at the start of the treatment group]× 100%.
6.4试验数据如下表3：6.4 The test data is as follows in Table 3:
表3table 3
分组Grouping 动物数量(只)Number of animals (only) 体重变化率(％)Weight change rate (%) 抑瘤率(％)Tumor inhibition rate (%)
实施例122-FAExample 122-FA 55 -0.89-0.89 55％55%
实施例128-FAExample 128-FA 55 2.572.57 80％80%
实施例150-FAExample 150-FA 55 -0.78-0.78 81％81%
实施例163-FAExample 163-FA 55 4.254.25 63％63%
注：FA为相应化合物的甲酸盐。Note: FA is the formate of the corresponding compound.
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，且安全性好。It can be seen from the above results that the above-mentioned compounds of this patent have a good tumor inhibition rate and good safety.

Claims (41)

  1. 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：A compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020097369-appb-100001
    Figure PCTCN2020097369-appb-100001
    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；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、烯基、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 ; wherein the hydroxyl, amino, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium, deuterium, alkyl, haloalkyl, Halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, -(CH 2 ) n C(O)R CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted oxo heterocyclic group, spiro ring Substituted by one or more substituents in alkyl, bridged cycloalkyl or fused cycloalkyl;
    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 to form a cycloalkyl group linked to the ring A1, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted selected from Hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocycle Substituted by one or more substituents in the group, -(CH 2 ) n R CC , aryl and heteroaryl;
    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, 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 Is substituted by 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, 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 linked to form a C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 3-6 aryl Group or 3-6 membered heteroaryl group, more preferably C 5-6 cycloalkyl group, 5-6 membered heterocyclic group, C 5-6 aryl group or 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0-2的整数；且m is an integer of 0-2; and
    n为0-2的整数。n is an integer of 0-2.
  2. 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，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、-(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； The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein 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 Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(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 , -(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或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 or 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.
  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(IA)进一步如通式(IB)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (IA) is further represented by the general formula (IB):
    Figure PCTCN2020097369-appb-100002
    Figure PCTCN2020097369-appb-100002
    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 PCTCN2020097369-appb-100003
    Figure PCTCN2020097369-appb-100004
    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 PCTCN2020097369-appb-100003
    Figure PCTCN2020097369-appb-100004
    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, 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 PCTCN2020097369-appb-100005
    Figure PCTCN2020097369-appb-100006
    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 PCTCN2020097369-appb-100005
    Figure PCTCN2020097369-appb-100006
    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 PCTCN2020097369-appb-100007
    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 PCTCN2020097369-appb-100007
    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.
  4. 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，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； The compound according to claim 3, its stereoisomers or pharmaceutically acceptable salts thereof, wherein R 1 or R 5 are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, and deuterated alkane Group, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxoheterocyclyl, spirocycloalkyl, Bridged cycloalkyl, fused ring alkyl, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, 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, heterocycle Group, 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 One of the heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted oxoheterocyclic group, spirocyclic alkyl group, bridged cycloalkyl group or fused ring alkyl group Or more substituents;
    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.
  5. 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 PCTCN2020097369-appb-100008
    Figure PCTCN2020097369-appb-100008
    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.
  6. 根据权利要求5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 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； The compound according to claim 5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkane Oxy, 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 is optionally further selected from hydrogen, deuterium, oxo, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkane One or more substituents in oxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl replace;
    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，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.
  7. 根据权利要求6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(IC-A)或通式(IC-B)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 6, wherein the general formula (IA) is further general formula (IC-A) or general formula (IC-B) Shown:
    Figure PCTCN2020097369-appb-100009
    Figure PCTCN2020097369-appb-100009
    M存在或不存在，存在时选自O、S、NR aa、CR aaR bb、NR aa(CR bbR cc) n、O(CR aaR bb) n或NR aaC(O)(CR bbR cc) n，优选O、S、NH、NCH 3、CH 2、CH 3CH、NHC(O)CH 2、NHC(O)CH 2CH 2、NHC(O)CH 2CH 2CH 2、OC(F 2)CH 2、NHCH 2CH 2或N(CH 3)CH 2CH 2； The presence or absence of M, when present, is selected from O, S, NR aa , CR aa R bb , NR aa (CR bb R cc ) n , O(CR aa R bb ) n or NR aa C(O)(CR bb R cc ) n , preferably O, S, NH, NCH 3 , CH 2 , CH 3 CH, NHC(O)CH 2 , NHC(O)CH 2 CH 2 , NHC(O)CH 2 CH 2 CH 2 , OC (F 2 )CH 2 , NHCH 2 CH 2 or N(CH 3 )CH 2 CH 2 ;
    M 0选自S、NR aa或N或CR aaR bb； M 0 is selected from S, NR aa or N or CR aa R bb ;
    M 6或M 7存在或不存在，存在时各自独立的选自N或CR aa； The presence or absence of M 6 or M 7 is independently selected from N or CR aa when present ;
    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
    Figure PCTCN2020097369-appb-100010
    Figure PCTCN2020097369-appb-100011
    The presence or absence of ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl when present, 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 condensed heterocyclic group, more preferably
    Figure PCTCN2020097369-appb-100010
    Figure PCTCN2020097369-appb-100011
    环C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C 3-6环烷基、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
    Figure PCTCN2020097369-appb-100012
    Figure PCTCN2020097369-appb-100013
    The presence or absence of ring C, when present, 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 C 3-6 cycloalkyl, containing 1 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group with -2 N or O atoms, more preferably
