WO2020239123A1 - Aromatic heterocyclic derivative modulator and preparation method therefor and use thereof - Google Patents

Aromatic heterocyclic derivative modulator and preparation method therefor and use thereof Download PDF

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Publication number
WO2020239123A1
WO2020239123A1 PCT/CN2020/093731 CN2020093731W WO2020239123A1 WO 2020239123 A1 WO2020239123 A1 WO 2020239123A1 CN 2020093731 W CN2020093731 W CN 2020093731W WO 2020239123 A1 WO2020239123 A1 WO 2020239123A1
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alkyl
group
alkoxy
amino
cyano
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PCT/CN2020/093731
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French (fr)
Chinese (zh)
Inventor
刘世强
袁逸达
鲍孟
黄胜爱
王婷司
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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
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Priority claimed from CN201910856187.8A external-priority patent/CN112552294B/en
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 CN202080012821.0A priority Critical patent/CN113396147A/en
Publication of WO2020239123A1 publication Critical patent/WO2020239123A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to an aromatic heterocyclic derivative inhibitor and a preparation method and application thereof.
  • Rat sarcoma encoded by the proto-oncogenes HRAS, NRAS, and KRAS, is divided into four proteins, HRAS, NRAS, KRAS4A and KRAS4B, and is a GTP (guanosine triphosphate) binding protein.
  • RAS is located on the inner surface of the cell membrane, upstream of which is receptor tyrosine kinase (RTK). After activation, it regulates downstream signaling pathways such as PI3K and RAF, thereby regulating cell growth, survival, migration and differentiation.
  • RAS has two main states in the body: inactive state combined with GDP (guanosine diphosphate) and activated state combined with GTP. Its activity is regulated by two proteins.
  • the guanine nucleotide exchange factor (GEF) promotes the release of GDP from the RAS protein, allowing GTP to bind to activate RAS;
  • GTPase activating protein (GTPase activating protein, GAP) activates the GTP of the RAS protein
  • Enzyme activity hydrolyzes the GTP bound to the RAS protein into GDP and inactivates RAS.
  • the RAS protein is in an inactive state, the conformation changes after mutation, RAS is in a continuously activated state, and downstream signaling pathways are also continuously activated, which leads to the occurrence of a variety of cancers.
  • RAS is the oncogene with the highest mutation rate, accounting for an average of 25% of human cancers.
  • the most common oncogenic mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are relatively rare.
  • KRAS mutations mainly occur in a series of cancers such as pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%).
  • the most common mutation mode of KRAS is point mutation, which mostly occurs in G12, G13 in p-loop (aa 10-17) and Q61 in Switch II region (aa59-76), of which G12 mutation is the most common (83%).
  • KRAS G12C is one of the most common mutations in non-small cell lung cancer (NSCLC) and colorectal cancer.
  • KRAS inhibitors are mainly due to two factors. First, the structure of the RAS protein is smooth, and small molecules are difficult to bind to the protein surface; second, the affinity of RAS GTPase for GTP is as high as picomolar (pM) level, and the endogenous GTP level is high. Small molecule drugs are difficult to block the combination of the two.
  • pM picomolar
  • KRAS G12C inhibitors are expected to become the first drugs that directly target KRAS.
  • KRAS G12C inhibitors have entered the clinical research phase, such as AMG 510 developed by Amgen, ARS-3248 developed by Wellspring Biosciences, and MTRX849 developed by Mirati, all of which are currently in clinical phase I research phase, but none of them have KRAS G12C inhibitor developed and marketed.
  • AMG 510 has shown good efficacy and good safety in early clinical trials, and it is expected to bring more treatment options to cancer patients with KRAS G12C mutations in the future.
  • KRAS G12C currently has no specific targeted drugs, and there is a large clinical demand. KRAS G12C inhibitors with higher selectivity, better activity and better safety have the potential to treat a variety of cancers and have broad market prospects.
  • 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:
  • X 1 is selected from N or CR 1 ;
  • X 2 is selected from N or CR 2 ;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -, -NH(CH 2 ) n C(O)R aa , -O(CH 2 ) n R aa , -(CH 2 ) n SR aa or -(CH 2 ) n C(O)R aa , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl
  • the group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optional
  • R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkane
  • the group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
  • R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkane
  • the group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
  • R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, The heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
  • R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo group, thioxo group, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy Oxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl , Alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further substituted;
  • R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cyano
  • the substituted alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
  • R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, and haloalkoxy , Hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkane Oxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
  • R bb and R cc and adjacent atoms form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further replace;
  • R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with a group, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy , Hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further substituted;
  • R cc and R dd and adjacent atoms form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further replace;
  • x is an integer from 0 to 6;
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 2;
  • X 1 is CR 1
  • X 2 is CR 2 .
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, -(CH 2 ) n -, -NH(CH 2 ) n C(O)R aa , -O( CH 2 ) n R aa , -(CH 2 ) n SR aa or -(CH 2 ) n C(O)R aa , the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2 -6alkenyl group, C 2 -6
  • R 1 is selected from 3-10 membered heterocyclic group or -(CH 2 ) n C(O)R aa , said 3-10 membered heterocyclic group is optionally hydrogenated , Hydroxy, halogen, amino, C 1-3 alkyl, C 2-6 alkenyl carbonyl and 3-10 membered heterocyclic group substituted by one or more substituents;
  • Raa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1- 6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, , 3-12 membered heterocyclic group, C 6-12 aryl group and
  • R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group.
  • R 2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
  • R 2 is selected from hydrogen, halogen and C 1-3 alkyl.
  • R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, oxo group, thio group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, Cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -O(CH 2 ) n R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc , -NR bb (CH 2 ) n NR cc R dd ,
  • R 3 is selected from hydrogen, amino, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, -O(CH 2 ) n R bb , -(CH 2 ) n C(O)NR bb R cc , -(CH 2 ) n C(O)R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc or -NR bb (CH 2 ) n NR cc R dd , the C 3-12 cycloalkyl group and 3-12 membered heterocyclic group are optionally hydrogen, C 1-6 alkyl group and 3-12 membered heterocyclic group Is substituted by one or more substituents.
  • R bb and R cc are independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cyclo
  • R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, deuterated C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyano Alkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, Cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl,
  • R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group.
  • R 4 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
  • R 4 is selected from hydrogen, halogen and C 1-3 alkyl.
  • R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane groups, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 1- 6 alkyl, C C2-6 alkenyl group, C C2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3 -12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl, said C 1- 6 alkyl
  • R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, oxo group, thio group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl C 1-6 alkyl group or cyano group, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, oxo group, thio group, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl and cyano substituted C 1-6 alkyl, optionally By hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6
  • R a is selected from hydrogen, halogen, amino, hydroxy, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3 -10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, optionally substituted by one of hydrogen, deuterium, halogen, amino, hydroxyl, cyano and C 1-6 alkyl Multiple substituents are substituted.
  • M 1 is selected from CR 6 R 7 or NR 6 ;
  • said 3-12 membered heterocyclic group Optional by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
  • R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen;
  • R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkane Group; preferably hydrogen, halogen or C 1-3 alkyl;
  • y is an integer of 0-6.
  • M 2 is selected from CR 8 R 9 or NR 8 ;
  • said 3-12 membered heterocyclic group Optional by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
  • R 9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen;
  • R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkane Group; preferably hydrogen, halogen or C 1-3 alkyl;
  • z is an integer of 0-6.
  • Ring B is selected from C 3-12 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably 3-12 membered heterocyclic group, C 6-12 aryl group And 5-12 membered heteroaryl groups;
  • R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12
  • t is an integer of 0-6.
  • R 2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
  • -N CHNR cc R dd , -NR bb C(O)R cc , -NR bb (CH 2 ) n R cc or -NH b (CH 2 ) n NR cc R dd ;
  • R 10 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
  • R 11 is selected from hydrogen, halogen, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 Membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3 -8 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano and C 1-6 One or more substituents in the alkyl group;
  • R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3
  • R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3
  • n and n are integers of 0-3.
  • ring A is selected from C 6-10 aryl groups and 5-12 membered heteroaryl groups, among which 5-12 membered heteroaryl groups are preferably heteroaryl groups containing 1-3 nitrogen atoms , Including 5-7 membered nitrogen-containing heteroaryl group, benzo 5-7 membered nitrogen-containing heteroaryl group or 5-7 membered nitrogen-containing heteroaryl phenyl group, more preferably the following groups:
  • ring B is selected from 5-12 membered heterocyclic groups containing 1-3 nitrogen atoms, more preferably the following groups:
  • the present invention provides a compound represented by general formula (VII), its stereoisomers or pharmaceutically acceptable salts thereof:
  • Ring C is selected from phenyl, pyridyl, 5-7 membered nitrogen-containing heteroaryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroaryl phenyl, and is more preferably selected from the following Group:
  • R 12 is selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
  • R e is selected from hydrogen, halogen, hydroxyl, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
  • p is an integer of 0-4.
  • the present invention provides a compound represented by general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof:
  • X 3 is selected from CH 2 , CH, N or NR 13 ;
  • M is selected from N or CH
  • L 3 is selected from -O- or -OCH 2 -;
  • L 4 is selected from -O- or -CH 2 -;
  • R 13 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
  • methyl or cyclopropyl Preferably methyl or cyclopropyl
  • R 14 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
  • R is selected from 3-8 membered nitrogen-containing heterocyclic group or benzo 3-8 membered nitrogen-containing heterocyclic group, more preferably 5-7 membered nitrogen-containing heterocyclic group or benzo 5-7 membered nitrogen-containing heterocyclic group, wherein The number of nitrogen atoms is 1-2, optionally substituted by halogen or one or more substituents in C 1-3 alkyl,
  • R 15 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group; preferably hydrogen or fluorine.
  • the present invention provides a compound represented by general formula (IX), its stereoisomers or pharmaceutically acceptable salts thereof:
  • Ring D is selected from the following groups:
  • the present invention also provides a preferred solution, and also relates to a pharmaceutical composition, which comprises a therapeutically effective dose of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof and a One or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention further relates to the application of any one of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of KRAS G12C inhibitor drugs.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I), and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the treatment, prevention and/ Or a method for pre-prepared therapy to treat a condition mediated by a KRAS G12C inhibitor, the method comprising administering to the patient a therapeutically effective dose of a compound represented by general formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, Or its pharmaceutical composition.
  • the compounds and compositions of the present invention can be used to treat Noonan’s syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, and gastric cancer. , Lung cancer and colon cancer and other diseases or diseases.
  • the compounds and compositions of the present invention can be used to treat diseases such as Noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer. Or the method in the disease.
  • the present invention provides a method of treating a cancer condition, which comprises administering a compound or composition of the present invention to a patient suffering from a cancer condition.
  • the cancer treated by the compound or composition of the present invention is Noonan’s syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck cancer, stomach cancer, lung cancer And its colon cancer; preferably non-small cell lung cancer, colon cancer, esophageal cancer, head and neck cancer.
  • 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 of 1 to 3 carbon atoms is most preferred.
  • 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
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups 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,
  • Alkyl groups may be substituted or unsubstituted. When substituted, substituents may be substituted at any available point of attachment.
  • 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, 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, which may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electron 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 3-membered/6-membered, 3-membered/5-membered, 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, 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, azepyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, Piperidinyl, azepanyl, 1,4-diazepanyl 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 3-membered/5-membered, 3-membered/6-membered, 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 of which 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 12 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 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group containing a sulfur atom; or 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 12 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, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrole And oxazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the thi
  • Heteroaryl 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, 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 alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl 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 , Heterocycloalkylthio, carboxyl or
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group 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, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
  • alkenylcarbonyl refers to -C(O)-(alkenyl), where alkenyl is as defined above.
  • alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
  • the alkenylcarbonyl 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.
  • groups 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
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carbonyl refers to -C(O)-.
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means acetonitrile
  • 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, that means 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 a deuterium atom.
  • 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, as well as 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 was measured with 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 C 18 150 ⁇ 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 4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester
  • the third step Preparation of (2-amino-4-bromo-5-chloro-3-fluorophenyl)(piperazin-1-yl)methanone
  • the fourth step preparation of 1-(4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazin-1-yl)prop-2-en-1-one
  • the fifth step 1-(4-(4-bromo-5-chloro-3-fluoro-2-(methylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one preparation
  • the sixth step 1-(4-(6-chloro-2,2'-difluoro-6'-methoxy-3-(methylamino)-[1,1'-biphenyl]-4- (Carbonyl) piperazin-1-yl) prop-2-en-1-one preparation
  • the seventh step 1-(4-(6-chloro-2,2'-difluoro-6'-hydroxy-3-(methylamino)-[1,1'-biphenyl]-4-carbonyl) Preparation of piperazin-1-yl)prop-2-en-1-one
  • Step 2 Add 1-(4-(6-chloro-3-(dimethylamino)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]- Preparation of 4-carbonyl)piperazin-1-yl)prop-2-en-1-one
  • the third step 1-(4-(6-chloro-3-(dimethylamino)-2,2'-difluoro-6'-hydroxy--[1,1'-biphenyl]-4- (Carbonyl) piperazin-1-yl) prop-2-en-1-one preparation
  • Step 1 Preparation of 4-(2-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Extract with ethyl acetate (3*30 mL), combine the organic layers, wash with water and saturated brine. Dry with anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (CH 2 Cl 2 /MeOH 10:1) to obtain the target product (S)-4-(6-bromo-5-methyl-2-((1 -Methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)tert-butyl piperazine-1-carboxylate (1.6 g, yield: 34%).
  • Step 4 Preparation of (S)-4-bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(piperazin-1-yl)pyrimidine
  • Example 21 For the preparation of Example 21, refer to Example 1.
  • Example 1 for the preparation of Example 22.
  • Example 1 for the preparation of Example 23.
  • Example 1 for the preparation of Example 24.
  • Example 1 for the preparation of Example 25.
  • the first step the preparation of tert-butyl(S)-4-(2,6-dichloro-5-fluoronicotinyl)-3-methylpiperazine-1-carboxylate
  • the fourth step (5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)pyridin-3-yl )((S)-2-Methylpiperazin-1-yl)methanone
  • the fifth step 1-((3S)-4-(5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridine-3- (Yl)amino)nicotyryl)-3-methylpiperazin-1-yl)prop-2-en-1-one
  • Methyl 2,6-dichloropyrimidine-4-carboxylate (10g, 48.3mmol), tert-butyl(S)-3-methylpiperazine-1-carboxylate (9.6g, 48mmol) and N , N-Diisopropylethylamine (12g, 100mmol) was stirred in tetrahydrofuran (150mL) at 50°C for 4 hours.
  • Add water (150mL), extract with ethyl acetate (150mL ⁇ 2) wash the organic phase with aqueous ammonium chloride solution (200mL) and then with sodium chloride aqueous solution (50mL), dry the organic phase with anhydrous sodium sulfate, and filter. After concentration, methyl (S)-6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxylate yellow solid (17g, The yield is 95%).
  • Step 2 6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidine-2 -(Yl)methoxy)pyrimidine-4-carboxylic acid preparation
  • the third step 6-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4- Preparation of carboxylic acid
  • the fifth step 6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(4-fluoro-3-hydroxyphenyl)-2-(((S)- Preparation of 1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide
  • reaction solution was filtered, concentrated, and purified by preparative HPLC to obtain 6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(4-fluoro-3-hydroxyphenyl)-2- (((S)-1-Methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide (15 mg, 10% yield in three steps) yellow solid.
  • Example 27 for the preparation of Example 28.
  • Example 27 for the preparation of Example 28.
  • Step 2 Preparation of tert-butyl 4-(5-bromo-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate
  • the third step preparation of tert-butyl 4-(5-formyl-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate
  • tert-butyl 4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1 -Carboxylic acid ester (1.8g, 4.0mmol) was added to NaOH aqueous solution (5M, 100mL), 2-fluoro-6-methoxybenzaldehyde (730mg, 4.8mmol) and trioctylmethylammonium chloride (220mg , 0.5mmol), heated to reflux, and stirred for 5 hours.
  • the sixth step 7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-4-(piperazin-1-yl)-5,6,7,8-tetra Preparation of Hydropyrido[4,3-d]pyrimidine
  • the seventh step 1-(4-(7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4 ,3-d)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  • the seventh step 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-2-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d) Preparation of pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  • the eighth step 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl) -4-methylpyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one
  • the first step the preparation of 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotamide
  • reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (40 mL ⁇ 3); the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated by column chromatography [eluent: water to acetonitrile/water From 0% to 24%] purified to obtain a yellow solid 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (380mg, yield 39 %).
  • Step 2 Preparation of 7-chloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
  • the third step preparation of 4,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
  • reaction solution was spin-dried and purified by column chromatography [eluent: dichloromethane-methanol (containing 1% ammonia)/dichloromethane from 0% to 5%] to obtain a yellow solid product (S)-4-(4-propylene) Acyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido [4,3-d]pyrimidin-2(1H)-one (50mg, yield 23%).
  • the fourth step 7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4- Preparation of (piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine
  • the fifth step 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methyl (Oxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  • the sixth step 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methyl (Oxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  • the seventh step 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy (Yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  • the first step preparation of tert-butyl 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate
  • the fourth step tert-butyl 4-(7-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxo)-2- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-yl)piperazine-1- Preparation of carboxylate
  • the fifth step 5-chloro-4-((2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7 -Dihydro-5H-cyclopenta[d]pyrimidin-7-yl)oxo)-1H-indazole
  • the sixth step 1-(4-(7-((5-chloro-1H-indazol-4-yl)oxo)-2-(((S)-1-methylpyrrolidin-2-yl) (Methoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
  • the first step the preparation of 2,6-dichloro-5-fluoronicotamide
  • Step 2 Preparation of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotamide
  • the third step 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H) -Preparation of diketone
  • the fifth step tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2 -Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
  • the sixth step tert-butyl(S)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-7-((2-( Trifluoromethyl)pyridin-3-yl)thio)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate preparation
  • the seventh step (S)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7-( (2-(Trifluoromethyl)pyridin-3-yl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Step 1 Preparation of tert-butyl 3-(4-chlorobutyrylamino)azetidine-1-carboxylate
  • Step 2 Preparation of tert-butyl 3-(2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate
  • reaction was quenched with aqueous ammonium chloride solution (60 mL), extracted with ethyl acetate (50 mL ⁇ 3), the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain tert-butyl 3-(2-carbonyl Pyrrolidin-1-yl)azetidine-1-carboxylate (2.3 g, yield 100%) colorless oil.
  • Step 3 Preparation of 1-(1-(tert-butoxycarbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid ethyl ester
  • Step 4 Preparation of 1-(1-(tert-butoxycarbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid
  • Step 5 Preparation of tert-butyl 3-(3-methylene-2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate
  • Step 8 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3-methylene-2-carbonylpyrrolidine-Preparation of 1-yl)azetidine-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Step 9 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3- Preparation of methylene-2-carbonylpyrrolidin-1-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Step 1 Preparation of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate
  • reaction solution was poured into aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L ⁇ 2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and then column chromatography [ Eluent: petroleum ether ⁇ ethyl acetate/petroleum ether from 0% to 2%] Purify to obtain a colorless oily product tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (15g , The yield is 42%).
  • Step 2 Preparation of tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate
  • reaction solution was poured into aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L ⁇ 2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and then column chromatography [ Eluent: Petroleum ether ⁇ ethyl acetate/petroleum ether from 0% to 5%] Purify to obtain a colorless oily product tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1 -Carboxylic acid ester (25 g, yield 90%).
  • the third step preparation of tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate
  • Step 4 Preparation of tert-butyl 1-carbonyl-8-azaspiro[4.5]dec-2-ene-8-carboxylate
  • reaction solution After the reaction solution is cooled, the reaction solution is concentrated and purified by column chromatography [eluent: petroleum ether ⁇ ethyl acetate/petroleum ether from 0% to 20%] to obtain the red-black solid product tert-butyl 1-carbonyl-8- Azaspiro[4.5]dec-2-ene-8-carboxylate (13g, yield 58%).
  • the seventh step 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8-azaspiro[4.5]dec-2 -En-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the eighth step 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8 -Azaspiro[4.5]dec-2-en-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Step 1 Preparation of tert-butyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate
  • Step 2 Preparation of 2-(tert-butyl)7-ethyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2,7-dicarboxylate
  • the third step Preparation of 2-(tert-butoxycarbonyl)-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid
  • Step 4 Preparation of tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate
  • reaction solution was concentrated and purified by column chromatography [eluent: petroleum ether ⁇ ethyl acetate/petroleum ether from 0% to 100%] to obtain tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a] pyrazine-2-carboxylate (280 mg, yield 48%) white solid.
  • the seventh step 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene-6-carbonyloctahydro-2H-pyridine Preparation of and [1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the eighth step 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene -6-Carbonyloctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the first step the preparation of tert-butyl(S)-4-(4-bromo-2,5-difluorobenzoyl)-3-methylpiperazine-1-carboxylate
  • the third step tert-butyl(S)-4-(4-bromo-5-fluoro-2-(N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitro (Acetylamino)benzoyl)-3-methylpiperazine-1-carboxylic acid ester
  • the fifth step tert-butyl(S)-4-(3-amino-7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl -1,2-Dihydroquinolin-4-yl)-3-methylpiperazine-1-carboxylate
  • the eighth step 1-((3S)-4-(7-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-4-methylpyridin-3-yl) )-4H-imidazo[4,5-b]quinolin-9-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one
  • the fifth step tert-butyl(2R)-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-di Carbonyl-1,2,4,4a,5,6,7,8-octahydro-3H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c ]Quinoline-3-carboxylate preparation
  • the seventh step (2R)-3-acryloyl-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2 ,3,4,4a,6,8-Hexahydro-1H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c]quinoline-5,7 -Preparation of diketone
  • Test Example 1 Determination of the inhibitory effect of the compound of the present invention on the proliferation activity of H358/Mia PaCa-2 cells
  • test case The purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of H358 and Mia PaCa-2 cells.
  • NCI-H358 was purchased from Nanjing Kebai Biotechnology Co., Ltd.;
  • Mia PaCa-2 was purchased from ATCC;
  • Cell Titer-Glo cells were purchased from Promega, the product number is G7573;
  • RPMI 1640 was purchased from Gibco, the article number is 22400089;
  • DMEM was purchased from Gibco, the article number is 11995065;
  • FBS was purchased from Gibco, the article number is 10091148;
  • PBS was purchased from Gibco, the article number is 10010023;
  • Pancreatin was purchased from Gibco, the product number is 25200056;
  • the cell culture plate was purchased from Corning, the article number is 3610.
  • H358 or Mia PaCa-2 cells When culturing H358 or Mia PaCa-2 cells to a suitable degree of confluence, collect H358 or Mia PaCa-2 cells, adjust the cells to a suitable cell concentration with complete medium, and spread the cell suspension on a 96-well plate, 90 ⁇ L per well , Put it in a 37°C, 5% CO 2 incubator overnight, use DMSO and culture medium to prepare compound solutions of different concentrations, set the solvent control, add the compound solution to a 96-well plate, 10 ⁇ L per well, put it in 37°C After culturing in a 5% CO 2 incubator for 72h ⁇ 144h, add CellTiter-Glo solution, shake and mix well, incubate in the dark for 10 minutes, and read with BioTek Synergy H1 microplate reader.
  • the luminescence signal value was used to calculate the inhibition rate, and the concentration and inhibition rate were fitted with Graphpad Prism software for nonlinear regression curve fitting to obtain the IC 50 value.
  • the compounds of the examples of the present invention have a good proliferation inhibitory effect on NCI-H358 and Mia PaCa-2 cells.

Abstract

The present invention relates to an aromatic heterocyclic derivative modulator, and a preparation method therefor and the use thereof. In particular, the present invention relates to a compound shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a KRAS G12C mutation inhibitor in the treatment of diseases or conditions such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer and colon cancer, wherein the definition of each substituent in general formula (I) is the same as that in the description.

Description

芳香杂环类衍生物调节剂、其制备方法和应用Aromatic heterocyclic derivative regulator, preparation method and application thereof
本申请要求申请日为2019年5月31日的中国专利申请CN201910471133.X、申请日为2019年9月10日的中国专利申请CN201910856186.3、申请日为2019年9月10日的中国专利申请CN201910856187.8、申请日为2019年9月11日的中国专利申请CN201910860731.6、申请日为2020年1月7日的中国专利申请CN 202010014845.1的优先权。本申请引用上述中国专利申请的全文。This application requires the Chinese patent application CN201910471133.X with the filing date of May 31, 2019, the Chinese patent application CN201910856186.3 with the filing date of September 10, 2019, and the Chinese patent application with the filing date of September 10, 2019 CN201910856187.8, the priority of the Chinese patent application CN201910860731.6 with the filing date of September 11, 2019, and the Chinese patent application CN 202010014845.1 with the filing date of January 7, 2020. This application quotes the full text of the aforementioned Chinese patent application.
技术领域Technical field
本发明属于药物合成领域，具体涉及一种芳香杂环类衍生物抑制剂及其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to an aromatic heterocyclic derivative inhibitor and a preparation method and application thereof.
背景技术Background technique
大鼠肉瘤(rat sarcoma，RAS)，由原癌基因HRAS，NRAS以及KRAS编码，分为4种蛋白HRAS，NRAS，KRAS4A和KRAS4B，是一种GTP(guanosine triphosphate)结合蛋白。RAS位于细胞膜内表面，上游为受体酪氨酸激酶(RTK)，激活后调控下游的PI3K，RAF等信号通路，从而调控细胞的生长、存活、迁移和分化等功能。Rat sarcoma (RAS), encoded by the proto-oncogenes HRAS, NRAS, and KRAS, is divided into four proteins, HRAS, NRAS, KRAS4A and KRAS4B, and is a GTP (guanosine triphosphate) binding protein. RAS is located on the inner surface of the cell membrane, upstream of which is receptor tyrosine kinase (RTK). After activation, it regulates downstream signaling pathways such as PI3K and RAF, thereby regulating cell growth, survival, migration and differentiation.
RAS在机体内主要有两种状态：与GDP(guanosine diphosphate)结合的失活状态和与GTP结合的激活状态。其活性受两个蛋白调控，鸟苷交换因子(guanine nucleotide exchange factor，GEF)促使GDP从RAS蛋白上释放，使GTP结合激活RAS；GTP酶激活蛋白(GTPase activating protein，GAP)激活RAS蛋白的GTP酶活性，将结合在RAS蛋白上的GTP水解成GDP，使RAS失活。正常情况下，RAS蛋白处于非活化状态，突变后构象发生改变，RAS处于持续激活状态，且下游信号通路也被持续激活，从而导致多种癌症的发生。RAS has two main states in the body: inactive state combined with GDP (guanosine diphosphate) and activated state combined with GTP. Its activity is regulated by two proteins. The guanine nucleotide exchange factor (GEF) promotes the release of GDP from the RAS protein, allowing GTP to bind to activate RAS; GTPase activating protein (GTPase activating protein, GAP) activates the GTP of the RAS protein Enzyme activity hydrolyzes the GTP bound to the RAS protein into GDP and inactivates RAS. Under normal circumstances, the RAS protein is in an inactive state, the conformation changes after mutation, RAS is in a continuously activated state, and downstream signaling pathways are also continuously activated, which leads to the occurrence of a variety of cancers.
RAS作为第一个被确认的癌基因，是突变率最高的致癌基因，在人类癌症中平均占25％。RAS家族中最常见的致癌突变为KRAS(85％)，而NRAS(12％)和HRAS(3％)则较为少见。KRAS突变主要高发于胰腺癌(95％)、结直肠癌(52％)和肺癌(31％)等一系列癌症。KRAS最常见的突变方式为点突变，多发生在p-loop(aa 10～17)中的G12、G13和Switch II区(aa59-76)的Q61，其中以G12突变最为常见(83％)。在非小细胞肺癌(NSCLC)和结直肠癌中，KRAS G12C是最常见的突变之一。As the first oncogene to be confirmed, RAS is the oncogene with the highest mutation rate, accounting for an average of 25% of human cancers. The most common oncogenic mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are relatively rare. KRAS mutations mainly occur in a series of cancers such as pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%). The most common mutation mode of KRAS is point mutation, which mostly occurs in G12, G13 in p-loop (aa 10-17) and Q61 in Switch II region (aa59-76), of which G12 mutation is the most common (83%). KRAS G12C is one of the most common mutations in non-small cell lung cancer (NSCLC) and colorectal cancer.
虽然存在极大的临床需求，但至今没有一个直接靶向KRAS的药物上市，目前临床 治疗KRAS突变的患者一般只能采取化疗。KRAS抑制剂的研发困难主要有两个因素，首先RAS蛋白结构平滑，小分子难以结合到蛋白表面；其次RAS GTP酶对GTP的亲和力高达皮摩尔(pM)级别，且内源性GTP水平高，小分子药物难以阻断二者结合。近期研究发现KRAS 12位甘氨酸(Glycine，Gly)突变为半胱氨酸(Cysteine，Cys)后，构象改变，形成一个新的口袋供小分子共价结合，不可逆的将KRAS G12C锁定在结合GDP的非活化状态。因此KRAS G12C抑制剂有望成为首个直接靶向KRAS的药物。Although there are great clinical needs, there is no drug that directly targets KRAS on the market. Currently, patients with KRAS mutations can only be treated with chemotherapy. The difficulty in the development of KRAS inhibitors is mainly due to two factors. First, the structure of the RAS protein is smooth, and small molecules are difficult to bind to the protein surface; second, the affinity of RAS GTPase for GTP is as high as picomolar (pM) level, and the endogenous GTP level is high. Small molecule drugs are difficult to block the combination of the two. Recent studies have found that after the mutation of Glycine (Gly) at position 12 of KRAS to Cysteine (Cys), the conformation changes, forming a new pocket for covalent binding of small molecules, irreversibly locking KRAS G12C in the binding GDP Inactive state. Therefore, KRAS G12C inhibitors are expected to become the first drugs that directly target KRAS.
目前已有多个KRAS G12C抑制剂进入临床研究阶段，如Amgen公司开发的AMG 510，Wellspring Biosciences公司开发的ARS-3248和Mirati公司开发的MTRX849，目前均处于临床I期研究阶段，但还没有一款开发上市的KRAS G12C抑制剂。其中AMG 510在早期临床中展示了不错的疗效以及很好的安全性，预期未来可以为KRAS G12C突变的癌症患者带来更多的治疗选择。At present, many KRAS G12C inhibitors have entered the clinical research phase, such as AMG 510 developed by Amgen, ARS-3248 developed by Wellspring Biosciences, and MTRX849 developed by Mirati, all of which are currently in clinical phase I research phase, but none of them have KRAS G12C inhibitor developed and marketed. Among them, AMG 510 has shown good efficacy and good safety in early clinical trials, and it is expected to bring more treatment options to cancer patients with KRAS G12C mutations in the future.
KRAS G12C目前没有特异的靶向药，存在较大的临床需求。选择性更高、活性更好、安全性更佳的KRAS G12C抑制剂有治疗多种癌症的潜力，具有广阔的市场前景。KRAS G12C currently has no specific targeted drugs, and there is a large clinical demand. KRAS G12C inhibitors with higher selectivity, better activity and better safety have the potential to treat a variety of cancers and have broad market prospects.
发明内容Summary of the invention
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 PCTCN2020093731-appb-000001
Figure PCTCN2020093731-appb-000001
其中：among them:
X 1选自N或CR 1； X 1 is selected from N or CR 1 ;
X 2选自N或CR 2； X 2 is selected from N or CR 2 ;
L选自键、-(CH 2) n-、-C(R bbR cc) n-、-O(CH 2) n-、-(CH 2) nO-、-S(CH 2) n-、-(CH 2) nS-、-NR bb(CH 2) n-、-NR bb(CH 2) nC(O)-、-CH＝CH(CH 2) n-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-、-(CH 2) nS(O) m-、-(CH 2) nNR bb-或-(CH 2) nNR bbS(O) m-； L is selected from bond, -(CH 2 ) n -, -C(R bb R cc ) n -, -O(CH 2 ) n -, -(CH 2 ) n O-, -S(CH 2 ) n- , -(CH 2 ) n S-, -NR bb (CH 2 ) n -, -NR bb (CH 2 ) n C(O)-, -CH=CH(CH 2 ) n -, -(CH 2 ) n C(O)NR bb -, -(CH 2 ) n C(O)-, -CH=CH(CH 2 ) n NR bb -, -(CH 2 ) n S(O) m -, -(CH 2 ) n NR bb - or- (CH 2 ) n NR bb S(O) m -;
环A选自环烷基、杂环基、芳基或杂芳基；Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aa或-(CH 2) nC(O)R aa，所述的氨基、烷基、烯 基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -, -NH(CH 2 ) n C(O)R aa , -O(CH 2 ) n R aa , -(CH 2 ) n SR aa or -(CH 2 ) n C(O)R aa , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl The group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkane The group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
R 3选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氧代基、硫代基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-O(CH 2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bbR cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR ccR dd、-(CH 2) nR bb、-(CH 2) nSR bb、-(CH 2) nC(O)R bb、-(CH 2) nC(O)OR bb、-(CH 2) nS(O) mR bb、-(CH 2) nNR bbR cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nNR bbC(O)R cc或-(CH 2) nNR bbS(O) mR cc，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂环基任选的可以进一步被取代； R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkane Oxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O(CH 2 ) n R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc , -NR bb (CH 2 ) n NR cc R dd , -CH=CH(CH 2 ) n R bb , -CH=CH(CH 2 ) n NR bb R cc 、-CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)R cc 、-CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)NR cc R dd , -(CH 2 ) n R bb , -(CH 2 ) n SR bb , -(CH 2 ) n C(O)R bb , -(CH 2 ) n C(O)OR bb , -( CH 2 ) n S(O) m R bb , -(CH 2 ) n NR bb R cc , -(CH 2 ) n C(O)NR bb R cc , -(CH 2 ) n NR bb C(O) R cc or -(CH 2 ) n NR bb S(O) m R cc , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxy Alkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heterocyclyl may optionally be further substituted;
R 4选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkane The group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
R 5选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, The heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
R a选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氧代基、硫代基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo group, thioxo group, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy Oxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl , Alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further substituted;
R aa选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷 基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cyano The substituted alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
R bb和R cc各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, and haloalkoxy , Hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkane Oxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
或者，R bb与R cc同相邻的原子形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； Alternatively, R bb and R cc and adjacent atoms form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further replace;
R dd选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted with a group, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy , Hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further substituted;
或者，R cc与R dd同相邻的原子形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； Alternatively, R cc and R dd and adjacent atoms form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further replace;
x为0～6的整数；x is an integer from 0 to 6;
n为0～3的整数；且n is an integer from 0 to 3; and
m为0～2的整数；m is an integer from 0 to 2;
其中，当X 1为N时，X 2为N； Wherein, when X 1 is N, X 2 is N;
或者，当X 1为CR 1，X 2为CR 2。 Or, when X 1 is CR 1 , X 2 is CR 2 .
