WO2021088839A1 - 咪唑烷酮类化合物及其制备方法与应用 - Google Patents

咪唑烷酮类化合物及其制备方法与应用 Download PDF

Info

Publication number
WO2021088839A1
WO2021088839A1 PCT/CN2020/126359 CN2020126359W WO2021088839A1 WO 2021088839 A1 WO2021088839 A1 WO 2021088839A1 CN 2020126359 W CN2020126359 W CN 2020126359W WO 2021088839 A1 WO2021088839 A1 WO 2021088839A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
carboxamide
dioxoimidazolidine
isopropyl
oxazepine
Prior art date
Application number
PCT/CN2020/126359
Other languages
English (en)
French (fr)
Inventor
祖厚贤
宋西镇
陈凯
刘湘永
陈洁
边雅敬
丁列明
王家炳
Original Assignee
贝达药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 贝达药业股份有限公司 filed Critical 贝达药业股份有限公司
Priority to CN202410229432.3A priority Critical patent/CN118084935A/zh
Priority to CA3156625A priority patent/CA3156625A1/en
Priority to MX2022005415A priority patent/MX2022005415A/es
Priority to BR112022008647A priority patent/BR112022008647A2/pt
Priority to IL292592A priority patent/IL292592A/en
Priority to CN202080074622.2A priority patent/CN114599655B/zh
Priority to AU2020379709A priority patent/AU2020379709A1/en
Priority to KR1020227018861A priority patent/KR20220097466A/ko
Priority to JP2022525930A priority patent/JP2023501324A/ja
Priority to EP20885710.2A priority patent/EP4056575A4/en
Priority to US17/773,771 priority patent/US20230053342A1/en
Publication of WO2021088839A1 publication Critical patent/WO2021088839A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to an imidazolidinone compound, which plays a role in regulating cell proliferation, apoptosis, migration, angiogenesis and other processes.
  • the invention also relates to a pharmaceutical composition containing the compound and its application in the treatment of PI3K-mediated diseases.
  • PI3K signaling pathway is a key signaling pathway that controls growth, proliferation, survival, differentiation, metastasis and apoptosis in cells. Because PI3K, Akt and mTOR are the key sites on this pathway, they are called PI3K/Akt/mTOR signaling pathway. In recent years, PI3K inhibitors have become a research hotspot of anti-tumor drugs at home and abroad.
  • PI3K is activated by RTK or Ras to catalyze phosphoinositol-3,4-diphosphate (PIP2) to phosphoinositol-3,4,5-triphosphate (PIP3).
  • PIP3 binds to protein kinases such as Akt and 3-phosphoinositide (PIP)-dependent protein kinase (PDK), activates Akt by phosphorylation, and transfers Akt from the cytoplasm to the nucleus.
  • the activated Akt can further phosphorylate downstream effector substrates to affect cell survival, cell cycle, growth and other cell activities (Ma K, Cheung SM, Marshall AJ, etc., Cell Signal, 2008, 20: 684-694). Therefore, The activation of PI3K/Akt/mTOR signaling pathway can inhibit cell apoptosis, enhance cell tolerance, promote cell survival and proliferation, participate in angiogenesis, and promote tumor growth and metastasis.
  • Phosphatidylinositol 3-kinase belongs to the Lipid kinase family. The members of this family are divided into three types: type I, type II, and type III according to the activation mechanism and structural characteristics of PI3K (Vanhaesebroeck B, Waterfield MD ; Exp Cell Res, 1999, 253:239-254). At present, the more thorough research is type I PI3K. According to the different types of cell surface receptors, type I PI3K is further divided into two different subtypes, IA and IB. These two subtypes are derived from tyrosine protein kinase receptors (RTKs) and G protein-coupled receptors.
  • RTKs tyrosine protein kinase receptors
  • Type II PI3K kinases are divided into three subtypes: PI3KC2 ⁇ , PI3KC2 ⁇ , and PI3KC2 ⁇ according to their C-terminal structure. However, their substrates in the body are not yet clear, and the understanding of their mechanism and specific functions is relatively limited (Falasca M, T. Muffucci; Biochem Soc Trans, 2007, 35:211-214).
  • Type III PI3K kinase has only one member, Vps34 (Vacuolar Protein Sorting 34), which plays a calibrated role at the protein level when regulating the downstream mTOR signal cascade (Schu P, Takegawa. K, Fry. M et al., Science, 1993, 260:88-91).
  • PI3K ⁇ has the closest relationship with the occurrence and development of tumors.
  • PI3K ⁇ catalytic subunit p110 ⁇ is PIK3CA, and its mutations are commonly found in various malignant tumors, including breast cancer, colon cancer, endometrial cancer, gastric cancer, Ovarian cancer and lung cancer (Steelman.LS, Chappell.WH, Abrams.SL, etc., Aging, 2011, 3:192-222). Abnormal activation of PI3K ⁇ will up-regulate and activate the PI3K signaling pathway, promote excessive cell proliferation, growth and metastasis, leading to tumor formation.
  • PI3K ⁇ The other three subtypes PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , although they play a role in thrombosis, immune function, allergies and inflammatory response, respectively, but by affecting the catalytic activity, physical and chemical properties, interaction and recognition, etc., they play a role in the occurrence of tumors. China also plays an important role.
  • the PI3K inhibitors that have been studied more in the early stage are wortmannin and LY294002, both of which play an important role in studying the physiological functions of PI3K and the mechanism of signaling pathways, and provide an important basis for subsequent research.
  • Known as the first generation PI3K inhibitor Known as the first generation PI3K inhibitor.
  • the second generation PI3K inhibitors with newer structure, higher activity and better pharmacokinetic properties have been developed, including morpholinoaryls, imidazopyridines and imidazo Quinolines, etc., have brought new hope to tumor treatment.
  • dozens of PI3K inhibitors are in the clinical research stage, which are mainly divided into pan-PI3K inhibitors, PI3K/mTOR dual inhibitors and PI3K subtype specific inhibitors.
  • Alpelisib (BYL719) is the first PI3K ⁇ selective inhibitor developed by Norvartis, and its inhibitory activity on p110 ⁇ is 5nM.
  • Preclinical data show that BYL719 can inhibit the phosphorylation of Akt, block the PI3K signaling pathway and inhibit the growth of breast cancer cells containing PIK3CA mutations (Dejan Juric et al., Cancer Res, 2012, 72:1).
  • the compound has been approved for marketing by the U.S. Food and Drug Administration (FDA) on May 24, 2019, for the treatment of patients with PIK3CA gene mutations, HR + /HER2 - advanced or metastatic breast cancer, and receiving endocrine therapy Postmenopausal women and men with disease progression during or after the program.
  • FDA U.S. Food and Drug Administration
  • this PI3K ⁇ -specific small molecule inhibitor has a good prospect in the treatment of diseases such as head and neck cancer, ovarian cancer, triple-negative breast cancer, HER2+ breast cancer, PIK3CA-related overgrowth disease spectrum and so on. If the drug can expand its indications, it will produce huge economic and social benefits.