    Figure PCTCN2020097369-appb-100012
    Figure PCTCN2020097369-appb-100013
    或者，环B与环C链接形成螺环烷基、稠环烷基、桥环烷基、螺杂环基、稠杂环基或桥杂环基，优选含有1-2个N或O原子的[3-6,3-6]螺杂环基，更优选
    Figure PCTCN2020097369-appb-100014
    Alternatively, ring B and ring C are linked to form a spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, spiroheterocyclic group, fused heterocyclic group or bridged heterocyclic group, preferably containing 1-2 N or O atoms [3-6,3-6] Spiro heterocyclyl, more preferably
    Figure PCTCN2020097369-appb-100014
    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，优选氢、烷基、烷氧基、卤代烷基、-NR aaC(O)R bb，更优选氢、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、-NR aaC(O)R bb，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、氟、氯、溴、卤代甲基或卤代乙基、-NR aaC(O)R 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 , preferably hydrogen, alkyl, alkoxy Group, haloalkyl group, -NR aa C(O)R bb , more preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, -NR aa C(O)R bb , More preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyano, fluorine, chlorine, bromine, halomethyl or haloethyl, -NR aa C(O)R bb ;
    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、芳基和杂芳基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、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 and heteroaryl are substituted by one or more substituents, 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, tetrahydrofuranyl or tetrahydropyranyl;
    或者，环C与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，优选C 3-8环烷基、3-8元杂环基，更优选C 4-7环烷基、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； Alternatively, ring C 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, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, The heterocyclic group, aryl group and heteroaryl group are substituted by one or more substituents, preferably C 3-8 cycloalkyl, 3-8 membered heterocyclic group, more preferably C 4-7 cycloalkyl, 5- 7-membered heterocyclic group, more preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
    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、腈基、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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaR bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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)C 3-6环烷基或-(CH 2) nN(C 1-3烷基) 2，更优选氢、甲基、乙基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、环丙基、甲酰基、
    Figure PCTCN2020097369-appb-100015
    Figure PCTCN2020097369-appb-100016
    R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl, oxo Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, C 1-3 haloalkyl, C 1-3 alkane Oxy, halogenated 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)C 3-6 cycloalkyl or -(CH 2 ) n N(C 1- 3 alkyl) 2 , more preferably hydrogen, methyl, ethyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, cyclopropyl, formyl,
    Figure PCTCN2020097369-appb-100015
    Figure PCTCN2020097369-appb-100016
    R 10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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、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、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或-(CH 2) nNR aaR bb，进一步优选氢、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、卤素、羟基、C 1-3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或-(CH 2) nNR aaR bb； R 10 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, -(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 , preferably hydrogen, C 1-6 alkyl, 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 or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, hydroxyl, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb ;
    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、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、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、氟、氯、溴、
    Figure PCTCN2020097369-appb-100017
    Figure PCTCN2020097369-appb-100018
    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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, fluorine, chlorine, bromine,
    Figure PCTCN2020097369-appb-100017
    Figure PCTCN2020097369-appb-100018
    t为0-4的整数；t is an integer from 0-4;
    z为0-4的整数；z is an integer of 0-4;
    r为0-4的整数。r is an integer from 0-4.
  8. 根据权利要求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，环B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
    Figure PCTCN2020097369-appb-100019
    The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 7, wherein when ring B is present, it is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, preferably C 3 -8 monocyclic cycloalkyl, bridged cycloalkyl, spirocyclic alkyl, fused ring alkyl, 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 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group containing 1-2 N or O atoms, and more preferably
    Figure PCTCN2020097369-appb-100019
    Figure PCTCN2020097369-appb-100020
    Figure PCTCN2020097369-appb-100020
    环C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C 3-6环烷基、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
    Figure PCTCN2020097369-appb-100021
    Figure PCTCN2020097369-appb-100022
    When ring C exists, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C 3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused cycloalkyl, 3-8 Member monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, containing 1-2 N or 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed heterocyclic group of O atom, more preferably
    Figure PCTCN2020097369-appb-100021
    Figure PCTCN2020097369-appb-100022
    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, further preferably cyclobutyl, cyclopentyl Group, piperidinyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydropyranyl;
    或者，环C与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 3-8环烷基、3-8元杂环基，更优选C 4-7环烷基、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； Alternatively, ring C 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, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) n R aa , -(CH 2 ) n NR aa R bb and -(CH 2 ) n C(O)R aa are substituted by one or more C 3-8 cycloalkyl group, 3-8 membered heterocyclic group are preferred, C 4-7 cycloalkyl group, 5-7 membered heterocyclic group are more preferred, and piperidinyl, tetrahydropyrrolyl, Cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;
    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、腈基、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) nR aa、-(CH 2) nOR aa、-(CH 2) nNR aaR bb或-(CH 2) nNR aaC(O)R bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaC(O)R bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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(O)C 1-3烷基、-(CH 2) nNHC(O)C 1-3烷基，更优选氢、甲基、乙基、羧基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、CH 3CH 2HN-、CH 3(O)C(CH 3)N-、CH 3(O)CHN-、(CH 3CH 2)(CH 3)N-、CH 3(O)C-、CH 3O(O)C-、环丙基、甲酰基、
    Figure PCTCN2020097369-appb-100023
    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、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 PCTCN2020097369-appb-100024
    R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl, oxo Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n NR aa C(O)R bb , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1- 6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen, hydroxy, 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 or -(CH 2 ) n NR aa C(O)R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, 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(O)C 1-3 alkyl, -(CH 2 ) n NHC(O)C 1-3 alkyl, more Preferably hydrogen, methyl, ethyl, carboxyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, CH 3 CH 2 HN-, CH 3 (O)C(CH 3 )N-, CH 3 (O)CHN-, ( CH 3 CH 2 )(CH 3 )N-, CH 3 (O)C-, CH 3 O(O)C-, cyclopropyl, formyl,