在本发明一种优选的实施方式中，R 1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-(CH 2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aa或-(CH 2) nC(O)R aa，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基和3-12元杂环基的一个或多个取代基所取代； In a preferred embodiment of the present invention, R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, -(CH 2 ) n -, -NH(CH 2 ) n C(O)R aa , -O( CH 2 ) n R aa , -(CH 2 ) n SR aa or -(CH 2 ) n C(O)R aa , the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2 -6alkynyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3- 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxyl, halogen, amino, C 1-6 alkyl, C 2- 6 -alkenylcarbonyl and 3-12 membered heterocyclic group substituted by one or more substituents;
在本发明进一步优选的实施方式中，R 1选自3-10元杂环基或-(CH 2) nC(O)R aa，所述的3-10元杂环基任选的被氢、羟基、卤素、氨基、C 1-3烷基、C 2-6烯基羰基和3-10元杂环基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 3-10 membered heterocyclic group or -(CH 2 ) n C(O)R aa , said 3-10 membered heterocyclic group is optionally hydrogenated , Hydroxy, halogen, amino, C 1-3 alkyl, C 2-6 alkenyl carbonyl and 3-10 membered heterocyclic group substituted by one or more substituents;
在本发明一种优选的实施方式中，R aa选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷 氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1- 6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代。 In a preferred embodiment of the present invention, Raa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1- 6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, , 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group, optionally substituted by hydrogen, hydroxyl, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl carbonyl , 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb are substituted by one or more substituents.
在本发明进一步优选的实施方式中，R aa选自3-10元杂环基，所述的3-12元杂环基任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代。 In a further preferred embodiment of the present invention, R aa is selected from 3-10 membered heterocyclic group, said 3-12 membered heterocyclic group is optionally substituted by hydrogen, hydroxy, halogen, amino, C 1-6 alkyl , C 2-6 alkenyl carbonyl, 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb or one of Multiple substituents are substituted.
在本发明一种优选的实施方式中，R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基。 In a preferred embodiment of the present invention, R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group.
在本发明进一步优选的实施方式中，R 2选自氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基。 In a further preferred embodiment of the present invention, R 2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
在本发明进一步优选的实施方式中，R 2选自氢、卤素和C 1-3烷基。 In a further preferred embodiment of the present invention, R 2 is selected from hydrogen, halogen and C 1-3 alkyl.
在本发明一种优选的实施方式中，R 3选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-O(CH 2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-CH＝CH(CH 2) nNR bbR cc或-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR ccR dd，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1- 6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基和3-12元杂环基的一个或多个取代基所取代。 In a preferred embodiment of the present invention, R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, oxo group, thio group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, Cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -O(CH 2 ) n R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc , -NR bb (CH 2 ) n NR cc R dd , -CH=CH(CH 2 ) n R bb , -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)R cc , -(CH 2 ) n C(O)NR bb R cc , -(CH 2 ) n C (O) R bb , -CH=CH(CH 2 ) n NR bb R cc or -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)NR cc R dd , the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl Oxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered hetero The aryl group is optionally substituted by one or more substituents of hydrogen, hydroxy, halogen, amino, C 1-6 alkyl and 3-12 membered heterocyclic group.
在本发明进一步优选的实施方式中，R 3选自氢、氨基、C 3-12环烷基、3-12元杂环基、-O(CH 2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc或-NR bb(CH 2) nNR ccR dd，所述C 3-12环烷基和3-12元杂环基任选的被氢、C 1-6烷基和3-12元杂环基中的一个或多个取代基所取代。 In a further preferred embodiment of the present invention, R 3 is selected from hydrogen, amino, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, -O(CH 2 ) n R bb , -(CH 2 ) n C(O)NR bb R cc , -(CH 2 ) n C(O)R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc or -NR bb (CH 2 ) n NR cc R dd , the C 3-12 cycloalkyl group and 3-12 membered heterocyclic group are optionally hydrogen, C 1-6 alkyl group and 3-12 membered heterocyclic group Is substituted by one or more substituents.
在本发明一种优选的实施方式中，R bb和R cc各自独立的氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12 芳基、5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1- 6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基和3-12元杂环基的一个或多个取代基所取代。 In a preferred embodiment of the present invention, R bb and R cc are independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally It is substituted by one or more substituents of hydrogen, hydroxy, halogen, amino, C 1-6 alkyl and 3-12 membered heterocyclic group.
在本发明一种优选的实施方式中，R dd选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、氰基、C 1-6烷基和3-12元杂环基的一个或多个取代基所取代。 In a preferred embodiment of the present invention, R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, deuterated C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyano Alkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, Cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally by hydrogen, hydroxyl, It is substituted by one or more substituents of halogen, amino, cyano, C 1-6 alkyl and 3-12 membered heterocyclic group.
在本发明一种优选的实施方式中，R 4选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基。 In a preferred embodiment of the present invention, R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group.
在本发明进一步优选的实施方式中，R 4选自氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基。 In a further preferred embodiment of the present invention, R 4 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.
在本发明进一步优选的实施方式中，R 4选自选氢、卤素和C 1-3烷基。 In a further preferred embodiment of the present invention, R 4 is selected from hydrogen, halogen and C 1-3 alkyl.
在本发明一种优选的实施方式中，R 5选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的C 1- 6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代。 In a preferred embodiment of the present invention, R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkane groups, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said C 1- 6 alkyl, C C2-6 alkenyl group, C C2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3 -12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group, optionally substituted by hydrogen, hydroxy, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl carbonyl, 3 -12-membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb are substituted by one or more substituents.
在本发明进一步优选的实施方式中，R 5选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 3-8环烷基或3-10元杂环基，所述的C 1-6烷基、C 3-8环烷基或3-10元杂环基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代。 In a further preferred embodiment of the present invention, R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered hetero Cyclic group, the C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic group, optionally substituted by hydrogen, hydroxyl, halogen, amino, C 1-6 alkyl, C 2 -6 alkenylcarbonyl, 3-12 membered heterocyclic group, one or more substitutions of -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb Substituted.
在本发明一种优选的实施方式中，R a选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基或氰基取代的C 1-6烷基，所述的C 1-6烷基、C 2-6烯基、 C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基和氰基取代的C 1-6烷基，任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代。 In a preferred embodiment of the present invention, R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, oxo group, thio group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl C 1-6 alkyl group or cyano group, the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, oxo group, thio group, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl and cyano substituted C 1-6 alkyl, optionally By hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- A 12-membered heterocyclic group, a C 6-12 aryl group, and a 5-12 membered heteroaryl group are substituted by one or more substituents.
在本发明进一步优选的实施方式中，R a选自氢、卤素、氨基、羟基、氧代基、C 1-6烷基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述的氨基、C 1-6烷基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基和C 1-6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 a is selected from hydrogen, halogen, amino, hydroxy, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3 -10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, optionally substituted by one of hydrogen, deuterium, halogen, amino, hydroxyl, cyano and C 1-6 alkyl Multiple substituents are substituted.
在本发明进一步优选的实施方式中，提供一种式(II)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (II), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020093731-appb-000002
Figure PCTCN2020093731-appb-000002
其中：among them:
M 1选自CR 6R 7或NR 6； M 1 is selected from CR 6 R 7 or NR 6 ;
R 6选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-C(O)(CH 2) nCH＝CHR bb或-C(O)CH＝CH(CH 2) nR bb，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； R 6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -C(O)(CH 2 ) n CH=CHR bb or -C(O)CH=CH(CH 2 ) n R bb , the C 1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkane Oxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally by hydrogen, deuterium, Halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
优选3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb，所述的3-12元杂环基任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代 的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； Preferably 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb , said 3-12 membered heterocyclic group Optional by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
R 7选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基；优选氢； R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen;
R b选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基或氰基取代的C 1-6烷基；优选氢、卤素或C 1-3烷基； R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkane Group; preferably hydrogen, halogen or C 1-3 alkyl;
y为0～6的整数。y is an integer of 0-6.
在本发明进一步优选的实施方式中，提供一种式(III)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (III), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020093731-appb-000003
Figure PCTCN2020093731-appb-000003
其中：among them:
M 2选自CR 8R 9或NR 8； M 2 is selected from CR 8 R 9 or NR 8 ;
R 8选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-C(O)(CH 2) nCH＝CHR bb或-C(O)CH＝CH(CH 2) nR bb，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -C(O)(CH 2 ) n CH=CHR bb or -C(O)CH=CH(CH 2 ) n R bb , the C 1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkane Oxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally by hydrogen, deuterium, Halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
优选3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb，所述的3-12元杂环基任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取 代基所取代； Preferably 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb , said 3-12 membered heterocyclic group Optional by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
R 9选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基；优选氢； R 9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen;
R c选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基或氰基取代的C 1-6烷基；优选氢、卤素或C 1-3烷基； R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkane Group; preferably hydrogen, halogen or C 1-3 alkyl;
z为0～6的整数。z is an integer of 0-6.
在本发明进一步优选的实施方式中，提供一种式(IV)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020093731-appb-000004
Figure PCTCN2020093731-appb-000004
在本发明进一步优选的实施方式中，提供一种式(V)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (V), its stereoisomer or its pharmaceutically acceptable salt, the specific structure of which is as follows:
Figure PCTCN2020093731-appb-000005
Figure PCTCN2020093731-appb-000005
其中：among them:
L 2选自键、-O(CH 2) n-、-OC(R bbR cc) n(CH 2) m-、-NR bb(CH 2) n-、-NR bb(CH 2) nNR cc-、-CH＝CH(CH 2) n-或-CH＝CH(CH 2) nNR bb(CH 2) mC(O)-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-或-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR cc-； L 2 is selected from bond, -O(CH 2 ) n -, -OC(R bb R cc ) n (CH 2 ) m -, -NR bb (CH 2 ) n -, -NR bb (CH 2 ) n NR cc -, -CH=CH(CH 2 ) n -or -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)-, -(CH 2 ) n C(O)NR bb -, -(CH 2 ) n C(O)-, -CH=CH(CH 2 ) n NR bb -or -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)NR cc -;
环B选自C 3-12环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基；优选3-12元杂环基、C 6-12芳基和5-12元杂芳基； Ring B is selected from C 3-12 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group; preferably 3-12 membered heterocyclic group, C 6-12 aryl group And 5-12 membered heteroaryl groups;
R d选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、 C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1- 6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基任选被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aromatic Substituted by one or more substituents in the 5-12 membered heteroaryl group;
t为0～6的整数。t is an integer of 0-6.
在本发明进一步优选的实施方式中，提供一种式(VI)化合物、其立体异构体或其药学上可接受盐，其具体结构如下：In a further preferred embodiment of the present invention, there is provided a compound of formula (VI), its stereoisomer or pharmaceutically acceptable salt thereof, the specific structure of which is as follows:
Figure PCTCN2020093731-appb-000006
Figure PCTCN2020093731-appb-000006
其中：among them:
R 2选自氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； R 2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
优选氢、氟、氯、溴、羟基、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基； Preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
更优选氟或羟基；More preferably fluorine or hydroxyl;
R 3选自氢、氨基、C 3-12环烷基、3-12元杂环基、-O(CH 2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-N＝CR bb(CH 2) nNR ccR dd、-NR bbC(O)(CH 2) nR cc、-NR bb(CH 2) nR cc或-NR bb(CH 2) nNR ccR dd，所述C 3-12环烷基和3-12元杂环基任选的被氢、C 1- 6烷基和3-12元杂环基中的一个或多个取代基所取代； R 3 is selected from hydrogen, amino, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, -O(CH 2 ) n R bb , -(CH 2 ) n C(O)NR bb R cc ,- (CH 2 ) n C(O)R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -N=CR bb (CH 2 ) n NR cc R dd , -NR bb C(O )(CH 2 ) n R cc , -NR bb (CH 2 ) n R cc or -NR bb (CH 2 ) n NR cc R dd , the C 3-12 cycloalkyl group and 3-12 membered heterocyclic group are optionally hydrogen, C 1- 6 alkyl, and 3-12 membered heterocyclic group with one or more substituents;
优选-N＝CHNR ccR dd、-NR bbC(O)R cc、-NR bb(CH 2) nR cc或-NH b(CH 2) nNR ccR dd； Preferably -N=CHNR cc R dd , -NR bb C(O)R cc , -NR bb (CH 2 ) n R cc or -NH b (CH 2 ) n NR cc R dd ;
更优选
Figure PCTCN2020093731-appb-000007
Figure PCTCN2020093731-appb-000008
More preferred
Figure PCTCN2020093731-appb-000007
Figure PCTCN2020093731-appb-000008
R 10选自氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； R 10 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
优选氢、卤素、羟基、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基； Preferably hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
更优选氢或甲基；More preferably hydrogen or methyl;
R 11选自氢、卤素、氨基、羟基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基和C 1-6烷基中的一个或多个取代基所取代； R 11 is selected from hydrogen, halogen, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 Membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3 -8 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano and C 1-6 One or more substituents in the alkyl group;
优选氢、氨基、羟基或C 1-3烷氧基； Preferably hydrogen, amino, hydroxyl or C 1-3 alkoxy;
更优选氢、氨基、羟基或甲氧基；More preferably hydrogen, amino, hydroxyl or methoxy;
R bb和R cc各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、氰基、C 1-6烷基烷基氨基酰基、氨基酰基、和3-12元杂环基的一个或多个取代基所取代； R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxyl, halogen, amino, cyanide Group, C 1-6 alkylalkylaminoacyl, aminoacyl, and 3-12 membered heterocyclic group substituted by one or more substituents;
R dd选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1- 6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 1-6烷基烷基氨基酰基、氨基酰基、和3-12元杂环基的一个或多个取代基所取代；且 R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Substituted with one or more substituents of alkyl, C 1-6 alkylalkylaminoacyl, aminoacyl, and 3-12 membered heterocyclic group; and
m和n为0～3的整数。m and n are integers of 0-3.
在本发明一种优选的实施方式中，环A选自C 6-10芳基和5-12元杂芳基，其中5-12元杂芳基优选含有1-3个氮原子的杂芳基，包括5-7元含氮杂芳基、苯并5-7元含氮杂芳基或5-7元含氮杂芳基并苯基，更优选以下基团： In a preferred embodiment of the present invention, ring A is selected from C 6-10 aryl groups and 5-12 membered heteroaryl groups, among which 5-12 membered heteroaryl groups are preferably heteroaryl groups containing 1-3 nitrogen atoms , Including 5-7 membered nitrogen-containing heteroaryl group, benzo 5-7 membered nitrogen-containing heteroaryl group or 5-7 membered nitrogen-containing heteroaryl phenyl group, more preferably the following groups:
Figure PCTCN2020093731-appb-000009
Figure PCTCN2020093731-appb-000009
在本发明一种优选的实施方式中，环B选自含有1-3个氮原子的5-12元杂环基，更优选如下基团：In a preferred embodiment of the present invention, ring B is selected from 5-12 membered heterocyclic groups containing 1-3 nitrogen atoms, more preferably the following groups:
Figure PCTCN2020093731-appb-000010
Figure PCTCN2020093731-appb-000010
本发明提供一种通式(VII)所示的化合物、其立体异构体或其药学上可接受盐：The present invention provides a compound represented by general formula (VII), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020093731-appb-000011
Figure PCTCN2020093731-appb-000011
环C选自苯基、吡啶基、5-7元含氮杂芳基、苯并5-7元含氮杂芳基或5-7元含氮杂芳基并苯基，进一步优选选自以下基团：Ring C is selected from phenyl, pyridyl, 5-7 membered nitrogen-containing heteroaryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroaryl phenyl, and is more preferably selected from the following Group:
Figure PCTCN2020093731-appb-000012
Figure PCTCN2020093731-appb-000012
R 12选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基； R 12 is selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
优选氢、氟、氯、甲基、乙基、丙基、甲氧基或乙氧基；Preferably hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy;
R e选自氢、卤素、羟基、氨基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟烷基、 C 3-8环烷基或3-8元杂环基； R e is selected from hydrogen, halogen, hydroxyl, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
优选氢、氟、氯、羟基、氨基或甲基；Preferably hydrogen, fluorine, chlorine, hydroxyl, amino or methyl;
p为0～4的整数。p is an integer of 0-4.
本发明提供一种通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：The present invention provides a compound represented by general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020093731-appb-000013
Figure PCTCN2020093731-appb-000013
其中：among them:
X 3选自CH 2、CH、N或NR 13； X 3 is selected from CH 2 , CH, N or NR 13 ;
X 4选自CH 2、C＝O、N或CR 14； X 4 is selected from CH 2 , C=O, N or CR 14 ;
M选自N或CH；M is selected from N or CH;
L 3选自-O-或-OCH 2-； L 3 is selected from -O- or -OCH 2 -;
L 4选自-O-或-CH 2-； L 4 is selected from -O- or -CH 2 -;
R 13选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基； R 13 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
优选甲基或环丙基；Preferably methyl or cyclopropyl;
R 14选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基； R 14 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
优选氢或甲基；Preferably hydrogen or methyl;
R选自3-8元含氮杂环基或苯并3-8元含氮杂环基，进一步优选5-7元含氮杂环基或苯并5-7元含氮杂环基，其中氮原子的个数为1-2个，任选的被卤素或C 1-3烷基中的一个或多个取代基所取代， R is selected from 3-8 membered nitrogen-containing heterocyclic group or benzo 3-8 membered nitrogen-containing heterocyclic group, more preferably 5-7 membered nitrogen-containing heterocyclic group or benzo 5-7 membered nitrogen-containing heterocyclic group, wherein The number of nitrogen atoms is 1-2, optionally substituted by halogen or one or more substituents in C 1-3 alkyl,
优选以下取代基：The following substituents are preferred:
Figure PCTCN2020093731-appb-000014
Figure PCTCN2020093731-appb-000014
Figure PCTCN2020093731-appb-000015
Figure PCTCN2020093731-appb-000015
R 15选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基；优选氢或氟。 R 15 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group; preferably hydrogen or fluorine.
本发明提供一种通式(IX)所示的化合物、其立体异构体或其药学上可接受盐：The present invention provides a compound represented by general formula (IX), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020093731-appb-000016
Figure PCTCN2020093731-appb-000016
其中：among them:
环D选自如下基团：Ring D is selected from the following groups:
Figure PCTCN2020093731-appb-000017
Figure PCTCN2020093731-appb-000017
在本发明最优选的实施方式中，包括以下具体化合物：In the most preferred embodiment of the present invention, the following specific compounds are included:
Figure PCTCN2020093731-appb-000018
Figure PCTCN2020093731-appb-000018
Figure PCTCN2020093731-appb-000019
Figure PCTCN2020093731-appb-000019
Figure PCTCN2020093731-appb-000020
Figure PCTCN2020093731-appb-000020
Figure PCTCN2020093731-appb-000021
Figure PCTCN2020093731-appb-000021
Figure PCTCN2020093731-appb-000022
Figure PCTCN2020093731-appb-000022
Figure PCTCN2020093731-appb-000023
Figure PCTCN2020093731-appb-000023
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通式(I)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 comprises a therapeutically effective dose of the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof and a One or more pharmaceutically acceptable carriers, diluents or excipients.
本发明进一步涉及任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药用组合物在制备KRAS G12C抑制剂药物中的应用。The present invention further relates to the application of any one of the compounds of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the preparation of KRAS G12C inhibitor drugs.
本发明还提供了一种优选方案，还涉及所述的通式(I)化合物、及其立体异构体或其药学上可接受的盐，或所述的药用组合物在治疗预防和/或治疗预制备治疗由KRAS G12C抑制剂介导的病症的方法，该方法包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药用组合物。The present invention also provides a preferred solution, and also relates to the compound of general formula (I), and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in the treatment, prevention and/ Or a method for pre-prepared therapy to treat a condition mediated by a KRAS G12C inhibitor, the method comprising administering to the patient a therapeutically effective dose of a compound represented by general formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, Or its pharmaceutical composition.
在一些实施例中，本发明的化合物和组合物可用于治疗在制备治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、食道癌、头颈部肿瘤、胃癌、肺癌及其结肠癌等疾病或病症中的用途。In some embodiments, the compounds and compositions of the present invention can be used to treat Noonan’s syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, and gastric cancer. , Lung cancer and colon cancer and other diseases or diseases.
本发明的化合物和组合物可用于治疗在制备治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、食道癌、头颈部肿瘤、肺癌及其结肠癌等疾病或病症中的方法。The compounds and compositions of the present invention can be used to treat diseases such as Noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer. Or the method in the disease.
在一些实施例中，本发明提供一种治疗癌症病症的方法，其包含将本发明的化合物或组合物给予患有癌症病症的患者。In some embodiments, the present invention provides a method of treating a cancer condition, which comprises administering a compound or composition of the present invention to a patient suffering from a cancer condition.
在一些实施例中，由本发明的化合物或组合物治疗的癌症为努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、食道癌、头颈部肿瘤、胃癌、肺癌及其结肠癌；优选非小细胞肺癌、结肠癌、食管癌、头颈部肿瘤。In some embodiments, the cancer treated by the compound or composition of the present invention is Noonan’s syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck cancer, stomach cancer, lung cancer And its colon cancer; preferably non-small cell lung cancer, colon cancer, esophageal cancer, head and neck cancer.
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 of 1 to 3 carbon atoms is most preferred. 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 are lower alkyl groups 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 point of attachment. 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, 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3元/6元、3元/5元、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, which may contain one or more double bonds, but none of the rings have complete conjugate 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 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 3-membered/6-membered, 3-membered/5-membered, 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 PCTCN2020093731-appb-000024
等；
Figure PCTCN2020093731-appb-000024
Wait;
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 and a heterocycloalkyl share a spiro atom. Non-limiting examples include:
Figure PCTCN2020093731-appb-000025
等。
Figure PCTCN2020093731-appb-000025
Wait.
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 PCTCN2020093731-appb-000026
等。
Figure PCTCN2020093731-appb-000026
Wait.
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, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2020093731-appb-000027
Figure PCTCN2020093731-appb-000027
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、吖庚基、1,4-二氮杂环庚基、吡喃基等，优选吡咯烷基、吗啉基、哌啶基、吖庚基、1,4-二氮杂环庚基和哌嗪基。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, azepyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, Piperidinyl, azepanyl, 1,4-diazepanyl 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3元/5元、3元/6元、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 3-membered/5-membered, 3-membered/6-membered, 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 PCTCN2020093731-appb-000028
Figure PCTCN2020093731-appb-000028
Figure PCTCN2020093731-appb-000029
等。
Figure PCTCN2020093731-appb-000029
Wait.
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 PCTCN2020093731-appb-000030
Figure PCTCN2020093731-appb-000030
Figure PCTCN2020093731-appb-000031
等。
Figure PCTCN2020093731-appb-000031
Wait.
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 PCTCN2020093731-appb-000032
Figure PCTCN2020093731-appb-000032
Figure PCTCN2020093731-appb-000033
等。
Figure PCTCN2020093731-appb-000033
Wait.
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 of which include:
Figure PCTCN2020093731-appb-000034
等。
Figure PCTCN2020093731-appb-000034
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12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5-10元杂芳基、苯并3-8元环烷基和苯并3-8元杂烷基，优选苯并5-6元杂芳基、苯并3-6元环烷基和苯并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 12 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 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group containing a sulfur atom; or 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 PCTCN2020093731-appb-000035
Figure PCTCN2020093731-appb-000035
Figure PCTCN2020093731-appb-000036
等。
Figure PCTCN2020093731-appb-000036
Wait.
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12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、噁唑基、嘧啶基或噻唑基；更有选吡唑基、吡咯基和噁唑基。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 12 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, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrole And oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2020093731-appb-000037
Figure PCTCN2020093731-appb-000037
Figure PCTCN2020093731-appb-000038
等。
Figure PCTCN2020093731-appb-000038
Wait.
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。Heteroaryl 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, 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 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, wherein the alkyl group 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, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
术语“烯基羰基”指-C(O)-(烯基)，其中烯基的定义如上所述。烯基羰基的非限制性实例包括：乙烯基羰基、丙烯基羰基、丁烯基羰基。烯基羰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 "alkenylcarbonyl" refers to -C(O)-(alkenyl), where alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. The alkenylcarbonyl 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.
“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 .
“羰基”指-C(O)-。"Carbonyl" refers to -C(O)-.
“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" refers to 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”指乙腈。"MeCN" means acetonitrile.
“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, that means 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 a deuterium atom.
“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 need not 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.
“药用组合物”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, as well as 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 C 18 150×4.6mm色谱柱)。 The liquid mass spectrometry LC-MS was measured with 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 C 18 150×4.6mm 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 dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.
实施例1Example 1
1-(4-(6-氯-2,2'-二氟-6'-羟基-3-(甲基氨基)-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮的制备1-(4-(6-Chloro-2,2'-difluoro-6'-hydroxy-3-(methylamino)-[1,1'-biphenyl]-4-carbonyl)piperazine-1 -Based) Preparation of prop-2-en-1-one
Figure PCTCN2020093731-appb-000039
Figure PCTCN2020093731-appb-000039
第一步：2-氨基-4-溴-5-氯-3-氟苯甲酸的制备Step 1: Preparation of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid
Figure PCTCN2020093731-appb-000040
Figure PCTCN2020093731-appb-000040
将2-氨基-4-溴-3-氟苯甲酸(10g，43mmol)溶于DMF中(100mL)，加入NCS(5.7g，43mmol)，氮气保护下，70℃搅拌15小时。冷却，倒入冰水中，析出固体，过滤，滤饼水洗，干燥得到目标产物2-氨基-4-溴-5-氯-3-氟苯甲酸(9.3g，产率：82％)。Dissolve 2-amino-4-bromo-3-fluorobenzoic acid (10 g, 43 mmol) in DMF (100 mL), add NCS (5.7 g, 43 mmol), and stir at 70°C for 15 hours under nitrogen protection. Cool, pour into ice water, precipitate solids, filter, wash the filter cake with water, and dry to obtain the target product 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (9.3 g, yield: 82%).
MS m/z(ESI):266.1[M-H] +,268.1[M-H+2] +. MS m/z(ESI): 266.1[MH] + ,268.1[M-H+2] + .
第二步：4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-羧酸叔丁酯的制备Step 2: Preparation of 4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2020093731-appb-000041
Figure PCTCN2020093731-appb-000041
将2-氨基-4-溴-5-氯-3-氟苯甲酸(9.0g，33.7mmol)溶于DMF(100mL)中，加入DIPEA(8.7g，67.4mmol)和HATU(15.4g，40.4mmol)，室温搅拌0.5小时。加入叔-丁基哌嗪-1-羧酸酯(12.5g，67.4mmol)，继续搅拌5小时。加入水，用二氯甲烷萃取(3*50mL)，水洗(20mL)，饱和食盐水(20mL)洗。有机层用无水硫酸钠干燥，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化目标产物4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-羧酸叔丁酯(11.5g，产率：78％)。 Dissolve 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (9.0g, 33.7mmol) in DMF (100mL), add DIPEA (8.7g, 67.4mmol) and HATU (15.4g, 40.4mmol) ), stirring at room temperature for 0.5 hours. Add tert-butylpiperazine-1-carboxylate (12.5 g, 67.4 mmol) and continue stirring for 5 hours. Add water, extract with dichloromethane (3*50mL), wash with water (20mL), and wash with saturated brine (20mL). The organic layer was dried with anhydrous sodium sulfate, concentrated, and the target product 4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl) was purified by column chromatography (CH 2 Cl 2 /MeOH=10:1) ) Tert-butyl piperazine-1-carboxylate (11.5 g, yield: 78%).
MS m/z(ESI):436.1[M+H] +,438.1[M+H+2] +. MS m/z(ESI): 436.1[M+H] + ,438.1[M+H+2] + .
第三步：(2-氨基-4-溴-5-氯-3-氟苯基)(哌嗪-1-基)甲酮的制备The third step: Preparation of (2-amino-4-bromo-5-chloro-3-fluorophenyl)(piperazin-1-yl)methanone
Figure PCTCN2020093731-appb-000042
Figure PCTCN2020093731-appb-000042
将4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-羧酸叔丁酯(11.2g，25.7mmol)溶于二氯甲烷(50mL)中，加入TFA(10mL，136mmol)，室温搅拌2小时。浓缩，加入水和饱和NaHCO 3水溶液调节至中性，二氯甲烷(3*50mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到目标产物(2-氨基-4-溴-5-氯-3-氟苯基)(哌嗪-1-基)甲酮(8.7g，粗品)。 4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (11.2g, 25.7mmol) was dissolved in dichloromethane (50mL), Add TFA (10 mL, 136 mmol) and stir at room temperature for 2 hours. Concentrate, add water and saturated aqueous NaHCO 3 to adjust to neutrality, and extract with dichloromethane (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the target product (2-amino-4-bromo-5-chloro-3-fluorophenyl)(piperazin-1-yl)methanone (8.7 g, crude product).
MS m/z(ESI):336.1[M+H] +,338.1[M+H+2] +. MS m/z(ESI): 336.1[M+H] + ,338.1[M+H+2] + .
第四步：1-(4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-基)丙-2-烯-1-酮的制备The fourth step: preparation of 1-(4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000043
Figure PCTCN2020093731-appb-000043
将(2-氨基-4-溴-5-氯-3-氟苯基)(哌嗪-1-基)甲酮(8.7g，25.7mmol)溶于二氯甲烷(100mL)中，加入DIPEA(9.9g，76.7mmol)，冰水浴下滴加丙烯酰氯(2.3g，25.7mmol)，加完 继续搅拌1小时。加水淬灭，二氯甲烷(30mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(7.3g，两步产率：73％)。 (2-Amino-4-bromo-5-chloro-3-fluorophenyl)(piperazin-1-yl)methanone (8.7g, 25.7mmol) was dissolved in dichloromethane (100mL), and DIPEA ( 9.9 g, 76.7 mmol), acryloyl chloride (2.3 g, 25.7 mmol) was added dropwise under an ice water bath, and stirring was continued for 1 hour after the addition. It was quenched with water and extracted three times with dichloromethane (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(2-amino-4-bromo-5-chloro) -3-Fluorobenzoyl)piperazin-1-yl)prop-2-en-1-one (7.3 g, two-step yield: 73%).
MS m/z(ESI):390.1[M+H] +,392.1[M+H+2] +. MS m/z(ESI): 390.1[M+H] + ,392.1[M+H+2] + .
第五步：1-(4-(4-溴-5-氯-3-氟-2-(甲基氨基)苯甲酰)哌嗪-1-基)丙-2-烯-1-酮的制备The fifth step: 1-(4-(4-bromo-5-chloro-3-fluoro-2-(methylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one preparation
Figure PCTCN2020093731-appb-000044
Figure PCTCN2020093731-appb-000044
将1-(4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(1g，2.6mmol)溶于DMF(30mL)中，0℃条件下，加入NaH(123mg，3.1mmol)，搅拌0.5小时，滴加入碘甲烷(364mg，2.6mmol)的DMF(5mL)溶液，升至室温，搅拌1小时。加入水和二氯甲烷(3*30mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(4-溴-5-氯-3-氟-2-(甲基氨基)苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(230mg，产率：23％)。 Dissolve 1-(4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazin-1-yl)prop-2-en-1-one (1g, 2.6mmol) Add NaH (123 mg, 3.1 mmol) to DMF (30 mL) at 0°C, stir for 0.5 hour, add dropwise a solution of methyl iodide (364 mg, 2.6 mmol) in DMF (5 mL), warm to room temperature, and stir for 1 hour. Add water and dichloromethane (3*30 mL) for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(4-bromo-5-chloro-3-fluoro -2-(methylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one (230 mg, yield: 23%).
MS m/z(ESI):404.1[M+H] +,406.1[M+H+2] +. MS m/z(ESI): 404.1[M+H] + ,406.1[M+H+2] + .
第六步：1-(4-(6-氯-2,2'-二氟-6'-甲氧基-3-(甲基氨基)-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮的制备The sixth step: 1-(4-(6-chloro-2,2'-difluoro-6'-methoxy-3-(methylamino)-[1,1'-biphenyl]-4- (Carbonyl) piperazin-1-yl) prop-2-en-1-one preparation
Figure PCTCN2020093731-appb-000045
Figure PCTCN2020093731-appb-000045
1-(4-(4-溴-5-氯-3-氟-2-(甲基氨基)苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(200mg，0.5mmol)溶于二氧六环(20mL)中，加入2-氟-6-甲氧基苯硼酸(127mg，0.75mmol)、三(二亚苄基丙酮)二钯(92mg，0.1mmol)、Xantphos(116mg，0.2mmol)以及Cs 2CO 3(492mg，1.5mmol)，氮气置换。将反应液加热至110℃反应过夜。冷却至室温后，加入水和二氯甲烷(3*20mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化 得到目标产物1-(4-(6-氯-2,2'-二氟-6'-甲氧基-3-(甲基氨基)-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮(120mg，产率：54％)。 1-(4-(4-Bromo-5-chloro-3-fluoro-2-(methylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one (200mg, 0.5mmol ) Was dissolved in dioxane (20mL), and 2-fluoro-6-methoxyphenylboronic acid (127mg, 0.75mmol), tris(dibenzylideneacetone) dipalladium (92mg, 0.1mmol), Xantphos ( 116 mg, 0.2 mmol) and Cs 2 CO 3 (492 mg, 1.5 mmol), replaced with nitrogen. The reaction solution was heated to 110°C for overnight reaction. After cooling to room temperature, water and dichloromethane (3*20 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(6-chloro-2,2'-difluoro -6'-Methoxy-3-(methylamino)-[1,1'-biphenyl]-4-carbonyl)piperazin-1-yl)prop-2-en-1-one (120mg, Yield: 54%).
MS m/z(ESI):450.1[M+H] +,452.1[M+H+2] +. MS m/z(ESI): 450.1[M+H] + ,452.1[M+H+2] + .
第七步：1-(4-(6-氯-2,2'-二氟-6'-羟基-3-(甲基氨基)-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮的制备The seventh step: 1-(4-(6-chloro-2,2'-difluoro-6'-hydroxy-3-(methylamino)-[1,1'-biphenyl]-4-carbonyl) Preparation of piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000046
Figure PCTCN2020093731-appb-000046
将1-(4-(6-氯-2,2'-二氟-6'-甲氧基-3-(甲基氨基)-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮(100mg，0.22mmol)溶于二氯甲烷(10mL)中，冷却到-40℃，滴加入BBr 3(550mg，2.20mmol)，升至室温搅拌1小时。用饱和NaHCO 3水溶液淬灭，二氯甲烷(3*20mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标产物1-(4-(6-氯-2,2'-二氟-6'-羟基-3-(甲基氨基)-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮(47mg，产率：48％)。 Add 1-(4-(6-chloro-2,2'-difluoro-6'-methoxy-3-(methylamino)-[1,1'-biphenyl]-4-carbonyl)piper (Azin-1-yl)prop-2-en-1-one (100mg, 0.22mmol) was dissolved in dichloromethane (10mL), cooled to -40°C, BBr 3 (550mg, 2.20mmol) was added dropwise to Stir at room temperature for 1 hour. It was quenched with saturated aqueous NaHCO 3 and extracted with dichloromethane (3*20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by preparative HPLC to obtain the target product 1-(4-(6-chloro-2,2'-difluoro-6'-hydroxy-3-(methylamino) -[1,1'-Biphenyl]-4-carbonyl)piperazin-1-yl)prop-2-en-1-one (47 mg, yield: 48%).