  • PI3K inhibitor In order to achieve better tumor treatment effects, better meet market demand, and provide a new drug choice for clinical use, we hope to develop a new generation of higher activity, better pharmacokinetics, and lower toxicity. PI3K inhibitor.
  • the object of the present invention is to provide an imidazolidinone compound as a PI3K inhibitor.
  • the present invention first provides a compound represented by formula (I) or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug,
  • X is selected from O or S
  • R 1 is selected from H, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl Group, C 5-8 heteroaryl, OR a or -NR a R b ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-8 aryl and C 5-8 heteroaryl may optionally be selected from halogen, CN, OR a , oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-6 heterocyclyl substituents;
  • R 2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6- 8 aryl and C 5-8 heteroaryl groups can be optionally substituted by one or more selected from halogen, CN, -OH, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3 -6 heterocyclic group, C 3-6 halogenated heterocyclic group, C 6-8
  • R 3 is selected from H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a or -NR a R b ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl can optionally be selected by one or more selected from halogen, CN, -OR a , -NR a R b , -C(O)R a , -C( O) OR a , -C(O)NR a R b , -S(O)R a or -S(O) 2 R a substituents;
  • R 4 is selected from H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, C 1-6 haloalkyl, C 2-6 haloalkenyl , C 2-6 haloalkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)R a or -S(O) 2 R a ;
  • R 5 is selected from H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2- 6 haloalkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR a, -NR a R b , -S (O) R a , or -S (O) 2 R a;
  • R 6 is selected from H, halogen, CN, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl , C 3-6 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl, -OR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -S(O)R a or -S(O) 2 R a ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl and C 5-8 heteroaryl may optionally be selected from 1 or more Halogen, CN, oxo, -NO 2 , C 1-6 alkyl,
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkane Oxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl, C 5-8 heteroaryl can be optionally substituted by halogen, CN, -OH, -NH 2 , C Substituted by 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, 2 or 3;
  • y is selected from 0, 1, 2, 3, 4, 5, or 6.
  • R 1 is a C 1-6 alkyl group or a C 3-6 cycloalkyl group, and the C 1-6 alkyl group and C 3-6 cycloalkyl group may be independently optionally substituted with halogen.
  • R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl or C 5-8 heteroaryl;
  • the C 1-6 alkyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group, C 6-8 aryl group and C 5-8 heteroaryl group may be optionally substituted by 1 or more halogens, -CN, -OH, -NR a R b , C 1-6 alkyl or C 1-6 haloalkyl groups; said R a and R b are each independently selected from H or C 1-6 alkyl.
  • R 3 is selected from H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl Or C 2-6 haloalkynyl.
  • R 6 is selected from H, halo, CN, -NH 2, oxo, -OH, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 Aryl or C 5-8 heteroaryl.
  • the compound represented by formula (I) is further a compound represented by formula (II):
  • the compound represented by formula (I) is further a compound represented by formula (III-1):
  • R 1 is a C 1-6 alkyl group or a C 1-6 haloalkyl group.
  • the compound represented by formula (I) is further a compound represented by formula (III-2):
  • R 3 is selected from H, halogen, C 1-6 alkyl, or C 2-6 alkenyl.
  • both R 4 and R 5 are H.
  • the compound represented by formula (I) is further a compound represented by formula (IV):
  • R 1 is C 1-6 alkyl or C 1-6 haloalkyl
  • R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl or C 5-8 heteroaryl; the C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-8 aryl and C 5-8 heteroaryl may optionally be substituted by one or more halogens, -CN, -OH , -NR a R b , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 3 is selected from H, halogen, C 1-6 alkyl or C 2-6 alkenyl
  • R 6 is selected from H, halogen, -NH 2 , oxo, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl or C 6-8 aryl;
  • R a and R b are each independently selected from H or C 1-6 alkyl
  • y is selected from 0, 1, 2, 3, 4, 5, or 6.
  • the X is O.
  • the compound represented by formula (I) is further a compound represented by formula (V):
  • R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl or C 5-6 heteroaryl; the C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl and C 5-6 heteroaryl may optionally be substituted by one or more halogens, -CN,- OH, -N-(CH 3 ) 2 , C 1-6 alkyl or C 1-6 haloalkyl.
  • R 6 is selected from H, halogen, -NH 2 , oxo, -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 6 aryl. base.
  • the compound represented by formula (I) is further a compound represented by formula (VI):
  • R 1 is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl or C 5-6 heteroaryl; the C 1-6 alkyl , C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl and C 5-6 heteroaryl may optionally be substituted by one or more halogens, -CN, -OH, -N- (CH 3 ) 2 , C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1 is C 1-4 alkyl
  • R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl or C 5- C 6 heteroaryl; said R 1 and R 2 may be independently optionally substituted with halogen.
  • R 2 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, phenyl or halophenyl.
  • R 1 is selected from -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CF 3 or -CHF 2 .
  • the compound represented by formula (I) is further represented by formula (VII):
  • said R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl or C 5-6 heteroaryl; said R 2 Optionally substituted by halogen.
  • R 1 is C 1-4 alkyl
  • R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6 aryl or C 5-6 heteroaryl; said R 1 and R 2 may be independently optionally substituted with F.
  • R 2 is selected from -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CF 3 , cyclopropyl, cyclobutyl, phenyl, or pyridyl; the- CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CF 3 , cyclopropyl, cyclobutyl, phenyl, or pyridyl can be optionally substituted with halogen.
  • the halogen is F.
  • R 2 is selected from -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, phenyl, or halogen-substituted phenyl.
  • R 1 is -CH(CH 3 ) 2 .
  • R 1 is -CHF 2 .
  • R 2 is selected from -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, phenyl, or F-substituted phenyl, pyridyl, or F-substituted pyridyl.
  • R 2 is selected from -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, phenyl, or F-substituted phenyl.
  • R 2 is -CH(CH 3 ) 2 or cyclopropyl.
  • the compound represented by formula (I) is further represented by formula (VIII):
  • the present invention further provides some particularly preferred technical solutions regarding the compound represented by formula (I) or its stereoisomers, geometric isomers or tautomers, and the compounds refer to:
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least any one compound represented by formula (I) of the present invention and at least one pharmaceutically acceptable excipient.
  • the present invention further provides a pharmaceutical composition in which the weight ratio of the compound represented by formula (I) to the adjuvant is in the range of 0.0001-10.
  • the present invention provides the application of the compound represented by formula (I) or the pharmaceutical composition containing formula (I) in the preparation of medicines.
  • the medicament is used to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.
  • the drug is used to treat cancer.
  • the drug is used as a PI3K inhibitor.
  • the drug is used to treat PI3K-mediated diseases.
  • the PI3K includes PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and/or PI3K ⁇ .
  • the PI3K is PI3K ⁇ .
  • the PI3K-mediated disease is cancer.
  • the cancer is selected from the group consisting of sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, and kidney cancer , Bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary platelets Hyperplasia.