    Figure PCTCN2020097369-appb-100023
    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, 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 C 3 -6 cycloalkyl, more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,
    Figure PCTCN2020097369-appb-100024
  9. 根据权利要求1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(IA)进一步为通式(ID-A)或通式(ID-B)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1 or 7, characterized in that the general formula (IA) is further general formula (ID-A) or general formula (ID- B) shows:
    Figure PCTCN2020097369-appb-100025
    Figure PCTCN2020097369-appb-100025
    其中：among them:
    M选自键、O、S、NR aa或CR aaR bb； M is selected from bond, O, S, NR aa or CR aa R bb ;
    M 8或M 9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 8 or M 9 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;
    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;
    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 aa或R bb独立地选自氢、C 1-6烷基或C 1-6烷氧基，优选氢、C 1-3烷基或C 1-3烷氧基； R aa or R bb are independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen, C 1-3 alkyl or C 1-3 alkoxy;
    P为0-4的整数。P is an integer from 0-4.
  10. 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(IE-A)或通式(IE-B)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (IA) is further general formula (IE-A) or general formula (IE-B) Shown:
    Figure PCTCN2020097369-appb-100026
    Figure PCTCN2020097369-appb-100026
  11. 根据权利要求5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 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (II):
    Figure PCTCN2020097369-appb-100027
    Figure PCTCN2020097369-appb-100027
  12. 根据权利要求5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(III)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 5, wherein the general formula (I) is further represented by the general formula (III):
    Figure PCTCN2020097369-appb-100028
    Figure PCTCN2020097369-appb-100028
    其中：among them:
    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、-(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和-(CH 2) nNR aaS(O) mR bb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 are optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy , Haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and 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 and -(CH 2 ) n NR aa S( O) substituted by one or more substituents in m R bb ;
    或者，R 6和R 7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 6 and R 7 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 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； 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;
    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、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 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 , Deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , Substituted by one or more substituents in aryl and heteroaryl;
    p为0-4的整数。p is an integer from 0-4.
  13. 根据权利要求5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(I-1)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 5, wherein the general formula (I) is further represented by the general formula (I-1):
    Figure PCTCN2020097369-appb-100029
    Figure PCTCN2020097369-appb-100029
    其中：among them:
    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 PCTCN2020097369-appb-100030
    Figure PCTCN2020097369-appb-100030
    R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，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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, 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 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、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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, 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 ;
    R 8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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo Group, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
    R 9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、腈基、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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaR bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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)C 3-6环烷基或-(CH 2) nN(C 1-3烷基) 2，更优选氢、甲基、乙基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、环丙基、甲酰基、
    Figure PCTCN2020097369-appb-100031
    R 9 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl , Oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, C 1-3 haloalkyl, C 1 -3 alkoxy, halogenated 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)C 3-6 cycloalkyl or -(CH 2 ) n N( C 1-3 alkyl) 2 , more preferably hydrogen, methyl, ethyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, cyclopropyl, formyl,
    Figure PCTCN2020097369-appb-100031
    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、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、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、氟、氯、溴、
    Figure PCTCN2020097369-appb-100032
    Figure PCTCN2020097369-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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, fluorine, chlorine, bromine,
    Figure PCTCN2020097369-appb-100032
    Figure PCTCN2020097369-appb-100033
    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；且z is an integer from 0-4; and
    p为0-8的整数。p is an integer of 0-8.
  14. 根据权利要求5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(V)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 5, wherein the general formula (I) is further represented by the general formula (V):
    Figure PCTCN2020097369-appb-100034
    Figure PCTCN2020097369-appb-100034
    其中：among them:
    M为O、S、NR aa或CR aaR bb。 M is O, S, NR aa or CR aa R bb .
  15. 根据权利要求12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(III-A)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 12, wherein the general formula (I) is further represented by the general formula (III-A):
    Figure PCTCN2020097369-appb-100035
    Figure PCTCN2020097369-appb-100035
    其中：among them:
    环B为杂环基；Ring B is a heterocyclic 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、-(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, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, oxo, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 ;
    z为0-4的整数。z is an integer from 0-4.
  16. 根据权利要求15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或-(CH 2) nNR aaC(O)R bb。 The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 15, wherein R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkane Oxy, 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 or- (CH 2 ) n NR aa C(O)R bb .
  17. 根据权利要求12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(III-B)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 12, wherein the general formula (I) is further represented by the general formula (III-B):
    Figure PCTCN2020097369-appb-100036
    Figure PCTCN2020097369-appb-100036
  18. 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(IA)进一步为通式(III-C1)或通式(III-C2)所示：The compound according to claim 3, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (IA) is further general formula (III-C1) or general formula (III-C2) Shown:
    Figure PCTCN2020097369-appb-100037
    Figure PCTCN2020097369-appb-100037
    M 10选自N或CR aa，优选N或CH； M 10 is selected from N or CR aa , preferably N or CH;
    R 11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 11 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl; 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.
  19. 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(IB)进一步为通式(IF-1)所示：The compound of claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula (IB) is further represented by the general formula (IF-1):
    Figure PCTCN2020097369-appb-100038
    Figure PCTCN2020097369-appb-100038
    其中：among them:
    P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
    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 PCTCN2020097369-appb-100039
    Figure PCTCN2020097369-appb-100039
    环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
    Figure PCTCN2020097369-appb-100040
    Figure PCTCN2020097369-appb-100041
    Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
    Figure PCTCN2020097369-appb-100040
    Figure PCTCN2020097369-appb-100041
    R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，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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, 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 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、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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, 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 ;
    R 8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、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 each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, oxo Group, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxy, cyano or oxo;
    R 9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、腈基、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) nR aa、-(CH 2) nOR aa或-(CH 2) nNR aaR bb，优选氢、C 1-6烷基、C 1-6烷基腈基、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或-(CH 2) nNR aaR bb，进一步优选氢、C 1-3烷基、C 1-3烷基腈基、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)C 3-6环烷基或-(CH 2) nN(C 1-3烷基) 2，更优选氢、甲基、乙基、-CH 2OH、CH 2OHCH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CH 2FCH 2-、CNCH 2-、(CH 3) 2N-、(CH 3CH 2) 2N-、CH 3CH 2O-、环丙基、甲酰基、
    Figure PCTCN2020097369-appb-100042
    R 9 is each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, nitrile, alkenyl, alkynyl , Oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(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 , preferably hydrogen, C 1-6 alkyl, C 1-6 alkyl nitrile, C 1-6 haloalkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, halogen, hydroxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb , more preferably hydrogen, C 1-3 alkyl, C 1-3 alkyl nitrile, C 1-3 haloalkyl, C 1 -3 alkoxy, halogenated 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)C 3-6 cycloalkyl or -(CH 2 ) n N( C 1-3 alkyl) 2 , more preferably hydrogen, methyl, ethyl, -CH 2 OH, CH 2 OHCH 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 CH 2 O-, cyclopropyl, formyl,
    Figure PCTCN2020097369-appb-100042
    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、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、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、氟、氯、溴、
    Figure PCTCN2020097369-appb-100043
    Figure PCTCN2020097369-appb-100044
    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, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably hydrogen, 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 C 3-6 cycloalkyl, More preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, fluorine, chlorine, bromine,
    Figure PCTCN2020097369-appb-100043
    Figure PCTCN2020097369-appb-100044
    q为0-4的整数；q is an integer of 0-4;
    y为0-4的整数；y is an integer from 0-4;
    z为0-4的整数；且z is an integer from 0-4; and
    p为0-8的整数。p is an integer of 0-8.
  20. 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(IF)所示：The compound of claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (IA) is further represented by the general formula (IF):
    Figure PCTCN2020097369-appb-100045
    Figure PCTCN2020097369-appb-100045
    其中：among them:
    P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
    环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
    Figure PCTCN2020097369-appb-100046
    Figure PCTCN2020097369-appb-100047
    Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
    Figure PCTCN2020097369-appb-100046
    Figure PCTCN2020097369-appb-100047
  21. 根据权利要求5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(VI)所示：The compound of claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (VI):
    Figure PCTCN2020097369-appb-100048
    Figure PCTCN2020097369-appb-100048
  22. 根据权利要求13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-1)进一步为通式(I-1a)所示The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 13, wherein the general formula (I-1) is further represented by the general formula (I-1a)
    Figure PCTCN2020097369-appb-100049
    Figure PCTCN2020097369-appb-100049
  23. 根据权利要求5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-A)：The compound of claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is further general formula (VIII-A):
    Figure PCTCN2020097369-appb-100050
    Figure PCTCN2020097369-appb-100050
    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.
  24. 根据权利要求3～23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 to 23, characterized in that:
    环A选自如下基团：Ring A is selected from the following groups:
    Figure PCTCN2020097369-appb-100051
    Figure PCTCN2020097369-appb-100051
    环B选自如下基团：Ring B is selected from the following groups:
    Figure PCTCN2020097369-appb-100052
    Figure PCTCN2020097369-appb-100052
  25. 根据权利要求3～6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 to 6, characterized in that:
    环A选自如下基团：Ring A is selected from the following groups:
    Figure PCTCN2020097369-appb-100053
    Figure PCTCN2020097369-appb-100053
    Figure PCTCN2020097369-appb-100054
    Figure PCTCN2020097369-appb-100054
  26. 根据权利要求7、8、9、15、19、20、21和22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 7, 8, 9, 15, 19, 20, 21 and 22, characterized in that:
    环B选自如下基团：Ring B is selected from the following groups:
    Figure PCTCN2020097369-appb-100055
    Figure PCTCN2020097369-appb-100055
  27. 根据权利要求7、8、9、15、19、20、21和22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 7, 8, 9, 15, 19, 20, 21 and 22, characterized in that:
    环B选自如下基团：Ring B is selected from the following groups:
    Figure PCTCN2020097369-appb-100056
    Figure PCTCN2020097369-appb-100056
  28. 根据权利要求7或20和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 7 or 20, characterized in that:
    环C选自如下基团：Ring C is selected from the following groups:
    Figure PCTCN2020097369-appb-100057
    Figure PCTCN2020097369-appb-100057
  29. 根据权利要求7、8、9、10、15、16、18、19、20、21和22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, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 7, 8, 9, 10, 15, 16, 18, 19, 20, 21 and 22, characterized in that: 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, -(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.
  30. 根据权利要求1～22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 1-22, 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 6和R 7各自独立的选自氢或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 each 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.