MS m/z(ESI):436.1[M+H] +,438.1[M+H+2] +. MS m/z(ESI): 436.1[M+H] + ,438.1[M+H+2] + .
实施例2Example 2
1-(4-(6-氯-3-(二甲基氨基)-2,2'-二氟-6'-羟基--[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮的制备1-(4-(6-Chloro-3-(dimethylamino)-2,2'-difluoro-6'-hydroxy--[1,1'-biphenyl]-4-carbonyl)piperazine -1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000047
Figure PCTCN2020093731-appb-000047
第一步：1-(4-(4-溴-5-氯-3-氟-2-(二甲基氨基)苯甲酰)哌嗪-1-基)丙-2-烯-1-酮的制备The first step: 1-(4-(4-bromo-5-chloro-3-fluoro-2-(dimethylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one Preparation
Figure PCTCN2020093731-appb-000048
Figure PCTCN2020093731-appb-000048
将1-(4-(2-氨基-4-溴-5-氯-3-氟苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(1g，2.6mmol)溶于DMF(30mL)中，0℃条件下，加入NaH(123mg，7.8mmol)，搅拌0.5小时，滴加入碘甲烷(364mg，7.8mmol)的DMF(5mL)溶液，升至室温，搅拌1小时。加入水和二氯甲烷(3*30mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(4-溴-5-氯-3-氟-2-(甲基氨基)苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(420mg，产率：13％)。 Dissolve 1-(4-(2-amino-4-bromo-5-chloro-3-fluorobenzoyl)piperazin-1-yl)prop-2-en-1-one (1g, 2.6mmol) Add NaH (123 mg, 7.8 mmol) to DMF (30 mL) at 0°C, stir for 0.5 hour, add dropwise a solution of methyl iodide (364 mg, 7.8 mmol) in DMF (5 mL), warm to room temperature, and stir for 1 hour. Add water and dichloromethane (3*30 mL) for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(4-bromo-5-chloro-3-fluoro -2-(Methylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one (420 mg, yield: 13%).
MS m/z(ESI):418.1[M+H] +,419.1[M+H+2] +. MS m/z(ESI): 418.1[M+H] + ,419.1[M+H+2] + .
第二步：将1-(4-(6-氯-3-(二甲基氨基)-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮的制备Step 2: Add 1-(4-(6-chloro-3-(dimethylamino)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]- Preparation of 4-carbonyl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000049
Figure PCTCN2020093731-appb-000049
1-(4-(4-溴-5-氯-3-氟-2-(二甲基氨基)苯甲酰)哌嗪-1-基)丙-2-烯-1-酮(209mg，0.5mmol)溶于二氧六环(20mL)中，加入2-氟-6-甲氧基苯硼酸(127mg，0.75mmol)、三(二亚苄基丙酮)二钯(92mg，0.1mmol)、Xantphos(116mg，0.2mmol)以及Cs 2CO 3(492mg，1.5mmol)，氮气置换。将反应液加热至110℃反应过夜。冷却至室温后，加入水和二氯甲烷(3*20mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物将1-(4-(6-氯-3-(二甲基氨基)-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮(100mg，产率：43％)。 1-(4-(4-Bromo-5-chloro-3-fluoro-2-(dimethylamino)benzoyl)piperazin-1-yl)prop-2-en-1-one (209mg, 0.5 mmol) was dissolved in dioxane (20mL), and 2-fluoro-6-methoxyphenylboronic acid (127mg, 0.75mmol), tris(dibenzylideneacetone)dipalladium (92mg, 0.1mmol), Xantphos (116 mg, 0.2 mmol) and Cs 2 CO 3 (492 mg, 1.5 mmol), replaced with nitrogen. The reaction solution was heated to 110°C for overnight reaction. After cooling to room temperature, water and dichloromethane (3*20 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product. 1-(4-(6-chloro-3-(dimethyl Amino)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-4-carbonyl)piperazin-1-yl)prop-2-en-1-one ( 100mg, yield: 43%).
MS m/z(ESI):464.1[M+H] +. MS m/z(ESI): 464.1[M+H] + .
第三步：1-(4-(6-氯-3-(二甲基氨基)-2,2'-二氟-6'-羟基--[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮的制备The third step: 1-(4-(6-chloro-3-(dimethylamino)-2,2'-difluoro-6'-hydroxy--[1,1'-biphenyl]-4- (Carbonyl) piperazin-1-yl) prop-2-en-1-one preparation
Figure PCTCN2020093731-appb-000050
Figure PCTCN2020093731-appb-000050
将1-(4-(6-氯-3-(二甲基氨基)-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮(100mg，0.22mmol)溶于二氯甲烷(10mL)中，冷却到-40℃，滴加入BBr 3(550mg，2.20mmol)，升至室温搅拌1小时。用饱和NaHCO 3水溶液淬灭，二氯甲烷(3*20mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标产物1-(4-(6-氯-3-(二甲基氨基)-2,2'-二氟-6'-羟基--[1,1'-联苯基]-4-羰基)哌嗪-1-基)丙-2-烯-1-酮(29mg，产率：29％)。 Add 1-(4-(6-chloro-3-(dimethylamino)-2,2'-difluoro-6'-methoxy-[1,1'-biphenyl]-4-carbonyl) Piperazin-1-yl)prop-2-en-1-one (100mg, 0.22mmol) was dissolved in dichloromethane (10mL), cooled to -40°C, and BBr 3 (550mg, 2.20mmol) was added dropwise. Stir at room temperature for 1 hour. It was quenched with saturated aqueous NaHCO 3 and extracted with dichloromethane (3*20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain the target product 1-(4-(6-chloro-3-(dimethylamino)-2,2'-difluoro-6'- Hydroxy—[1,1'-biphenyl]-4-carbonyl)piperazin-1-yl)prop-2-en-1-one (29 mg, yield: 29%).
MS m/z(ESI):450.1[M+H] +. MS m/z(ESI): 450.1[M+H] + .
1H NMR(400MHz,Chloroform)δ7.72(s,1H),7.37(s,1H),6.94(s,1H),6.74(s,1H),6.17(s,1H),6.00(s,1H),5.53(s,1H),4.85(s,1H),3.59(s,4H),3.39(s,4H),3.00(s,6H). 1 H NMR (400MHz, Chloroform) δ 7.72 (s, 1H), 7.37 (s, 1H), 6.94 (s, 1H), 6.74 (s, 1H), 6.17 (s, 1H), 6.00 (s, 1H) ), 5.53(s, 1H), 4.85(s, 1H), 3.59(s, 4H), 3.39(s, 4H), 3.00(s, 6H).
实施例3～10的制备参照实施例1路线。The preparation of Examples 3-10 refers to the route of Example 1.
实施例11Example 11
(S)-1-(4-(6-(8-羟基萘-2-基)-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备(S)-1-(4-(6-(8-hydroxynaphthalen-2-yl)-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4 -Yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000051
Figure PCTCN2020093731-appb-000051
第一步：4-(2-氯-5-甲基嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备Step 1: Preparation of 4-(2-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2020093731-appb-000052
Figure PCTCN2020093731-appb-000052
将2,4-二氯-5-甲基嘧啶(10g，61.7mmol)溶于DMF(100mL)中，加入哌嗪-1-羧酸叔丁酯(13.7g，74.1mmol)，DIPEA(23.9g，185mmol)，氮气保护下，加热到80℃，搅拌5小时。冷却，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(EtOAc/Petro ether＝1：10)纯化得到目标产物4-(2-氯-5-甲基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(15.8g，产率：82％)。Dissolve 2,4-dichloro-5-methylpyrimidine (10g, 61.7mmol) in DMF (100mL), add piperazine-1-carboxylic acid tert-butyl ester (13.7g, 74.1mmol), DIPEA (23.9g , 185mmol), under the protection of nitrogen, heat to 80°C and stir for 5 hours. Cool, add water and ethyl acetate (3*50mL) for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EtOAc/Petroether=1:10) to obtain the target product 4-(2-chloro-5-methylpyrimidin-4-yl)piperazine Tert-Butyl-1-carboxylate (15.8 g, yield: 82%).
MS m/z(ESI):313.1[M+H] +,315.1[M+H+2] +. MS m/z(ESI): 313.1[M+H] + ,315.1[M+H+2] + .
第二步：(S)-4-(5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备The second step: (S)-4-(5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl Preparation of ester
Figure PCTCN2020093731-appb-000053
Figure PCTCN2020093731-appb-000053
将4-(2-氯-5-甲基嘧啶-4-基)哌嗪-1-羧酸叔丁酯(5g，16.0mmol)溶于THF(100mL)中，加入(S)-(1-甲基吡咯烷-2-基)甲醇(3.7g，32.2mmol)和叔丁醇钠(4.6g，48.0mmol)，氮气保护下，室温搅拌5小时。加水淬灭，乙酸乙酯(30mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物(S)-4-(5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(4.6g，产率：73％)。 4-(2-Chloro-5-methylpyrimidin-4-yl)tert-butyl piperazine-1-carboxylate (5g, 16.0mmol) was dissolved in THF (100mL), and (S)-(1- Methylpyrrolidin-2-yl)methanol (3.7g, 32.2mmol) and sodium tert-butoxide (4.6g, 48.0mmol) were stirred at room temperature for 5 hours under nitrogen protection. It was quenched with water, and extracted with ethyl acetate (30 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product (S)-4-(5-methyl-2-((1 -Methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)tert-butyl piperazine-1-carboxylate (4.6 g, yield: 73%).
MS m/z(ESI):392.1[M+H] +. MS m/z(ESI): 392.1[M+H] + .
第三步：(S)-4-(6-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯的制备The third step: (S)-4-(6-bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1- Preparation of tert-butyl carboxylate
Figure PCTCN2020093731-appb-000054
Figure PCTCN2020093731-appb-000054
将(S)-4-(5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(3.9g，10mmol)溶于MeOH/H 2O(50mL/50mL)中，加入NaHCO 3(1.2g，14mmol)，室温下滴加入液溴(3.0g，18.7mmol)，滴完搅拌1小时。再加入NaHCO 3(2.4g，28mmol)，继续搅拌3小时。乙酸乙酯(3*30mL)萃取，合并有机层，用水洗，饱和食盐水洗。无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物(S)-4-(6-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1.6g，产率：34％)。 Add (S)-4-(5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (3.9 g, 10 mmol) was dissolved in MeOH/H 2 O (50 mL/50 mL), NaHCO 3 (1.2 g, 14 mmol) was added, liquid bromine (3.0 g, 18.7 mmol) was added dropwise at room temperature, and stirring was completed for 1 hour. Then NaHCO 3 (2.4 g, 28 mmol) was added, and stirring was continued for 3 hours. Extract with ethyl acetate (3*30 mL), combine the organic layers, wash with water and saturated brine. Dry with anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product (S)-4-(6-bromo-5-methyl-2-((1 -Methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)tert-butyl piperazine-1-carboxylate (1.6 g, yield: 34%).
MS m/z(ESI):470.1[M+H] +，472.1[M+H+2] +. MS m/z(ESI): 470.1[M+H] + , 472.1[M+H+2] + .
第四步：(S)-4-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)-6-(哌嗪-1-基)嘧啶的制备Step 4: Preparation of (S)-4-bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(piperazin-1-yl)pyrimidine
Figure PCTCN2020093731-appb-000055
Figure PCTCN2020093731-appb-000055
将(S)-4-(6-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸叔丁酯(1.5g，3.2mmol)溶于二氯甲烷(50mL)中，加入TFA(2mL)，室温搅拌2小时。用饱和NaHCO 3水溶液调节至中性，乙酸乙酯(3*50mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到目标产物(S)-4-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)-6-(哌嗪-1-基)嘧啶(1.2g，粗品)。 (S)-4-(6-Bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert Butyl ester (1.5 g, 3.2 mmol) was dissolved in dichloromethane (50 mL), TFA (2 mL) was added, and stirred at room temperature for 2 hours. It was adjusted to neutral with saturated aqueous NaHCO 3 solution, and extracted with ethyl acetate (3*50 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the target product (S)-4-bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-6-( Piperazin-1-yl)pyrimidine (1.2 g, crude).
MS m/z(ESI):370.1[M+H] +，372.1[M+H+2] +. MS m/z(ESI): 370.1[M+H] + , 372.1[M+H+2] + .
第五步：(S)-1-(4-(6-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The fifth step: (S)-1-(4-(6-bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine -1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000056
Figure PCTCN2020093731-appb-000056
将(S)-4-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)-6-(哌嗪-1-基)嘧啶(1.2g，3.2mmol)溶于二氯甲烷(50mL)中，加入DIPEA(1.2g，9.3mmol)，室温滴加丙烯酰氯(345mg，3.8mmol)，加完室温搅拌1小时。加水淬灭，二氯甲烷(20mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物(S)-1-(4-(6- 溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(1.1g，产率：81％)。 The (S)-4-bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(piperazin-1-yl)pyrimidine (1.2g, 3.2 mmol) was dissolved in dichloromethane (50 mL), DIPEA (1.2 g, 9.3 mmol) was added, acryloyl chloride (345 mg, 3.8 mmol) was added dropwise at room temperature, and the addition was completed and stirred at room temperature for 1 hour. It was quenched with water, and extracted with dichloromethane (20 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product (S)-1-(4-(6-bromo-5-methyl) 2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (1.1g, yield: 81%).
MS m/z(ESI):424.1[M+H] +，426.1[M+H+2] +. MS m/z(ESI): 424.1[M+H] + , 426.1[M+H+2] + .
第六步：(S)-1-(4-(6-(8-羟基萘-2-基)-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The sixth step: (S)-1-(4-(6-(8-hydroxynaphthalen-2-yl)-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy )Pyrimidine-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000057
Figure PCTCN2020093731-appb-000057
将(S)-1-(4-(6-溴-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(100mg，0.24mmol)溶于二氧六环(20mL)中，加入7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-酚(96mg，0.36mmol)、三(二亚苄基丙酮)二钯(46mg，0.05mmol)、Xantphos(58mg，0.1mmol)以及Cs 2CO 3(236mg，0.72mmol)，氮气置换。将反应液加热至110℃反应过夜。浓缩，二氯甲烷(20mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标产物(S)-1-(4-(6-(8-羟基萘-2-基)-5-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(23mg，产率：20％)。 (S)-1-(4-(6-Bromo-5-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1- Base) prop-2-en-1-one (100mg, 0.24mmol) was dissolved in dioxane (20mL), and 7-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)naphthalene-1-phenol (96mg, 0.36mmol), tris(dibenzylideneacetone)dipalladium (46mg, 0.05mmol), Xantphos (58mg, 0.1mmol) and Cs 2 CO 3 (236mg, 0.72mmol), replaced with nitrogen. The reaction solution was heated to 110°C for overnight reaction. Concentrate and extract three times with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by preparative HPLC to obtain the target product (S)-1-(4-(6-(8-hydroxynaphthalen-2-yl)-5-methyl-2- ((1-Methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (23 mg, yield: 20%).
MS m/z(ESI):488.1[M+H] +. MS m/z(ESI): 488.1[M+H] + .
实施例12～20的制备参照实施例11路线。The preparation of Examples 12 to 20 refers to the route of Example 11.
实施例21Example 21
N-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-羰基)-6-氯-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-3-基)-4-乙基苯酰胺的制备N-(4-((S)-4-acryloyl-2-methylpiperazine-1-carbonyl)-6-chloro-2,2'-difluoro-6'-methoxy-[1,1 '-Biphenyl]-3-yl)-4-ethylbenzamide
Figure PCTCN2020093731-appb-000058
Figure PCTCN2020093731-appb-000058
实施例21的制备参照实施例1。For the preparation of Example 21, refer to Example 1.
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
1H NMR(400MHz,CDCl 3)δ8.03(d,J＝30.4Hz,1H),7.77(d,J＝7.4Hz,2H),7.40(dd, J＝15.1,8.3Hz,1H),7.28(d,J＝8.0Hz,2H),6.86–6.78(m,2H),6.55(s,1H),6.34(d,J＝16.6Hz,1H),5.74(d,J＝10.3Hz,1H),4.56(d,J＝56.7Hz,3H),3.79(s,4H),3.52(s,2H),3.04(s,2H),2.70(q,J＝7.6Hz,2H),1.25(t,J＝7.6Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.03 (d, J = 30.4Hz, 1H), 7.77 (d, J = 7.4Hz, 2H), 7.40 (dd, J = 15.1, 8.3Hz, 1H), 7.28 (d,J=8.0Hz,2H),6.86-6.78(m,2H),6.55(s,1H),6.34(d,J=16.6Hz,1H),5.74(d,J=10.3Hz,1H) ,4.56(d,J=56.7Hz,3H),3.79(s,4H),3.52(s,2H),3.04(s,2H),2.70(q,J=7.6Hz,2H),1.25(t, J=7.6Hz, 6H).
19F NMR(376MHz,CDCl 3)δ-111.70–-111.81(m),-111.83–-112.11(m). 19 F NMR(376MHz, CDCl 3 )δ-111.70---111.81(m), -111.83---112.11(m).
实施例22Example 22
(E)-N'-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-羰基)-6-氯-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-3-基)-N,N-二甲基甲脒的制备(E)-N'-(4-((S)-4-acryloyl-2-methylpiperazine-1-carbonyl)-6-chloro-2,2'-difluoro-6'-methoxy -[1,1'-Biphenyl]-3-yl)-N,N-Dimethylformamidine
Figure PCTCN2020093731-appb-000059
Figure PCTCN2020093731-appb-000059
实施例22的制备参照实施例1。Refer to Example 1 for the preparation of Example 22.
MS m/z(ESI):505.1[M+H] +. MS m/z(ESI): 505.1[M+H] + .
1H NMR(400MHz,CDCl 3)δ7.67(s,1H),7.37(dd,J＝15.5,7.9Hz,1H),7.21–7.05(m,1H),6.81(t,J＝8.3Hz,2H),6.56(dd,J＝16.6,10.6Hz,1H),6.36(d,J＝16.5Hz,1H),5.76(d,J＝10.4Hz,1H),5.00(s,1H),4.57(d,J＝16.5Hz,2H),3.86–3.76(m,3H),3.48(s,2H),3.27–3.01(m,2H),2.90(dd,J＝51.6,39.6Hz,6H),1.32–1.23(m,3H). 1 H NMR(400MHz, CDCl 3 )δ7.67(s,1H), 7.37(dd,J=15.5,7.9Hz,1H), 7.21–7.05(m,1H), 6.81(t,J=8.3Hz, 2H), 6.56 (dd, J = 16.6, 10.6 Hz, 1H), 6.36 (d, J = 16.5 Hz, 1H), 5.76 (d, J = 10.4 Hz, 1H), 5.00 (s, 1H), 4.57 ( d, J = 16.5Hz, 2H), 3.86–3.76 (m, 3H), 3.48 (s, 2H), 3.27–3.01 (m, 2H), 2.90 (dd, J = 51.6, 39.6 Hz, 6H), 1.32 –1.23(m,3H).
实施例23Example 23
N-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-羰基)-6-氯-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-3-基)-3-氰基苯酰胺的制备N-(4-((S)-4-acryloyl-2-methylpiperazine-1-carbonyl)-6-chloro-2,2'-difluoro-6'-methoxy-[1,1 '-Biphenyl]-3-yl)-3-cyanobenzamide
Figure PCTCN2020093731-appb-000060
Figure PCTCN2020093731-appb-000060
实施例23的制备参照实施例1。Refer to Example 1 for the preparation of Example 23.
MS m/z(ESI):579.1[M+H] +. MS m/z(ESI): 579.1[M+H] + .
1H NMR(400MHz,CDCl 3)δ12.22(d,J＝31.3Hz,2H),11.91(d,J＝7.7Hz,1H),11.66 (t,J＝7.9Hz,1H),11.43(dt,J＝46.6,23.4Hz,2H),11.00–10.67(m,3H),10.22(d,J＝16.8Hz,1H),9.74(d,J＝10.2Hz,1H),8.48(d,J＝61.2Hz,2H),8.05(d,J＝64.2Hz,1H),7.77(s,3H),7.51(s,2H),7.27(s,3H),7.10(s,1H),5.32–5.01(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ 12.22 (d, J = 31.3 Hz, 2H), 11.91 (d, J = 7.7 Hz, 1H), 11.66 (t, J = 7.9 Hz, 1H), 11.43 (dt ,J=46.6,23.4Hz,2H),11.00-10.67(m,3H),10.22(d,J=16.8Hz,1H), 9.74(d,J=10.2Hz,1H), 8.48(d,J= 61.2Hz,2H), 8.05(d,J=64.2Hz,1H),7.77(s,3H),7.51(s,2H),7.27(s,3H),7.10(s,1H),5.32–5.01( m,3H).
19F NMR(400MHz,CDCl 3)δ-109.00–-111.89(m),-113.34(d,J＝1.0Hz),-113.37–-114.24(m). 19 F NMR (400MHz, CDCl 3 )δ-109.00---111.89(m), -113.34(d, J=1.0Hz), -113.37---114.24(m).
实施例24Example 24
N1-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-羰基)-6-氯-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-3-基)-N4-甲基对苯二甲酰胺的制备N1-(4-((S)-4-acryloyl-2-methylpiperazine-1-carbonyl)-6-chloro-2,2'-difluoro-6'-methoxy-[1,1 '-Biphenyl]-3-yl)-N4-methylterephthalamide
Figure PCTCN2020093731-appb-000061
Figure PCTCN2020093731-appb-000061
实施例24的制备参照实施例1。Refer to Example 1 for the preparation of Example 24.
MS m/z(ESI):611.1[M+H] +. MS m/z(ESI): 611.1[M+H] + .
19F NMR(400MHz,CDCl 3)δ-111.77(s),-111.94(ddd,J＝18.6,9.3,6.8Hz),-115.73(d,J＝1.5Hz). 19 F NMR (400MHz, CDCl 3 )δ-111.77(s), -111.94(ddd, J=18.6, 9.3, 6.8Hz), -115.73(d, J=1.5Hz).
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝24.6Hz,4H),7.41(dd,J＝15.4,7.4Hz,1H),7.16(s,1H),6.82(t,J＝10.0Hz,2H),6.35(d,J＝17.0Hz,2H),5.75(d,J＝10.3Hz,1H),4.81–4.23(m,3H),3.79(s,3H),3.53(s,4H),3.03(d,J＝4.4Hz,3H),1.25(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ 7.84 (d, J = 24.6 Hz, 4H), 7.41 (dd, J = 15.4, 7.4 Hz, 1H), 7.16 (s, 1H), 6.82 (t, J = 10.0Hz, 2H), 6.35 (d, J = 17.0 Hz, 2H), 5.75 (d, J = 10.3 Hz, 1H), 4.81-4.23 (m, 3H), 3.79 (s, 3H), 3.53 (s, 4H),3.03(d,J=4.4Hz,3H),1.25(s,3H).
实施例25Example 25
N-(4-((S)-4-丙烯酰-2-甲基哌嗪-1-羰基)-6-氯-2,2'-二氟-6'-甲氧基-[1,1'-联苯基]-3-基)异酞酰胺的制备N-(4-((S)-4-acryloyl-2-methylpiperazine-1-carbonyl)-6-chloro-2,2'-difluoro-6'-methoxy-[1,1 '-Biphenyl]-3-yl)isophthalamide
Figure PCTCN2020093731-appb-000062
Figure PCTCN2020093731-appb-000062
实施例25的制备参照实施例1。Refer to Example 1 for the preparation of Example 25.
MS m/z(ESI):597.0[M+H] +. MS m/z(ESI): 597.0[M+H] + .
19F NMR(400MHz,CDCl 3)δ-110.92–-111.16(m),-113.21(s),-113.27–-113.42(m). 19 F NMR(400MHz, CDCl 3 )δ-110.92---111.16(m), -113.21(s), -113.27---113.42(m).
1H NMR(400MHz,CDCl 3)δ12.41(s,1H),12.04(d,J＝7.6Hz,2H),11.58(t,J＝7.2Hz,1H),11.42(dt,J＝45.9,23.0Hz,2H),10.93(d,J＝8.1Hz,1H),10.87–10.61(m,2H),10.21(d,J＝16.8Hz,1H),9.75(s,1H),8.56(s,1H),8.40–8.20(m,1H),8.12(s,1H),7.77(s,3H),7.48(s,1H),7.27(s,3H),7.09(s,1H),5.25(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ 12.41 (s, 1H), 12.04 (d, J = 7.6 Hz, 2H), 11.58 (t, J = 7.2 Hz, 1H), 11.42 (dt, J = 45.9, 23.0Hz, 2H), 10.93 (d, J = 8.1 Hz, 1H), 10.87-10.61 (m, 2H), 10.21 (d, J = 16.8 Hz, 1H), 9.75 (s, 1H), 8.56 (s, 1H), 8.40-8.20(m, 1H), 8.12(s, 1H), 7.77(s, 3H), 7.48(s, 1H), 7.27(s, 3H), 7.09(s, 1H), 5.25(s ,3H).
实施例26Example 26
1-((3S)-4-(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)尼古丁酰)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的制备1-((3S)-4-(5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino) Preparation of nicotinyl)-3-methylpiperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000063
Figure PCTCN2020093731-appb-000063
第一步：叔-丁基(S)-4-(2,6-二氯-5-氟尼古丁酰)-3-甲基哌嗪-1-羧酸酯的制备The first step: the preparation of tert-butyl(S)-4-(2,6-dichloro-5-fluoronicotinyl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000064
Figure PCTCN2020093731-appb-000064
在0℃，N 2保护下将草酰氯(2.7mL，5.3mmol)滴加到2,6-二氯-5-氟尼古丁酸(1g，4.8mmol)的二氯甲烷(20mL)溶液中，滴加2滴DMF，室温搅拌1小时。反应液冷却至0℃，加入三乙胺(2mL，9.6mmol)，室温搅拌1小时。反应液加水,二氯甲烷(3*10mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝10：1到5：1)纯化得到目标产物叔-丁基(S)-4-(2,6-二氯-5-氟尼古丁酰)-3-甲基哌嗪-1-羧酸酯(1.5g，产率79％)。 Add oxalyl chloride (2.7mL, 5.3mmol) dropwise to 2,6-dichloro-5-fluoronicotinic acid (1g, 4.8mmol) in dichloromethane (20mL) solution under the protection of N 2 Add 2 drops of DMF and stir at room temperature for 1 hour. The reaction solution was cooled to 0°C, triethylamine (2 mL, 9.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with water and extracted with dichloromethane (3*10mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (Petro ether/EtOAc = 10:1 to 5:1) to obtain the target product tert-butyl(S)-4-(2, 6-Dichloro-5-fluoronicotinyl)-3-methylpiperazine-1-carboxylate (1.5 g, yield 79%).
MS m/z(ESI):392.1[M+H] +,394.1[M+H+2] +. MS m/z(ESI): 392.1[M+H] + ,394.1[M+H+2] + .
第二步：叔-丁基(3S)-4-(2-氯-5-氟-6-(2-氟-6-羟基苯基)尼古丁酰)-3-甲基哌嗪-1-羧酸酯的制备The second step: tert-butyl(3S)-4-(2-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)nicotyryl)-3-methylpiperazine-1-carboxy Preparation of acid esters
Figure PCTCN2020093731-appb-000065
Figure PCTCN2020093731-appb-000065
N 2保护下，将叔-丁基(S)-4-(2,6-二氯-5-氟尼古丁酰)-3-甲基哌嗪-1-羧酸酯(950mg，2.4mmol)溶于1,4-二氧六环中(3mL)中，加入(2-氟-6-羟基苯基)硼酸(740mg，4.9mmol)，Pd(dppf)Cl 2.DCM(200mg，0.24mmol)，K 2CO 3(1.0g，7.2mmol)，120℃反应12小时。反应液加水,二氯甲烷(3*10mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝200：1到80：1)纯化得到目标产物叔-丁基(3S)-4-(2-氯-5-氟-6-(2-氟-6-羟基苯基)尼古丁酰)-3-甲基哌嗪-1-羧酸酯(800mg，产率71％)。 Under N 2 protection, dissolve tert-butyl(S)-4-(2,6-dichloro-5-fluoronicotyryl)-3-methylpiperazine-1-carboxylate (950mg, 2.4mmol) In 1,4-dioxane (3mL), add (2-fluoro-6-hydroxyphenyl)boronic acid (740mg, 4.9mmol), Pd(dppf)Cl 2 .DCM (200mg, 0.24mmol), K 2 CO 3 (1.0 g, 7.2 mmol) was reacted at 120°C for 12 hours. The reaction solution was added with water and extracted with dichloromethane (3*10mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 200:1 to 80:1) to obtain the target product tert-butyl(3S)-4-( 2-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)nicotyryl)-3-methylpiperazine-1-carboxylate (800 mg, yield 71%).
MS m/z(ESI):468.1[M+H] +,470.1[M+H+2] +. MS m/z(ESI): 468.1[M+H] + ,470.1[M+H+2] + .
第三步：叔-丁基(3S)-4-(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)尼古丁酰)-3-甲基哌嗪-1-羧酸酯的制备The third step: tert-butyl(3S)-4-(5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridine-3 -Amino)nicotyryl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000066
Figure PCTCN2020093731-appb-000066
N 2保护下，将叔-丁基(3S)-4-(2-氯-5-氟-6-(2-氟-6-羟基苯基)尼古丁酰)-3-甲基哌嗪-1-羧酸酯(300mg，0.64mmol)溶于1,4-二氧六环中(3mL)中，加入2-异丙基-4-甲基吡啶-3-胺(200mg，1.3mmol)，Pd(OAC) 2(20mg，0.3mmol)，Xantphos(40mg，0.3mmol),K 2CO 3(188mg，1.3mmol)，110℃反应12小时。反应液加水,二氯甲烷(3*10mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝100：1到80：1)纯化得到目标产物叔-丁基(3S)-4-(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)尼古丁酰)-3-甲基哌嗪-1-羧酸酯(60mg，产率16％)。 Under N 2 protection, the tert-butyl(3S)-4-(2-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)nicotyryl)-3-methylpiperazine-1 -Carboxylate (300mg, 0.64mmol) was dissolved in 1,4-dioxane (3mL), 2-isopropyl-4-methylpyridine-3-amine (200mg, 1.3mmol), Pd (OAC) 2 (20 mg, 0.3 mmol), Xantphos (40 mg, 0.3 mmol), K 2 CO 3 (188 mg, 1.3 mmol), react at 110°C for 12 hours. The reaction solution was added with water and extracted with dichloromethane (3*10mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 100:1 to 80:1) to obtain the target product tert-butyl(3S)-4-( 5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotyryl)-3-methylpiperazine -1-carboxylate (60 mg, yield 16%).
MS m/z(ESI):582.1[M+H] +. MS m/z(ESI): 582.1[M+H] + .
第四步：(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)吡啶-3-基)((S)-2-甲基哌嗪-1-基)甲酮的制备The fourth step: (5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)pyridin-3-yl )((S)-2-Methylpiperazin-1-yl)methanone
Figure PCTCN2020093731-appb-000067
Figure PCTCN2020093731-appb-000067
将叔-丁基(3S)-4-(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)尼古丁酰)-3-甲基哌嗪-1-羧酸酯(60mg，0.1mmol)溶于MeOH(10mL)中，加入HCl/1,4-二氧六环溶液(1.0mL，4mmol)，搅拌0.5小时。浓缩得到(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)吡啶-3-基)((S)-2-甲基哌嗪-1-基)甲酮(50mg，产率97％)。Add tert-butyl(3S)-4-(5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl) Amino) nicotinyl)-3-methylpiperazine-1-carboxylate (60 mg, 0.1 mmol) was dissolved in MeOH (10 mL), and HCl/1,4-dioxane solution (1.0 mL, 4 mmol) was added , Stir for 0.5 hours. Concentrate to obtain (5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)pyridin-3-yl)( (S)-2-Methylpiperazin-1-yl)methanone (50 mg, 97% yield).
MS m/z(ESI):482.1[M+H] +. MS m/z(ESI): 482.1[M+H] + .
第五步：1-((3S)-4-(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)尼古丁酰)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的制备The fifth step: 1-((3S)-4-(5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridine-3- (Yl)amino)nicotyryl)-3-methylpiperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000068
Figure PCTCN2020093731-appb-000068
N 2保护下将(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)吡啶-3-基)((S)-2-甲基哌嗪-1-基)甲酮(50mg，0.97mmol)溶于二氯甲烷(10mL)中，加入DIEA(5mL，28mmol),在0℃滴加丙烯酰氯(0.02mL,0.97mmol)，滴完搅拌0.5小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，经酸法Prep-HPLC纯化得到目标产物1-((3S)-4-(5-氟-6-(2-氟-6-羟基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)尼古丁酰)-3-甲基哌嗪-1-基)丙-2-烯-1-酮(2mg，产率0.04％)。 Under the protection of N 2 (5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)pyridine-3- ((S)-2-methylpiperazin-1-yl)methanone (50mg, 0.97mmol) was dissolved in dichloromethane (10mL), DIEA (5mL, 28mmol) was added, and propylene was added dropwise at 0℃ Acid chloride (0.02mL, 0.97mmol), after dropping and stirring for 0.5 hour. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by acid method Prep-HPLC to obtain the target product 1-((3S)-4-(5-fluoro-6-(2-fluoro-6-hydroxy) Phenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotyryl)-3-methylpiperazin-1-yl)prop-2-en-1-one (2mg, yield 0.04%).
1H NMR(400MHz,Methanol-d 4)δ8.39-8.34(m,2H),7.25–7.20(m,2H),6.86-6.80(m,1H),6.67-6.58(m,2H),6.32-6.27(dd,J＝16.6,4.0Hz,1H),5.83-5.79(dd,J＝12.0,4.0Hz,1H),4.65-4.48(m,4H),4.40-4.24(m,1H),3.84-3.72(m,2H),2.82-2.75(m,1H),2.36(s,3H),1.50-1.44(d,J＝6.6Hz,3H),1.20-1.05(m,6H) 1 H NMR (400MHz, Methanol-d 4 ) δ 8.39-8.34 (m, 2H), 7.25-7.20 (m, 2H), 6.86-6.80 (m, 1H), 6.67-6.58 (m, 2H), 6.32 -6.27(dd,J=16.6,4.0Hz,1H),5.83-5.79(dd,J=12.0,4.0Hz,1H),4.65-4.48(m,4H),4.40-4.24(m,1H),3.84 -3.72(m,2H),2.82-2.75(m,1H),2.36(s,3H),1.50-1.44(d,J=6.6Hz,3H),1.20-1.05(m,6H)
MS m/z(ESI):536.1[M+H] +. MS m/z(ESI): 536.1[M+H] + .