  • the present invention also provides a method for treating and/or preventing patients suffering from PI3K-mediated diseases, the method is to administer a therapeutically effective amount of at least any one of the compounds represented by formula (I) or containing The pharmaceutical composition of the compound represented by formula (I).
  • the PI3K includes PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and/or PI3K ⁇ .
  • the PI3K is PI3K ⁇ .
  • the PI3K-mediated disease is cancer.
  • the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma Tumor, kidney cancer, bladder cancer, uterine cancer, vagina cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, Essential thrombocytosis.
  • the present invention also provides a method for the treatment of cancer, which comprises administering a therapeutically effective amount of at least one compound represented by formula (I) or a pharmaceutical composition containing the compound represented by formula (I) to a subject.
  • Said cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterus Cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary thrombocytosis.
  • the treatment target is a human being.
  • the present invention relates to compounds as PI3K inhibitors, and the use of these compounds to prepare drugs for the treatment or prevention of diseases mediated by PI3K in vivo.
  • the compound As an active ingredient, the compound has the characteristics of good therapeutic effect, high selectivity, and high bioavailability.
  • the compound As a medicine to be marketed, the compound has the characteristics of low cost and convenient administration, which is more conducive to the wide application of these medicines, and can more effectively help patients overcome pain and improve the quality of life.
  • alkyl includes linear, branched or cyclic saturated alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl and Cyclohexyl.
  • C 1-4 in C 1-4 alkyl refers to a group containing 1, 2, 3 or 4 carbon atoms arranged in a linear, branched or cyclic form.
  • Cycloalkyl refers to a cyclic saturated monovalent hydrocarbon group.
  • C 3-6 in C 3-6 cycloalkyl refers to a saturated monovalent hydrocarbon group containing 3, 4, 5 or 6 carbon atoms arranged in a cyclic form.
  • Representative cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, or cyclohexane and similar groups.
  • heterocyclic group refers to a substituted or unsubstituted non-aromatic 3- to 6-membered monocyclic ring system consisting of a C atom and 1 to 3 selected from N, O or S It is composed of heteroatoms, and the N or S heteroatoms can be selectively oxidized, and the N heteroatoms can also be quaternized arbitrarily.
  • the heterocycloalkyl group can be attached to any heteroatom or carbon atom that can produce a stable structure.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazetidine, nitrogen Heteropyranyl, tetrahydrofuranyl, dioxolane, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl Sulfone group, thiomorpholine sulfone group and oxadiazole group.
  • Halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Preferred halogen groups refer to fluorine, chlorine and bromine.
  • Halo refers to a fluoro, chloro, bromo or iodo group.
  • substitution means that one or more hydrogen atoms in a group are replaced by the same or different substituents.
  • substituents include, but are not limited to, halogen, amino, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, aryl, haloaryl, arylalkyl Group, arylalkenyl, heterocyclyl, cycloalkoxy, alkylamino.
  • aryl refers to a substituted or unsubstituted monocyclic or polycyclic ring system containing carbon atoms.
  • the preferred aryl group is phenyl.
  • heteroaryl refers to an unsubstituted or substituted stable 5-membered or 6-membered monoaromatic ring system, or an unsubstituted or substituted 9-membered or 10-membered benzo-fused
  • a heteroaromatic ring system or a di-heteroaromatic ring system is composed of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, where N or The S heteroatom can be optionally oxidized, and the N heteroatom can be optionally quaternized.
  • heteroaryl group can be attached to any heteroatom or carbon atom that can produce a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, Pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazole Group, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl or isoquinolinyl.
  • the "compound” of the present invention includes the compound of formula (I) and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), geometrically different Conformers, isotopically-labeled compounds, tautomers, prodrugs, or any mixture of all the above forms.
  • the “enantiomers” are a pair of non-superimposable stereoisomers that are mirror images of each other, and a 1:1 mixture of a pair of enantiomers is a "racemic" mixture.
  • the conventional RS system is used (for example (1S, 2S) specifies a single stereoisomer of known relative and absolute configuration with two chiral centers).
  • the “diastereomers” are stereoisomers having at least two asymmetric atoms, but they are not mirror images of each other.
  • the stereochemistry on each chiral carbon can be designated by R or S.
  • the resolved compounds with unknown absolute configuration can be named (+) or (-) according to the direction (right-handed or left-handed) they rotate the plane-polarized light at the wavelength of the sodium D line.
  • the resolved compound can be defined by the corresponding retention time of the corresponding enantiomer/diastereomer of chiral HPLC.
  • the compounds of the present invention contain chiral centers and therefore can exist in different isomeric forms. Unless otherwise specified, the compounds of the present invention are intended to include all these possible isomers, including racemic mixtures, optically pure forms, and isomer mixtures in any ratio.
  • the compound represented by formula (VIII) includes the compound of Example 2, the compound of Example 32, the compound of Example 33, and the mixture of Example 32 and Example 33 in any ratio.
  • Optically active (R)- and (S)-isomers can be prepared using optically active raw materials synthesis or chiral reagents, or they can be resolved using conventional techniques (for example, separation on a chiral SFC or HPLC column ).
  • the “pharmaceutically acceptable” refers to those that are well-known for use in animals, especially those that can be used in humans.
  • composition in the present invention includes a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition including the compound of the present invention as an active ingredient and a method for preparing the compound are the content of the present invention. Furthermore, the crystal forms of some compounds may exist in the form of polymorphs, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and such solvates are also included in the present invention.
  • “Therapeutically effective amount” means that when a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical symptom of a disease, condition, symptom, indication, and/or discomfort, it is sufficient for the disease, condition, A dose that produces a certain effect for the treatment of symptoms, indications or discomfort.
  • the specific "therapeutically effective amount” may vary according to the compound, the route of administration, the age of the patient, the weight of the patient, the type, symptoms and severity of the disease or discomfort to be treated, etc. Whenever possible, an appropriate dose may be obvious to those skilled in the art, or it may be determined by conventional experimental methods.
  • the compounds provided by the present invention may also exist in the form of "pharmaceutically acceptable salts".
  • the salts of the compounds provided by the present invention refer to non-toxic pharmaceutically acceptable salts.
  • the form of a pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or base/cation salt.
  • Pharmaceutically acceptable acid/anionic salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids.
  • Typical organic or inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid , Malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylamine sulfonic acid , Salicylic acid, saccharinic acid or trifluoroacetic acid.
  • Pharmaceutically acceptable base/cation salts include, but are not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium salts and Zinc salt.
  • the "prodrug” of the compound of the present invention is included in the protection scope of the present invention.
  • the “prodrug” is a functional derivative that is easily converted into the desired compound in the body. Therefore, the term “administration” involved in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be converted into the compound disclosed in the present invention in vivo after administration to the subject. disease.
  • the conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compound of the present invention can be selected according to the prior art of the subject to select suitable substituents or substitution forms to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, potassium, sodium, zinc and the like. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred.
  • non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.
  • citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% is weight ratio) .