  31. 根据权利要求1～30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，所述化合物的结构如下：The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-30, wherein the structure of the compound is as follows:
    Figure PCTCN2020097369-appb-100058
    Figure PCTCN2020097369-appb-100058
    Figure PCTCN2020097369-appb-100059
    Figure PCTCN2020097369-appb-100059
    Figure PCTCN2020097369-appb-100060
    Figure PCTCN2020097369-appb-100060
    Figure PCTCN2020097369-appb-100061
    Figure PCTCN2020097369-appb-100061
    Figure PCTCN2020097369-appb-100062
    Figure PCTCN2020097369-appb-100062
    Figure PCTCN2020097369-appb-100063
    Figure PCTCN2020097369-appb-100063
    Figure PCTCN2020097369-appb-100064
    Figure PCTCN2020097369-appb-100064
    Figure PCTCN2020097369-appb-100065
    Figure PCTCN2020097369-appb-100065
    Figure PCTCN2020097369-appb-100066
    Figure PCTCN2020097369-appb-100066
    Figure PCTCN2020097369-appb-100067
    Figure PCTCN2020097369-appb-100067
    Figure PCTCN2020097369-appb-100068
    Figure PCTCN2020097369-appb-100068
    Figure PCTCN2020097369-appb-100069
    Figure PCTCN2020097369-appb-100069
    Figure PCTCN2020097369-appb-100070
    Figure PCTCN2020097369-appb-100070
    Figure PCTCN2020097369-appb-100071
    Figure PCTCN2020097369-appb-100071
    Figure PCTCN2020097369-appb-100072
    Figure PCTCN2020097369-appb-100072
    Figure PCTCN2020097369-appb-100073
    Figure PCTCN2020097369-appb-100073
    Figure PCTCN2020097369-appb-100074
    Figure PCTCN2020097369-appb-100074
    Figure PCTCN2020097369-appb-100075
    Figure PCTCN2020097369-appb-100075
    Figure PCTCN2020097369-appb-100076
    Figure PCTCN2020097369-appb-100076
    Figure PCTCN2020097369-appb-100077
    Figure PCTCN2020097369-appb-100077
    Figure PCTCN2020097369-appb-100078
    Figure PCTCN2020097369-appb-100078
  32. 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 PCTCN2020097369-appb-100079
    Figure PCTCN2020097369-appb-100079
    其中：among them:
    P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
    环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
    Figure PCTCN2020097369-appb-100080
    Figure PCTCN2020097369-appb-100081
    Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
    Figure PCTCN2020097369-appb-100080
    Figure PCTCN2020097369-appb-100081
    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 ;
    n为0-4的整数；n is an integer from 0-4;
    m1为0-2的整数；且m1 is an integer of 0-2; and
    q为0-2的整数。q is an integer of 0-2.
  33. 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 PCTCN2020097369-appb-100082
    Figure PCTCN2020097369-appb-100082
    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;
    P和Q不同，且各自独立地选自C或N；P and Q are different, and each is independently selected from C or N;
    环E选自取代或未取代的杂环基或取代或未取代的杂芳基，优选取代或未取代的5-6元杂环基或取代或未取代的5-6元杂芳基，更优选含有1-3个氮原子的5元杂芳基，进一步优选
    Figure PCTCN2020097369-appb-100083
    Figure PCTCN2020097369-appb-100084
    Ring E is selected from substituted or unsubstituted heterocyclic groups or substituted or unsubstituted heteroaryl groups, preferably substituted or unsubstituted 5-6 membered heterocyclic groups or substituted or unsubstituted 5-6 membered heteroaryl groups, and more Preferably, a 5-membered heteroaryl group containing 1-3 nitrogen atoms is more preferable
    Figure PCTCN2020097369-appb-100083
    Figure PCTCN2020097369-appb-100084
    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;
    n为0-4的整数；n is an integer from 0-4;
    m1为0-2的整数；且m1 is an integer of 0-2; and
    q为0-2的整数。q is an integer of 0-2.
  34. 一种制备根据权利要求33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 33, its stereoisomer or its pharmaceutically acceptable salt, characterized by comprising the following steps:
    Figure PCTCN2020097369-appb-100085
    Figure PCTCN2020097369-appb-100085
    通式(A)所示的化合物与通式(A-2)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-2) 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.
  35. 一种制备根据权利要求12所述的通式(III)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 (III), its stereoisomer or its pharmaceutically acceptable salt according to claim 12, characterized by comprising the following steps:
    Figure PCTCN2020097369-appb-100086
    Figure PCTCN2020097369-appb-100086
    通式(A-1)所示的化合物与通式(A-3)所示的化合物反应，得到通式(III)所示的目标化合物；The compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-3) to obtain the target compound represented by the general formula (III);
    其中：among them:
    R 3为溴； R 3 is bromine;
    R 4为氢； R 4 is hydrogen;
    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.
  36. 一种制备根据权利要求13所述的通式(III)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 (III), its stereoisomer or its pharmaceutically acceptable salt according to claim 13, characterized by comprising the following steps:
    Figure PCTCN2020097369-appb-100087
    Figure PCTCN2020097369-appb-100087
    通式(III)所示的化合物与含环B的化合物反应，得到通式(I-1)所示的目标化合物；The compound represented by the general formula (III) reacts with the compound containing ring B to obtain the target compound represented by the general formula (I-1);
    其中：among them:
    R 3为溴； R 3 is bromine;
    R 4为氢； R 4 is hydrogen;
    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 PCTCN2020097369-appb-100088
    Figure PCTCN2020097369-appb-100088
  37. 一种制备根据权利要求19所述的通式(IF-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 (IF-1) according to claim 19, its stereoisomer or its pharmaceutically acceptable salt, characterized by comprising the following steps:
    Figure PCTCN2020097369-appb-100089
    Figure PCTCN2020097369-appb-100089
    通式(A-1)所示的化合物与通式(A-4)所示的的化合物反应，得到通式(IF-1)所示的目标化合物；The compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-4) to obtain the target compound represented by the general formula (IF-1);
    其中：among them:
    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 PCTCN2020097369-appb-100090
    Figure PCTCN2020097369-appb-100090
  38. 一种药用组合物，其包括治疗有效剂量的权利要求1～31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 comprising a therapeutically effective dose of the compound described in claims 1 to 31, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, Diluent or excipient.
  39. 根据权利要求1～31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38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 to 31, and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 38 when preparing MEK inhibitors, EGFR inhibitors and Application of EGFR monoclonal antibody and related drugs in combination.
  40. 根据权利要求1～31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38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 to 31 and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 38 in the preparation and treatment of cancer-related diseases; wherein The cancer is lung cancer.
  41. 根据权利要求1～31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38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、宫颈癌、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 to 31 and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 38 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.
PCT/CN2020/097369 2019-06-21 2020-06-22 Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof WO2020253862A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080004109.6A CN112513029B (en) 2019-06-21 2020-06-22 Nitrogen-containing aryl phosphorus oxide derivative, preparation method and application thereof