实施例27Example 27
6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-N-(4-氟-3-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲 氧基)嘧啶-4-甲酰胺的制备6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(4-fluoro-3-hydroxyphenyl)-2-(((S)-1-methyl Preparation of pyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide
Figure PCTCN2020093731-appb-000069
Figure PCTCN2020093731-appb-000069
第一步：甲基(S)-6-(4-(叔-丁氧基羰基)-2-甲基哌嗪-1-基)-2-氯嘧啶-4-羧酸酯的制备The first step: Preparation of methyl (S)-6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxylate
Figure PCTCN2020093731-appb-000070
Figure PCTCN2020093731-appb-000070
甲基2,6-二氯嘧啶-4-羧酸酯(10g,48.3mmol)，叔-丁基(S)-3-甲基哌嗪-1-羧酸酯(9.6g,48mmol)和N,N-二异丙基乙胺(12g,100mmol)在四氢呋喃(150mL)中50℃搅拌4小时。加水(150mL)，用乙酸乙酯(150mL×2)萃取，有机相用氯化铵水溶液(200mL)洗，再用氯化钠水溶液(50mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩后得到甲基(S)-6-(4-(叔-丁氧基羰基)-2-甲基哌嗪-1-基)-2-氯嘧啶-4-羧酸酯黄色固体(17g,产率95％)。Methyl 2,6-dichloropyrimidine-4-carboxylate (10g, 48.3mmol), tert-butyl(S)-3-methylpiperazine-1-carboxylate (9.6g, 48mmol) and N , N-Diisopropylethylamine (12g, 100mmol) was stirred in tetrahydrofuran (150mL) at 50°C for 4 hours. Add water (150mL), extract with ethyl acetate (150mL×2), wash the organic phase with aqueous ammonium chloride solution (200mL) and then with sodium chloride aqueous solution (50mL), dry the organic phase with anhydrous sodium sulfate, and filter. After concentration, methyl (S)-6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxylate yellow solid (17g, The yield is 95%).
MS m/z(ESI):371.1[M+H] +,373.1[M+H+2] +. MS m/z(ESI): 371.1[M+H] + ,373.1[M+H+2] + .
第二步：6-((S)-4-(叔-丁氧基羰基)-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸的制备Step 2: 6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidine-2 -(Yl)methoxy)pyrimidine-4-carboxylic acid preparation
Figure PCTCN2020093731-appb-000071
Figure PCTCN2020093731-appb-000071
甲基(S)-6-(4-(叔-丁氧基羰基)-2-甲基哌嗪-1-基)-2-氯嘧啶-4-羧酸酯(2g,5.4mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(3.1g,27mmol)，碳酸铯(5.26g,16.2mmol)和N,N-二异丙基乙胺(6.6g,54mmol)在二氧六环(5mL)中微波160℃搅拌3小时。加水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用氯化铵水溶液(200mL)洗涤，再用氯化钠水溶液(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩后得到6-((S)-4-(叔-丁氧基羰基)-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸(2g,产率85％)黄色固体。Methyl (S)-6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxylate (2g, 5.4mmol), ( S)-(1-methylpyrrolidin-2-yl)methanol (3.1g, 27mmol), cesium carbonate (5.26g, 16.2mmol) and N,N-diisopropylethylamine (6.6g, 54mmol) in Dioxane (5 mL) was stirred in microwave at 160°C for 3 hours. Add water (200mL), extract with ethyl acetate (200mL×3), wash the organic phase with aqueous ammonium chloride solution (200mL), then wash with aqueous sodium chloride solution (100mL), dry the organic phase with anhydrous sodium sulfate, and filter. After concentration, 6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidine-2- (Yl)methoxy)pyrimidine-4-carboxylic acid (2g, yield 85%) yellow solid.
MS m/z(ESI):436.3[M+H] +. MS m/z(ESI): 436.3[M+H] + .
第三步：6-((S)-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸的制 备The third step: 6-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4- Preparation of carboxylic acid
Figure PCTCN2020093731-appb-000072
Figure PCTCN2020093731-appb-000072
往6-((S)-4-(叔-丁氧基羰基)-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸(2g,4.6mmol)的甲醇(60mL)溶液里加硫酸(1mL)，加完65℃搅拌2小时。用碳酸钠水溶液慢慢调至中性，直接浓缩干得到6-((S)-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸(4g)白色固体。To 6-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) Sulfuric acid (1 mL) was added to the methanol (60 mL) solution of methoxy)pyrimidine-4-carboxylic acid (2 g, 4.6 mmol), and the mixture was stirred at 65°C for 2 hours. Slowly adjust to neutral with sodium carbonate aqueous solution, directly concentrate to dry to obtain 6-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidine-2 -Yl)methoxy)pyrimidine-4-carboxylic acid (4g) white solid.
MS m/z(ESI):336.2[M+H] +. MS m/z(ESI): 336.2[M+H] + .
第四步：6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸的制备The fourth step: 6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy ) Preparation of pyrimidine-4-carboxylic acid
Figure PCTCN2020093731-appb-000073
Figure PCTCN2020093731-appb-000073
往6-((S)-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸(200mg,0.6mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入N,N-二异丙基乙胺(240mg,2mmol)，再在0℃加丙烯酰氯(108mg,1.2mmol)，加完搅拌1小时。反应用氯化铵水溶液(30mL)淬灭，乙酸乙酯(30mL×3)萃取，有机相用饱和NaCl水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸(200mg)黄色固体。To 6-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid ( Add N,N-diisopropylethylamine (240mg, 2mmol) to a solution of 200mg, 0.6mmol) in N,N-dimethylformamide (15mL), then add acryloyl chloride (108mg, 1.2mmol) at 0℃ , After adding, stir for 1 hour. The reaction was quenched with aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated aqueous NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-((S)- 4-acryloyl-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxylic acid (200mg) yellow solid.
MS m/z(ESI):390.2[M+H] +. MS m/z(ESI): 390.2[M+H] + .
第五步：6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-N-(4-氟-3-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-甲酰胺的制备The fifth step: 6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(4-fluoro-3-hydroxyphenyl)-2-(((S)- Preparation of 1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide
Figure PCTCN2020093731-appb-000074
Figure PCTCN2020093731-appb-000074
6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-羧酸 (200mg,0.6mmol)，5-氨基-2-氟苯酚(152mg,1.2mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(456mg,1.2mmol)和N,N-二异丙基乙胺(240mg,2mmol)在N,N-二甲基甲酰胺(6mL)中室温搅拌18小时。过滤反应液，浓缩，制备HPLC纯化得到6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-N-(4-氟-3-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-甲酰胺(15mg,三步产率10％)黄色固体。6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine-4 -Carboxylic acid (200mg, 0.6mmol), 5-amino-2-fluorophenol (152mg, 1.2mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (456 mg, 1.2 mmol) and N,N-diisopropylethylamine (240 mg, 2 mmol) were stirred in N,N-dimethylformamide (6 mL) at room temperature for 18 hours. The reaction solution was filtered, concentrated, and purified by preparative HPLC to obtain 6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(4-fluoro-3-hydroxyphenyl)-2- (((S)-1-Methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide (15 mg, 10% yield in three steps) yellow solid.
MS m/z(ESI):499.2[M+H] +。 MS m/z (ESI): 499.2 [M+H] + .
1H NMR(400MHz,MeOD-d 4)δ7.56–7.42(m,1H),7.19–7.08(m,2H),7.07–6.97(m,1H),6.92–6.73(m,1H),6.29(d,J＝16Hz,1H),5.89–5.74(m,1H),4.79–4.56(m,1H),4.55–4.29(m,4H),4.24–3.99(m,1H),3.67–3.53(m,1H),3.50–3.37(m,2H),3.24–3.01(m,2H),2.86–2.73(m,1H),2.53(s,3H),2.46–2.33(m,1H),1.93–1.68(m,3H),1.23(d,J＝8Hz,3H). 1 H NMR (400MHz, MeOD-d 4 ) δ7.56–7.42(m,1H), 7.19–7.08(m,2H), 7.07–6.97(m,1H), 6.92–6.73(m,1H), 6.29 (d,J=16Hz,1H), 5.89–5.74(m,1H), 4.79–4.56(m,1H), 4.55–4.29(m,4H), 4.24–3.99(m,1H), 3.67–3.53( m,1H), 3.50--3.37(m,2H), 3.24--3.01(m,2H), 2.86--2.73(m,1H), 2.53(s,3H), 2.46--2.33(m,1H), 1.93-- 1.68(m,3H),1.23(d,J=8Hz,3H).
实施例28Example 28
6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-N-(1H-苯并[d]咪唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-甲酰胺的制备6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(1H-benzo[d]imidazol-4-yl)-2-(((S)-1 -Methylpyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide
Figure PCTCN2020093731-appb-000075
Figure PCTCN2020093731-appb-000075
实施例28的制备参照实施例27。Refer to Example 27 for the preparation of Example 28.
1H NMR(400MHz,MeOD-d 4)δ8.18(s,1H),7.56–7.42(m,2H),7.40–7.32(m,2H),6.92–6.73(m,1H),6.28(d,J＝16Hz,1H),5.88–5.75(m,1H),4.77–4.53(m,1H),4.56–4.29(m,4H),4.23–3.99(m,1H),3.68–3.54(m,1H),3.51–3.38(m,2H),3.25–3.00(m,2H),2.87–2.74(m,1H),2.54(s,3H),2.47–2.33(m,1H),1.94–1.69(m,3H),1.24(d,J＝8Hz,3H). 1 H NMR(400MHz, MeOD-d 4 )δ8.18(s,1H), 7.56-7.42(m,2H), 7.40-7.32(m,2H), 6.92-6.73(m,1H), 6.28(d ,J=16Hz,1H), 5.88–5.75(m,1H), 4.77–4.53(m,1H), 4.56–4.29(m,4H), 4.23–3.99(m,1H), 3.68–3.54(m, 1H), 3.51–3.38(m, 2H), 3.25–3.00(m, 2H), 2.87–2.74(m, 1H), 2.54(s, 3H), 2.47–2.33(m, 1H), 1.94–1.69( m,3H),1.24(d,J=8Hz,3H).
实施例29Example 29
6-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-N-(2-氟-6-羟基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-甲酰胺的制备6-((S)-4-acryloyl-2-methylpiperazin-1-yl)-N-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methyl Preparation of pyrrolidin-2-yl)methoxy)pyrimidine-4-carboxamide
Figure PCTCN2020093731-appb-000076
Figure PCTCN2020093731-appb-000076
实施例28的制备参照实施例27。Refer to Example 27 for the preparation of Example 28.
1H NMR(400MHz,MeOD-d 4)δ7.57–7.43(m,1H),7.15–7.08(m,1H),7.03–6.93(m,2H),6.92–6.75(m,1H),6.29(d,J＝16Hz,1H),5.89–5.75(m,1H),4.78–4.54(m,1H),4.54–4.29(m,4H),4.25–3.98(m,1H),3.66–3.53(m,1H),3.51–3.38(m,2H),3.25–3.01(m,2H),2.87–2.74(m,1H),2.53(s,3H),2.47–2.32(m,1H),1.91–1.69(m,3H),1.22(d,J＝8Hz,3H). 1 H NMR (400MHz, MeOD-d 4 ) δ7.57-7.43(m,1H), 7.15-7.08(m,1H), 7.03-6.93(m,2H), 6.92-6.75(m,1H), 6.29 (d,J=16Hz,1H), 5.89–5.75(m,1H), 4.78–4.54(m,1H), 4.54–4.29(m,4H), 4.25–3.98(m,1H), 3.66–3.53( m,1H),3.51--3.38(m,2H), 3.25--3.01(m,2H), 2.87--2.74(m,1H), 2.53(s,3H), 2.47--2.32(m,1H), 1.91-- 1.69(m,3H),1.22(d,J=8Hz,3H).
实施例30Example 30
4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-2(1H)-酮的制备4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methyl Pyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000077
Figure PCTCN2020093731-appb-000077
第一步：叔-丁基4-(5-溴-2-氯-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯的制备The first step: Preparation of tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000078
Figure PCTCN2020093731-appb-000078
将5-溴-2,4-二氯-6-甲基嘧啶(5g，20.8mmol)溶于ACN(50mL)中，加入叔-丁基哌嗪-1-羧酸酯(5.1g，27.4mmol)，DIPEA(8.1g，62.7mmol)，室温搅拌15小时。加入水，乙酸乙酯(50mL)萃取三次。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝5：1)纯化得到目标产物叔-丁基4-(5-溴-2-氯-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(7.9g，产率：97％)。Dissolve 5-bromo-2,4-dichloro-6-methylpyrimidine (5g, 20.8mmol) in ACN (50mL), add tert-butylpiperazine-1-carboxylate (5.1g, 27.4mmol) ), DIPEA (8.1 g, 62.7 mmol), stirred at room temperature for 15 hours. Water was added, and ethyl acetate (50 mL) was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (Petroether/EtOAc=5:1) to obtain the target product tert-butyl 4-(5-bromo-2-chloro-6- Methylpyrimidin-4-yl)piperazine-1-carboxylate (7.9 g, yield: 97%).
MS m/z(ESI):391.1[M+H] +,393.1[M+H+2] +. MS m/z(ESI): 391.1[M+H] + ,393.1[M+H+2] + .
第二步：叔-丁基4-(5-溴-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯的制备Step 2: Preparation of tert-butyl 4-(5-bromo-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000079
Figure PCTCN2020093731-appb-000079
将叔-丁基4-(5-溴-2-氯-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(5g，12.8mmol)溶于MeOH(30mL)中，冰浴下加入NaOH(1.5g，37.5mmol)，逐渐升至室温搅拌5小时；加水和乙酸乙酯(50mL)萃取三次。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝5：1)纯化得到目标产物叔-丁基4-(5-溴-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(3.5g，产率：71％)。Dissolve tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (5g, 12.8mmol) in MeOH (30mL), ice bath NaOH (1.5 g, 37.5 mmol) was added, gradually warming to room temperature and stirring for 5 hours; water and ethyl acetate (50 mL) were added for extraction three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by column chromatography (Petroether/EtOAc=5:1) gave the target product tert-butyl 4-(5-bromo-2-methoxy- 6-Methylpyrimidin-4-yl)piperazine-1-carboxylate (3.5 g, yield: 71%).
MS m/z(ESI):387.1[M+H] +，389.1[M+H+2] +. MS m/z(ESI): 387.1[M+H] + , 389.1[M+H+2] + .
第三步：叔-丁基4-(5-甲酰基-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯的制备The third step: preparation of tert-butyl 4-(5-formyl-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000080
Figure PCTCN2020093731-appb-000080
将叔-丁基4-(5-溴-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(3.2g，8.3mmol)溶于无水THF(100mL)中，氮气保护下，冷却至-78℃，加入n-BuLi(9.9mL，9.9mmol)，搅拌0.5小时。加入DMF/THF(1mL/5mL)，-78℃搅拌1小时，逐渐升至室温。继续搅拌2小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基4-(5-甲酰基-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(2.0g，产率：72％)。 Dissolve tert-butyl 4-(5-bromo-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (3.2g, 8.3mmol) in anhydrous THF (100mL ), under the protection of nitrogen, cool to -78°C, add n-BuLi (9.9 mL, 9.9 mmol), and stir for 0.5 hour. Add DMF/THF (1mL/5mL), stir at -78°C for 1 hour, and gradually warm to room temperature. Continue stirring for 2 hours. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl 4-(5-formyl-2-methyl) Oxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (2.0 g, yield: 72%).
MS m/z(ESI):337.1[M+H] +. MS m/z(ESI): 337.1[M+H] + .
第四步：叔-丁基4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯的制备The fourth step: tert-butyl 4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piper Preparation of oxazine-1-carboxylate
Figure PCTCN2020093731-appb-000081
Figure PCTCN2020093731-appb-000081
将叔-丁基4-(5-甲酰基-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(1.8g，5.4mmol)溶于二氯甲烷(50mL)中，加入甲胺盐酸盐(710mg，10.6mmol)，NaBH(OAc) 3(1.4g，6.7mmol)和冰醋酸(30mg，0.5mmol)。室温搅拌过夜。加入Boc 2O(2.3g，10.6mmol)，室温搅拌3小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(1.9g，产率：79％)。 Dissolve tert-butyl 4-(5-formyl-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (1.8g, 5.4mmol) in dichloromethane ( 50 mL), methylamine hydrochloride (710 mg, 10.6 mmol), NaBH(OAc) 3 (1.4 g, 6.7 mmol) and glacial acetic acid (30 mg, 0.5 mmol) were added. Stir at room temperature overnight. Add Boc 2 O (2.3 g, 10.6 mmol) and stir at room temperature for 3 hours. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl 4-(5-(((tert-butyl (Oxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (1.9 g, yield: 79%).
MS m/z(ESI):452.1[M+H] +. MS m/z(ESI): 452.1[M+H] + .
第五步：叔-丁基(E)-4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-6-(2-氟-6-甲氧基苯乙烯基)-2-甲氧基嘧啶-4-基)哌嗪-1-羧酸酯的制备The fifth step: tert-butyl(E)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(2-fluoro-6-methoxybenzene Preparation of (vinyl)-2-methoxypyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000082
Figure PCTCN2020093731-appb-000082
将叔-丁基4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-2-甲氧基-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(1.8g，4.0mmol)加入NaOH水溶液(5M，100mL)中，加入2-氟-6-甲氧基苯甲醛(730mg，4.8mmol)和三辛基甲基氯化铵(220mg，0.5mmol)，加热至回流，搅拌5小时。冷却，过滤，滤饼用水洗涤，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基(E)-4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-6-(2-氟-6-甲氧基苯乙烯基)-2-甲氧基嘧啶-4-基)哌嗪-1-羧酸酯(1.7g，产率：73％)。 The tert-butyl 4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1 -Carboxylic acid ester (1.8g, 4.0mmol) was added to NaOH aqueous solution (5M, 100mL), 2-fluoro-6-methoxybenzaldehyde (730mg, 4.8mmol) and trioctylmethylammonium chloride (220mg , 0.5mmol), heated to reflux, and stirred for 5 hours. Cool, filter, wash the filter cake with water, and purify by column chromatography (CH 2 Cl 2 /MeOH=10:1) to obtain the target product tert-butyl(E)-4-(5-(((tert-butoxycarbonyl) )(Methyl)amino)methyl)-6-(2-fluoro-6-methoxystyryl)-2-methoxypyrimidin-4-yl)piperazine-1-carboxylate (1.7g , Yield: 73%).
MS m/z(ESI):588.1[M+H] +. MS m/z(ESI):588.1[M+H] + .
第六步：7-(2-氟-6-甲氧苯基)-2-甲氧基-6-甲基-4-(哌嗪-1-基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶的制备The sixth step: 7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-4-(piperazin-1-yl)-5,6,7,8-tetra Preparation of Hydropyrido[4,3-d]pyrimidine
Figure PCTCN2020093731-appb-000083
Figure PCTCN2020093731-appb-000083
将叔-丁基(E)-4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-6-(2-氟-6-甲氧基苯乙烯基)-2-甲氧基嘧啶-4-基)哌嗪-1-羧酸酯(1.5g，2.6mmol)溶于乙酸乙酯(50mL)中，加入2M HCl的乙酸乙酯溶液(6mL)，室温搅拌5小时，浓缩除去溶剂；粗品溶于水(20mL)，加入K 2CO 3(720mg，5.2mmol)和KI(430mg，2.6mmol)，加热至100℃，搅拌15小时，冷却，加入水和乙酸乙酯(3*30mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物7-(2-氟-6-甲氧苯基)-2-甲氧基-6-甲基-4-(哌嗪-1-基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶(560mg，产率：57％)。 Add tert-butyl(E)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(2-fluoro-6-methoxystyryl) -2-Methoxypyrimidin-4-yl)piperazine-1-carboxylate (1.5g, 2.6mmol) was dissolved in ethyl acetate (50mL), and 2M HCl in ethyl acetate (6mL) was added at room temperature Stir for 5 hours, concentrate to remove the solvent; dissolve the crude product in water (20mL), add K 2 CO 3 (720mg, 5.2mmol) and KI (430mg, 2.6mmol), heat to 100°C, stir for 15 hours, cool, add water and Extract with ethyl acetate (3*30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 7-(2-fluoro-6-methoxyphenyl)-2- Methoxy-6-methyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (560 mg, yield: 57%).
MS m/z(ESI):388.1[M+H] +. MS m/z(ESI): 388.1[M+H] + .
第七步：1-(4-(7-(2-氟-6-甲氧苯基)-2-甲氧基-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The seventh step: 1-(4-(7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4 ,3-d)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000084
Figure PCTCN2020093731-appb-000084
将7-(2-氟-6-甲氧苯基)-2-甲氧基-6-甲基-4-(哌嗪-1-基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶(500mg，1.3mmol)溶于二氯甲烷(20mL)中，加入DIPEA(820mg，3.9mmol)，室温滴加丙烯酰氯(140mg，1.6mmol),加完继续搅拌1小时。加水淬灭，二氯甲烷(20mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(7-(2-氟-6-甲氧苯基)-2-甲氧基-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(480mg，产率：84％)。 The 7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidine (500mg, 1.3mmol) was dissolved in dichloromethane (20mL), DIPEA (820mg, 3.9mmol) was added, acryloyl chloride (140mg, 1.6mmol) was added dropwise at room temperature, and the addition was complete and stirring was continued. hour. It was quenched with water, and extracted with dichloromethane (20 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(7-(2-fluoro-6-methoxy (Phenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)propan-2 -En-1-one (480 mg, yield: 84%).
MS m/z(ESI):442.1[M+H] +. MS m/z(ESI): 442.1[M+H] + .
第七步：1-(4-(7-(2-氟-6-羟基苯基)-2-羟基-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The seventh step: 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-2-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d) Preparation of pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000085
Figure PCTCN2020093731-appb-000085
将1-(4-(7-(2-氟-6-甲氧苯基)-2-甲氧基-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(450mg，1.0mmol)溶于二氯甲烷(50mL)中，冷却到-40℃，滴加入 BBr 3(1.3g，5.2mmol)，逐渐升至室温，搅拌2小时。加入饱和NaHCO 3水溶液搅拌1小时，乙酸乙酯(10mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(7-(2-氟-6-羟基苯基)-2-羟基-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(350mg，产率：85％)。 The 1-(4-(7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d]Pyrimidine-4-yl)piperazin-1-yl)prop-2-en-1-one (450mg, 1.0mmol) was dissolved in dichloromethane (50mL), cooled to -40°C, and BBr 3 was added dropwise (1.3g, 5.2mmol), gradually warm to room temperature, and stir for 2 hours. A saturated aqueous NaHCO 3 solution was added and stirred for 1 hour, and extracted with ethyl acetate (10 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(7-(2-fluoro-6-hydroxybenzene) Yl)-2-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-ene- 1-ketone (350 mg, yield: 85%).
MS m/z(ESI):414.1[M+H] +. MS m/z(ESI): 414.1[M+H] + .
第八步：4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-2(1H)-酮的制备The eighth step: 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl) -4-methylpyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000086
Figure PCTCN2020093731-appb-000086
将4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-2(1H)-酮(100mg，0.24mmol)溶于MeOH(20mL)中，加入2-异丙基-4-甲基-3-吡啶硼酸(90mg，0.5mmol)，醋酸铜(100mg，0.5mmol)，四甲基乙二胺(58mg，0.5mmol)，加热至60℃，搅拌15小时。加入水和乙酸乙酯(10mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标产物4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-2(1H)-酮(12mg，产率：9％)。Add 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6- Methylphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one (100mg, 0.24mmol) dissolved in MeOH (20mL) Add 2-isopropyl-4-methyl-3-pyridineboronic acid (90mg, 0.5mmol), copper acetate (100mg, 0.5mmol), tetramethylethylenediamine (58mg, 0.5mmol), and heat to 60 ℃, stir for 15 hours. Water and ethyl acetate (10 mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain the target product 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro -6-Hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3- d] Pyrimidine-2(1H)-one (12 mg, yield: 9%).
MS m/z(ESI):561.1[M+H] +. MS m/z(ESI): 561.1[M+H] + .
实施例36Example 36
4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-6-甲基苯基)-6-甲基-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-2(1H)-酮的制备4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methyl Phenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000087
Figure PCTCN2020093731-appb-000087
第一步：4,6-二氯-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰)尼克酰胺的制备The first step: the preparation of 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotamide
Figure PCTCN2020093731-appb-000088
Figure PCTCN2020093731-appb-000088
室温下滴加草酰氯(501mg,3.95mmol)到4,6-二氯尼克酰胺(500mg,2.63mmol)的四氢呋喃(30mL)溶液里，加完升高温度到70℃，搅拌1小时，反应冷却至室温，加三乙胺(1063mg,10.5mmol)，再加2-异丙基-4-甲基吡啶-3-胺(1184mg,7.89mmol)的四氢呋喃(10mL)溶液，搅拌1小时。加水(50mL)淬灭反应，用乙酸乙酯(40mL×3)萃取；乙酸乙酯层用饱和NaCl溶液洗涤后，无水硫酸钠干燥，浓缩柱层析[洗脱剂:水～乙腈/水从0％到24％]纯化得到黄色固体4,6-二氯-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰)尼克酰胺(380mg,产率39％)。Add oxalyl chloride (501mg, 3.95mmol) to 4,6-dichloronic amide (500mg, 2.63mmol) in tetrahydrofuran (30mL) solution dropwise at room temperature, increase the temperature to 70℃ after adding, stir for 1 hour, and cool the reaction To room temperature, add triethylamine (1063mg, 10.5mmol), then add 2-isopropyl-4-methylpyridin-3-amine (1184mg, 7.89mmol) in tetrahydrofuran (10mL) and stir for 1 hour. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (40 mL×3); the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated by column chromatography [eluent: water to acetonitrile/water From 0% to 24%] purified to obtain a yellow solid 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (380mg, yield 39 %).
MS m/z(ESI):367.1[M+H] +,369.1[M+H+2] +。 MS m/z (ESI): 367.1 [M+H] + , 369.1 [M+H+2] + .
第二步：7-氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备Step 2: Preparation of 7-chloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000089
Figure PCTCN2020093731-appb-000089
0℃往4,6-二氯-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰)尼克酰胺(343mg,0.937mmol)的四氢呋喃(25mL)溶液里滴加六甲基二硅胺基钾(2.5mL,2.5mmol)，加完搅拌2小时。用氯化铵水溶液(40mL)淬灭反应，乙酸乙酯(20mL×3)萃取，乙酸乙酯层用饱和NaCl溶液洗涤后，无水硫酸钠干燥，浓缩得到浅黄色固体7-氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮(250mg,产率81％)。Drop 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotamide (343mg, 0.937mmol) in tetrahydrofuran (25mL) solution at 0℃ Add potassium hexamethyldisilazide (2.5 mL, 2.5 mmol), and stir for 2 hours after the addition. The reaction was quenched with ammonium chloride aqueous solution (40 mL), extracted with ethyl acetate (20 mL×3), the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow solid 7-chloro-4- Hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (250 mg, yield 81%).
MS m/z(ESI):331.1[M+H] +,369.1[M+H+2] +。 MS m/z (ESI): 331.1 [M+H] + , 369.1 [M+H+2] + .
第三步：4,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备The third step: preparation of 4,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000090
Figure PCTCN2020093731-appb-000090
室温下往7-氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮(240mg,0.727mmol)的乙腈(20mL)溶液里加N,N-二异丙基乙胺(1.4g,11mmol)，再加三氯氧磷(671mg,4.36mmol)，80℃搅拌1小时。冷却至室温，直接用于下一步反应。To 7-chloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (240mg, Add N,N-diisopropylethylamine (1.4g, 11mmol) to a solution of 0.727mmol) in acetonitrile (20mL), then add phosphorus oxychloride (671mg, 4.36mmol), and stir at 80°C for 1 hour. Cool to room temperature and use it directly in the next reaction.
第四步：叔-丁基(S)-4-(7-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯的制备The fourth step: tert-butyl(S)-4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydropyridine Preparation of and [4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000091
Figure PCTCN2020093731-appb-000091
往上一步反应液里加N,N-二异丙基乙胺(938mg,7.27mmol)，加完搅拌5分钟，再加叔-丁基(S)-3-甲基哌嗪-1-羧酸酯(290mg,1.45mmol)，搅拌1小时。补加叔-丁基(S)-3-甲基哌嗪-1-羧酸酯(436mg,2.18mmol)，搅拌1小时。反应用氯化铵水溶液(100mL)淬灭，乙酸乙酯(30mL×3)萃取，有机相用氯化钠水溶液(30mL)洗，旋干柱层析[洗脱剂:二氯甲烷～甲醇(含1％氨水)/二氯甲烷从0％到5％]纯化得到黄色固体产物叔-丁基(S)-4-(7-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(730mg,2步产率196％)。Add N,N-diisopropylethylamine (938mg, 7.27mmol) to the reaction solution of the previous step, stir for 5 minutes after the addition, and then add tert-butyl(S)-3-methylpiperazine-1-carboxylic acid Ester (290mg, 1.45mmol), stirred for 1 hour. Additional tert-butyl (S)-3-methylpiperazine-1-carboxylate (436 mg, 2.18 mmol) was added, and the mixture was stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was washed with aqueous sodium chloride solution (30 mL), and spin-dried column chromatography [eluent: dichloromethane ~ methanol ( Containing 1% ammonia water)/dichloromethane from 0% to 5%] to obtain yellow solid product tert-butyl(S)-4-(7-chloro-1-(2-isopropyl-4-methylpyridine) -3-yl)-2-carbonyl-1,2-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (730mg, 2 steps Rate 196%).
MS m/z(ESI):513.2[M+H] +,515.1[M+H+2] +。 MS m/z (ESI): 513.2 [M+H] + , 515.1 [M+H+2] + .
第五步：(S)-7-氯-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备The fifth step: (S)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[4 ,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000092
Figure PCTCN2020093731-appb-000092
室温下往叔-丁基(S)-4-(7-氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(586mg,1.14mmol)的二氯甲烷(30mL)溶液里加2,6二甲基吡啶(306mg,2.85mmol)，三氟甲磺酸三甲基硅酯(762mg,3.43mmol)。没反应完，补加三氟甲磺酸三甲基硅酯(762mg,3.43mmol)，搅拌1小时。反应液直接用于下一步。To tert-butyl(S)-4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydropyrido at room temperature [4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (586mg, 1.14mmol) in dichloromethane (30mL), add 2,6 lutidine (306mg , 2.85 mmol), trimethylsilyl trifluoromethanesulfonate (762 mg, 3.43 mmol). If the reaction is not complete, add trimethylsilyl trifluoromethanesulfonate (762 mg, 3.43 mmol) and stir for 1 hour. The reaction solution was used directly in the next step.
MS m/z(ESI):413.2[M+H] +,415.1[M+H+2] +。 MS m/z (ESI): 413.2 [M+H] + , 415.1 [M+H+2] + .
第六步：(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备The sixth step: (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl) )Pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000093
Figure PCTCN2020093731-appb-000093
往上一步反应液加入N,N-二异丙基乙胺(1.2mL)，冷却至0℃，加入丙烯酰氯(261mg,2.9mmol)，加完搅拌1小时。反应液用氯化铵水溶液(30mL)淬灭，二氯甲烷(20mL×3)萃取，二氯甲烷层分别用饱和碳酸氢钠水溶液(20mL)，饱和NaCl水溶液(20mL)洗涤，无水硫酸钠干燥后柱层析[洗脱剂:二氯甲烷～甲醇(含1％氨水)/二氯甲烷从0％到5％]纯化得到黄色油状产物(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮(400mg,2步产率75％)。Add N,N-diisopropylethylamine (1.2 mL) to the reaction solution in the previous step, cool to 0°C, add acryloyl chloride (261 mg, 2.9 mmol), and stir for 1 hour after addition. The reaction solution was quenched with aqueous ammonium chloride solution (30 mL) and extracted with dichloromethane (20 mL×3). The dichloromethane layer was washed with saturated aqueous sodium bicarbonate (20 mL) and saturated aqueous NaCl (20 mL), and anhydrous sodium sulfate. After drying, column chromatography [eluent: dichloromethane～methanol (containing 1% ammonia water)/dichloromethane from 0% to 5%] was purified to obtain a yellow oily product (S)-4-(4-acryloyl-2) -Methylpiperazin-1-yl)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidine-2(1H)- Ketone (400 mg, 75% yield in 2 steps).
MS m/z(ESI):467.2[M+H] +,469.1[M+H+2] +。 MS m/z (ESI): 467.2 [M+H] + , 469.1 [M+H+2] + .
第七步：(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-甲氧苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备The seventh step: (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl) Preparation of 4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000094
Figure PCTCN2020093731-appb-000094
(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮(180mg,0.386mmol)，(2-氟-6-甲氧苯基)硼酸(131mg,0.773mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(31mg,0.0386mmol)和碳酸铯(376mg,1.16mmol)在二氧六环(7mL)和水(1mL)中100℃微波搅拌1小时。旋干反应液，柱层析[洗脱剂:二氯甲烷～甲醇(含1％氨水)/二氯甲烷从0％到5％]纯化得到黄色固体产物(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-甲氧苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮(50mg,产率23％)。(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[ 4,3-d]pyrimidin-2(1H)-one (180mg, 0.386mmol), (2-fluoro-6-methoxyphenyl)boronic acid (131mg, 0.773mmol), [1,1'-bis(two Phenylphosphine) ferrocene] dichloropalladium dichloride dichloromethane complex (31mg, 0.0386mmol) and cesium carbonate (376mg, 1.16mmol) in dioxane (7mL) and water (1mL) at 100℃ microwave Stir for 1 hour. The reaction solution was spin-dried and purified by column chromatography [eluent: dichloromethane-methanol (containing 1% ammonia)/dichloromethane from 0% to 5%] to obtain a yellow solid product (S)-4-(4-propylene) Acyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido [4,3-d]pyrimidin-2(1H)-one (50mg, yield 23%).
MS m/z(ESI):557.3[M+H] +。 MS m/z (ESI): 557.3 [M+H] + .