  • the pharmaceutical composition provided by the present invention includes a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
  • the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the compound represented by formula (I) of the present invention can be combined with drugs as the active component and mixed with a drug carrier to form Pharmaceutical composition.
  • the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients.
  • the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two.
  • the product can be easily prepared into the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and one or more other compounds having therapeutic activity in combination are also included in the pharmaceutical composition of the present invention.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
  • solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers include syrup, peanut oil, olive oil and water.
  • gas carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral preparations.
  • standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
  • the tablet containing the compound or pharmaceutical composition of the present invention can be prepared by compression or molding together with one or more auxiliary components or adjuvants.
  • the active ingredient is in a free-flowing form such as powder or granules, mixed with lubricants, inert diluents, surface-active or dispersing agents, and compressed in a suitable machine to produce compressed tablets.
  • the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
  • each tablet contains about 0.05 mg to 5 g of active ingredient
  • each cachet or capsule contains about 0.05 mg to 5 g of active ingredient.
  • a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition.
  • the unit dosage form generally contains about 1 mg to about 2 g of the effective ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water.
  • a suitable surfactant such as hydroxypropyl cellulose may be included.
  • glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared.
  • a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersion systems.
  • the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injections.
  • the final injection form must be sterile, and for easy injection, it must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical combination provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting powder, or other similar dosage forms.
  • the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • these preparations can be prepared by conventional processing methods.
  • an emulsion or ointment is prepared by adding a hydrophilic material and water (the total amount of the two is about 5 wt% to 10 wt% of the compound) to prepare a cream or ointment with the desired consistency.
  • the pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier.
  • Suppositories in which the mixture forms a unit dose are the most preferred dosage form.
  • Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, then cooling and moulding.
  • the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc.
  • other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • the pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof can also be prepared in the form of a powder or a concentrated solution.
  • the present invention will use the following examples to further illustrate the preparation of the compound of formula (I) of the present invention, but there is no limitation to the present invention.
  • PE Petroleum ether
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • LiHMDS Lithium bis(trimethylsilyl)amide
  • the compound of formula (VI) can be prepared by the following route:
  • compound 32 pre-peak
  • compound 33 post-peak
  • racemate compounds in Table 1 can be synthesized and prepared using corresponding chiral raw materials to obtain the corresponding enantiomers, or basically follow the method described in step 7 of Example 2 to separate the enantiomers on a chiral column. body.
  • Example 102 in WO2017001658 using the corresponding starting materials, intermediates and appropriate reagents, the compounds of Comparative Example 1 (Example 102 in WO2017001658) and Comparative Example 2 in Table 2 can be obtained; Comparative Example 3
  • the preparation method of the compound is shown below.
  • step 2 The reaction solution obtained in step 2 was quenched by adding water (500 mL) under ice-water bath conditions, and then adding trifluoroacetic acid (50 mL), and stirring was continued for 3 hours at room temperature. After the reaction, the system was concentrated and extracted with EA. The organic phase was washed with brine, dried with anhydrous Na 2 SO 4 , concentrated, and purified by column chromatography (Hex/EA 100:1-10:1) to obtain a brown solid, which was mixed with a mixed solution of HEX and EA (volume ratio 50:1) The solid was washed, filtered with suction, and the filtrate was collected and concentrated to obtain 395 g of compound D3-4.
  • the following experiments show that the preferred compounds of the present invention can effectively inhibit the activity of PI3K ⁇ kinase in vitro.
  • the anti-PI3K ⁇ mutant tumor cell proliferation activity and pharmacokinetic test results of the preferred compound of the present invention are better than those of the control example, and have significant progress.
  • PI3K ⁇ , PI3K ⁇ , PI3K ⁇ kinases and their substrates ATP, PIP2:3PS carry out enzymatic reactions, and the amount of the product is detected by ADP-Glo reagent and luminescence method to reflect the enzymatic activity of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ (ATP final concentration 10 ⁇ M).
  • the above method was used to test the inhibitory activity of some compounds of the present invention on PI3K ⁇ , PI3K ⁇ and PI3K ⁇ kinases.
  • Reagents basic kinase buffer (pH 7.5); PI3K ⁇ , PI3K ⁇ , PI3K ⁇ enzyme solutions; PIP2:3PS and ATP solutions; ADP-Glo kit (containing 10mM MgCl 2 ).
  • the buffer components 50mM Hepes (pH7.2-7.5), 3mM MgCl 2 , 1mM EGTA, 0.03% CHAPS, 100mM NaCl, 2mM DTT;
  • Reaction process 1) Add PI3K ⁇ , PI3K ⁇ , PI3K ⁇ protein solution to 384 reaction plate (6008280, PerkinElmer), and centrifuge at 1000rpm for 1 minute for use.
  • RLU relative luminescence unit
  • Y minimum inhibition rate+(maximum inhibition rate-minimum inhibition rate)/(1+10 ⁇ ((LogIC 50 -X)*slope)); where X is the log value of the concentration of the test compound, and Y is the inhibition of the test compound Rate (%inh).
  • A represents IC 50 values ⁇ 5nM
  • B Representative IC 50 value of 5 ⁇ 20nM
  • C Representative IC 50 value of 300 ⁇ 600nM
  • D Representative IC 50 values of> 600nM.
  • the compound provided by the present invention has good PI3K ⁇ kinase inhibitory activity, and has good PI3K ⁇ and PI3K ⁇ kinase subtype selectivity, which can avoid potential side effects caused by multi-target inhibition.
  • Detection method Suspend MCF-7 cells in DMEM medium to form a cell suspension, adjust the cell concentration to 25000 cells/mL; suspend HGC27 cells in RPMI-1640 medium to form a cell suspension, adjust the cell concentration to 5000 cells/mL .
  • the compound to be tested was dissolved in DMSO, and a 3-fold dilution was performed to obtain a total of 10 concentrations. Transfer 10 concentrations of the compound to be tested or DMSO negative control substance to the wells containing 100 ⁇ L of culture medium, and incubate at 37° C.
  • Compound inhibition rate (%inh) 100%-(compound to be tested RLU-blank control RLU)/(negative control substance RLU-blank control substance RLU)*100%
  • Negative control DMSO well
  • Blank control blank medium well, no compound and no cells
  • Y minimum inhibition rate+(maximum inhibition rate-minimum inhibition rate)/(1+10 ⁇ ((LogIC 50 -X)*slope)); where X: the log value of the concentration of the test compound; Y: the inhibition of the test compound Rate (%inh).
  • Example Compound against MCF cells IC 50 ( ⁇ M) Comparative example 1 0.444 Comparative example 2 0.549 Comparative example 3 0.519 Example 1 0.176 Example 2 0.070 Example 5 0.373 Example 9 0.142 Example 23 0.074 Example 28 0.468 Example 32 0.107 Example 33 0.047
  • Example Compound IC 50 for HGC-27 cells Comparative example 1 1.579 Comparative example 3 2.067 Example 2 0.361 Example 5 4.071 Example 28 3.921 Example 32 0.415 Example 33 0.267
  • the compound provided by the present invention has better cell proliferation inhibitory activity for cell lines with PI3K ⁇ point mutations than the control compound, and has a better anti-tumor effect at the same concentration. Therefore, the compound provided by the present invention is expected to become a PI3K ⁇ kinase inhibitor with better anti-tumor effect.