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN201910544927 2019-06-21
CN201910544927.4 2019-06-21
CN201910927802 2019-09-27
CN201910927802.X 2019-09-27
CN202010033871 2020-01-13
CN202010033871.9 2020-01-13
CN202010334631.2 2020-04-24
CN202010334631 2020-04-24

Publications (1)

Publication Number Publication Date
WO2020253862A1 true WO2020253862A1 (en) 2020-12-24

Family

ID=74036891

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2020/097369 WO2020253862A1 (en) 2019-06-21 2020-06-22 Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof
PCT/CN2020/097362 WO2020253860A1 (en) 2019-06-21 2020-06-22 Aryl phosphorus oxide derivative inhibitor, preparation method therefor and use thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/097362 WO2020253860A1 (en) 2019-06-21 2020-06-22 Aryl phosphorus oxide derivative inhibitor, preparation method therefor and use thereof

Country Status (3)

Country Link
CN (2) CN112469713B (en)
TW (1) TW202115042A (en)
WO (2) WO2020253862A1 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113717156A (en) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 EGFR inhibitor, preparation method and application thereof
WO2021244502A1 (en) * 2020-06-03 2021-12-09 江苏先声药业有限公司 Polyaryl compound and use
WO2022100688A1 (en) * 2020-11-13 2022-05-19 南京红云生物科技有限公司 Hpk1 kinase modulator, preparation method therefor, and application thereof
WO2022127807A1 (en) * 2020-12-18 2022-06-23 江苏豪森药业集团有限公司 Crystal form of aryl phosphorus oxide derivative free base, preparation method therefor, and application thereof
WO2022146027A1 (en) * 2020-12-29 2022-07-07 주식회사 비투에스바이오 Heteroaryl derivative compound and use thereof
WO2022227032A1 (en) * 2021-04-30 2022-11-03 Beigene (Beijing) Co., Ltd. Egfr degraders and associated methods of use
WO2022271612A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Heterocyclic egfr inhibitors for use in the treatment of cancer
WO2022271630A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Egfr inhibitors
WO2022271613A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Heterocyclic egfr inhibitors for use in the treatment of cancer
WO2022271749A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Heterocyclic egfr inhibitors for use in the treatment of cancer
AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof
WO2024005516A1 (en) * 2022-06-28 2024-01-04 보로노이 주식회사 Heteroaryl derivative compound and use thereof
WO2024072075A1 (en) * 2022-09-30 2024-04-04 주식회사 테라펙스 Pyrimidine derivative having protein kinase inhibitory activity, and therapeutic pharmaceutical composition comprising same

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111410667A (en) * 2019-01-08 2020-07-14 武汉宇科源医药生物科技有限公司 Novel (1,2,4) triazolo (1,5-a) pyridylphosphine oxides and use thereof
CN112168820B (en) * 2019-07-05 2023-09-29 中国科学院生物物理研究所 Application of SRCAP ATPase inhibitor in colorectal cancer treatment
AU2022306297A1 (en) 2021-07-09 2024-02-08 Plexium, Inc. Aryl compounds and pharmaceutical compositions that modulate ikzf2
TW202321228A (en) * 2021-08-06 2023-06-01 大陸商南京紅云生物科技有限公司 Benzodioxane compound, preparation method therefor and application thereof
CN116178434A (en) * 2021-11-26 2023-05-30 南京正大天晴制药有限公司 Mono-p-toluene sulfonate and crystal forms of AXL kinase inhibitor
CN116178433A (en) * 2021-11-26 2023-05-30 南京正大天晴制药有限公司 Salts of AXL kinase inhibitors, methods of preparation and use thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018021A1 (en) * 2001-08-22 2003-03-06 Amgen Inc. 2,4-disubstituted pyrimidinyl derivatives for use as anticancer agents
WO2008128231A1 (en) * 2007-04-16 2008-10-23 Hutchison Medipharma Enterprises Limited Pyrimidine derivatives
WO2012051587A1 (en) * 2010-10-14 2012-04-19 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in egfr-driven cancers
CN106831730A (en) * 2017-01-11 2017-06-13 温州医科大学 A kind of substituted diaminopyrimidines and its purposes in anti-malignant tumor medicine is prepared
CN108101926A (en) * 2018-02-07 2018-06-01 郑州大学 Pyrimido five-membered heterocycles containing quinolinone, preparation method and applications
WO2019015655A1 (en) * 2017-07-19 2019-01-24 正大天晴药业集团股份有限公司 Aryl-phosphorus-oxygen compound as egfr kinase inhibitor
WO2019070167A1 (en) * 2017-10-06 2019-04-11 Закрытое Акционерное Общество "Биокад" Epidermal growth factor receptor inhibitors