第八步：(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备The eighth step: (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl) Preparation of -4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000095
Figure PCTCN2020093731-appb-000095
0℃往(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-甲氧苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的二氯甲烷(10mL)溶液中滴加三溴化硼(0.45mL,0.45mmol)，溶液慢慢变混浊，加N,N-二异丙基乙胺(0.1mL)，溶液变澄清，反应在0℃搅拌30分钟，再升到室温搅拌1.5小时。把反应液倒入碳酸氢钠水溶液，二氯甲烷萃取(20mL×3)，二氯甲烷相用饱和NaCl溶液洗涤(20mL)，无水硫酸钠干燥后浓缩有机相，制备色谱纯化得到灰色固体产物(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮(1.9mg,产率4％)。0℃ to (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl) -4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one in dichloromethane (10mL) was added dropwise boron tribromide (0.45mL, 0.45mmol) , The solution slowly became turbid, add N,N-diisopropylethylamine (0.1mL), the solution became clear, the reaction was stirred at 0°C for 30 minutes, and then raised to room temperature and stirred for 1.5 hours. Pour the reaction solution into aqueous sodium bicarbonate solution, extract with dichloromethane (20mL×3), wash the dichloromethane phase with saturated NaCl solution (20mL), dry with anhydrous sodium sulfate, concentrate the organic phase, and purify by preparative chromatography to obtain a gray solid product (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methyl Pyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (1.9 mg, yield 4%).
1H NMR(400MHz,Chloroform-d)δ9.32(br,1H),8.64(s,1H),8.26(d,J＝12Hz,1H),7.36-7.30(m,2H),6.88–7.07(m,2H),6.61–6.72(m,2H),6.42(d,J＝16Hz,1H),5.83(d,J＝12Hz,1H),4.53-4.10(m,5H),3.32–3.00(m,3H),1.26(d,J＝4Hz,3H). 1 H NMR(400MHz, Chloroform-d) δ9.32(br,1H), 8.64(s,1H), 8.26(d,J=12Hz,1H), 7.36-7.30(m,2H), 6.88–7.07( m, 2H), 6.61–6.72 (m, 2H), 6.42 (d, J = 16Hz, 1H), 5.83 (d, J = 12Hz, 1H), 4.53-4.10 (m, 5H), 3.32–3.00 (m ,3H),1.26(d,J=4Hz,3H).
MS m/z(ESI):543.2[M+H] +。 MS m/z (ESI): 543.2 [M+H] + .
实施例37Example 37
4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-8-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl) Preparation of -4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000096
Figure PCTCN2020093731-appb-000096
4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-8-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备参照实施例36路线。4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl) The preparation of -4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one refers to the route in Example 36.
1H NMR(400MHz,Chloroform-d)δ9.99(s,1H),8.86(s,1H),8.68(s,1H),7.74–7.68(m,1H),7.49–7.45(m,1H),7.34–7.32(m,1H),6.86(d,J＝8.0Hz,1H),6.68–6.54(m,1H),6.43(d,J＝16.8Hz,1H),5.84(d,J＝10.0Hz,1H),5.33–5.24(m,1H),4.89–4.70(m,1H),4.61–4.40(m,1H),4.12–3.93(m,1H),3.79–3.53(m,2H),3.18–3.93(m,2H),2.26(s,3H),1.50–1.31(m,3H),1.25(s,6H). 1 H NMR (400MHz, Chloroform-d) δ9.99 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 7.74-7.68 (m, 1H), 7.49-7.45 (m, 1H) ,7.34–7.32(m,1H), 6.86(d,J=8.0Hz,1H), 6.68–6.54(m,1H), 6.43(d,J=16.8Hz,1H), 5.84(d,J=10.0 Hz,1H), 5.33-5.24(m,1H), 4.89-4.70(m,1H), 4.61-4.40(m,1H), 4.12-3.93(m,1H), 3.79-3.53(m,2H), 3.18--3.93 (m, 2H), 2.26 (s, 3H), 1.50--1.31 (m, 3H), 1.25 (s, 6H).
MS m/z(ESI):561.1[M+H] +。 MS m/z (ESI): 561.1 [M+H] + .
实施例40Example 40
4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-8-氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-8-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7- Preparation of (5-Methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000097
Figure PCTCN2020093731-appb-000097
4-((S)-4-丙烯酰-2-甲基哌嗪-1-基)-8-氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-2(1H)-酮的制备参照实施例36路线。4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-8-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7- The preparation of (5-methyl-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-2(1H)-one refers to the route in Example 36.
1H NMR(400MHz,Chloroform-d)δ12.2(s,1H),8.85(s,1H),8.66(s,1H),8.40–8.34(m,1H),8.20(s,1H),7.45–7.43(m,1H),6.86(d,J＝8.0Hz,1H),6.69–6.55(m,1H),6.42(d,J＝16.8Hz,1H),5.84(d,J＝10.0Hz,1H),5.32–5.25(m,1H),4.87–4.66(m,1H),4.65–4.43(m,1H),4.10–3.94(m,1H),3.82–3.52(m,2H),3.17–3.96(m,2H),2.35(s,3H),2.26(s,3H),1.48–1.32(m,3H),1.25(s,6H). 1 H NMR (400MHz, Chloroform-d) δ 12.2 (s, 1H), 8.85 (s, 1H), 8.66 (s, 1H), 8.40-8.34 (m, 1H), 8.20 (s, 1H), 7.45 –7.43(m,1H), 6.86(d,J=8.0Hz,1H), 6.69–6.55(m,1H), 6.42(d,J=16.8Hz,1H), 5.84(d,J=10.0Hz, 1H), 5.32--5.25(m,1H), 4.87--4.66(m,1H), 4.65--4.43(m,1H), 4.10--3.94(m,1H), 3.82--3.52(m,2H), 3.17-- 3.96(m, 2H), 2.35(s, 3H), 2.26(s, 3H), 1.48-1.32(m, 3H), 1.25(s, 6H).
MS m/z(ESI):581.1[M+H] +。 MS m/z (ESI): 581.1 [M+H] + .
实施例46Example 46
1-(4-(7-(2-氟-6-羟基苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备1-(4-(7-(2-Fluoro-6-hydroxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5 ,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000098
Figure PCTCN2020093731-appb-000098
第一步：叔-丁基(S)-4-(5-溴-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯的制备The first step: tert-butyl(S)-4-(5-bromo-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piper Preparation of oxazine-1-carboxylate
Figure PCTCN2020093731-appb-000099
Figure PCTCN2020093731-appb-000099
将叔-丁基4-(5-溴-2-氯-6-甲基嘧啶-4-基)哌嗪-1-羧酸酯(6g，15.3mmol)溶于THF(100mL)中，冰浴下加入(S)-(1-甲基吡咯烷-2-基)甲醇(2.3g，20.0mmol)，NaH(800mg，20.0mmol),逐渐升至室温搅拌0.5小时，加热到70℃，继续反应15小时；降至室温，加水淬灭，加入乙酸乙酯(50mL)萃取三次。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基(S)-4-(5-溴-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯(4.3g，产率：60％)。 Dissolve tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (6g, 15.3mmol) in THF (100mL), ice bath Add (S)-(1-methylpyrrolidin-2-yl)methanol (2.3g, 20.0mmol), NaH (800mg, 20.0mmol), gradually increase to room temperature and stir for 0.5 hours, heat to 70°C, continue the reaction 15 hours; cooled to room temperature, quenched with water, and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl(S)-4-(5-bromo- 6-Methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (4.3 g, yield: 60%).
MS m/z(ESI):470.1[M+H] +，472.1[M+H+2] +. MS m/z(ESI): 470.1[M+H] + , 472.1[M+H+2] + .
第二步：叔-丁基(S)-4-(5-甲酰基-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯的制备The second step: tert-butyl(S)-4-(5-formyl-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl) Preparation of piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000100
Figure PCTCN2020093731-appb-000100
将叔-丁基(S)-4-(5-溴-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯(3.5g，7.4mmol)溶于无水THF(100mL)中，氮气保护下，冷却至-78℃，加入n-BuLi(8.9mL，8.9mmol)，搅拌0.5小时。加入DMF/THF(1mL/5mL)，-78℃搅拌1小时，逐渐升至室温。继续搅拌2小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基(S)-4-(5-甲酰基-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯(2.1g，产率：68％)。 Add tert-butyl(S)-4-(5-bromo-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1 -Carboxylate (3.5g, 7.4mmol) was dissolved in dry THF (100mL), cooled to -78°C under nitrogen protection, n-BuLi (8.9mL, 8.9mmol) was added, and stirred for 0.5 hour. Add DMF/THF (1mL/5mL), stir at -78°C for 1 hour, and gradually warm to room temperature. Continue stirring for 2 hours. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by column chromatography (CH 2 Cl 2 /MeOH = 10:1) gave the target product tert-butyl(S)-4-(5-formyl) -6-Methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (2.1 g, yield: 68%).
MS m/z(ESI):420.1[M+H] +. MS m/z(ESI): 420.1[M+H] + .
第三步：叔-丁基(S)-4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯的制备The third step: tert-butyl(S)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-methyl-2-((1-methyl Preparation of pyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000101
Figure PCTCN2020093731-appb-000101
将叔-丁基(S)-4-(5-甲酰基-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯(2g，4.8mmol)溶于二氯甲烷(50mL)中，加入甲胺盐酸盐(640mg，9.6mmol)，NaBH(OAc) 3(1.2g，5.7mmol)和冰醋酸(30mg，0.5mmol)。室温搅拌过夜。加入Boc 2O(2.1g，9.6mmol)，室温搅拌3小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基(S)-4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯(2.1g，产率：83％)。 Add tert-butyl(S)-4-(5-formyl-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine- 1-Carboxylate (2g, 4.8mmol) was dissolved in dichloromethane (50mL), methylamine hydrochloride (640mg, 9.6mmol), NaBH(OAc) 3 (1.2g, 5.7mmol) and glacial acetic acid ( 30mg, 0.5mmol). Stir at room temperature overnight. Add Boc 2 O (2.1 g, 9.6 mmol) and stir at room temperature for 3 hours. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl(S)-4-(5-(( (Tert-Butoxycarbonyl)(methyl)amino)methyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine -1-carboxylate (2.1 g, yield: 83%).
MS m/z(ESI):535.1[M+H] +. MS m/z(ESI): 535.1[M+H] + .
第四步：7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶的制备The fourth step: 7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4- Preparation of (piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine
Figure PCTCN2020093731-appb-000102
Figure PCTCN2020093731-appb-000102
将叔-丁基(S)-4-(5-(((叔-丁氧基羰基)(甲基)氨基)甲基)-6-甲基-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶-4-基)哌嗪-1-羧酸酯(1.8g，3.4mmol)加入NaOH水溶液(5M，100mL)中，加入2-氟-6-甲氧基苯甲醛(630mg，4.1mmol)和三辛基甲基氯化铵(220mg，0.5mmol)，加热至回流，搅拌5小时。冷却，过滤，滤饼用水洗涤，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶(1.5g，产率：66％)。 Add tert-butyl(S)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-methyl-2-((1-methylpyrrolidine- 2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (1.8g, 3.4mmol) was added to aqueous NaOH (5M, 100mL), and 2-fluoro-6-methoxybenzene was added Formaldehyde (630mg, 4.1mmol) and trioctylmethylammonium chloride (220mg, 0.5mmol) were heated to reflux and stirred for 5 hours. Cool, filter, wash the filter cake with water, and purify by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 7-(2-fluoro-6-methoxyphenyl)-6-methyl-2- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3- d] Pyrimidine (1.5 g, yield: 66%).
MS m/z(ESI):671.1[M+H] +. MS m/z(ESI): 671.1[M+H] + .
第五步：1-(4-(7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The fifth step: 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methyl (Oxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000103
Figure PCTCN2020093731-appb-000103
将7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶(1g，1.5mmol)溶于乙酸乙酯(50mL)中，加入2M HCl的乙酸乙酯溶液(6mL)，室温搅拌5小时，浓缩除去溶剂；粗品溶于水(20mL)，加入K 2CO 3(420mg，3.0mmol)和KI(250mg，1.5mmol)，加热至100℃，搅拌15小时，冷却，加入水和乙酸乙酯(3*30mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(320mg，产率：45％)。 7-(2-Fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazine -1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1g, 1.5mmol) was dissolved in ethyl acetate (50mL), and 2M HCl in ethyl acetate was added (6mL), stirred at room temperature for 5 hours, concentrated to remove the solvent; the crude product was dissolved in water (20mL), K 2 CO 3 (420mg, 3.0mmol) and KI (250mg, 1.5mmol) were added, heated to 100°C, stirred for 15 hours, Cool, add water and ethyl acetate (3*30mL) for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(7-(2-fluoro-6-methoxy Phenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3- d] Pyrimidine-4-yl)piperazin-1-yl)prop-2-en-1-one (320 mg, yield: 45%).
MS m/z(ESI):471.1[M+H] +. MS m/z(ESI): 471.1[M+H] + .
第六步：1-(4-(7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The sixth step: 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methyl (Oxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000104
Figure PCTCN2020093731-appb-000104
将1-(4-(7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(300mg，0.64mmol)溶于二氯甲烷(10mL)中，加入DIPEA(400mg，1.9mmol)，室温滴加丙烯酰氯(69mg，0.77mmol),加完继续搅拌1小时。加水淬灭，二氯甲烷(10mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物1-(4-(7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(310mg，产率：93％)。 Add 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) -5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (300mg, 0.64mmol) dissolved in DIPEA (400 mg, 1.9 mmol) was added to dichloromethane (10 mL), acryloyl chloride (69 mg, 0.77 mmol) was added dropwise at room temperature, and stirring was continued for 1 hour after the addition. It was quenched with water, and extracted three times with dichloromethane (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product 1-(4-(7-(2-fluoro-6-methoxy Phenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3- d] Pyrimidine-4-yl)piperazin-1-yl)prop-2-en-1-one (310 mg, yield: 93%).
MS m/z(ESI):525.1[M+H] +. MS m/z(ESI): 525.1[M+H] + .
第七步：1-(4-(7-(2-氟-6-羟基苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The seventh step: 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy (Yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000105
Figure PCTCN2020093731-appb-000105
将1-(4-(7-(2-氟-6-甲氧苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(100mg，0.19mmol)溶于二氯甲烷(20mL)中，冷却到-40℃，滴加入BBr 3(240mg，0.96mmol)，逐渐升至室温，搅拌2小时。加入饱和NaHCO 3水溶液搅拌1小时，乙酸乙酯(10mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标产物1-(4-(7-(2-氟-6-羟基苯基)-6-甲基-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[4,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(23mg，产率：24％)。 Add 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) -5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (100mg, 0.19mmol) dissolved in In dichloromethane (20 mL), cool to -40°C, add BBr 3 (240 mg, 0.96 mmol) dropwise, gradually warm to room temperature, and stir for 2 hours. A saturated aqueous NaHCO 3 solution was added and stirred for 1 hour, and extracted with ethyl acetate (10 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by preparative HPLC to obtain the target product 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-methyl-2-((( S)-1-Methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl ) Pro-2-en-1-one (23 mg, yield: 24%).
MS m/z(ESI):511.1[M+H] +. MS m/z(ESI): 511.1[M+H] + .
实施例47～52的制备参照实施例46路线。The preparation of Examples 47 to 52 refers to the route of Example 46.
实施例i-1Example i-1
1-(4-(7-((5-氯-1H-吲唑-4-基)氧代)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备1-(4-(7-((5-chloro-1H-indazol-4-yl)oxo)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000106
Figure PCTCN2020093731-appb-000106
第一步：叔-丁基4-(2-氯-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯的制备The first step: preparation of tert-butyl 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000107
Figure PCTCN2020093731-appb-000107
将2,4-二氯-6,7-二氢-5H-环戊二烯并[d]嘧啶(5g，26.6mmol)溶于ACN(100mL)中，加入叔-丁基哌嗪-1-羧酸酯(5.9g，31.7mmol)，DIPEA(1.7g，80.9mmol)，室温搅拌5小时。加入水，乙酸乙酯(50mL)萃取三次。合并有机层，无水硫酸钠干燥，过滤，浓缩得 到粗品，柱层析(Petro ether/EtOAc＝5：1)纯化得到目标产物叔-丁基4-(2-氯-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(8.4g，产率：92％)。Dissolve 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5g, 26.6mmol) in ACN (100mL), add tert-butylpiperazine-1- Carboxylate (5.9g, 31.7mmol), DIPEA (1.7g, 80.9mmol), stirred at room temperature for 5 hours. Water was added, and ethyl acetate (50 mL) was extracted three times. The organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography (Petroether/EtOAc=5:1) to obtain the target product tert-butyl 4-(2-chloro-6,7-dihydro) -5H-Cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (8.4 g, yield: 92%).
MS m/z(ESI):339.1[M+H] +,341.1[M+H+2] +. MS m/z(ESI): 339.1[M+H] + ,341.1[M+H+2] + .
第二步：叔-丁基(S)-4-(2-((1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯的制备The second step: tert-butyl(S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta[ d) Preparation of pyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000108
Figure PCTCN2020093731-appb-000108
将叔-丁基4-(2-氯-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(7g，20.7mmol)溶于THF(100mL)中，冰浴下加入(S)-(1-甲基吡咯烷-2-基)甲醇(3.6g，31.3mmol)和NaH(1.3g，32.5mmol)，逐渐升至室温搅拌1小时，加热至回流反应13小时；冷却，加水淬灭，加入乙酸乙酯(50mL)萃取三次。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝5：1)纯化得到目标产物叔-丁基(S)-4-(2-((1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(4.8g，产率：55％)。Dissolve tert-butyl 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (7g, 20.7mmol) In THF (100mL), (S)-(1-methylpyrrolidin-2-yl)methanol (3.6g, 31.3mmol) and NaH (1.3g, 32.5mmol) were added under ice bath, gradually warming to room temperature and stirring It was heated to reflux for 1 hour and reacted for 13 hours; cooled, quenched with water, and extracted with ethyl acetate (50 mL) for three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (Petroether/EtOAc=5:1) to obtain the target product tert-butyl(S)-4-(2-((1- Methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (4.8g, yield Rate: 55%).
MS m/z(ESI):418.1[M+H] +. MS m/z(ESI): 418.1[M+H] + .
第三步：叔-丁基4-(7-溴-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯的制备The third step: tert-butyl 4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta Preparation of Dieno[d]pyrimidin-4-yl)piperazine-1-carboxylate
Figure PCTCN2020093731-appb-000109
Figure PCTCN2020093731-appb-000109
将叔-丁基(S)-4-(2-((1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(4g，9.6mmol)溶于冰醋酸(30mL)中，室温下，加入液溴(2.3g，14.3mmol)，搅拌15小时。加入饱和碳酸氢钠水溶液调节至碱性，乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基4-(7-溴-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(2.6g，产率：54％)。 Add tert-butyl(S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine -4-yl)piperazine-1-carboxylate (4 g, 9.6 mmol) was dissolved in glacial acetic acid (30 mL), and liquid bromine (2.3 g, 14.3 mmol) was added at room temperature, and the mixture was stirred for 15 hours. Saturated aqueous sodium bicarbonate solution was added to adjust to basicity, and extracted with ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl 4-(7-bromo-2-(( (S)-1-Methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-yl)piperazine-1-carboxylic acid Esters (2.6 g, yield: 54%).
MS m/z(ESI):496.1[M+H] +,498.1[M+H+2] +. MS m/z(ESI): 496.1[M+H] + ,498.1[M+H+2] + .
第四步：叔-丁基4-(7-((5-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧代)-2-(((S)-1-甲 基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯的制备The fourth step: tert-butyl 4-(7-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxo)-2- (((S)-1-Methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-yl)piperazine-1- Preparation of carboxylate
Figure PCTCN2020093731-appb-000110
Figure PCTCN2020093731-appb-000110
将叔-丁基4-(7-溴-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(200mg，0.4mmol)溶于DMF(50mL)中，加入5-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-醇(200mg，0.8mmol)，冰浴下加入NaH(35mg，8.8mmol)。逐渐升至室温搅拌过夜。加水淬灭，乙酸乙酯(3*20mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基4-(7-((5-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧代)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(160mg，产率：60％)。 The tert-butyl 4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopentadieno [d]Pyrimidine-4-yl)piperazine-1-carboxylate (200mg, 0.4mmol) was dissolved in DMF (50mL), and 5-chloro-1-(tetrahydro-2H-pyran-2-yl )-1H-indazol-4-ol (200mg, 0.8mmol), NaH (35mg, 8.8mmol) was added under ice bath. It was gradually raised to room temperature and stirred overnight. It was quenched with water, and extracted with ethyl acetate (3*20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl 4-(7-((5-chloro- 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxo)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy Yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (160 mg, yield: 60%).
MS m/z(ESI):668.1[M+H] +. MS m/z(ESI): 668.1[M+H] + .
第五步：5-氯-4-((2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-7-基)氧代)-1H-吲唑的制备The fifth step: 5-chloro-4-((2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7 -Dihydro-5H-cyclopenta[d]pyrimidin-7-yl)oxo)-1H-indazole
Figure PCTCN2020093731-appb-000111
Figure PCTCN2020093731-appb-000111
将叔-丁基4-(7-((5-氯-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧代)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-羧酸酯(150mg，0.22mmol)加入TFA(10mL)中，室温搅拌2小时。浓缩，得到粗品目标产物5-氯-4-((2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-7-基)氧代)-1H-吲唑(180mg)。The tert-butyl 4-(7-((5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxo)-2-((( S)-1-Methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-yl)piperazine-1-carboxylate (150mg, 0.22mmol) was added to TFA (10mL) and stirred at room temperature for 2 hours. Concentrate to obtain the crude target product 5-chloro-4-((2-((((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6 ,7-Dihydro-5H-cyclopenta[d]pyrimidin-7-yl)oxo)-1H-indazole (180mg).
MS m/z(ESI):484.1[M+H] +. MS m/z(ESI): 484.1[M+H] + .
第六步：1-(4-(7-((5-氯-1H-吲唑-4-基)氧代)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的制备The sixth step: 1-(4-(7-((5-chloro-1H-indazol-4-yl)oxo)-2-(((S)-1-methylpyrrolidin-2-yl) (Methoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000112
Figure PCTCN2020093731-appb-000112
将5-氯-4-((2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-7-基)氧代)-1H-吲唑(180mg，0.22mmol)溶于二氯甲烷(30mL)中，加入DIPEA(140mg，0.66mmol)，室温滴加丙烯酰氯(30mg，0.33mmol),加完继续搅拌1小时。加入饱和NaHCO 3水溶液搅拌1小时，二氯甲烷(10mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标产物1-(4-(7-((5-氯-1H-吲唑-4-基)氧代)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮(53mg，产率：57％)。 Add 5-chloro-4-((2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-6,7-dihydro -5H-Cyclopenta[d]pyrimidin-7-yl)oxo)-1H-indazole (180mg, 0.22mmol) was dissolved in dichloromethane (30mL), DIPEA (140mg, 0.66mmol) was added, Add acryloyl chloride (30mg, 0.33mmol) dropwise at room temperature, and continue stirring for 1 hour after the addition. A saturated aqueous NaHCO 3 solution was added and stirred for 1 hour, and extracted with dichloromethane (10 mL) three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain the target product 1-(4-(7-((5-chloro-1H-indazol-4-yl)oxo)-2-( ((S)-1-Methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-cyclopenta(d)pyrimidin-4-yl)piperazin-1-yl ) Pro-2-en-1-one (53 mg, yield: 57%).
MS m/z(ESI):538.1[M+H] +,540.1[M+H+2] +. MS m/z(ESI): 538.1[M+H] + ,540.1[M+H+2] + .
实施例i-2～i-6的制备参照实施例i-1路线。The preparation of Examples i-2 to i-6 refers to the route of Example i-1.
实施例ii-1Example ii-1
(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-((2-(三氟甲基)吡啶-3-基)硫代)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7- ((2-(Trifluoromethyl)pyridin-3-yl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000113
Figure PCTCN2020093731-appb-000113
第一步：2,6-二氯-5-氟尼克酰胺的制备The first step: the preparation of 2,6-dichloro-5-fluoronicotamide
Figure PCTCN2020093731-appb-000114
Figure PCTCN2020093731-appb-000114
将2,6-二氯-5-氟尼古丁酸(25g，119mmol)溶于THF(100mL)中，分批加入N,N'-羰基二咪唑(21.2g，131mmol)，50℃搅拌2小时。反应液冷却至25℃，加入甲苯(100mL)，浓缩至80mL。浓缩物冷却至0℃，滴加氨水(30mL)，反应液逐渐升至室温搅拌2小时。加入大量水，乙酸乙酯(100mL)萃取三次。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝3：1)纯化得到目标产物2,6-二氯-5-氟尼克酰胺(13g，产率：53％)。2,6-Dichloro-5-fluoronicotinic acid (25g, 119mmol) was dissolved in THF (100mL), N,N'-carbonyldiimidazole (21.2g, 131mmol) was added in portions, and the mixture was stirred at 50°C for 2 hours. The reaction solution was cooled to 25°C, toluene (100 mL) was added, and the mixture was concentrated to 80 mL. The concentrate was cooled to 0°C, ammonia water (30 mL) was added dropwise, and the reaction solution was gradually raised to room temperature and stirred for 2 hours. A large amount of water was added, and ethyl acetate (100 mL) was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography (Petroether/EtOAc=3:1) gave the target product 2,6-dichloro-5-fluoronicotamide (13g, yield : 53%).
第二步：2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰)尼克酰胺的制备Step 2: Preparation of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotamide
Figure PCTCN2020093731-appb-000115
Figure PCTCN2020093731-appb-000115
将2,6-二氯-5-氟尼克酰胺(3g，14.4mmol)溶于THF(50mL)中，室温滴加草酰氯(1.4mL，15.9mmol)，室温搅拌1小时，60℃搅拌3小时，反应液冷却至0℃，滴加三乙胺(9mL，58mmol)，滴加2-异丙基-4-甲基吡啶-3-胺的THF溶液(2.5g，15.9mmol)，室温搅拌12小时。加水淬灭，加水和乙酸乙酯(3*100mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝3：1)纯化得到目标产物2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰)尼克酰胺(1g，产率：18％)。Dissolve 2,6-Dichloro-5-fluoronicotamide (3g, 14.4mmol) in THF (50mL), add oxalyl chloride (1.4mL, 15.9mmol) dropwise at room temperature, stir at room temperature for 1 hour, and at 60°C for 3 hours The reaction solution was cooled to 0°C, triethylamine (9mL, 58mmol) was added dropwise, 2-isopropyl-4-methylpyridin-3-amine THF solution (2.5g, 15.9mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hour. It was quenched with water, and extracted with water and ethyl acetate (3*100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (Petroether/EtOAc=3:1) to obtain the target product 2,6-dichloro-5-fluoro-N-((2- Isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotamide (1 g, yield: 18%).
MS m/z(ESI):385.1[M+H] +，387.1[M+H+2] +. MS m/z(ESI): 385.1[M+H] + , 387.1[M+H+2] + .
第三步：7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的制备The third step: 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H) -Preparation of diketone
Figure PCTCN2020093731-appb-000116
Figure PCTCN2020093731-appb-000116
将2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)氨基甲酰)尼克酰胺(1g，2.6mmol)溶于无水THF(50mL)中，氮气保护下，冷却至0℃，滴加KHMDS(5.5mL，5.5mmol)，搅拌0.5小时。加饱和氯化铵水溶液淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(Petro ether/EtOAc＝2：1)纯化得到目标产物7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(800mg，产率：88％)。2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (1g, 2.6mmol) was dissolved in dry THF ( 50mL), cooled to 0°C under the protection of nitrogen, KHMDS (5.5mL, 5.5mmol) was added dropwise, and stirred for 0.5 hour. It was quenched with saturated aqueous ammonium chloride solution, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by column chromatography (Petroether/EtOAc=2:1) gave the target product 7-chloro-6-fluoro-1-(2-isopropyl- 4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (800 mg, yield: 88%).
MS m/z(ESI):349.1[M+H] +,351.1[M+H+2] +. MS m/z(ESI): 349.1[M+H] + ,351.1[M+H+2] + .
第四步：4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The fourth step: 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Preparation of ketones
Figure PCTCN2020093731-appb-000117
Figure PCTCN2020093731-appb-000117
将7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(200mg，0.6mmol)溶于ACN(10mL)中，加入DIEA(0.6mL，3mmol),POCl 3(0.1mL,0.86mmol)，80℃搅拌0.5小时。直接用于下一步反应。 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 0.6 mmol) was dissolved in ACN (10 mL), DIEA (0.6 mL, 3 mmol), POCl 3 (0.1 mL, 0.86 mmol) were added, and the mixture was stirred at 80°C for 0.5 hours. Used directly in the next reaction.
MS m/z(ESI):367.1[M+H] +,369.1[M+H+2] +. MS m/z(ESI): 367.1[M+H] + ,369.1[M+H+2] + .
第五步：叔-丁基(S)-4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯的制备The fifth step: tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2 -Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000118
Figure PCTCN2020093731-appb-000118
将4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(200mg，0.6mmol)的ACN(10mL)中，加入DIEA(0.6mL，3mmol)，加入叔-丁基(S)-3-甲基哌嗪-1-羧酸酯(170mg，0.9mmol)，室温搅拌1小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝20：1)纯化得到目标产物叔-丁基(S)-4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(160mg，产率：50％)。 The 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (200mg , 0.6mmol) of ACN (10mL), add DIEA (0.6mL, 3mmol), add tert-butyl(S)-3-methylpiperazine-1-carboxylate (170mg, 0.9mmol), stir at room temperature 1 hour. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 20:1) to obtain the target product tert-butyl(S)-4-(7-chloro- 6-Fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (160 mg, yield: 50%).
MS m/z(ESI):531.1[M+H] +,533.1[M+H+2] +. MS m/z(ESI): 531.1[M+H] + ,533.1[M+H+2] + .
第六步：叔-丁基(S)-4-(6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-7-((2-(三氟甲基)吡啶-3-基)硫代)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯的制备The sixth step: tert-butyl(S)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-7-((2-( Trifluoromethyl)pyridin-3-yl)thio)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate preparation
Figure PCTCN2020093731-appb-000119
Figure PCTCN2020093731-appb-000119
将叔-丁基(S)-4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(130mg，0.25mmol)溶于ACN(10mL)中，加入K 2CO 3(34mg，0.25mmol)，2-(三氟甲基)吡啶-3-硫醇酸钾(110mg，0.5mmol)，室温搅拌2小时。加入水和乙酸乙酯(3*30mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标产物叔-丁基(S)-4-(6-氟-1-(2-异丙基-4-甲 基吡啶-3-基)-2-羰基-7-((2-(三氟甲基)吡啶-3-基)硫代)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(150mg，产率：89％)。 Add tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (130mg, 0.25mmol) was dissolved in ACN (10mL), and K 2 CO 3 (34mg, 0.25 mmol), potassium 2-(trifluoromethyl)pyridine-3-thiolate (110 mg, 0.5 mmol), stirred at room temperature for 2 hours. Water and ethyl acetate (3*30 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target product tert-butyl(S)-4-(6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-7-((2-(trifluoromethyl)pyridin-3-yl)thio)-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (150 mg, yield: 89%).
MS m/z(ESI):674.1[M+H] +. MS m/z(ESI): 674.1[M+H] + .
第七步：(S)-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-((2-(三氟甲基)吡啶-3-基)硫代)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The seventh step: (S)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7-( (2-(Trifluoromethyl)pyridin-3-yl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000120
Figure PCTCN2020093731-appb-000120
将叔-丁基(S)-4-(6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-7-((2-(三氟甲基)吡啶-3-基)硫代)-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(150mg，0.22mmol)溶于二氯甲烷(10mL)中，加入TFA(1mL)，室温搅拌2小时。0℃下把反应液倒入饱和NaHCO 3水溶液中，二氯甲烷(20mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品目标产物(S)-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-((2-(三氟甲基)吡啶-3-基)硫代)吡啶并[2,3-d]嘧啶-2(1H)-酮(130mg，产率：100％)。 Add tert-butyl(S)-4-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-7-((2-(trifluoromethyl (Yl)pyridin-3-yl)thio)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (150mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated NaHCO 3 aqueous solution at 0°C, and dichloromethane (20 mL) was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude target product (S)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methyl Piperazin-1-yl)-7-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one (130mg, yield Rate: 100%).
MS m/z(ESI):574.1[M+H] +. MS m/z(ESI): 574.1[M+H] + .
第八步：(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-((2-(三氟甲基)吡啶-3-基)硫代)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The eighth step: (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl) )-7-((2-(Trifluoromethyl)pyridin-3-yl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000121
Figure PCTCN2020093731-appb-000121
将(S)-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(2-甲基哌嗪-1-基)-7-((2-(三氟甲基)吡啶-3-基)硫代)吡啶并[2,3-d]嘧啶-2(1H)-酮(130mg，0.22mmol)溶于二氯甲烷(10mL)中，加入DIEA(0.2mL，0.6mmol)，加入丙烯酰氯(40mg，0.44mmol)，室温搅拌1小时。加水淬灭，加水和乙酸乙酯(3*50mL)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝20：1)纯化得到目标产物(S)-4-(4-丙烯酰-2-甲基哌嗪-1-基)-6- 氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-((2-(三氟甲基)吡啶-3-基)硫代)吡啶并[2,3-d]嘧啶-2(1H)-酮(5mg，产率：4％)。 (S)-6-Fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)-7-((2- (Trifluoromethyl)pyridin-3-yl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one (130mg, 0.22mmol) was dissolved in dichloromethane (10mL), and DIEA was added (0.2mL, 0.6mmol), add acryloyl chloride (40mg, 0.44mmol), stir at room temperature for 1 hour. It was quenched with water, and extracted with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 20:1) to obtain the target product (S)-4-(4-acryloyl-2-methyl) Piperazine-1-yl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-((2-(trifluoromethyl)pyridin-3-yl )Thio)pyrido[2,3-d]pyrimidin-2(1H)-one (5mg, yield: 4%).
1H NMR(400MHz,Methanol-d 4)δ8.60(dd,J＝4.8,1.6Hz,1H),8.33(d,J＝5.0Hz,1H),8.12(d,J＝6.8Hz,1H),7.83(dd,J＝8.0,1.6Hz,1H),7.37(dd,J＝8.0,4.8Hz,1H),7.06(d,J＝5.0Hz,1H),6.82(d,J＝12Hz,1H),6.44–6.24(m,1H),5.82(dd,J＝10.6,2.0Hz,1H),4.98(d,J＝59.0Hz,2H),4.40(m,2H),4.11(dd,J＝48.8,13.6Hz,1H),3.93–3.48(m,2H),2.70–2.50(m,1H),1.79(d,J＝3.8Hz,3H),1.52–1.36(m,3H),1.08(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H). 1 H NMR(400MHz,Methanol-d 4 )δ8.60(dd,J＝4.8,1.6Hz,1H), 8.33(d,J＝5.0Hz,1H), 8.12(d,J＝6.8Hz,1H) ,7.83(dd,J=8.0,1.6Hz,1H), 7.37(dd,J=8.0,4.8Hz,1H), 7.06(d,J=5.0Hz,1H), 6.82(d,J=12Hz,1H ), 6.44–6.24 (m, 1H), 5.82 (dd, J = 10.6, 2.0 Hz, 1H), 4.98 (d, J = 59.0 Hz, 2H), 4.40 (m, 2H), 4.11 (dd, J = 48.8, 13.6 Hz, 1H), 3.93–3.48 (m, 2H), 2.70–2.50 (m, 1H), 1.79 (d, J = 3.8 Hz, 3H), 1.52–1.36 (m, 3H), 1.08 (d ,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).