  • Detection method 42 male SD rats, weight: 150-300g. They were randomly divided into 7 groups, with 6 rats in each group. Among the 6 rats in each group, 3 rats were given a single intravenous injection of 2 mg/mL of the example compound, and the other 3 rats were given a single intravenous injection of 10 mg/mL of the example compound. The blood was collected, the plasma was separated, and stored in the refrigerator at -80°C for later use.
  • the compound provided by the present invention has an unexpectedly higher oral exposure than the compound of the control example, and at the same time has a lower in vivo clearance rate; it can have a higher oral exposure rate at the same dose. Circulatory system drug concentration in the body. On the premise that the anti-tumor effect is equivalent, the administered dose of the compound of the present invention is lower, thereby reducing possible toxic reactions and safety risk probability, and effectively increasing the compound's druggability.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

一种式(I)所示的咪唑烷酮类化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐，含有所述化合物的药物组合物、合成方法及其应用。

Description

咪唑烷酮类化合物及其制备方法与应用 技术领域
本发明涉及一种咪唑烷酮类化合物，其通过参与调节细胞增殖、凋亡、迁移、新生血管生成等多个过程而发挥作用。本发明还涉及含有该类化合物的药物组合物及其在治疗PI3K介导的疾病中的应用。
背景技术
PI3K信号通路是细胞内控制生长、增殖、存活、分化、转移和凋亡等生命活动的关键信号传导通路。由于PI3K、Akt和mTOR是这条通路上的关键位点，所以被称为PI3K/Akt/mTOR信号通路。近年来，PI3K抑制剂已成为国内外抗肿瘤药物的一个研究热点。
PI3K被RTK或Ras激活后催化磷酸肌醇-3,4-二磷酸(PIP2)生成磷酸肌醇-3,4,5-三磷酸(PIP3)。PIP3与Akt和3-磷酸肌醇(PIP)依赖性蛋白激酶(PDK)等蛋白激酶结合，通过磷酸化Akt而使其激活，并将Akt从细胞质转移到细胞核内。激活后的Akt能进一步磷酸化下游的效应底物以影响细胞存活、细胞周期、生长等细胞活动(Ma K,Cheung SM,Marshall AJ等，Cell Signal,2008,20:684-694)，因此，PI3K/Akt/mTOR信号通路激活后会抑制细胞凋亡，增强细胞的耐受性，促进细胞存活、增殖并参与血管形成，促进肿瘤的生长与转移。
磷脂酰肌醇3-激酶(PI3K)属于脂激酶(Lipid kinase)家族，该家族成员根据PI3K活化机制和结构特征的不同分为I型、II型和III型3种类型(Vanhaesebroeck B,Waterfield MD；Exp Cell Res,1999,253:239-254)。目前，研究比较透彻的是I型PI3K。根据细胞表面受体的类型不同，I型PI3K又进一步分为IA和IB两个不同的亚型，这两种亚型分别从酪氨酸蛋白激酶受体(RTKs)和G蛋白偶联受体(GPCRs)接受传递信号(Wu P,Liu T,Hu Y；Curr Med Chem,2009,16:916-930)。IA类PI3K包含PI3Kα、PI3Kβ和PI3Kδ3个亚型，IB类PI3K仅含PI3Kγ一个亚型。II型PI3K激酶根据C末端结构不同分为PI3KC2α、PI3KC2β和PI3KC2γ共3个亚型，但其在体内底物尚不明确，对其作用机制和具体功能的认识也相对有限 (Falasca M,T.Muffucci；Biochem Soc Trans,2007,35:211-214)。III型PI3K激酶只有一个成员Vps34(Vacuolar Protein Sorting 34)，它在调节下游mTOR信号级联作用时在蛋白层面起到校准作用(Schu P，Takegawa.K,Fry.M等人，Science,1993,260:88-91)。
I型PI3K的4个亚型中，PI3Kα和PI3Kβ在各种器官中均有表达，而PI3Kδ和PI3Kγ主要分布在骨髓细胞中(Kong D,Yamori T；Cancer Sci,2008,99:1734-1740)。其中PI3Kα和肿瘤的发生发展有最密切的联系，编码PI3Kα催化亚基p110α的基因是PIK3CA，它的突变普遍存在于各种恶性肿瘤中，包括乳腺癌、结肠癌、子宫内膜癌、胃癌、卵巢癌和肺癌等(Steelman.LS,Chappell.WH,Abrams.SL等,Aging,2011,3:192-222)。PI3Kα的异常激活会上调活化PI3K信号通路，促进细胞过度增殖、生长和转移，导致肿瘤的形成。而其它三种亚型PI3Kβ、PI3Kδ和PI3Kγ，虽然分别在血栓形成、免疫功能和过敏及炎症反应中发挥作用，但通过影响催化活性、理化性质、相互作用及识别等使他们在肿瘤的发生过程中也起到重要作用。
早期研究较多的PI3K抑制剂是渥曼青霉素(wortmannin)和LY294002，两者在研究PI3K的生理学功能和信号通路的作用机制等方面起到重要的作用，为后续的研究提供了重要的基础，被称为第一代PI3K抑制剂。通过对渥曼青霉素和LY294002的研究，具有更新结构、更高活性和更优药代动力学性质的第二代PI3K抑制剂被开发出来，包括吗啉芳基类、咪唑并吡啶类和咪唑并喹啉类等，给肿瘤治疗带来了新的希望。其中已有几十种PI3K抑制剂处于临床研究阶段，主要分为泛PI3K抑制剂、PI3K/mTOR双重抑制剂和PI3K亚型特异性抑制剂。
Alpelisib(BYL719)是由Norvartis公司开发的第一种PI3Kα选择性抑制剂，对p110α的抑制活性为5nM。临床前数据显示BYL719能够抑制Akt的磷酸化，阻断PI3K信号通路并抑制含有PIK3CA变异的乳腺癌细胞生长(Dejan Juric等，Cancer Res,2012,72:1)。该化合物已经于2019年05月24日由美国食品药品监督管理局(FDA)批准上市，用于治疗携带PIK3CA基因突变的、患有HR +/HER2 -晚期或转移性乳腺癌的、接受内分泌治疗方案之中或之后疾病进展的绝经后女性和男性患者。同时前期结果显示此PI3Kα特异性的小分子抑制剂在头颈癌、卵巢癌、三阴性乳腺癌、HER2 +乳腺癌、PIK3CA相关过度生长病谱等疾病的治疗中均具有较好的前景。如果该药物能够实现适应症扩展，将会产生巨大的经济和社会效益。
为了达到更好的肿瘤治疗效果的目的，更好地满足市场需求，为临床上提供一种新的用药选择，我们希望开发出新一代活性更高、药代动力学更佳、毒性更低的PI3K抑制剂。
发明内容
本发明的目的是提供一种作为PI3K抑制剂的咪唑烷酮类化合物。
本发明首先提供了式(Ⅰ)所示的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，
Figure PCTCN2020126359-appb-000001
其中，
X选自O或S；
R 1选自H、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基、OR a或-NR aR b；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环烷基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个选自卤素、CN、OR a、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-6杂环基的取代基所取代；
R 2选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个选自卤素、CN、-OH、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6卤代烯基、C 2-6炔基、C 2-6卤代炔基、C 3-6环烷基、C 3-6卤代环烷基、C 3-6杂环基、C 3-6卤代杂环基、C 6-8芳基、C 6-8卤代芳基、C 5-8杂芳基、C 5-8卤代杂芳基、氧代基、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a的取代基所取代；