CN111410667A (en) * 2019-01-08 2020-07-14 武汉宇科源医药生物科技有限公司 Novel (1,2,4) triazolo (1,5-a) pyridylphosphine oxides and use thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2214405C2 (en) * 1998-02-18 2003-10-20 НьюроСёрч А/С Novel compounds and their application as positive modulators of ampa-receptors
GB0206215D0 (en) * 2002-03-15 2002-05-01 Novartis Ag Organic compounds
GB0321710D0 (en) * 2003-09-16 2003-10-15 Novartis Ag Organic compounds
JP2007505858A (en) * 2003-09-18 2007-03-15 ノバルティス アクチエンゲゼルシャフト 2,4-Di (phenylamino) pyrimidine useful for the treatment of proliferative disorders
WO2007120596A1 (en) * 2006-04-12 2007-10-25 Wyeth DIHYDRO[1,4]DIOXINO[2,3-e]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS
CA2680583A1 (en) * 2007-03-15 2008-09-25 Schering Corporation Pyridazinone derivatives useful as glucan synthase inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018021A1 (en) * 2001-08-22 2003-03-06 Amgen Inc. 2,4-disubstituted pyrimidinyl derivatives for use as anticancer agents
WO2008128231A1 (en) * 2007-04-16 2008-10-23 Hutchison Medipharma Enterprises Limited Pyrimidine derivatives
WO2012051587A1 (en) * 2010-10-14 2012-04-19 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in egfr-driven cancers
CN106831730A (en) * 2017-01-11 2017-06-13 温州医科大学 A kind of substituted diaminopyrimidines and its purposes in anti-malignant tumor medicine is prepared
WO2019015655A1 (en) * 2017-07-19 2019-01-24 正大天晴药业集团股份有限公司 Aryl-phosphorus-oxygen compound as egfr kinase inhibitor
WO2019070167A1 (en) * 2017-10-06 2019-04-11 Закрытое Акционерное Общество "Биокад" Epidermal growth factor receptor inhibitors
CN108101926A (en) * 2018-02-07 2018-06-01 郑州大学 Pyrimido five-membered heterocycles containing quinolinone, preparation method and applications
CN111410667A (en) * 2019-01-08 2020-07-14 武汉宇科源医药生物科技有限公司 Novel (1,2,4) triazolo (1,5-a) pyridylphosphine oxides and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BUCHANAN, JOHN L. ET AL.: "Discovery of 2,4-bis-arylamino-1,3-pyrimidines as Insulin-like Growth Factor-1 receptor (IGF-1R) Inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, 23 February 2011 (2011-02-23), XP055376699, DOI: 20200908105337X *
CHEN, LINGFENG ET AL.: "Structure-based Design and Synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M Selective Inhibitors for NSCLC", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 140, 20 September 2017 (2017-09-20), XP085227230, DOI: 20200908105828X *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof
WO2021238827A1 (en) * 2020-05-25 2021-12-02 南京红云生物科技有限公司 Egfr inhibitor and preparation method and use thereof
CN113717156A (en) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 EGFR inhibitor, preparation method and application thereof
CN113717156B (en) * 2020-05-25 2023-05-09 南京红云生物科技有限公司 EGFR inhibitor, preparation method and application thereof
WO2021244502A1 (en) * 2020-06-03 2021-12-09 江苏先声药业有限公司 Polyaryl compound and use
WO2022100688A1 (en) * 2020-11-13 2022-05-19 南京红云生物科技有限公司 Hpk1 kinase modulator, preparation method therefor, and application thereof
WO2022127807A1 (en) * 2020-12-18 2022-06-23 江苏豪森药业集团有限公司 Crystal form of aryl phosphorus oxide derivative free base, preparation method therefor, and application thereof
WO2022146027A1 (en) * 2020-12-29 2022-07-07 주식회사 비투에스바이오 Heteroaryl derivative compound and use thereof
WO2022227032A1 (en) * 2021-04-30 2022-11-03 Beigene (Beijing) Co., Ltd. Egfr degraders and associated methods of use
WO2022271613A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Heterocyclic egfr inhibitors for use in the treatment of cancer
WO2022271749A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Heterocyclic egfr inhibitors for use in the treatment of cancer
WO2022271630A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Egfr inhibitors
WO2022271612A1 (en) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Heterocyclic egfr inhibitors for use in the treatment of cancer
WO2024005516A1 (en) * 2022-06-28 2024-01-04 보로노이 주식회사 Heteroaryl derivative compound and use thereof
WO2024072075A1 (en) * 2022-09-30 2024-04-04 주식회사 테라펙스 Pyrimidine derivative having protein kinase inhibitory activity, and therapeutic pharmaceutical composition comprising same