MS m/z(ESI):628.1[M+H] +. MS m/z(ESI):628.1[M+H] + .
实施例ii-2～ii-3的制备参照实施例ii-1路线。The preparation of Examples ii-2 to ii-3 refers to the route of Example ii-1.
实施例ii-8Example ii-8
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-甲基-3-亚甲基-2-羰基-1,8-二氮杂螺[4.5]癸烷-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-methyl-3-methylene Preparation of 2-carbonyl-1,8-diazaspiro[4.5]decane-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000122
Figure PCTCN2020093731-appb-000122
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-甲基-3-亚甲基-2-羰基-1,8-二氮杂螺[4.5]癸烷-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-methyl-3-methylene 2-carbonyl-1,8-diazaspiro[4.5]decane-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.
1H NMR(400MHz,MeOD)δ8.30(d,J＝8Hz,1H),8.20(d,J＝8Hz,1H),7.21–7.08(m,2H),6.61–6.43(m,2H),5.88(s,1H),5.40(s,1H),4.68–4.56(m,2H),4.49(s,2H),3.53–3.34(m,2H),2.85(s,3H),2.79–2.64(m,1H),2.38–2.16(m,2H),1.93(s,3H),1.62–1.42(m,2H),1.10(d,J＝8Hz,3H),0.93(d,J＝8Hz,3H). 1 H NMR (400MHz, MeOD) δ8.30 (d, J = 8Hz, 1H), 8.20 (d, J = 8Hz, 1H), 7.21-7.08 (m, 2H), 6.61-6.43 (m, 2H), 5.88(s, 1H), 5.40(s, 1H), 4.68-4.56(m, 2H), 4.49(s, 2H), 3.53-3.34(m, 2H), 2.85(s, 3H), 2.79-2.64( m,1H),2.38–2.16(m,2H),1.93(s,3H),1.62–1.42(m,2H),1.10(d,J=8Hz,3H),0.93(d,J=8Hz,3H ).
MS m/z(ESI):587.3[M+H] +。 MS m/z (ESI): 587.3 [M+H] + .
实施例ii-10Example ii-10
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3-methylene- Preparation of 2-carbonylpyrrolidin-1-yl)azetidine-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000123
Figure PCTCN2020093731-appb-000123
第1步：叔-丁基3-(4-氯丁酰氨基)吖丁啶-1-羧酸酯的制备Step 1: Preparation of tert-butyl 3-(4-chlorobutyrylamino)azetidine-1-carboxylate
Figure PCTCN2020093731-appb-000124
Figure PCTCN2020093731-appb-000124
0℃往叔-丁基3-氨基吖丁啶-1-羧酸酯(2g,11.63mmol)和三乙胺(2.3g,23.26mmol)的二氯甲烷(50mL)溶液中加4-氯丁酰氯(2g,13.95mmol)，加完室温搅拌2小时。加水(60mL)，二氯甲烷(40mL×3)萃取，二氯甲烷相用饱和食盐水洗涤，浓缩后柱层析[洗脱剂:二氯甲烷～甲醇/二氯甲烷从0％到3％]纯化得到叔-丁基3-(4-氯丁酰氨基)吖丁啶-1-羧酸酯(3g,产率97％)无色油。Add 4-chlorobutane to a solution of tert-butyl 3-aminoazetidine-1-carboxylate (2g, 11.63mmol) and triethylamine (2.3g, 23.26mmol) in dichloromethane (50mL) at 0°C Acid chloride (2g, 13.95mmol), after adding, stir at room temperature for 2 hours. Add water (60mL), extract with dichloromethane (40mL×3), wash the dichloromethane phase with saturated brine, concentrate and column chromatography [eluent: dichloromethane～methanol/dichloromethane from 0% to 3% ] Purified to obtain tert-butyl 3-(4-chlorobutyrylamino)azetidine-1-carboxylate (3g, yield 97%) as a colorless oil.
MS m/z(ESI):267.2[M+H] +，269.2[M+H+2] +. MS m/z(ESI): 267.2[M+H] + , 269.2[M+H+2] + .
第2步：叔-丁基3-(2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯的制备Step 2: Preparation of tert-butyl 3-(2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate
Figure PCTCN2020093731-appb-000125
Figure PCTCN2020093731-appb-000125
0℃往叔-丁基3-(4-氯丁酰氨基)吖丁啶-1-羧酸酯(2.5g,9.36mmol)的四氢呋喃(80mL)溶液中加钠氢(543mg,13.6mmol)，加完搅拌2小时。反应用氯化铵水溶液(60mL)淬灭，乙酸乙酯(50mL×3)萃取，乙酸乙酯层用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到叔-丁基3-(2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯(2.3g,产率100％)无色油。Add sodium hydrogen (543mg, 13.6mmol) to the solution of tert-butyl 3-(4-chlorobutyrylamino)azetidine-1-carboxylate (2.5g, 9.36mmol) in tetrahydrofuran (80mL) at 0°C, Stir for 2 hours after adding. The reaction was quenched with aqueous ammonium chloride solution (60 mL), extracted with ethyl acetate (50 mL×3), the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain tert-butyl 3-(2-carbonyl Pyrrolidin-1-yl)azetidine-1-carboxylate (2.3 g, yield 100%) colorless oil.
MS m/z(ESI):241.2[M+H] +。 MS m/z (ESI): 241.2 [M+H] + .
第3步：1-(1-(叔-丁氧基羰基)吖丁啶-3-基)-2-羰基吡咯烷-3-羧酸乙酯的制备Step 3: Preparation of 1-(1-(tert-butoxycarbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid ethyl ester
Figure PCTCN2020093731-appb-000126
Figure PCTCN2020093731-appb-000126
-78℃下往叔-丁基3-(2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯(500mg,2.08mmol)的四氢呋喃(12mL)溶液里滴加六甲基二硅胺基锂(4.2mL,4.2mmol)，加完-78℃搅拌1小时，滴 加碳酸二乙酯(492mg,4.17mmol)的四氢呋喃(3mL)溶液，加完-78℃搅拌1小时，慢慢升至0℃搅拌30分钟。反应用氯化铵水溶液(40mL)淬灭，乙酸乙酯(40mL×3)萃取，乙酸乙酯层用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到1-(1-(叔-丁氧基羰基)吖丁啶-3-基)-2-羰基吡咯烷-3-羧酸乙酯(900mg,产率138％)无色油。To tert-butyl 3-(2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate (500mg, 2.08mmol) in tetrahydrofuran (12mL) at -78℃, add hexamethyl bis Lithium silylamide (4.2mL, 4.2mmol), stir for 1 hour at -78°C after adding, add dropwise a solution of diethyl carbonate (492mg, 4.17mmol) in tetrahydrofuran (3mL), stir for 1 hour at -78°C after adding, slowly Slowly raise to 0°C and stir for 30 minutes. The reaction was quenched with aqueous ammonium chloride (40mL), extracted with ethyl acetate (40mL×3), the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1-(1-(tert-butoxy) Carbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid ethyl ester (900mg, yield 138%) colorless oil.
MS m/z(ESI):313.2[M+H] +。 MS m/z (ESI): 313.2 [M+H] + .
第4步：1-(1-(叔-丁氧基羰基)吖丁啶-3-基)-2-羰基吡咯烷-3-羧酸的制备Step 4: Preparation of 1-(1-(tert-butoxycarbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid
Figure PCTCN2020093731-appb-000127
Figure PCTCN2020093731-appb-000127
1-(1-(叔-丁氧基羰基)吖丁啶-3-基)-2-羰基吡咯烷-3-羧酸乙酯粗品(900mg,2.08mmol)和一水合氢氧化锂(349mg,8.32mmol)在四氢呋喃(15mL)和水(3mL)中室温搅拌1.5小时。加水(50mL)，用乙酸乙酯(30mL×2)洗，然后用盐酸把水相调到pH～3，乙酸乙酯(30mL×3)萃取，乙酸乙酯相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到1-(1-(叔-丁氧基羰基)吖丁啶-3-基)-2-羰基吡咯烷-3-羧酸(360mg,产率44％)黄色油。1-(1-(tert-Butoxycarbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid ethyl ester (900mg, 2.08mmol) and lithium hydroxide monohydrate (349mg, 8.32mmol) was stirred in tetrahydrofuran (15mL) and water (3mL) for 1.5 hours at room temperature. Add water (50mL), wash with ethyl acetate (30mL×2), then adjust the aqueous phase to pH~3 with hydrochloric acid, extract with ethyl acetate (30mL×3), wash the ethyl acetate phase with saturated brine, anhydrous It was dried over sodium sulfate and concentrated to obtain 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid (360 mg, yield 44%) as a yellow oil.
MS m/z(ESI):285.1[M+H] +。 MS m/z (ESI): 285.1 [M+H] + .
第5步：叔-丁基3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯的制备Step 5: Preparation of tert-butyl 3-(3-methylene-2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate
Figure PCTCN2020093731-appb-000128
Figure PCTCN2020093731-appb-000128
0℃往1-(1-(叔-丁氧基羰基)吖丁啶-3-基)-2-羰基吡咯烷-3-羧酸(360mg,1.27mmol)和多聚甲醛(57mg,1.91mmol)的乙酸乙酯(10mL)中加二甲胺四氢呋喃溶液(0.76mL,1.2mol/L)，加完80℃搅拌2小时。浓缩反应液，柱层析[洗脱剂:石油醚～乙酸乙酯/石油醚从0％到50％到二氯甲烷/乙酸乙酯＝1/1]纯化得到叔-丁基3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯(250mg,产率78％)白色固体。0℃ to 1-(1-(tert-butoxycarbonyl)azetidine-3-yl)-2-carbonylpyrrolidine-3-carboxylic acid (360mg, 1.27mmol) and paraformaldehyde (57mg, 1.91mmol) Add dimethylamine tetrahydrofuran solution (0.76 mL, 1.2 mol/L) to ethyl acetate (10 mL), and stir at 80°C for 2 hours after the addition. The reaction solution was concentrated and purified by column chromatography [eluent: petroleum ether ~ ethyl acetate/petroleum ether from 0% to 50% to dichloromethane/ethyl acetate = 1/1] to obtain tert-butyl 3-(3 -Methylene-2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate (250 mg, yield 78%) white solid.
MS m/z(ESI):253.2[M+H] +。 MS m/z (ESI): 253.2 [M+H] + .
第6步：7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 6: 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H) -Preparation of ketones
Figure PCTCN2020093731-appb-000129
Figure PCTCN2020093731-appb-000129
室温下往叔-丁基3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯(100mg,0.4mmol)的甲醇(1mL)溶液中加盐酸二氧六环溶液(5mL,4mol/L)，加完室温搅拌1小时，浓缩反应液得到7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮盐酸盐(100mg,产率133％)无色油。Add hydrochloric acid to a solution of tert-butyl 3-(3-methylene-2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate (100mg, 0.4mmol) in methanol (1mL) at room temperature Dioxane solution (5mL, 4mol/L), add to room temperature and stir for 1 hour, concentrate the reaction solution to obtain 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridine) -3-yl)pyrido[2,3-d]pyrimidine-2(1H)-one hydrochloride (100 mg, yield 133%) colorless oil.
MS m/z(ESI):153.1[M+H] +. MS m/z(ESI): 153.1[M+H] + .
第7步：4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 7: 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Preparation of ketones
Figure PCTCN2020093731-appb-000130
Figure PCTCN2020093731-appb-000130
室温下往7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(100mg,0.287mmol)的乙腈(8mL)溶液里加N,N-二异丙基乙胺(370mg,2.87mmol)，再加三氯氧磷(133mg,0.862mmol)，80℃搅拌1小时。冷却至室温，直接用于下一步反应。To 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- at room temperature Add N,N-diisopropylethylamine (370mg, 2.87mmol) to the acetonitrile (8mL) solution of ketone (100mg, 0.287mmol), then add phosphorus oxychloride (133mg, 0.862mmol), and stir at 80°C for 1 hour. Cool to room temperature and directly use in the next reaction.
第8步：7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 8: 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3-methylene-2-carbonylpyrrolidine- Preparation of 1-yl)azetidine-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000131
Figure PCTCN2020093731-appb-000131
将上一步反应液加到7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮盐酸盐粗品(100mg,0.4mmol)和N,N-二异丙基乙胺(370mg,2.87mmol)的乙腈(5mL)溶液中，室温搅拌1小时。加水(60mL)，用乙酸乙酯(40mL×3)萃取，有机相用氯化铵水溶液(40mL)洗涤，再用氯化钠水溶液(30mL)洗涤，浓缩后制备色谱[洗脱剂:乙酸乙酯]纯化得到7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(70mg,产率50％)黄色油。Add the reaction solution from the previous step to 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2 (1H)-ketone hydrochloride crude product (100mg, 0.4mmol) and N,N-diisopropylethylamine (370mg, 2.87mmol) in acetonitrile (5mL) solution, stirred at room temperature for 1 hour. Add water (60mL), extract with ethyl acetate (40mL×3), wash the organic phase with ammonium chloride aqueous solution (40mL), then with sodium chloride aqueous solution (30mL), concentrate and prepare chromatography [eluent: ethyl acetate Ester] was purified to obtain 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3-methylene-2-carbonylpyrrolidine- 1-yl)azetidine-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (70 mg, yield 50%) yellow oil.
MS m/z(ESI):482.2[M+H] +，484.2[M+H+2] + MS m/z(ESI): 482.2[M+H] + , 484.2[M+H+2] +
第9步：6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备Step 9: 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3- Preparation of methylene-2-carbonylpyrrolidin-1-yl)azetidin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000132
Figure PCTCN2020093731-appb-000132
7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(35mg,0.073mmol)，(2-氟-6-羟基苯基)硼酸(23mg,0.145mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(6mg,0.0073mmol)和碳酸铯(71mg,0.219mmol)在二氧六环(2mL)和水(4滴)中100℃微波搅拌1小时。过滤反应液，浓缩滤液，制备色谱[洗脱剂:二氯甲烷/甲醇＝12/1]纯化得到6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(3-(3-亚甲基-2-羰基吡咯烷-1-基)吖丁啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(13mg,产率32％)黄色固体。7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-(3-methylene-2-carbonylpyrrolidin-1-yl) Azetidine-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (35mg, 0.073mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (23mg, 0.145mmol) , [1,1'-Bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (6mg, 0.0073mmol) and cesium carbonate (71mg, 0.219mmol) in dioxane (2mL ) And water (4 drops) with microwave stirring at 100°C for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative chromatography [eluent: dichloromethane/methanol=12/1] to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-iso Propyl-4-methylpyridin-3-yl)-4-(3-(3-methylene-2-carbonylpyrrolidin-1-yl)azetidine-1-yl)pyrido[2,3 -d] Pyrimidine-2(1H)-one (13 mg, yield 32%) yellow solid.
1H NMR(400MHz,CDCl 3)δ9.20(s,1H),8.61(d,J＝4Hz,1H),7.92(d,J＝12Hz,1H),7.33–7.27(m,2H),6.77–6.60(m,2H),6.08(s,1H),5.46(s,1H),5.34–5.19(m,1H),4.92(s,4H),3.77–3.57(m,2H),2.99–2.88(m,2H),2.87–2.64(m,1H),2.12(s,3H),1.29(d,J＝4Hz,3H),1.12(d,J＝4Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ9.20(s,1H), 8.61(d,J=4Hz,1H),7.92(d,J=12Hz,1H),7.33-7.27(m,2H),6.77 --6.60 (m, 2H), 6.08 (s, 1H), 5.46 (s, 1H), 5.34 - 5.19 (m, 1H), 4.92 (s, 4H), 3.77 - 3.57 (m, 2H), 2.99 - 2.88 (m, 2H), 2.87–2.64 (m, 1H), 2.12 (s, 3H), 1.29 (d, J = 4 Hz, 3H), 1.12 (d, J = 4 Hz, 3H).
MS m/z(ESI):559.2[M+H] +。 MS m/z (ESI): 559.2 [M+H] + .
实施例ii-11Example ii-11
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-羰基-8-氮杂螺[4.5]癸-2-烯-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8-azaspiro [4.5] Preparation of dec-2-en-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000133
Figure PCTCN2020093731-appb-000133
第一步：叔-丁基4-烯丙基-4-甲酰基哌啶-1-羧酸酯的制备Step 1: Preparation of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate
Figure PCTCN2020093731-appb-000134
Figure PCTCN2020093731-appb-000134
在0℃下，往叔-丁基4-甲酰基哌啶-1-羧酸酯(30g,14.1mmol)的N,N-二甲基甲酰胺 (300mL)中加叔丁醇锂(13.5g,16.9mmol)，加完搅拌30分钟，再加烯丙基溴(19g,16.2mmol)，加完0℃搅拌2小时。把反应液倒入氯化铵水溶液(1L)里，用乙酸乙酯萃取(1L×2)，乙酸乙酯层用饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥后柱层析[洗脱剂:石油醚～乙酸乙酯/石油醚从0％到2％]纯化得到无色油状产物叔-丁基4-烯丙基-4-甲酰基哌啶-1-羧酸酯(15g,产率42％)。Add lithium tert-butoxide (13.5g) to the N,N-dimethylformamide (300mL) of tert-butyl 4-formylpiperidine-1-carboxylate (30g, 14.1mmol) at 0°C , 16.9mmol), stir for 30 minutes after the addition, then add allyl bromide (19g, 16.2mmol), and stir for 2 hours at 0°C after the addition. The reaction solution was poured into aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L×2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and then column chromatography [ Eluent: petroleum ether ~ ethyl acetate/petroleum ether from 0% to 2%] Purify to obtain a colorless oily product tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (15g , The yield is 42%).
第二步：叔-丁基4-烯丙基-4-(1-羟基烯丙基)哌啶-1-羧酸酯的制备Step 2: Preparation of tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate
Figure PCTCN2020093731-appb-000135
Figure PCTCN2020093731-appb-000135
在-78℃下，往叔-丁基4-烯丙基-4-甲酰基哌啶-1-羧酸酯(25g,99mmol)的四氢呋喃(300mL)溶液中滴加乙烯基氯化镁(65mL,123.5mmol)，加完慢慢升至室温搅拌30分钟。把反应液倒入氯化铵水溶液(1L)里，用乙酸乙酯萃取(1L×2)，乙酸乙酯层用饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥后柱层析[洗脱剂:石油醚～乙酸乙酯/石油醚从0％到5％]纯化得到无色油状产物叔-丁基4-烯丙基-4-(1-羟基烯丙基)哌啶-1-羧酸酯(25g,产率90％)。At -78℃, to tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (25g, 99mmol) in tetrahydrofuran (300mL) was added dropwise vinylmagnesium chloride (65mL, 123.5 mmol), slowly warm up to room temperature and stir for 30 minutes. The reaction solution was poured into aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L×2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and then column chromatography [ Eluent: Petroleum ether ~ ethyl acetate/petroleum ether from 0% to 5%] Purify to obtain a colorless oily product tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1 -Carboxylic acid ester (25 g, yield 90%).
第三步：叔-丁基4-丙烯酰-4-烯丙基哌啶-1-羧酸酯的制备The third step: preparation of tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate
Figure PCTCN2020093731-appb-000136
Figure PCTCN2020093731-appb-000136
在0℃下往叔-丁基4-烯丙基-4-(1-羟基烯丙基)哌啶-1-羧酸酯(25g,89mmol)的二氯甲烷(400mL)溶液里加戴斯马丁试剂(41.5g,98mmol)，加完40℃搅拌1小时。把反应液慢慢倒入碳酸氢钠/亚硫酸钠水溶液(1/1,1L)里，用二氯甲烷萃取(1L×2)，二氯甲烷层用饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥后旋干，再加正庚烷(200mL)，搅拌5分钟，过滤掉不溶物，浓缩滤液得到无色油状产物叔-丁基4-丙烯酰-4-烯丙基哌啶-1-羧酸酯(24.8g,产率100％)，快速投下一步。Add Dess Martin to a solution of tert-butyl 4-allyl-4-(1-hydroxyallyl)piperidine-1-carboxylate (25g, 89mmol) in dichloromethane (400mL) at 0°C Reagent (41.5g, 98mmol), after adding it, stir for 1 hour at 40°C. Pour the reaction solution slowly into sodium bicarbonate/sodium sulfite aqueous solution (1/1, 1L), extract with dichloromethane (1L×2), wash the dichloromethane layer with saturated sodium chloride aqueous solution (500mL), anhydrous After drying over sodium sulfate, spin dry, add n-heptane (200 mL), stir for 5 minutes, filter out the insoluble matter, concentrate the filtrate to obtain the colorless oily product tert-butyl 4-acryloyl-4-allylpiperidine-1 -Carboxylic acid ester (24.8g, yield 100%), quickly cast to the next step.
第四步：叔-丁基1-羰基-8-氮杂螺[4.5]癸-2-烯-8-羧酸酯的制备Step 4: Preparation of tert-butyl 1-carbonyl-8-azaspiro[4.5]dec-2-ene-8-carboxylate
Figure PCTCN2020093731-appb-000137
Figure PCTCN2020093731-appb-000137
叔-丁基4-丙烯酰-4-烯丙基哌啶-1-羧酸酯(24.8g,89mmol)和二氯(邻异丙氧基苯基亚甲基)(三环己基膦)钌(II)(1.2g,1.4mmol)在甲苯(700mL)中90℃搅拌2小时。待反应液冷却后，浓缩反应液，柱层析[洗脱剂:石油醚～乙酸乙酯/石油醚从0％到20％]纯化得 到红黑色固体产物叔-丁基1-羰基-8-氮杂螺[4.5]癸-2-烯-8-羧酸酯(13g,产率58％)。Tert-Butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (24.8g, 89mmol) and dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium (II) (1.2 g, 1.4 mmol) was stirred in toluene (700 mL) at 90°C for 2 hours. After the reaction solution is cooled, the reaction solution is concentrated and purified by column chromatography [eluent: petroleum ether ~ ethyl acetate/petroleum ether from 0% to 20%] to obtain the red-black solid product tert-butyl 1-carbonyl-8- Azaspiro[4.5]dec-2-ene-8-carboxylate (13g, yield 58%).
MS m/z(ESI):252.1[M+H] +。 MS m/z (ESI): 252.1 [M+H] + .
第五步：8-氮杂螺[4.5]癸-2-烯-1-酮的制备Step 5: Preparation of 8-azaspiro[4.5]dec-2-en-1-one
Figure PCTCN2020093731-appb-000138
Figure PCTCN2020093731-appb-000138
室温下往叔-丁基1-羰基-8-氮杂螺[4.5]癸-2-烯-8-羧酸酯(100mg,0.4mmol)的甲醇(1mL)溶液中加盐酸二氧六环溶液(5mL,4mol/L)，加完室温搅拌1小时，浓缩反应液得到无色油状物8-氮杂螺[4.5]癸-2-烯-1-酮(80mg,产率133％)。Add a solution of dioxane hydrochloride to tert-butyl 1-carbonyl-8-azaspiro[4.5]dec-2-ene-8-carboxylate (100mg, 0.4mmol) in methanol (1mL) at room temperature (5mL, 4mol/L), after adding to room temperature and stirring for 1 hour, the reaction solution was concentrated to obtain 8-azaspiro[4.5]dec-2-en-1-one (80mg, yield 133%) as a colorless oil.
MS m/z(ESI):152.1[M+H] +. MS m/z(ESI): 152.1[M+H] + .
第六步：4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The sixth step: 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Preparation of ketones
Figure PCTCN2020093731-appb-000139
Figure PCTCN2020093731-appb-000139
室温下往7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(100mg,0.287mmol)的乙腈(8mL)溶液里加N,N-二异丙基乙胺(370mg,2.87mmol)，再加三氯氧磷(133mg,0.862mmol)，80℃搅拌1小时。冷却至室温，直接用于下一步反应。To 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- at room temperature Add N,N-diisopropylethylamine (370mg, 2.87mmol) to the ketone (100mg, 0.287mmol) in acetonitrile (8mL) solution, then add phosphorus oxychloride (133mg, 0.862mmol), and stir at 80°C for 1 hour. Cool to room temperature and use it directly in the next reaction.
第七步：7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-羰基-8-氮杂螺[4.5]癸-2-烯-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The seventh step: 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8-azaspiro[4.5]dec-2 -En-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000140
Figure PCTCN2020093731-appb-000140
将上一步反应液加到8-氮杂螺[4.5]癸-2-烯-1-酮盐酸盐粗品(100mg,0.4mmol)和N,N-二异丙基乙胺(370mg,2.87mmol)的乙腈(5mL)溶液中，室温搅拌1小时。加水(60mL)，用乙酸乙酯(40mL×3)萃取，有机相用氯化铵水溶液(40mL)洗，氯化钠水溶液(30mL)洗，浓缩后薄层层析[洗脱剂:乙酸乙酯]纯化得到目标产物7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-羰基-8-氮杂螺[4.5]癸-2-烯-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(43mg,两步产率31％)。Add the reaction solution of the previous step to the crude 8-azaspiro[4.5]dec-2-en-1-one hydrochloride (100mg, 0.4mmol) and N, N-diisopropylethylamine (370mg, 2.87mmol) ) In acetonitrile (5 mL) and stirred at room temperature for 1 hour. Add water (60mL), extract with ethyl acetate (40mL×3), wash the organic phase with aqueous ammonium chloride solution (40mL), wash with aqueous sodium chloride solution (30mL), concentrate and thin-layer chromatography [eluent: ethyl acetate Ester] Purification to obtain the target product 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8-azaspiro[4.5]deca -2-En-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (43 mg, 31% yield for two steps).
MS m/z(ESI):482.2[M+H] +，484.2[M+H+2] +. MS m/z(ESI): 482.2[M+H] + , 484.2[M+H+2] + .
第八步：6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-羰基-8-氮杂螺[4.5]癸-2-烯-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The eighth step: 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8 -Azaspiro[4.5]dec-2-en-8-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000141
Figure PCTCN2020093731-appb-000141
7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-羰基-8-氮杂螺[4.5]癸-2-烯-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(43mg,0.088mmol)，(2-氟-6-羟基苯基)硼酸(27mg,0.18mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(7mg,0.0088mmol)和碳酸铯(86mg,0.26mmol)在二氧六环(2mL)和水(0.5mL)中100℃微波搅拌1小时。过滤反应液，旋干滤液，薄层层析[洗脱剂:二氯甲烷/甲醇＝12/1]纯化得到黄色固体6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(1-羰基-8-氮杂螺[4.5]癸-2-烯-8-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(13mg,产率26％)。7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8-azaspiro[4.5]dec-2-ene-8 -Yl)pyrido[2,3-d]pyrimidin-2(1H)-one (43mg, 0.088mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (27mg, 0.18mmol), [1,1 '-Bis (diphenylphosphine) ferrocene) dichloropalladium dichloromethane complex (7mg, 0.0088mmol) and cesium carbonate (86mg, 0.26mmol) in dioxane (2mL) and water (0.5 mL) was stirred in microwave at 100°C for 1 hour. The reaction solution was filtered, the filtrate was spin-dried, and thin layer chromatography [eluent: dichloromethane/methanol=12/1] was purified to obtain a yellow solid 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1 -(2-isopropyl-4-methylpyridin-3-yl)-4-(1-carbonyl-8-azaspiro[4.5]dec-2-en-8-yl)pyrido[2,3 -d] Pyrimidine-2(1H)-one (13 mg, yield 26%).
1H NMR(400MHz,CDCl 3)δ9.32(s,1H),8.58(d,J＝4Hz,1H),7.89(d,J＝8Hz,1H),7.74–7.63(m,1H),7.24–7.21(m,2H),6.69–6.56(m,2H),6.19(d,J＝4Hz,1H),4.50–4.45(m,2H),3.58–3.55(m,2H),3.39–3.35(m,2H),2.79–2.64(m,1H),2.38–2.16(m,2H),2.03(s,3H),1.62–1.42(m,2H),1.22(d,J＝4Hz,3H),1.06(d,J＝4Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ9.32(s,1H), 8.58(d,J=4Hz,1H), 7.89(d,J=8Hz,1H), 7.74–7.63(m,1H), 7.24 –7.21(m,2H),6.69–6.56(m,2H),6.19(d,J=4Hz,1H),4.50–4.45(m,2H),3.58–3.55(m,2H),3.39–3.35( m,2H),2.79–2.64(m,1H),2.38–2.16(m,2H),2.03(s,3H),1.62–1.42(m,2H),1.22(d,J=4Hz,3H), 1.06(d,J=4Hz,3H).
MS m/z(ESI):558.2[M+H] +。 MS m/z (ESI): 558.2 [M+H] + .
实施例ii-15Example ii-15
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene-6-carbonyl) Preparation of octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000142
Figure PCTCN2020093731-appb-000142
第一步：叔-丁基6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸酯的制备Step 1: Preparation of tert-butyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate
Figure PCTCN2020093731-appb-000143
Figure PCTCN2020093731-appb-000143
0℃往八氢-6H-吡啶并[1,2-a]吡嗪-6-酮(500mg,2.6mmol)和三乙胺(800mg,7.8mmol) 的二氯甲烷(50mL)溶液中加二-叔-丁基二碳酸酯(1.1g,5.2mmol)，加完室温搅拌2小时。加水(60mL)，二氯甲烷(40mL×3)萃取，二氯甲烷层用饱和食盐水洗涤，浓缩后柱层析[洗脱剂:石油醚～乙酸乙酯/石油醚从0％到50％]纯化得到叔-丁基6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸酯(700mg,产率93％)黄色油。Add two to the solution of octahydro-6H-pyrido[1,2-a]pyrazine-6-one (500mg, 2.6mmol) and triethylamine (800mg, 7.8mmol) in dichloromethane (50mL) at 0℃ -Tert-butyl dicarbonate (1.1 g, 5.2 mmol), stir at room temperature for 2 hours after adding. Add water (60mL), extract with dichloromethane (40mL×3), wash the dichloromethane layer with saturated brine, concentrate and column chromatography [eluent: petroleum ether ~ ethyl acetate/petroleum ether from 0% to 50% ] Purification gave tert-butyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (700 mg, yield 93%) as a yellow oil.
MS m/z(ESI):255.1[M+H] +. MS m/z(ESI): 255.1[M+H] + .
第二步：2-(叔-丁基)7-乙基6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2,7-二羧酸酯的制备Step 2: Preparation of 2-(tert-butyl)7-ethyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2,7-dicarboxylate
Figure PCTCN2020093731-appb-000144
Figure PCTCN2020093731-appb-000144
-78℃下往叔-丁基3-(2-羰基吡咯烷-1-基)吖丁啶-1-羧酸酯(700mg,2.4mmol)的四氢呋喃(12mL)溶液里滴加六甲基二硅胺基锂(4.8mL,4.8mmol)，加完-78℃搅拌1小时，滴加碳酸二乙酯(570mg,4.8mmol)的四氢呋喃(3mL)溶液，加完-78℃搅拌1小时，慢慢升至0℃搅拌30分钟。反应用氯化铵水溶液(40mL)淬灭，乙酸乙酯(40mL×3)萃取，乙酸乙酯层用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到2-(叔-丁基)7-乙基6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2,7-二羧酸酯(800mg,产率100％)黄色油。To the tert-butyl 3-(2-carbonylpyrrolidin-1-yl)azetidine-1-carboxylate (700mg, 2.4mmol) in tetrahydrofuran (12mL) solution was added dropwise hexamethyl bis Lithium silylamide (4.8mL, 4.8mmol), after the addition, stir for 1 hour at -78°C, add dropwise a solution of diethyl carbonate (570mg, 4.8mmol) in tetrahydrofuran (3mL), and stir for 1 hour at -78°C after addition. Slowly raise to 0°C and stir for 30 minutes. The reaction was quenched with aqueous ammonium chloride solution (40 mL), extracted with ethyl acetate (40 mL×3), the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2-(tert-butyl)7- Ethyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2,7-dicarboxylate (800 mg, yield 100%) yellow oil.
MS m/z(ESI):327.2[M+H] +。 MS m/z (ESI): 327.2 [M+H] + .
第三步：2-(叔-丁氧基羰基)-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-7-羧酸的制备The third step: Preparation of 2-(tert-butoxycarbonyl)-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid
Figure PCTCN2020093731-appb-000145
Figure PCTCN2020093731-appb-000145
2-(叔-丁基)7-乙基6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2,7-二羧酸酯粗品(800mg,2.45mmol)和一水合氢氧化锂(500mg,9.8mmol)在四氢呋喃(10mL)和水(2mL)中室温搅拌2小时。加水(50mL)，用乙酸乙酯(30mL×2)洗，然后用2N稀盐酸把水相调到pH～3，乙酸乙酯(30mL×3)萃取，乙酸乙酯层用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到2-(叔-丁氧基羰基)-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-7-羧酸(650mg,产率89％)黄色油。2-(tert-butyl)7-ethyl 6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2,7-dicarboxylate crude product (800mg, 2.45mmol) and monohydrate Lithium hydroxide (500 mg, 9.8 mmol) was stirred in tetrahydrofuran (10 mL) and water (2 mL) at room temperature for 2 hours. Add water (50mL), wash with ethyl acetate (30mL×2), then adjust the aqueous phase to pH~3 with 2N dilute hydrochloric acid, extract with ethyl acetate (30mL×3), and wash the ethyl acetate layer with saturated brine. Dry with anhydrous sodium sulfate and concentrate to obtain 2-(tert-butoxycarbonyl)-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (650mg, yield 89% ) Yellow oil.
MS m/z(ESI):299.1[M+H] +。 MS m/z (ESI): 299.1 [M+H] + .