R 3选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-OR a或-NR aR b；所述C 1-6烷基、C 2-6烯基、C 2-6炔基可任选地被1个或多个选自卤素、CN、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a的取代基所取代；
R 4选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、C 1-6卤代烷基、C 2-6卤代烯基、C 2-6卤代炔基、C 1-6烷氧基、C 1-6卤代烷氧基、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a；
R 5选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 2-6卤代烯基、C 2-6卤代炔基、C 1-6烷氧基、C 1-6卤代烷氧基、-OR a、-NR aR b、-S(O)R a或-S(O) 2R a；
R 6选自H、卤素、CN、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个选自卤素、CN、氧代基、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a的基团所取代；或者，
两个R 6与其相连接的C原子共同形成C 3-6环烷基或C 3-6杂环基；
R a和R b分别独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基可任选地被卤素、CN、-OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基所取代；
m选自0、1、2、3或4；
n选自0、1、2或3；
y选自0、1、2、3、4、5或6。
关于式(Ⅰ)所示的化合物或其立体异构体、几何异构体或互变异构体，本发明进一步提供了一些优选的技术方案：
一些实施方式中，R 1为C 1-6烷基或C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基可独立任选地经卤素所取代。
一些实施方式中，R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基或C 5-8杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个卤素、-CN、-OH、-NR aR b、C 1-6烷基或C 1-6卤代烷基所取代；所述R a和R b分别独立地选自H或C 1-6烷基。
一些实施方式中，R 3选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 2-6卤代烯基或C 2-6卤代炔基。
一些实施方式中，R 6选自H、卤素、CN、-NH 2、氧代基、-OH、C 1-6烷基、C 2- 6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 2-6卤代烯基、C 2-6卤代炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基或C 5-8杂芳基。
一些实施方式中，式(Ⅰ)所示化合物进一步地为式(Ⅱ)所示化合物：
Figure PCTCN2020126359-appb-000002
一些实施方式中，式(Ⅰ)所示化合物进一步地为式(Ⅲ-1)所示化合物：
Figure PCTCN2020126359-appb-000003
其中，所述R 1为C 1-6烷基或C 1-6卤代烷基。
一些实施方式中，式(Ⅰ)所示化合物进一步地为式(Ⅲ-2)所示化合物：
Figure PCTCN2020126359-appb-000004
一些实施方式中，R 3选自H、卤素、C 1-6烷基或C 2-6烯基。
一些实施方式中，R 4和R 5均为H。
一些实施方式中，式(Ⅰ)所示化合物进一步地为式(Ⅳ)所示化合物：
Figure PCTCN2020126359-appb-000005
Figure PCTCN2020126359-appb-000006
其中：
R 1为C 1-6烷基或C 1-6卤代烷基；
R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基或C 5-8杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个卤素、-CN、-OH、-NR aR b、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基所取代；
R 3选自选自H、卤素、C 1-6烷基或C 2-6烯基；
R 6选自H、卤素、-NH 2、氧代基、-OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-6环烷基或C 6-8芳基；
R a和R b分别独立地选自H或C 1-6烷基；
y选自0、1、2、3、4、5或6。
一些实施方式中，所述X为O。
一些实施方式中，式(Ⅰ)所示化合物进一步地为式(Ⅴ)所示化合物：
Figure PCTCN2020126359-appb-000007
一些实施方式中，R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基和C 5-6杂芳基可任选地被1个或多个卤素、-CN、-OH、-N-(CH 3) 2、C 1-6烷基或C 1-6卤代烷基所取代。
一些实施方式中，R 6选自H、卤素、-NH 2、氧代基、-OH、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或C 6芳基。
一些实施方式中，式(Ⅰ)所示化合物进一步地为式(Ⅵ)所示化合物：
Figure PCTCN2020126359-appb-000008
其中，
R 1选自C 1-6烷基或C 1-6卤代烷基；
R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基和C 5-6杂芳基可任选地被1个或多个卤素、-CN、-OH、-N-(CH 3) 2、C 1-6烷基或C 1-6卤代烷基所取代。
一些实施方式中，R 1为C 1-4烷基；R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-C 6杂芳基；所述R 1和R 2可以独立任选地经卤素取代。
一些实施方式中，R 2选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6卤代环烷基、苯基或卤代苯基。
一些实施方式中，R 1选自-CH(CH 3) 2、-C(CH 3) 3、-CF 3或-CHF 2。
一些实施方式中，式(I)所示化合物进一步如式(Ⅶ)所示：
Figure PCTCN2020126359-appb-000009
其中，所述R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述R 2任选地经卤素取代。
一些实施方式中，R 1为C 1-4烷基；R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述R 1和R 2可以独立任选地经F取代。
一些实施方式中，R 2选自-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2CF 3、环丙基、环丁基、苯基或吡啶基；所述-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2CF 3、环丙基、环丁基、苯基或吡啶基可任选的经卤素取代。
一些实施方式中，所述卤素为F。
一些实施方式中，R 2选自-CH 3、-CH(CH 3) 2、环丙基、苯基或卤素取代的苯基。
一些实施方式中，R 1为-CH(CH 3) 2。
一些实施方式中，R 1为-CHF 2。
一些实施方式中，R 2选自-CH 3、-CH(CH 3) 2、环丙基、苯基或F取代的苯基、吡啶基或F取代的吡啶基。
一些实施方式中，R 2选自-CH 3、-CH(CH 3) 2、环丙基、苯基或F取代的苯基。
一些实施方式中，R 2为-CH(CH 3) 2或环丙基。
一些实施方式中，式(Ⅰ)所示化合物进一步如式(Ⅷ)所示：
Figure PCTCN2020126359-appb-000010
本发明进一步提供了一些关于式(Ⅰ)所示化合物或其立体异构体、几何异构体或互变异构体的特别优选的技术方案，所述化合物是指：
1)(2S)-1-(2-(5-异丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000011
-9-基)吡咯烷-2-甲酰胺；
2)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000012
-9-基)吡咯烷-2-甲酰胺；
3)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-(2,2,2-三氟乙基)咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000013
-9-基)吡咯烷-2-甲酰胺；
4)(2S)-1-(2-(3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000014
-9-基)吡咯烷-2-甲酰胺；
5)(2S)-1-(2-(5-环丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000015
-9-基)吡咯烷-2-甲酰胺；
6)(2S)-1-(2-(3-环丁基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000016
