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WO2020239123A1 - Modulateur de dérivé hétérocyclique aromatique et son procédé de préparation et son utilisation - Google Patents

Modulateur de dérivé hétérocyclique aromatique et son procédé de préparation et son utilisation 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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Prior art keywords
alkyl
group
alkoxy
amino
cyano
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PCT/CN2020/093731
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English (en)
Chinese (zh)
Inventor
刘世强
袁逸达
鲍孟
黄胜爱
王婷司
Original Assignee
上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority claimed from CN201910856187.8A external-priority patent/CN112552294B/zh
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/CN113396147B/zh
Publication of WO2020239123A1 publication Critical patent/WO2020239123A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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.

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Abstract

La présente invention concerne un modulateur de dérivé hétérocyclique aromatique, son procédé de préparation et son utilisation. En particulier, la présente invention concerne un composé représenté dans la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le composé, et son utilisation en tant qu'inhibiteur de mutation de KRAS G12C dans le traitement de maladies ou d'états tels que la leucémie, le neuroblastome, le mélanome, le cancer du sein, le cancer du poumon et le cancer du côlon, la définition de chaque substituant dans la formule générale (I) étant la même que celle dans la description.
PCT/CN2020/093731 2019-05-31 2020-06-01 Modulateur de dérivé hétérocyclique aromatique et son procédé de préparation et son utilisation WO2020239123A1 (fr)

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