第四步：叔-丁基7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸酯的制备Step 4: Preparation of tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate
Figure PCTCN2020093731-appb-000146
Figure PCTCN2020093731-appb-000146
0℃往2-(叔-丁氧基羰基)-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-7-羧酸(650mg,2.2mmol)和多聚甲醛(100mg,3.3mmol)的乙酸乙酯(10mL)溶液中加二甲胺四氢呋喃溶液(1.3mL, 2.6mol/L)，加完80℃搅拌2小时。浓缩反应液，柱层析[洗脱剂:石油醚～乙酸乙酯/石油醚从0％到100％]纯化得到叔-丁基7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸酯(280mg,产率48％)白色固体。0℃ to 2-(tert-butoxycarbonyl)-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (650mg, 2.2mmol) and paraformaldehyde (100mg , 3.3mmol) in ethyl acetate (10mL) was added dimethylamine tetrahydrofuran solution (1.3mL, 2.6mol/L), after adding, stirred at 80°C for 2 hours. The reaction solution was concentrated and purified by column chromatography [eluent: petroleum ether ~ ethyl acetate/petroleum ether from 0% to 100%] to obtain tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a] pyrazine-2-carboxylate (280 mg, yield 48%) white solid.
MS m/z(ESI):267.2[M+H] +。 MS m/z (ESI): 267.2 [M+H] + .
第五步：7-亚甲基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮的制备Step 5: Preparation of 7-methyleneoctahydro-6H-pyrido[1,2-a]pyrazin-6-one
Figure PCTCN2020093731-appb-000147
Figure PCTCN2020093731-appb-000147
室温下往叔-丁基7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-羧酸酯(130mg,0.5mmol)的甲醇(2mL)溶液中加盐酸二氧六环溶液(5mL,4mol/L)，加完室温搅拌1小时，浓缩反应液得到7-亚甲基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮盐酸盐(150mg,产率150％)无色油。To tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (130mg, 0.5mmol) in methanol (2mL) at room temperature Add hydrochloric acid dioxane solution (5mL, 4mol/L), stir at room temperature for 1 hour, concentrate the reaction solution to obtain 7-methyleneoctahydro-6H-pyrido[1,2-a]pyrazine-6 -Ketone hydrochloride (150 mg, yield 150%) colorless oil.
MS m/z(ESI):167.1[M+H] +. MS m/z(ESI): 167.1[M+H] + .
第六步：4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The sixth step: 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- Preparation of ketones
Figure PCTCN2020093731-appb-000148
Figure PCTCN2020093731-appb-000148
室温下往7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(100mg,0.287mmol)的乙腈(8mL)溶液里加N,N-二异丙基乙胺(370mg,2.87mmol)，再加三氯氧磷(133mg,0.862mmol)，80℃搅拌1小时。冷却至室温，直接用于下一步反应。To 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2(1H)- at room temperature Add N,N-diisopropylethylamine (370mg, 2.87mmol) to the acetonitrile (8mL) solution of ketone (100mg, 0.287mmol), then add phosphorus oxychloride (133mg, 0.862mmol), and stir at 80°C for 1 hour. Cool to room temperature and directly use in the next reaction.
第七步：7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The seventh step: 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene-6-carbonyloctahydro-2H-pyridine Preparation of and [1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000149
Figure PCTCN2020093731-appb-000149
将上一步反应液加到7-亚甲基八氢-6H-吡啶并[1,2-a]吡嗪-6-酮盐酸盐粗品(150mg,0.5mmol)和N,N-二异丙基乙胺(0.6mL,2.5mmol)的乙腈(10mL)溶液中，室温搅拌1小 时。加水(60mL)，用乙酸乙酯(40mL×3)萃取，有机相用氯化铵水溶液(40mL)洗，氯化钠水溶液(30mL)洗，浓缩后薄层层析[洗脱剂:二氯甲烷/甲醇＝20/1]纯化得到7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(150mg,产率60％)黄色油。Add the reaction solution from the previous step to the crude 7-methyleneoctahydro-6H-pyrido[1,2-a]pyrazine-6-one hydrochloride (150mg, 0.5mmol) and N,N-diisopropyl In a solution of ethylamine (0.6 mL, 2.5 mmol) in acetonitrile (10 mL), the mixture was stirred at room temperature for 1 hour. Add water (60mL), extract with ethyl acetate (40mL×3), wash the organic phase with ammonium chloride aqueous solution (40mL), wash with sodium chloride aqueous solution (30mL), concentrate and then thin-layer chromatography [eluent: dichloro Methane/methanol=20/1] Purified to obtain 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene-6-carbonyl Octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (150 mg, yield 60%) yellow oil.
MS m/z(ESI):497.1[M+H] +. MS m/z(ESI): 497.1[M+H] + .
第八步：6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备The eighth step: 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene -6-Carbonyloctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000150
Figure PCTCN2020093731-appb-000150
7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-4-(7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(80mg,0.16mmol)，((2-氟-6-羟基苯基)硼酸(50mg,0.32mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10mg,0.02mmol)和醋酸钾(80mg,0.8mmol)在二氧六环(3mL)和水(0.5mL)中90℃微波搅拌1小时。过滤反应液，旋干滤液，薄层层析[洗脱剂:二氯甲烷/甲醇＝20/1]纯化得到6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(7-亚甲基-6-羰基八氢-2H-吡啶并[1,2-a]吡嗪-2-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(30mg,产率32％)黄色固体。7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene-6-carbonyloctahydro-2H-pyrido[1, 2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (80mg, 0.16mmol), ((2-fluoro-6-hydroxyphenyl)boronic acid (50mg ,0.32mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (10mg, 0.02mmol) and potassium acetate (80mg, 0.8mmol) in dioxygen Hexacyclic ring (3mL) and water (0.5mL) were stirred in microwave at 90°C for 1 hour. The reaction solution was filtered, the filtrate was spin-dried, and thin layer chromatography [eluent: dichloromethane/methanol=20/1] purified to obtain 6 Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(7-methylene-6-carbonyloctahydro) -2H-pyrido[1,2-a]pyrazin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (30 mg, yield 32%) yellow solid.
1H NMR(400MHz,CDCl 3)δ9.20(s,1H),8.61(d,J＝4Hz,1H),7.92(d,J＝12Hz,1H),7.33–7.27(m,2H),6.77–6.60(m,2H),6.08(s,1H),5.46(s,1H),5.34–5.19(m,2H),4.92(s,4H),3.77–3.57(m,2H),1.99–1.88(m,2H),1.87–1.64(m,2H),2.12(s,3H),1.29(d,J＝4Hz,3H),1.12(d,J＝4Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ9.20(s,1H), 8.61(d,J=4Hz,1H),7.92(d,J=12Hz,1H),7.33-7.27(m,2H),6.77 --6.60 (m, 2H), 6.08 (s, 1H), 5.46 (s, 1H), 5.34 - 5.19 (m, 2H), 4.92 (s, 4H), 3.77 - 3.57 (m, 2H), 1.99 - 1.88 (m, 2H), 1.87-1.64 (m, 2H), 2.12 (s, 3H), 1.29 (d, J = 4 Hz, 3H), 1.12 (d, J = 4 Hz, 3H).
MS m/z(ESI):573.2[M+H] +。 MS m/z (ESI): 573.2 [M+H] + .
实施例ii-22Example ii-22
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(4-(2-羰基-2,5-二氢-1H-吡咯-1-基)哌啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(4-(2-carbonyl-2, Preparation of 5-dihydro-1H-pyrrol-1-yl)piperidin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000151
Figure PCTCN2020093731-appb-000151
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(4-(3-亚甲基-2-羰基吡咯烷-1-基)哌啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备参考实施例ii-10。6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(4-(3-methylene- Preparation of 2-carbonylpyrrolidin-1-yl)piperidin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one Refer to Example ii-10.
1H NMR(400MHz,CD 3OD)δ8.64(d,J＝7.9Hz,1H),8.30(s,1H),8.24(d,J＝7.5Hz,1H),7.32(td,J＝7.4,5.0Hz,1H),7.22(td,J＝7.7,1.5Hz,1H),7.11(dq,J＝7.5,0.8Hz,1H),6.78(dd,J＝7.5,1.7Hz,1H),6.43(dt,J＝10.8,6.2Hz,1H),6.03(dt,J＝11.0,0.9Hz,1H),4.65(p,J＝7.1Hz,1H),3.80(dd,J＝6.2,1.1Hz,2H),3.63–3.49(m,4H),3.13(hept,J＝6.8Hz,1H),2.34(s,2H),2.07–1.92(m,4H),1.46(d,J＝6.8Hz,6H). 1 H NMR(400MHz,CD 3 OD)δ8.64(d,J=7.9Hz,1H), 8.30(s,1H), 8.24(d,J=7.5Hz,1H), 7.32(td,J=7.4 ,5.0Hz,1H),7.22(td,J=7.7,1.5Hz,1H),7.11(dq,J=7.5,0.8Hz,1H),6.78(dd,J=7.5,1.7Hz,1H),6.43 (dt, J = 10.8, 6.2 Hz, 1H), 6.03 (dt, J = 11.0, 0.9 Hz, 1H), 4.65 (p, J = 7.1 Hz, 1H), 3.80 (dd, J = 6.2, 1.1 Hz, 2H),3.63–3.49(m,4H),3.13(hept,J=6.8Hz,1H),2.34(s,2H),2.07–1.92(m,4H),1.46(d,J=6.8Hz,6H ).
MS m/z(ESI):573.1[M+H] +。 MS m/z (ESI): 573.1 [M+H] + .
实施例ii-23Example ii-23
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(4-(3-亚甲基-2-羰基吡咯烷-1-基)哌啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(4-(3-methylene- Preparation of 2-carbonylpyrrolidin-1-yl)piperidin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
Figure PCTCN2020093731-appb-000152
Figure PCTCN2020093731-appb-000152
6-氟-7-(2-氟-6-羟基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-4-(4-(3-亚甲基-2-羰基吡咯烷-1-基)哌啶-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮的制备参考实施例ii-10。6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(4-(3-methylene- Preparation of 2-carbonylpyrrolidin-1-yl)piperidin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one Refer to Example ii-10.
1H NMR(400MHz,CD 3OD)δ9.39(s,1H),8.65(s,1H),7.96(d,J＝9.0Hz,1H),7.30(s,2H),6.82–6.57(m,2H),6.04(s,1H),5.39(s,1H),4.75(s,2H),4.50(s,1H),3.45(s,4H),2.83(s,2H),2.06(d,J＝29.5Hz,7H),1.29(s,3H),1.12(s,3H). 1 H NMR(400MHz,CD 3 OD)δ9.39(s,1H),8.65(s,1H),7.96(d,J=9.0Hz,1H),7.30(s,2H),6.82-6.57(m , 2H), 6.04(s, 1H), 5.39(s, 1H), 4.75(s, 2H), 4.50(s, 1H), 3.45(s, 4H), 2.83(s, 2H), 2.06(d, J = 29.5Hz, 7H), 1.29 (s, 3H), 1.12 (s, 3H).
MS m/z(ESI):587.1[M+H] +。 MS m/z (ESI): 587.1 [M+H] + .
实施例iii-1Example iii-1
1-((3S)-4-(7-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的制备1-((3S)-4-(7-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-4-methylpyridin-3-yl)-4H- Preparation of imidazo[4,5-b]quinolin-9-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000153
Figure PCTCN2020093731-appb-000153
第一步：叔-丁基(S)-4-(4-溴-2,5-二氟苯甲酰)-3-甲基哌嗪-1-羧酸酯的制备The first step: the preparation of tert-butyl(S)-4-(4-bromo-2,5-difluorobenzoyl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000154
Figure PCTCN2020093731-appb-000154
将4-溴-2,5-二氟苯甲酸(5g,21.2mmol)溶于DMF(100mL)中，加入DIPEA(5.47g，42.4mmol)和HATU(9.7g，25.4mmol)，室温搅拌0.5小时。加入叔-丁基(S)-3-甲基哌嗪-1-羧酸酯(8.48g，42.4mmol)，继续搅拌6小时。加入水，用二氯甲烷萃取(3*50mL)，有机相水洗(20mL)，再用饱和食盐水(20mL)洗涤。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(S)-4-(4-溴-2,5-二氟苯甲酰)-3-甲基哌嗪-1-羧酸酯(8.2g，产率92％)。 Dissolve 4-bromo-2,5-difluorobenzoic acid (5g, 21.2mmol) in DMF (100mL), add DIPEA (5.47g, 42.4mmol) and HATU (9.7g, 25.4mmol), and stir at room temperature for 0.5 hours . Tert-butyl (S)-3-methylpiperazine-1-carboxylate (8.48 g, 42.4 mmol) was added, and stirring was continued for 6 hours. Add water, extract with dichloromethane (3*50mL), wash the organic phase with water (20mL), and then with saturated brine (20mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(S)-4-(4-bromo-2,5) -Difluorobenzoyl)-3-methylpiperazine-1-carboxylate (8.2 g, yield 92%).
MS m/z(ESI):419.1[M+H] +，421.1[M+H+2] +. MS m/z(ESI): 419.1[M+H] + , 421.1[M+H+2] + .
第二步：叔-丁基(S)-4-(4-溴-5-氟-2-((2-异丙基-4-甲基吡啶-3-基)氨基)苯甲酰)-3-甲基哌嗪-1-羧酸酯的制备The second step: tert-butyl(S)-4-(4-bromo-5-fluoro-2-((2-isopropyl-4-methylpyridin-3-yl)amino)benzoyl)- Preparation of 3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000155
Figure PCTCN2020093731-appb-000155
将叔-丁基(S)-4-(4-溴-2,5-二氟苯甲酰)-3-甲基哌嗪-1-羧酸酯(8.0g,19.1mmol),2-异丙基-4-甲基吡啶-3-胺(2.86g,19.1mmol)加入DMF(100mL)中，加入叔丁醇钠(2.38g,24.8mmol)，在室温条件下反应过夜，加入水，用乙酸乙酯萃取(3*50mL)，有机相水洗(20mL)，再用饱和食盐水(20mL)洗涤。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(S)-4-(4-溴-5-氟-2-((2-异丙基-4-甲基吡啶-3-基)氨基)苯甲酰)-3-甲基哌嗪-1-羧酸酯(8.5g，产率81％)。 The tert-butyl (S)-4-(4-bromo-2,5-difluorobenzoyl)-3-methylpiperazine-1-carboxylate (8.0g, 19.1mmol), 2-iso Propyl-4-methylpyridine-3-amine (2.86g, 19.1mmol) was added to DMF (100mL), sodium tert-butoxide (2.38g, 24.8mmol) was added, and reacted overnight at room temperature. Water was added. Extract with ethyl acetate (3*50 mL), wash the organic phase with water (20 mL), and then with saturated brine (20 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(S)-4-(4-bromo-5-fluoro -2-((2-isopropyl-4-methylpyridin-3-yl)amino)benzoyl)-3-methylpiperazine-1-carboxylate (8.5 g, yield 81%).
MS m/z(ESI):549.1[M+H] +，551.1[M+H+2] +. MS m/z(ESI): 549.1[M+H] + , 551.1[M+H+2] + .
第三步：叔-丁基(S)-4-(4-溴-5-氟-2-(N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰氨基)苯甲酰)-3-甲基哌嗪-1-羧酸酯的制备The third step: tert-butyl(S)-4-(4-bromo-5-fluoro-2-(N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitro (Acetylamino)benzoyl)-3-methylpiperazine-1-carboxylic acid ester
Figure PCTCN2020093731-appb-000156
Figure PCTCN2020093731-appb-000156
将叔-丁基(S)-4-(4-溴-5-氟-2-((2-异丙基-4-甲基吡啶-3-基)氨基)苯甲酰)-3-甲基哌嗪-1-羧酸酯(8.1g,14.7mmol),2-硝基乙酸(1.86g,17.7mmol)加入DMF(100mL)中，在0℃条件下加入三乙胺(7.4g,73.7mmol)和T 3P(14.1g,44.3mmol，50％in EtOAc)，逐渐升至室温反应过夜，加入水，用二氯甲烷萃取(3*50mL)，有机相水洗(20mL)，再用饱和食盐水(20mL)洗涤。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(S)-4-(4-溴-5-氟-2-(N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰氨基)苯甲酰)-3-甲基哌嗪-1-羧酸酯(6.3g，产率68％)。 Add tert-butyl(S)-4-(4-bromo-5-fluoro-2-((2-isopropyl-4-methylpyridin-3-yl)amino)benzoyl)-3-methyl Piperazine-1-carboxylate (8.1g, 14.7mmol), 2-nitroacetic acid (1.86g, 17.7mmol) was added to DMF (100mL), and triethylamine (7.4g, 73.7 mmol) and T 3 P (14.1 g, 44.3 mmol, 50% in EtOAc), gradually warm to room temperature and react overnight, add water, extract with dichloromethane (3*50 mL), wash the organic phase with water (20 mL), and then saturate Wash with brine (20 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(S)-4-(4-bromo-5-fluoro -2-(N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitroacetamido)benzoyl)-3-methylpiperazine-1-carboxylate (6.3 g, yield 68%).
MS m/z(ESI):636.1[M+H] +，638.1[M+H+2] +. MS m/z(ESI): 636.1[M+H] + , 638.1[M+H+2] + .
第四步：叔-丁基(S)-4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-羰基-1,2-二氢喹啉-4-基)-3-甲基哌嗪-1-羧酸酯的制备The fourth step: tert-butyl(S)-4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2- Preparation of carbonyl-1,2-dihydroquinolin-4-yl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000157
Figure PCTCN2020093731-appb-000157
将叔-丁基(S)-4-(4-溴-5-氟-2-(N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰氨基)苯甲酰)-3-甲基哌嗪-1-羧酸酯(5.8g,9.1mmol)加入DMF(50mL)中，在0℃条件下加入NaH(437mg,10.9mmol)，室温反应3小时，加热到70℃继续反应15小时，加入水淬灭，用二氯甲烷萃取(3*50mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(S)-4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-羰基-1,2-二氢喹啉-4-基)-3-甲基哌嗪-1-羧酸酯(2.7g，产率48％)。 Add tert-butyl(S)-4-(4-bromo-5-fluoro-2-(N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitroacetamido) Benzoyl)-3-methylpiperazine-1-carboxylate (5.8g, 9.1mmol) was added to DMF (50mL), NaH (437mg, 10.9mmol) was added at 0°C, and reacted at room temperature for 3 hours. Heat to 70°C to continue the reaction for 15 hours, add water to quench, and extract with dichloromethane (3*50 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(S)-4-(7-bromo-6-fluoro -1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-carbonyl-1,2-dihydroquinolin-4-yl)-3-methylpiperazine -1-carboxylate (2.7 g, yield 48%).
MS m/z(ESI):618.1[M+H] +，620.1[M+H+2] +. MS m/z(ESI): 618.1[M+H] + , 620.1[M+H+2] + .
第五步：叔-丁基(S)-4-(3-氨基-7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)-3-甲基哌嗪-1-羧酸酯的制备The fifth step: tert-butyl(S)-4-(3-amino-7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl -1,2-Dihydroquinolin-4-yl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000158
Figure PCTCN2020093731-appb-000158
将叔-丁基(S)-4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-羰基-1,2-二氢喹啉-4-基)-3-甲基哌嗪-1-羧酸酯(2.5g,4.1mmol)加入溶剂(乙醇：水＝5：1)(60mL)中,加入铁粉(1.15g,20.5mmol)和NH 4Cl(220mg,4.1mmol)，加热回流3小时，冷却，过滤，滤液加入饱和食盐水，用二氯甲烷萃取(3*50mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(S)-4-(3-氨基-7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)-3-甲基哌嗪-1-羧酸酯(2.1g，产率88％)。 The tert-butyl(S)-4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-carbonyl-1 ,2-Dihydroquinolin-4-yl)-3-methylpiperazine-1-carboxylate (2.5g, 4.1mmol) was added to the solvent (ethanol: water = 5:1) (60mL), and iron was added Powder (1.15g, 20.5mmol) and NH 4 Cl (220mg, 4.1mmol), heated to reflux for 3 hours, cooled, filtered, the filtrate was added with saturated brine and extracted with dichloromethane (3*50mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(S)-4-(3-amino-7-bromo -6-Fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinolin-4-yl)-3-methylpiperazine- 1-carboxylate (2.1 g, yield 88%).
MS m/z(ESI):588.1[M+H] +，590.1[M+H+2] +. MS m/z(ESI): 588.1[M+H] + , 590.1[M+H+2] + .
第六步：叔-丁基(S)-4-(6-溴-7-氟-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-羧酸酯的制备The sixth step: tert-butyl(S)-4-(6-bromo-7-fluoro-4-(2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4, Preparation of 5-b]quinolin-9-yl)-3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-appb-000159
Figure PCTCN2020093731-appb-000159
将叔-丁基(S)-4-(3-氨基-7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氢喹啉-4-基)-3-甲基哌嗪-1-羧酸酯(1.5g,2.55mmol)加入甲酰胺(30mL)中，加热到180℃反应5小时，冷却，浓缩，加入水，用二氯甲烷萃取(3*30mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(S)-4-(6-溴-7-氟-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-羧酸酯(350mg，产率23％)。 The tert-butyl (S)-4-(3-amino-7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1, 2-Dihydroquinolin-4-yl)-3-methylpiperazine-1-carboxylate (1.5g, 2.55mmol) was added to formamide (30mL), heated to 180°C and reacted for 5 hours, cooled and concentrated , Add water and extract with dichloromethane (3*30mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(S)-4-(6-bromo-7-fluoro -4-(2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4,5-b]quinolin-9-yl)-3-methylpiperazine-1-carboxy Ester (350 mg, 23% yield).
MS m/z(ESI):597.1[M+H] +，599.1[M+H+2] +. MS m/z(ESI): 597.1[M+H] + , 599.1[M+H+2] + .
第七步：(S)-1-(4-(6-溴-7-氟-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9- 基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的制备The seventh step: (S)-1-(4-(6-bromo-7-fluoro-4-(2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4,5 -b) Preparation of quinolin-9-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000160
Figure PCTCN2020093731-appb-000160
将叔-丁基(S)-4-(6-溴-7-氟-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-羧酸酯(300mg,0.5mmol),溶于二氯甲烷(10mL)中，加入TFA(2mL)，室温搅拌2小时。浓缩，加入水和饱和NaHCO 3水溶液调节至中性，二氯甲烷(3*50mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品。溶于二氯甲烷(10mL)中，加入DIPEA(195mg，1.5mmol)，冰水浴下滴加丙烯酰氯(49mg，0.55mmol)，加完继续搅拌1小时。加水淬灭，二氯甲烷(20mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物(S)-1-(4-(6-溴-7-氟-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮(235mg，产率85％)。 The tert-butyl (S)-4-(6-bromo-7-fluoro-4-(2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4,5-b ] Quinolin-9-yl)-3-methylpiperazine-1-carboxylate (300 mg, 0.5 mmol) was dissolved in dichloromethane (10 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrate, add water and saturated NaHCO 3 aqueous solution to adjust to neutrality, and extract with dichloromethane (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Dissolve in dichloromethane (10 mL), add DIPEA (195 mg, 1.5 mmol), add acryloyl chloride (49 mg, 0.55 mmol) dropwise under an ice water bath, and continue stirring for 1 hour after the addition. It was quenched by adding water and extracted three times with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound (S)-1-(4-(6-bromo-7-fluoro) -4-(2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4,5-b]quinolin-9-yl)-3-methylpiperazin-1-yl ) Pro-2-en-1-one (235 mg, 85% yield).
MS m/z(ESI):551.1[M+H] +，553.1[M+H+2] +. MS m/z(ESI): 551.1[M+H] + , 553.1[M+H+2] + .
第八步：1-((3S)-4-(7-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的制备The eighth step: 1-((3S)-4-(7-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-4-methylpyridin-3-yl) )-4H-imidazo[4,5-b]quinolin-9-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one
Figure PCTCN2020093731-appb-000161
Figure PCTCN2020093731-appb-000161
将(S)-1-(4-(6-溴-7-氟-4-(2-异丙基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮(30mg,0.05mmol),溶于二氧六环(3mL)中，加入2-氟-6-羟基苯硼酸(13mg，0.08mmol)、三(二亚苄基丙酮)二钯(18mg，0.02mmol)、Xantphos(23mg，0.04mmol)以及Cs 2CO 3(49mg，0.15mmol)，氮气置换。微波加热至110℃反应1小时。冷却至室温后，加入水和二氯甲烷(3*20mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标化合物1-((3S)-4-(7-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙 基-4-甲基吡啶-3-基)-4H-咪唑并[4,5-b]喹啉-9-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮(11mg，产率34％)。 (S)-1-(4-(6-Bromo-7-fluoro-4-(2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4,5-b] Quinolin-9-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (30mg, 0.05mmol), dissolved in dioxane (3mL), add 2-fluoro -6-Hydroxyphenylboronic acid (13mg, 0.08mmol), tris(dibenzylideneacetone) dipalladium (18mg, 0.02mmol), Xantphos (23mg, 0.04mmol) and Cs 2 CO 3 (49mg, 0.15mmol), nitrogen Replacement. Microwave heating to 110°C for 1 hour. After cooling to room temperature, water and dichloromethane (3*20 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain the target compound 1-((3S)-4-(7-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4- (2-isopropyl-4-methylpyridin-3-yl)-4H-imidazo[4,5-b]quinolin-9-yl)-3-methylpiperazin-1-yl)prop- 2-en-1-one (11 mg, yield 34%).
MS m/z(ESI):583.1[M+H] +. MS m/z(ESI): 583.1[M+H] + .
实施例iii-12Example iii-12
(2R)-3-丙烯酰-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-5,7-二酮的制备(2R)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6 -Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c] Preparation of quinoline-5,7-dione
Figure PCTCN2020093731-appb-000162
Figure PCTCN2020093731-appb-000162
第一步：1-(叔-丁基)3-甲基(6R)-4-(4-溴-2,5-二氟苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯的制备The first step: 1-(tert-butyl)3-methyl(6R)-4-(4-bromo-2,5-difluorobenzoyl)-6-methylpiperazine-1,3-di Preparation of carboxylate
Figure PCTCN2020093731-appb-000163
Figure PCTCN2020093731-appb-000163
将4-溴-2,5-二氟苯甲酸(10g,42.4mmol)溶于DMF(100mL)中，加入DIPEA(16.4g，127.2mmol)和HATU(19.3g，50.9mmol)，室温搅拌0.5小时。加入1-(叔-丁基)3-甲基(6R)-6-甲基哌嗪-1,3-二羧酸酯(13.1g，50.9mmol)，继续搅拌13小时。加入水，用二氯甲烷萃取(3*50mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物1-(叔-丁基)3-甲基(6R)-4-(4-溴-2,5-二氟苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯(17.6g，产率87％)。 Dissolve 4-bromo-2,5-difluorobenzoic acid (10g, 42.4mmol) in DMF (100mL), add DIPEA (16.4g, 127.2mmol) and HATU (19.3g, 50.9mmol), and stir at room temperature for 0.5 hours . 1-(tert-butyl)3-methyl(6R)-6-methylpiperazine-1,3-dicarboxylate (13.1 g, 50.9 mmol) was added, and stirring was continued for 13 hours. Add water and extract with dichloromethane (3*50 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound 1-(tert-butyl)3-methyl(6R)-4- (4-Bromo-2,5-difluorobenzoyl)-6-methylpiperazine-1,3-dicarboxylate (17.6 g, yield 87%).
MS m/z(ESI):477.1[M+H] +，479.1[M+H+2] +. MS m/z(ESI): 477.1[M+H] + , 479.1[M+H+2] + .
第二步：1-(叔-丁基)3-甲基(6R)-4-(4-溴-5-氟-2-((2-异丙基-4-甲基吡啶-3-基)氨基)苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯的制备The second step: 1-(tert-butyl)3-methyl(6R)-4-(4-bromo-5-fluoro-2-((2-isopropyl-4-methylpyridin-3-yl) )Amino)benzoyl)-6-methylpiperazine-1,3-dicarboxylate preparation
Figure PCTCN2020093731-appb-000164
Figure PCTCN2020093731-appb-000164
将1-(叔-丁基)3-甲基(6R)-4-(4-溴-2,5-二氟苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯(10g,21.0mmol),2-异丙基-4-甲基吡啶-3-胺(3.8g,25.2mmol)加入DMF(100mL)中，0℃加入氢化钠(1.0g,25.2mmol)，在室温条件下反应过夜；加水淬灭，用乙酸乙酯萃取(3*50mL)，有机相水洗(20mL)，再用饱和食盐水(20mL)洗涤。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物1-(叔-丁基)3-甲基(6R)-4-(4-溴-5-氟-2-((2-异丙基-4-甲基吡啶-3-基)氨基)苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯(11.8g，产率77％)。 Add 1-(tert-butyl)3-methyl(6R)-4-(4-bromo-2,5-difluorobenzoyl)-6-methylpiperazine-1,3-dicarboxylate (10g, 21.0mmol), 2-isopropyl-4-methylpyridin-3-amine (3.8g, 25.2mmol) was added to DMF (100mL), sodium hydride (1.0g, 25.2mmol) was added at 0°C, Reacted overnight at room temperature; quenched with water, extracted with ethyl acetate (3*50 mL), washed the organic phase with water (20 mL), and then washed with saturated brine (20 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound 1-(tert-butyl)3-methyl(6R)-4- (4-Bromo-5-fluoro-2-((2-isopropyl-4-methylpyridin-3-yl)amino)benzoyl)-6-methylpiperazine-1,3-dicarboxylic acid Esters (11.8 g, 77% yield).
MS m/z(ESI):607.1[M+H] +，609.1[M+H+2] +. MS m/z(ESI): 607.1[M+H] + , 609.1[M+H+2] + .
第三步：1-(叔-丁基)3-甲基(6R)-4-(4-溴-5-氟-2-(N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰氨基)苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯的制备The third step: 1-(tert-butyl)3-methyl(6R)-4-(4-bromo-5-fluoro-2-(N-(2-isopropyl-4-methylpyridine-3) -Yl)-2-nitroacetamido)benzoyl)-6-methylpiperazine-1,3-dicarboxylate
Figure PCTCN2020093731-appb-000165
Figure PCTCN2020093731-appb-000165
将1-(叔-丁基)3-甲基(6R)-4-(4-溴-5-氟-2-((2-异丙基-4-甲基吡啶-3-基)氨基)苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯(5g,8.2mmol),2-硝基乙酸(1.04g,9.9mmol)加入DMF(60mL)中，在0℃条件下加入三乙胺(4.1g,41mmol)和T 3P(7.8g,24.6mmol，50％in EtOAc)，逐渐升至室温反应过夜，加入水，用二氯甲烷萃取(3*50mL)，有机相水洗(20mL)，再用饱和食盐水(20mL)洗涤。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物1-(叔-丁基)3-甲基(6R)-4-(4-溴-5-氟-2-(N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰氨基)苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯(3.1g，产率54％)。 Add 1-(tert-butyl)3-methyl(6R)-4-(4-bromo-5-fluoro-2-((2-isopropyl-4-methylpyridin-3-yl)amino) Benzoyl)-6-methylpiperazine-1,3-dicarboxylate (5g, 8.2mmol), 2-nitroacetic acid (1.04g, 9.9mmol) was added to DMF (60mL), and the condition was 0℃ Add triethylamine (4.1g, 41mmol) and T 3 P (7.8g, 24.6mmol, 50% in EtOAc), gradually warm to room temperature and react overnight, add water, extract with dichloromethane (3*50mL), organic The phase was washed with water (20 mL), and then washed with saturated brine (20 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound 1-(tert-butyl)3-methyl(6R)-4- (4-Bromo-5-fluoro-2-(N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitroacetamido)benzoyl)-6-methylpiperazine -1,3-dicarboxylate (3.1 g, yield 54%).
MS m/z(ESI):694.1[M+H] +，696.1[M+H+2] +. MS m/z(ESI): 694.1[M+H] + , 696.1[M+H+2] + .
第四步：1-(叔-丁基)3-甲基(6R)-4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-羰基-1,2-二氢喹啉-4-基)-6-甲基哌嗪-1,3-二羧酸酯的制备The fourth step: 1-(tert-butyl)3-methyl(6R)-4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl) Preparation of -3-nitro-2-carbonyl-1,2-dihydroquinolin-4-yl)-6-methylpiperazine-1,3-dicarboxylate
Figure PCTCN2020093731-appb-000166
Figure PCTCN2020093731-appb-000166
将1-(叔-丁基)3-甲基(6R)-4-(4-溴-5-氟-2-(N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰氨基)苯甲酰)-6-甲基哌嗪-1,3-二羧酸酯(2.8g,4.0mmol)加入DMF(50mL)中，在0℃条件下加入NaH(192mg,4.8mmol)，室温反应1小时，加热到70℃继续反应15小时，加入水淬灭，用二氯甲烷萃取(3*50mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物1-(叔-丁基)3-甲基(6R)-4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-羰基-1,2-二氢喹啉-4-基)-6-甲基哌嗪-1,3-二羧酸酯(0.8g，产率30％)。 Add 1-(tert-butyl)3-methyl(6R)-4-(4-bromo-5-fluoro-2-(N-(2-isopropyl-4-methylpyridin-3-yl) -2-Nitroacetamido)benzoyl)-6-methylpiperazine-1,3-dicarboxylate (2.8g, 4.0mmol) was added to DMF (50mL), and NaH( 192mg, 4.8mmol), reacted at room temperature for 1 hour, heated to 70°C and continued to react for 15 hours, quenched by adding water, and extracted with dichloromethane (3*50mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound 1-(tert-butyl)3-methyl(6R)-4- (7-Bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-carbonyl-1,2-dihydroquinolin-4-yl )-6-methylpiperazine-1,3-dicarboxylate (0.8 g, yield 30%).
MS m/z(ESI):676.1[M+H] +，678.1[M+H+2] +. MS m/z(ESI): 676.1[M+H] + , 678.1[M+H+2] + .
第五步：叔-丁基(2R)-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二羰基-1,2,4,4a,5,6,7,8-八氢-3H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-3-羧酸酯的制备The fifth step: tert-butyl(2R)-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-di Carbonyl-1,2,4,4a,5,6,7,8-octahydro-3H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c ]Quinoline-3-carboxylate preparation
Figure PCTCN2020093731-appb-000167
Figure PCTCN2020093731-appb-000167
将1-(叔-丁基)3-甲基(6R)-4-(7-溴-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-羰基-1,2-二氢喹啉-4-基)-6-甲基哌嗪-1,3-二羧酸酯(700mg,1.0mmol)加入溶剂(乙醇：水＝5：1)(50mL)中,加入铁粉(280mg,5mmol)和NH 4Cl(110mg,2.1mmol)，加热回流3小时，冷却，过滤，滤液加入饱和食盐水，用二氯甲烷萃取(3*30mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(2R)-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二羰基-1,2,4,4a,5,6,7,8-八氢-3H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-3-羧酸酯(420mg，产率66％)。 Add 1-(tert-butyl)3-methyl(6R)-4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-3- Nitro-2-carbonyl-1,2-dihydroquinolin-4-yl)-6-methylpiperazine-1,3-dicarboxylate (700mg, 1.0mmol) was added to the solvent (ethanol: water = 5 :1) Add iron powder (280mg, 5mmol) and NH 4 Cl (110mg, 2.1mmol) to (50mL), heat to reflux for 3 hours, cool, filter, add saturated brine to the filtrate, and extract with dichloromethane (3* 30mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(2R)-10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dicarbonyl-1,2,4,4a,5,6,7,8-octahydro-3H -Pyranazinyl [1',2':4,5] pyranazinyl [2,3-c]quinoline-3-carboxylate (420 mg, yield 66%).