-9-基)吡咯烷-2-甲酰胺；
7)(2S)-1-(2-(3-乙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000017
-9-基)吡咯烷-2-甲酰胺；
8)(2S)-1-(2-(5-二氟甲基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000018
-9-基)吡咯烷-2-甲酰胺；
9)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000019
-9-基)吡咯烷-2-甲酰胺；
10)(S)-1-(2-((S)-5-异丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000020
-9-基)吡咯烷-2-甲酰胺；
11)(S)-1-(2-((R)-5-异丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000021
-9-基)吡咯烷-2-甲酰胺；
12)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-(4-(三氟甲基)苯基)咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000022
-9-基)吡咯烷-2-甲酰胺；
13)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-丙基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000023
-9-基)吡咯烷-2-甲酰胺；
14)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000024
-9-基)-2-甲基吡咯烷-2-甲酰胺；
15)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)-4,4-二氟吡咯烷-2-甲酰胺；
16)(2S)-1-(2-(5-异丙基-3-(1-甲基-1H-1,2,4-三唑-5-基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000025
-9-基)吡咯烷-2-甲酰胺；
17)(2S,4S)-4-氨基-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000026
-9-基)吡咯烷-2-甲酰胺；
18)(2S)-1-(2-(3-(2-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000027
-9-基)吡咯烷-2-甲酰胺；
19)(2S)-1-(2-(3-(4-氯苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000028
-9-基)吡咯烷-2-甲酰胺；
20)(2S)-4-(叔丁氧基)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2]-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000029
-9-基)吡咯烷-2-甲酰胺；
21)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000030
-9-基)-4,4-二甲基吡咯烷-2-甲酰胺；
22)(2S)-1-(2-(3-(2,2-二氟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000031
-9-基)吡咯烷-2-甲酰胺；
23)(2S)-1-(2-(3,5-二异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000032
-9-基)吡咯烷-2-甲酰胺；
24)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000033
-9-基)-4-苯基吡咯烷-2-甲酰胺；
25)(2S)-1-(2-(3-(3-氯5-氰基苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
26)(2S)-1-(2-(3,5-二异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
27)(2S)-1-(2-(3-氮杂环丁烷-3-基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000034
-9-基)吡咯烷-2-甲酰胺；
28)(2S)-1-(2-(3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000035
-9-基)吡咯烷-2-甲酰胺；
29)(2S)-1-(2-(5-叔丁基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000036
-9-基)吡咯烷-2-甲酰胺；
30)(S)-1-(2-((R)-3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2]-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000037
-9-基)吡咯烷-2-甲酰胺；
31)(S)-1-(2-((S)-3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2]-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000038
-9-基)吡咯烷-2-甲酰胺；
32)(2S)-1-(2-((5R)-3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000039
-9-基)吡咯烷-2-甲酰胺；
33)(2S)-1-(2-((5S)-3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000040
-9-基)吡咯烷-2-甲酰胺；
34)(2S)-1-(2-(3-(2-羟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000041
-9-基)吡咯烷-2-甲酰胺；
35)(2S)-1-(2-(3-(2-氟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000042
-9-基)吡咯烷-2-甲酰胺；
36)(2S)-1-(2-(3-(2-(二甲基氨基)乙基)-5-)异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000043
-9-基)吡咯烷-2-甲酰胺；
37)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
38)(2S)-1-(2-(3-(6-氟吡啶-3-基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000044
-9-基)吡咯烷-2-甲酰胺；
39)(2S)-1-(2-(3-(5-氟吡啶-3-基)-5-异丙基-2,4-二氧代咪唑烷1-基)-5,6-二氢苯并[f]咪唑并[1,2]-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000045
-9-基)吡咯烷-2-甲酰胺；
40)(2S)-1-(2-(3-(3-氰基-5-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000046
-9-基)-4-氟吡咯烷-2-甲酰胺；
41)(2S)-1-(2-(3-(3-氯嘧啶-2-基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000047
-9-基)吡咯烷-2-甲酰胺；
42)(2S)-1-(2-(3-环戊基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000048
-9-基)吡咯烷-2-甲酰胺；
43)(2S)-1-(2-(3-(氰基甲基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000049
-9-基)吡咯烷-2-甲酰胺；
44)(2S)-1-(2-(5-异丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
45)(2S)-1-(2-(3-(2,2-二氟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
46)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-3-乙烯基-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000050
-9-基)吡咯烷-2-甲酰胺；
47)(2S)-1-(3-氯-2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000051
-9-基)吡咯烷-2-甲酰胺；
48)(2S)-1-(2-(3-环丙基-5-(二氟甲基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