Also Published As

Publication number Publication date
CN112513029A (en) 2021-03-16
CN112513029B (en) 2023-10-24
WO2020253860A1 (en) 2020-12-24
TW202115042A (en) 2021-04-16
CN112469713B (en) 2023-09-01
CN112469713A (en) 2021-03-09

Similar Documents

Publication Publication Date Title
WO2020253862A1 (en) Nitrogen-containing aryl phosphorus oxide derivative, preparation method therefor and use thereof
CN112105419B (en) Condensed ring compound
CN112119075B (en) Condensed ring compound
CN115353509B (en) Nitrogen-containing heteroaromatic derivative regulator, preparation method and application thereof
TWI714567B (en) Heterocyclic compounds as lsd1 inhibitors
AU2015280138B2 (en) Phosphatidylinositol 3-kinase inhibitors
WO2020239077A1 (en) Nitrogen-containing heterocyclic derivative regulator, preparation method therefor and application thereof
WO2020073945A1 (en) Bicyclic derivative inhibitor, preparation method therefor, and application thereof
CN115835908A (en) Bicyclic heterocycles as FGFR inhibitors
CN113795483A (en) Carboxamide-pyrimidine derivatives as SHP2 antagonists
CN112079830B (en) Inhibitor containing fused ring derivative, preparation method and application thereof
AU2011228703A1 (en) Spirocyclic compounds and their use as therapeutic agents and diagnostic probes
CN114163454A (en) Pyridine-containing polycyclic derivative inhibitor, and preparation method and application thereof
WO2023061294A1 (en) Nitrogen-containing heterocyclic derivative regulator, preparation method therefor and application thereof
CN110546150B (en) Pyrazolyl-containing tricyclic derivatives, preparation method and application thereof
KR20160086404A (en) Thienopyrimidines as mknk1 and mknk2 inhibitors
WO2020233669A1 (en) Indole derivative-containing inhibitor, preparation method therefor and application thereof
CN113387962A (en) Pyrazolo [3,4-d ] pyrimidine-3-one derivative, pharmaceutical composition and application thereof
EP4320132A1 (en) Oxazepine compounds and uses thereof in the treatment of cancer
WO2020103897A1 (en) Heterocyclic fused pyrimidine derivative, pharmaceutical composition thereof, and application thereof
TW202229272A (en) Methods for treating cancer
WO2023122140A1 (en) Parp1 inhibitors
RU2783706C1 (en) Compounds with condensed rings
TW202300152A (en) Egfr inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20826660

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20826660

Country of ref document: EP

Kind code of ref document: A1