MS m/z(ESI):614.1[M+H] +，616.1[M+H+2] +. MS m/z(ESI): 614.1[M+H] + , 616.1[M+H+2] + .
第六步：叔-丁基(2R)-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二 羰基-1,2,4,4a,5,6,7,8-八氢-3H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-3-羧酸酯的制备The sixth step: tert-butyl(2R)-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5, 7-Dicarbonyl-1,2,4,4a,5,6,7,8-octahydro-3H-pyranazinyl[1',2':4,5]pyranazinyl[2, 3-c] Preparation of quinoline-3-carboxylate
Figure PCTCN2020093731-appb-000168
Figure PCTCN2020093731-appb-000168
将叔-丁基(2R)-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二羰基-1,2,4,4a,5,6,7,8-八氢-3H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-3-羧酸酯(400mg,0.65mmol)加入DMF(20mL)中，在0℃条件下加入NaH(31mg,0.78mmol)，碘甲烷(101mg,0.72mmol)，搅拌1小时，升至室温继续反应2小时，加水淬灭，加入水，用二氯甲烷萃取(3*30mL)。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物叔-丁基(2R)-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二羰基-1,2,4,4a,5,6,7,8-八氢-3H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-3-羧酸酯(330mg，产率80％)。 Add tert-butyl(2R)-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dicarbonyl-1 ,2,4,4a,5,6,7,8-octahydro-3H-pyranazo[1',2':4,5]pyranazo[2,3-c]quinoline -3-Carboxylate (400mg, 0.65mmol) was added to DMF (20mL), NaH (31mg, 0.78mmol) and methyl iodide (101mg, 0.72mmol) were added at 0℃, stirred for 1 hour, warmed to room temperature and continued React for 2 hours, quench by adding water, add water, and extract with dichloromethane (3*30 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound tert-butyl(2R)-10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dicarbonyl-1,2,4,4a,5,6,7,8-octa Hydrogen-3H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c]quinoline-3-carboxylate (330mg, yield 80%).
MS m/z(ESI):628.1[M+H] +，630.1[M+H+2] +. MS m/z(ESI): 628.1[M+H] + , 630.1[M+H+2] + .
第七步：(2R)-3-丙烯酰-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-5,7-二酮的制备The seventh step: (2R)-3-acryloyl-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2 ,3,4,4a,6,8-Hexahydro-1H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c]quinoline-5,7 -Preparation of diketone
Figure PCTCN2020093731-appb-000169
Figure PCTCN2020093731-appb-000169
将叔-丁基(2R)-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二羰基-1,2,4,4a,5,6,7,8-八氢-3H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-3-羧酸酯(300mg,0.48mmol),溶于二氯甲烷(10mL)中，加入TFA(2mL)，室温搅拌2小时。浓缩，加入水和饱和NaHCO 3水溶液调节至中性，二氯甲烷(3*50mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品。溶于二氯甲烷(10mL)中，加入DIPEA(195mg，1.5mmol)，冰水浴下滴加丙烯酰氯(47mg，0.53mmol)，加完继续搅拌1小时。加水淬灭，二氯甲烷(20 mL)萃取三次。合并有机层，无水硫酸钠干燥，浓缩得到粗品，柱层析(CH 2Cl 2/MeOH＝10：1)纯化得到目标化合物(2R)-3-丙烯酰-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-5,7-二酮(210mg，产率76％)。 The tert-butyl(2R)-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-di Carbonyl-1,2,4,4a,5,6,7,8-octahydro-3H-pyranazinyl[1',2':4,5]pyranazyl[2,3-c ] Quinoline-3-carboxylate (300 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrate, add water and saturated aqueous NaHCO 3 to adjust to neutrality, and extract with dichloromethane (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Dissolve in dichloromethane (10 mL), add DIPEA (195 mg, 1.5 mmol), add acryloyl chloride (47 mg, 0.53 mmol) dropwise under ice-water bath, and continue stirring for 1 hour after the addition. It was quenched with water and extracted three times with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (CH 2 Cl 2 /MeOH = 10:1) to obtain the target compound (2R)-3-acryloyl-10-bromo-11-fluoro- 8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyranazyl [1',2':4,5]pyranazino[2,3-c]quinoline-5,7-dione (210 mg, yield 76%).
MS m/z(ESI):582.1[M+H] +，584.1[M+H+2] +. MS m/z(ESI): 582.1[M+H] + , 584.1[M+H+2] + .
第八步：(2R)-3-丙烯酰-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-5,7-二酮的制备The eighth step: (2R)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) -2,6-Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyranazo[1',2':4,5]pyranazo[2, 3-c) Preparation of quinoline-5,7-dione
Figure PCTCN2020093731-appb-000170
Figure PCTCN2020093731-appb-000170
将(2R)-3-丙烯酰-10-溴-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-5,7-二酮(20mg,0.03mmol)，溶于二氧六环(3mL)中，加入2-氟-6-羟基苯硼酸(7mg，0.04mmol)、三(二亚苄基丙酮)二钯(18mg，0.02mmol)、Xantphos(23mg，0.04mmol)以及Cs 2CO 3(33mg，0.1mmol)，氮气置换。微波加热至110℃反应1小时。冷却至室温后，加入水和二氯甲烷(3*20mL)萃取。合并有机层，无水硫酸钠干燥，浓缩得到粗品，制备HPLC纯化得到目标化合物(2R)-3-丙烯酰-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡喃联氮基[1',2':4,5]吡喃联氮基[2,3-c]喹啉-5,7-二酮(6mg，产率29％)。 Add (2R)-3-acryloyl-10-bromo-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3, 4,4a,6,8-hexahydro-1H-pyranazinyl[1',2':4,5]pyranazinyl[2,3-c]quinoline-5,7-dione (20mg, 0.03mmol), dissolved in dioxane (3mL), add 2-fluoro-6-hydroxyphenylboronic acid (7mg, 0.04mmol), tris(dibenzylideneacetone) dipalladium (18mg, 0.02mmol) ), Xantphos (23mg, 0.04mmol) and Cs 2 CO 3 (33mg, 0.1mmol), replaced with nitrogen. Microwave heating to 110°C for 1 hour. After cooling to room temperature, water and dichloromethane (3*20 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, and purified by preparative HPLC to obtain the target compound (2R)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-( 2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrandiazo[1',2':4,5]pyranazino[2,3-c]quinoline-5,7-dione (6mg, yield 29%).
MS m/z(ESI):614.1[M+H] +. MS m/z(ESI): 614.1[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H358/Mia PaCa-2细胞增殖活性抑制作用的测定Test Example 1. Determination of the inhibitory effect of the compound of the present invention on the proliferation activity of H358/Mia PaCa-2 cells
1.1实验目的：1.1 The purpose of the experiment:
该测试例的目的是测量化合物对H358和Mia PaCa-2细胞增殖活性的抑制作用。The purpose of this test case is to measure the inhibitory effect of the compound on the proliferation activity of H358 and Mia PaCa-2 cells.
1.2实验仪器和试剂：1.2 Experimental instruments and reagents:
1.2.1仪器：1.2.1 Instrument:
酶标仪(BioTek Synergy H1)；Microplate reader (BioTek Synergy H1);
移液器(Eppendorf&Rainin)。Pipette (Eppendorf & Rainin).
1.2.2试剂：1.2.2 Reagents:
NCI-H358购自南京科佰生物科技有限公司；NCI-H358 was purchased from Nanjing Kebai Biotechnology Co., Ltd.;
Mia PaCa-2购自ATCC；Mia PaCa-2 was purchased from ATCC;
Cell Titer-Glo细胞购自Promega公司，货号为G7573；Cell Titer-Glo cells were purchased from Promega, the product number is G7573;
RPMI 1640购自Gibco，货号为22400089；RPMI 1640 was purchased from Gibco, the article number is 22400089;
DMEM购自Gibco，货号为11995065；DMEM was purchased from Gibco, the article number is 11995065;
FBS购自Gibco，货号为10091148；FBS was purchased from Gibco, the article number is 10091148;
PBS购自Gibco，货号为10010023；PBS was purchased from Gibco, the article number is 10010023;
胰酶购自Gibco，货号为25200056；Pancreatin was purchased from Gibco, the product number is 25200056;
细胞培养板购自Corning公司，货号为3610。The cell culture plate was purchased from Corning, the article number is 3610.
1.3实验方法：1.3 Experimental method:
培养H358或Mia PaCa-2细胞至合适的融合度时，收集H358或Mia PaCa-2细胞，使用完全培养基将细胞调整为合适的细胞浓度，将细胞悬液铺于96孔板，每孔90μL，放入37℃，5％CO 2培养箱贴壁过夜，使用DMSO以及培养基配制不同浓度的化合物溶液，设置溶媒对照，将化合物溶液加入到96孔板中，每孔10μL，放入37℃，5％CO 2培养箱中继续培养72h～144h后，加入CellTiter-Glo溶液，振荡混合均匀后，避光孵育10分钟，用BioTek Synergy H1酶标仪进行读数。 When culturing H358 or Mia PaCa-2 cells to a suitable degree of confluence, collect H358 or Mia PaCa-2 cells, adjust the cells to a suitable cell concentration with complete medium, and spread the cell suspension on a 96-well plate, 90 μL per well , Put it in a 37℃, 5% CO 2 incubator overnight, use DMSO and culture medium to prepare compound solutions of different concentrations, set the solvent control, add the compound solution to a 96-well plate, 10μL per well, put it in 37℃ After culturing in a 5% CO 2 incubator for 72h～144h, add CellTiter-Glo solution, shake and mix well, incubate in the dark for 10 minutes, and read with BioTek Synergy H1 microplate reader.
1.4实验数据处理方法：1.4 Experimental data processing method:
使用发光信号值计算抑制率，将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到IC 50值。 The luminescence signal value was used to calculate the inhibition rate, and the concentration and inhibition rate were fitted with Graphpad Prism software for nonlinear regression curve fitting to obtain the IC 50 value.
1.5实验结果：1.5 Experimental results:
实验结果如表1所示，实施例化合物对NCI-H358和Mia PaCa-2细胞增殖抑制活性的IC 50值。 The results of the experiment are shown in Table 1. The IC 50 values of the compounds of the examples against the proliferation inhibitory activity of NCI-H358 and Mia PaCa-2 cells.
表1Table 1
Figure PCTCN2020093731-appb-000171
Figure PCTCN2020093731-appb-000171
Figure PCTCN2020093731-appb-000172
Figure PCTCN2020093731-appb-000172
1.6.实验结论：1.6. Experimental conclusion:
根据数据显示，本发明实施例化合物对NCI-H358和Mia PaCa-2细胞具有良好的的增殖抑制作用。According to the data, the compounds of the examples of the present invention have a good proliferation inhibitory effect on NCI-H358 and Mia PaCa-2 cells.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (21)

  1. 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：A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020093731-appb-100001
    Figure PCTCN2020093731-appb-100001
    其中：among them:
    X 1选自N或CR 1； X 1 is selected from N or CR 1 ;
    X 2选自N或CR 2； X 2 is selected from N or CR 2 ;
    L选自键、-(CH 2) n-、-C(R bbR cc) n-、-O(CH 2) n-、-(CH 2) nO-、-S(CH 2) n-、-(CH 2) nS-、-NR bb(CH 2) n-、-NR bb(CH 2) nC(O)-、-CH＝CH(CH 2) n-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-、-(CH 2) nS(O) m-、-(CH 2) nNR bb-或-(CH 2) nNR bbS(O) m-； L is selected from bond, -(CH 2 ) n -, -C(R bb R cc ) n -, -O(CH 2 ) n -, -(CH 2 ) n O-, -S(CH 2 ) n- , -(CH 2 ) n S-, -NR bb (CH 2 ) n -, -NR bb (CH 2 ) n C(O)-, -CH=CH(CH 2 ) n -, -(CH 2 ) n C(O)NR bb -, -(CH 2 ) n C(O)-, -CH=CH(CH 2 ) n NR bb -, -(CH 2 ) n S(O) m -, -(CH 2 ) n NR bb - or- (CH 2 ) n NR bb S(O) m -;
    环A选自环烷基、杂环基、芳基或杂芳基；Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
    R 1选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aa或-(CH 2) nC(O)R aa，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -, -NH(CH 2 ) n C(O)R aa , -O(CH 2 ) n R aa , -(CH 2 ) n SR aa or -(CH 2 ) n C(O)R aa , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl The group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
    R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkane The group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
    R 3选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氧代基、硫代基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-O(CH 2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bbR cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR ccR dd、-(CH 2) nR bb、-(CH 2) nSR bb、-(CH 2) nC(O)R bb、-(CH 2) nC(O)OR bb、-(CH 2) nS(O) mR bb、-(CH 2) nNR bbR cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nNR bbC(O)R cc或-(CH 2) nNR bbS(O) mR cc，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂环基任选的可以进一步被取代； R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkane Oxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O(CH 2 ) n R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc , -NR bb (CH 2 ) n NR cc R dd , -CH=CH(CH 2 ) n R bb , -CH=CH(CH 2 ) n NR bb R cc 、-CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)R cc 、-CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)NR cc R dd , -(CH 2 ) n R bb , -(CH 2 ) n SR bb , -(CH 2 ) n C(O)R bb , -(CH 2 ) n C(O)OR bb , -( CH 2 ) n S(O) m R bb , -(CH 2 ) n NR bb R cc , -(CH 2 ) n C(O)NR bb R cc , -(CH 2 ) n NR bb C(O) R cc or -(CH 2 ) n NR bb S(O) m R cc , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxy Alkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heterocyclyl may optionally be further substituted;
    R 4选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cycloalkane The group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
    R 5选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, The heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
    R a选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氧代基、硫代基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R a is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo group, thioxo group, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy Oxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl , Alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further substituted;
    R aa选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, cyano The substituted alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further substituted;
    R bb和R cc各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, and haloalkoxy , Hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkane Oxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
    或者，R bb与R cc同相邻的原子形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； Alternatively, R bb and R cc and adjacent atoms form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups may optionally be further replace;
    R dd选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、烯基、炔基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano Group-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy , Hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further substituted;
    或者，R cc与R dd同相邻的原子形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选的可以进一步被取代； Alternatively, R cc and R dd and adjacent atoms form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may optionally be further replace;
    x为0～6的整数；x is an integer from 0 to 6;
    n为0～3的整数；且n is an integer from 0 to 3; and
    m为0～2的整数；m is an integer from 0 to 2;
    其中，当X 1为N时，X 2为N； Wherein, when X 1 is N, X 2 is N;
    或者，当X 1为CR 1，X 2为CR 2。 Or, when X 1 is CR 1 , X 2 is CR 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，R 1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-(CH 2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aa或-(CH 2) nC(O)R aa，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基和3-12元杂环基的一个或多个取代基所取代； The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -(CH 2 ) n -, -NH (CH 2 ) n C(O)R aa , -O(CH 2 ) n R aa , -(CH 2 ) n SR aa or -(CH 2 ) n C(O)R aa , the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 halo Alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally hydrogen, hydroxyl , Halogen, amino, C 1-6 alkyl, C 2-6 alkenyl carbonyl and 3-12 membered heterocyclic group substituted by one or more substituents;
    优选3-10元杂环基或-(CH 2) nC(O)R aa，所述的3-10元杂环基任选的被氢、羟基、卤素、氨基、C 1-3烷基、C 2-6烯基羰基和3-10元杂环基的一个或多个取代基所取代； Preferably 3-10 membered heterocyclic group or -(CH 2 ) n C(O)R aa , said 3-10 membered heterocyclic group is optionally substituted by hydrogen, hydroxy, halogen, amino, C 1-3 alkyl , C 2-6 alkenyl carbonyl and 3-10 membered heterocyclic group substituted by one or more substituents;
    R aa选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代； R aa is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6 -12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl carbonyl, 3-12 membered heterocyclyl, -C (O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb substituted by one or more substituents;
    优选3-10元杂环基，所述的3-12元杂环基任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代； Preferably 3-10 membered heterocyclic group, said 3-12 membered heterocyclic group is optionally substituted by hydrogen, hydroxy, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl carbonyl, 3-12 membered Heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb are substituted by one or more substituents;
    R bb和n如权利要求1所述。 R bb and n are as described in claim 1.
  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，R 2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基； The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1, wherein R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl;
    优选氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； Preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
    更优选氢、卤素或C 1-3烷基。 More preferred is hydrogen, halogen or C 1-3 alkyl.
  4. 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，R 3选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-O(CH 2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-CH＝CH(CH 2) nNR bbR cc或-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR ccR dd，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基和3-12元杂环基的一个或多个取代基所取代； The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R 3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5 -12-membered heteroaryl, -O(CH 2 ) n R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc , -NR bb (CH 2 ) n NR cc R dd , -CH=CH(CH 2 ) n R bb , -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)R cc , -(CH 2 ) n C (O)NR bb R cc , -(CH 2 ) n C(O)R bb , -CH=CH(CH 2 ) n NR bb R cc or -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)NR cc R dd , the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group Group, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered hetero Cyclic, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by one or more of hydrogen, hydroxyl, halogen, amino, C 1-6 alkyl and 3-12 membered heterocyclic group Substituted by
    优选氢、氨基、C 3-12环烷基、3-12元杂环基、-O(CH 2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc或-NR bb(CH 2) nNR ccR dd，所述C 3-12环烷基和3-12元杂环基任选的被氢、C 1-6烷基和3-12元杂环基中的一个或多个取代基所取代； Preferably hydrogen, amino, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, -O(CH 2 ) n R bb , -(CH 2 ) n C(O)NR bb R cc , -(CH 2 ) n C(O)R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -NR bb (CH 2 ) n R cc or -NR bb (CH 2 ) n NR cc R dd , The C 3-12 cycloalkyl and 3-12 membered heterocyclic group are optionally substituted by one or more substituents among hydrogen, C 1-6 alkyl and 3-12 membered heterocyclic group;
    R bb和R cc各自独立的氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基和3-12元杂环基的一个或多个取代基所取代； R bb and R cc are independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterium Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1- 6 alkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group, optionally substituted by hydrogen, hydroxyl, halogen, amino, C 1- 6 alkyl and 3-12 membered heterocyclic group substituted by one or more substituents;
    R dd选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1- 6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、氰基、C 1-6烷基和3-12元杂环基的一个或多个取代基所取代； R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C 1-6 Substituted by one or more substituents of an alkyl group and a 3-12 membered heterocyclic group;
    m和n如权利要求1所述。m and n are as described in claim 1.
  5. 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，R 4选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘 代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基； The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R 4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl;
    优选氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； Preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
    更优选氢、卤素或C 1-3烷基。 More preferred is hydrogen, halogen or C 1-3 alkyl.
  6. 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，R 5选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代； The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1 -6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxyl, halogen, amino, C 1-6 alkyl, C 2-6 alkenylcarbonyl, 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n Substituted by one or more substituents of R bb ;
    优选氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 3-8环烷基或3-10元杂环基，所述的C 1-6烷基、C 3-8环烷基和3-10元杂环基，任选的被氢、羟基、卤素、氨基、C 1-6烷基、C 2-6烯基羰基、3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb的一个或多个取代基所取代； Preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic group, said C 1-6 alkyl, C 3-8 cycloalkyl and 3-10 membered heterocyclic group, optionally substituted by hydrogen, hydroxy, halogen, amino, C 1-6 alkyl, C 2-6 alkenyl carbonyl, 3-12 membered heterocyclic group , -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb substituted by one or more substituents;
    R bb和n如权利要求1所述。 R bb and n are as described in claim 1.
  7. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R a选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基或氰基取代的C 1-6烷基，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基和氰基取代的C 1-6烷基，任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1- 6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein Ra is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogen Substituted C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, oxo group, thio group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl C 1-6 alkyl group and cyano group, optionally with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1 - 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and a 5-12 membered heteroaryl or more substituents;
    优选氢、卤素、氨基、羟基、氧代基、C 1-6烷基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述的氨基、C 1-6烷基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基和5-10元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基和C 1-6烷基中的一个或多个取代基所取代。 Preferably hydrogen, halogen, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl group Or 5-10 membered heteroaryl groups, the amino group, C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 aryl group And 5-10 membered heteroaryl groups, optionally substituted by one or more substituents of hydrogen, deuterium, halogen, amino, hydroxyl, cyano and C 1-6 alkyl.
  8. 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， 通式(I)进一步如通式(II)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (II):
    Figure PCTCN2020093731-appb-100002
    Figure PCTCN2020093731-appb-100002
    其中：among them:
    M 1选自CR 6R 7或NR 6； M 1 is selected from CR 6 R 7 or NR 6 ;
    R 6选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-C(O)(CH 2) nCH＝CHR bb或-C(O)CH＝CH(CH 2) nR bb，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； R 6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -C(O)(CH 2 ) n CH=CHR bb or -C(O)CH=CH(CH 2 ) n R bb , said C 1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkane Oxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, Halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
    优选3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb或-C(O)CH＝CH(CH 2) nR bb，所述的3-12元杂环基任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； Preferably a 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb or -C(O)CH=CH(CH 2 ) n R bb , the 3-12 membered heterocyclic group Optional by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
    R 7选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基；优选氢； R 7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen;
    R b选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基或氰基取代的C 1-6烷基；优选氢、卤素或C 1-3烷基； R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkane Group; preferably hydrogen, halogen or C 1-3 alkyl;
    y为0～6的整数。y is an integer of 0-6.
  9. 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， 通式(I)进一步如通式(III)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (III):
    Figure PCTCN2020093731-appb-100003
    Figure PCTCN2020093731-appb-100003
    其中：among them:
    M 2选自CR 8R 9或NR 8； M 2 is selected from CR 8 R 9 or NR 8 ;
    R 8选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-C(O)(CH 2) nCH＝CHR bb或-C(O)CH＝CH(CH 2) nR bb，所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； R 8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, -C(O)(CH 2 ) n CH=CHR bb or -C(O)CH=CH(CH 2 ) n R bb , said C 1 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkane Oxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, Halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
    优选3-12元杂环基、-C(O)(CH 2) nCH＝CHR bb和-C(O)CH＝CH(CH 2) nR bb，所述的3-12元杂环基任选的被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； Preferably 3-12 membered heterocyclic group, -C(O)(CH 2 ) n CH=CHR bb and -C(O)CH=CH(CH 2 ) n R bb , said 3-12 membered heterocyclic group Optional hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group and 5-12 membered heteroaryl group substituted by one or more substituents;
    R 9选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基；优选氢； R 9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl; preferably hydrogen;
    R c选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基或氰基取代的C 1-6烷基；优选氢、卤素或C 1-3烷基； R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl or cyano substituted C 1-6 alkane Group; preferably hydrogen, halogen or C 1-3 alkyl;
    z为0～6的整数。z is an integer of 0-6.
  10. 根据权利要求8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，通式(II)进一步如通式(IV)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 8, wherein the general formula (II) is further represented by the general formula (IV):
    Figure PCTCN2020093731-appb-100004
    Figure PCTCN2020093731-appb-100004
  11. 根据权利要求9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，通式(III)进一步如通式(V)所示：The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 9, wherein the general formula (III) is further represented by the general formula (V):
    Figure PCTCN2020093731-appb-100005
    Figure PCTCN2020093731-appb-100005
    其中：among them:
    L 2选自键、-O(CH 2) n-、-OC(R bbR cc) n(CH 2) m-、-NR bb(CH 2) n-、-NR bb(CH 2) nNR cc-、-CH＝CH(CH 2) n-或-CH＝CH(CH 2) nNR bb(CH 2) mC(O)-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-或-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR cc-； L 2 is selected from bond, -O(CH 2 ) n -, -OC(R bb R cc ) n (CH 2 ) m -, -NR bb (CH 2 ) n -, -NR bb (CH 2 ) n NR cc -, -CH=CH(CH 2 ) n -or -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)-, -(CH 2 ) n C(O)NR bb -, -(CH 2 ) n C(O)-, -CH=CH(CH 2 ) n NR bb -or -CH=CH(CH 2 ) n NR bb (CH 2 ) m C(O)NR cc -;
    环B选自C 3-12环烷基、3-14元杂环基、C 6-14芳基或5-14元杂芳基； Ring B is selected from C 3-12 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl;
    优选3-12元杂环基、C 6-12芳基或5-12元杂芳基； Preferably a 3-12 membered heterocyclic group, a C 6-12 aryl group or a 5-12 membered heteroaryl group;
    R d选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1- 6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基任选被氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、硫代基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aromatic Substituted by one or more substituents in the 5-12 membered heteroaryl group;
    t为0～6的整数。t is an integer of 0-6.
  12. 根据权利要求10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，通式(IV)进一步如通式(VI)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 10, characterized in that the general formula (IV) is further represented by the general formula (VI):
    Figure PCTCN2020093731-appb-100006
    Figure PCTCN2020093731-appb-100006
    其中：among them:
    R 2选自氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； R 2 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
    优选氢、氟、氯、溴、羟基、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基； Preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
    更优选氟或羟基；More preferably fluorine or hydroxyl;
    R 3选自氢、氨基、C 3-12环烷基、3-12元杂环基、-O(CH 2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-N＝CR bb(CH 2) nNR ccR dd、-NR bbC(O)(CH 2) nR cc、-NR bb(CH 2) nR cc或-NR bb(CH 2) nNR ccR dd，所述C 3-12环烷基和3-12元杂环基，任选的被氢、C 1-6烷基和3-12元杂环基中的一个或多个取代基所取代； R 3 is selected from hydrogen, amino, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, -O(CH 2 ) n R bb , -(CH 2 ) n C(O)NR bb R cc ,- (CH 2 ) n C(O)R bb , -OC(R bb R cc ) n (CH 2 ) m R dd , -N=CR bb (CH 2 ) n NR cc R dd , -NR bb C(O )(CH 2 ) n R cc , -NR bb (CH 2 ) n R cc or -NR bb (CH 2 ) n NR cc R dd , the C 3-12 cycloalkyl group and 3-12 membered heterocyclic group , Optionally substituted by one or more substituents of hydrogen, C 1-6 alkyl and 3-12 membered heterocyclic group;
    优选-N＝CHNR ccR dd、-NR bbC(O)R cc、-NR bb(CH 2) nR cc或-NH b(CH 2) nNR ccR dd； Preferably -N=CHNR cc R dd , -NR bb C(O)R cc , -NR bb (CH 2 ) n R cc or -NH b (CH 2 ) n NR cc R dd ;
    更优选
    Figure PCTCN2020093731-appb-100007
    Figure PCTCN2020093731-appb-100008
    More preferred
    Figure PCTCN2020093731-appb-100007
    Figure PCTCN2020093731-appb-100008
    R 10选自氢、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基； R 10 is selected from hydrogen, halogen, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
    优选氢、卤素、羟基、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基； Preferably hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
    更优选氢或甲基；More preferably hydrogen or methyl;
    R 11选自氢、卤素、氨基、羟基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基或5-10元杂芳基，所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基和5-10元杂芳基，任选的被氢、氘、卤素、氨基、羟基、氰基和C 1-6烷基中的一个或多个取代基所取代； R 11 is selected from hydrogen, halogen, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 Membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 3 -8 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano and C 1-6 Substituted by one or more substituents in the alkyl group;
    优选氢、氨基、羟基或C 1-3烷氧基； Preferably hydrogen, amino, hydroxyl or C 1-3 alkoxy;
    更优选氢、氨基、羟基或甲氧基；More preferably hydrogen, amino, hydroxyl or methoxy;
    R bb和R cc各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、氰基、C 1-6烷基烷基氨基酰基、氨基酰基和3-12元杂环基的一个或多个取代基所取代； R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, the amino group, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxyl, halogen, amino, cyanide Group, C 1-6 alkylalkylaminoacyl, aminoacyl and 3-12 membered heterocyclic group substituted by one or more substituents;
    R dd选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1- 6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基或5-12元杂芳基，所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、氰基取代的C 1-6烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基和5-12元杂芳基，任选的被氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 1-6烷基烷基氨基酰基、氨基酰基和3-12元杂环基的一个或多个取代基所取代；且 R dd is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl group or 5-12 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxyl, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 alkylalkylaminoacyl, aminoacyl and 3-12 membered heterocyclic group are substituted by one or more substituents; and
    m和n为0～3的整数。m and n are integers of 0-3.
  13. 根据权利要求1或8～11中任一项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，其特征在于，The compound represented by each general formula, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 or 8 to 11, characterized in that:
    环A选自C 6-10芳基或5-12元杂芳基，所述的5-12元杂芳基优选含有1-3个氮原子的杂芳基，包括5-7元含氮杂芳基、苯并5-7元含氮杂芳基或5-7元含氮杂芳基并苯基，更优选以下基团： Ring A is selected from a C 6-10 aryl group or a 5-12 membered heteroaryl group. The 5-12 membered heteroaryl group is preferably a heteroaryl group containing 1-3 nitrogen atoms, including 5-7 membered nitrogen-containing heteroaryl groups. Aryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroaryl phenyl, more preferably the following groups:
    Figure PCTCN2020093731-appb-100009
    Figure PCTCN2020093731-appb-100009
  14. 根据权利要求9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，其特征在于，The compound represented by each general formula, its stereoisomer or its pharmaceutically acceptable salt according to claim 9, characterized in that:
    环B选自含有1-3个氮原子的5-12元杂环基，更优选如下基团：Ring B is selected from 5-12 membered heterocyclic groups containing 1-3 nitrogen atoms, more preferably the following groups:
    Figure PCTCN2020093731-appb-100010
    Figure PCTCN2020093731-appb-100011
    Figure PCTCN2020093731-appb-100010
    Figure PCTCN2020093731-appb-100011
  15. 一种通式(VII)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 (VII), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020093731-appb-100012
    Figure PCTCN2020093731-appb-100012
    环C选自苯基、吡啶基、5-7元含氮杂芳基、苯并5-7元含氮杂芳基或5-7元含氮杂芳基并苯基，进一步优选选自以下基团：Ring C is selected from phenyl, pyridyl, 5-7 membered nitrogen-containing heteroaryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroaryl phenyl, and is more preferably selected from the following Group:
    Figure PCTCN2020093731-appb-100013
    Figure PCTCN2020093731-appb-100013
    R 12选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基； R 12 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
    优选氢、氟、氯、甲基、乙基、丙基、甲氧基或乙氧基。Preference is given to hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy.
    R e选自氢、卤素、羟基、氨基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基或3-8元杂环基； R e is selected from hydrogen, halogen, hydroxy, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group;
    优选氢、氟、氯、羟基、氨基或甲基；Preferably hydrogen, fluorine, chlorine, hydroxyl, amino or methyl;
    p为0～4的整数。p is an integer of 0-4.
  16. 一种通式(VIII)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 (VIII), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020093731-appb-100014
    Figure PCTCN2020093731-appb-100014
    其中：among them:
    X 3选自CH 2、CH、N或NR 13； X 3 is selected from CH 2 , CH, N or NR 13 ;
    X 4选自CH 2、C＝O、N或CR 14； X 4 is selected from CH 2 , C=O, N or CR 14 ;
    M选自N或CH；M is selected from N or CH;
    L 3选自-O-或-OCH 2-； L 3 is selected from -O- or -OCH 2 -;
    L 4选自-O-或-CH 2-； L 4 is selected from -O- or -CH 2 -;
    R 13选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基； R 13 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
    优选甲基或环丙基；Preferably methyl or cyclopropyl;
    R 14选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基； R 14 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group;
    优选氢或甲基；Preferably hydrogen or methyl;
    R选自3-8元含氮杂环基或苯并3-8元含氮杂环基，进一步优选5-7元含氮杂环基或苯并5-7元含氮杂环基，其中氮原子的个数为1-2个，任选的被卤素或C 1-3烷基中的一个或多个取代基所取代， R is selected from 3-8 membered nitrogen-containing heterocyclic group or benzo 3-8 membered nitrogen-containing heterocyclic group, more preferably 5-7 membered nitrogen-containing heterocyclic group or benzo 5-7 membered nitrogen-containing heterocyclic group, wherein The number of nitrogen atoms is 1-2, optionally substituted by halogen or one or more substituents in C 1-3 alkyl,
    优选以下取代基：The following substituents are preferred:
    Figure PCTCN2020093731-appb-100015
    Figure PCTCN2020093731-appb-100015
    R 15选自氢、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-8环烷基或3-8元杂环基；优选氢或氟。 R 15 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-8 cycloalkyl or 3- 8-membered heterocyclic group; preferably hydrogen or fluorine.
  17. 一种通式(IX)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 (IX), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020093731-appb-100016
    Figure PCTCN2020093731-appb-100016
    其中：among them:
    环D选自如下基团：Ring D is selected from the following groups:
    Figure PCTCN2020093731-appb-100017
    Figure PCTCN2020093731-appb-100017
  18. 根据权利要求1～17中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-17, characterized in that it is selected from the following compounds:
    Figure PCTCN2020093731-appb-100018
    Figure PCTCN2020093731-appb-100018
    Figure PCTCN2020093731-appb-100019
    Figure PCTCN2020093731-appb-100019
    Figure PCTCN2020093731-appb-100020
    Figure PCTCN2020093731-appb-100020
    Figure PCTCN2020093731-appb-100021
    Figure PCTCN2020093731-appb-100021
    Figure PCTCN2020093731-appb-100022
    Figure PCTCN2020093731-appb-100022
    Figure PCTCN2020093731-appb-100023
    Figure PCTCN2020093731-appb-100023
  19. 一种药用组合物，其包括治疗有效剂量的权利要求1～18中任一项所示的化合 物、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 according to any one of claims 1 to 18, its stereoisomer or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable The carrier, diluent or excipient.
  20. 根据权利要求1～18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，或权利要求19所述的药用组合物在制备治疗KRAS G12C抑制剂药物中的应用。The compound according to any one of claims 1 to 18, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 19 in the preparation of drugs for treating KRAS G12C inhibitors application.
  21. 根据权利要求1～18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，或权利要求19所述的药用组合物在制备治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、食管癌、头颈部肿瘤、乳腺癌、肺癌及其结肠癌等疾病或病症的药物中的应用；优选非小细胞肺癌、结肠癌、食管癌和头颈部肿瘤。The compound according to any one of claims 1 to 18, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 19 is used for the treatment of Noonan’s syndrome, leopard skin Syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer and colon cancer and other diseases or diseases of the drug; preferably non-small cell lung cancer, colon cancer, esophageal cancer and Head and neck tumors.
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