49)(2S,3S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000052
-9-基)-3-羟基吡咯烷-2-甲酰胺；
50)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-3-甲基-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000053
-9-基)-4-氧代吡咯烷-2-甲酰胺；
51)(2S)-4-环己基-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000054
-9-基)吡咯烷-2-甲酰胺；
52)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)-5-氧代吡咯烷-2-甲酰胺。
本发明还提供了一种药物组合物，所述药物组合物包含治疗有效量的本发明的至少任意一种式(Ⅰ)所示化合物和至少一种药学上可接受的辅料。
本发明进一步提供了一种药物组合物，所述药物组合物中式(Ⅰ)所示化合物与所述辅料的重量比范围是0.0001-10。
本发明提供了式(Ⅰ)所示化合物或含有式(Ⅰ)的药物组合物在制备药物中的应用。
本发明进一步提供了所述应用的优选技术方案：
作为优选，所述药物用于治疗、预防、延迟或阻止癌症或癌转移的发生或进展。
作为优选，所述药物用于治疗癌症。
作为优选，所述药物用作PI3K抑制剂。
作为优选，所述药物用于治疗PI3K介导的疾病。
作为优选，所述PI3K包括PI3Kα、PI3Kβ、PI3Kδ和/或PI3Kγ。
作为优选，所述PI3K为PI3Kα。
作为优选，所述PI3K介导的疾病是癌症。
作为优选，所述癌症选自肉瘤、前列腺癌、乳腺癌、胰腺癌、胃肠癌、结肠直肠癌、甲状腺癌、肝癌、肾上腺癌、神经胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、子宫癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、脑癌、口腔和咽癌、喉癌、淋巴瘤、基底细胞癌、真性红细胞增多症、原发性血小板增多症。
本发明还提供了一种治疗和/或预防患有PI3K介导的疾病患者的方法，所述方法为向需要的患者施用治疗有效量的至少任意一种式(Ⅰ)所示的化合物或含有式(Ⅰ)所示化合物的药物组合物。
作为优选，在上述方法中，所述PI3K包括PI3Kα、PI3Kβ、PI3Kδ和/或PI3Kγ。
作为优选，在上述方法中，所述PI3K是PI3Kα。
作为优选，在上述方法中，所述PI3K介导的疾病是癌症。
作为优选，在上述方法中，所述癌症是肉瘤、前列腺癌、乳腺癌、胰腺癌、胃肠癌、结肠直肠癌、甲状腺癌、肝癌、肾上腺癌、神经胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、子宫癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、脑癌、口腔和咽癌、喉癌、淋巴瘤、基底细胞癌、真性红细胞增多症、原发性血小板增多症。
本发明还提供了一种治疗癌症的方法，所述方法为向治疗对象施用治疗有效量的至少一种式(Ⅰ)所示的化合物或含有式(Ⅰ)所示化合物的药物组合物，所述癌症是肉瘤、前列腺癌、乳腺癌、胰腺癌、胃肠癌、结肠直肠癌、甲状腺癌、肝癌、肾上腺癌、神经胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、子宫癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、脑癌、口腔和咽癌、喉癌、淋巴瘤、基底细胞癌、真性红细胞增多症、原发性血小板增多症。
作为优选，上述方法中，所述治疗对象为人类。
本发明涉及了作为PI3K抑制剂的化合物，和采用这些化合物制备治疗或预防与体内PI3K介导的疾病的药物。所述化合物作为活性成分具有治疗效果好、选择性高、 生物利用度高的特点。所述化合物作为一种即将上市的药物，具有成本低、服用方便的特点，更有利于这些药物的广泛应用，能更有效地帮助病人克服病痛，提高生活质量。
本发明所用术语含义如下：
本发明中，除另有说明，术语“烷基”包括直链、支链或环状的饱和烷基。例如，烷基包括但不限于，甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、环戊基和环己基。类似的，C 1-4烷基中的“C 1-4”是指含有1、2、3或4个碳原子以直链、支链或环状形式排列的基团。
“环烷基”指环状的饱和单价烃基基团。类似的，C 3-6环烷基中的“C 3-6”是指含有3、4、5或6个碳原子以环状形式排列的饱和单价烃基基团。有代表性的环烷基基团包括但不限于，环丙烷、环丁烷、环戊烷或环己烷等类似基团。
本发明中，除另有说明，术语“杂环基”是指取代或未取代的非芳香族3到6元单环系，其由C原子及1到3个选自N、O或S的杂原子组成，并且其中N或S杂原子可选择性的被氧化，N杂原子也可以任意地被季铵化。杂环烷基可以与任何能够产生稳定结构的杂原子或碳原子连接。有代表性杂环基包括但不限于，氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧代氮杂卓基、氮杂卓基、四氢呋喃基、二氧戊烷基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉亚砜基、硫代吗啉砜基和噁二唑基。
“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。优选的卤素基团是指氟、氯和溴。
“卤代基”是指氟代、氯代、溴代或碘代基团。
“取代”是指一个基团中的一个或多个氢原子分别被相同的或不同的取代基所取代。具有代表性的取代基包括但不限于卤素、氨基、羟基、氰基、烷基、烯基、炔基、环烷基、卤代烷基、烷氧基、芳基、卤代芳基、芳基烷基、芳基烯基、杂环基、环烷氧基、烷基氨基。
本发明中，除另有说明，术语“芳基”是指取代或未取代含有碳原子的单环或多环环系。优选的芳基为苯基。
本发明中，除另有说明，术语“杂芳基”，是指未取代或取代的稳定的5元或6元单芳环系，或未取代或取代的9元或10元苯并稠合杂芳环系或双杂芳环系，所述苯并稠合杂芳环系或双杂芳环系由碳原子及1到4个选自N、O或S的杂原子组成， 其中N或S杂原子可任选地被氧化，N杂原子可以被任意地季铵化。杂芳基可以与任何能够产生稳定结构的杂原子或碳原子连接。杂芳基的实例包括但不限于，噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并恶唑基、苯并吡唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基、腺嘌呤基、喹啉基或异喹啉基。
本发明所述“化合物”包括式(Ⅰ)的化合物，及其所有药学上可接受的形式。这些药学上可接受的形式包括盐、溶剂化物、非共价复合物、螯合物、立体异构体(包括非对映异构体、对映异构体和外消旋体)、几何异构体、同位素标记的化合物、互变异构体、前体药物、或上述所有形式的任意混合物。
所述“对映异构体”是一对彼此不可重叠、互为镜像的立体异构体，一对对映异构体的1:1混合物是一种“外消旋”混合物。当指定本发明化合物的立体化学时，使用常规RS系统(例如(1S,2S)指定具有两个手性中心的已知相对和绝对构型的单一立体异构体)。
所述“非对映异构体”是具有至少两个不对称原子的立体异构体，但其不是彼此的镜像。当化合物为纯对映体时，每个手性碳上的立体化学可以由R或S指定。
绝对构型未知的拆分化合物可以根据他们在钠D线的波长处旋转平面偏振光的方向(右旋或左旋)命名为(+)或(-)。或者，拆分的化合物可以通过手性HPLC的相应对应异构体/非对应异构体的相应保留时间来定义。
本领域技术人员将认识到，本发明化合物含有手性中心，因此可以以不同的异构形式存在。除非另有说明，否则本发明化合物意在包括所有这些可能的异构体，包括外消旋混合物、光学纯形式和任意比例的异构体混合物。例如式(Ⅷ)所示的化合物，包括实施例2化合物、实施例32化合物、实施例33化合物、以及任意比例的实施例32和实施例33的混合物。光学活性(R)-和(S)-异构体可以使用光学活性的原料合成来制备或手性试剂来制备，或者使用常规技术来拆分(例如，在手性SFC或HPLC色谱柱上分离)。
所述“药学上可接受的”是指公知的用于动物的，特别是可用于人体的。
本发明中术语“组合物”包括含有特定数量的特定组分的产品，也包括任何由特定数量的特定组分直接或间接得到的产品。因此，包括本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法都是本发明的内容。而且，一些化合物的 晶型可以多晶型形式存在，这些也包括在本发明中。此外，一些化合物与水(如水合物)或普通有机溶剂形成溶剂化物，这样的溶剂化物也包含在本发明中。
“治疗有效量”是指一个化合物施用于治疗主体时治疗并且预防和/或抑制一种疾病、病情、症状、适应症和/或不适的至少一种临床症状时，足以这种疾病、病情、症状、适应症或不适的治疗产生一定效果的剂量。具体的“治疗有效量”可以根据化合物，给药途径、患者年龄、患者体重，所治疗的疾病或不适的类型、症状和严重程度等的不同而变化。在任意可能的情况下，一个合适的剂量对那些在本领域的专业人员可以是显而易见的，也可以是用常规实验方法确定的。
本发明提供的化合物也可以以“药学上可接受的盐”的形式存在。药物应用方面，本发明提供的化合物的盐是指无毒的药学上可接受的盐。药学上可接受的盐的形式包括药学上可接受的酸/阴离子或碱/阳离子盐。药学上可接受的酸/阴离子盐一般以碱性氮与无机酸或有机酸质子化的形式存在。典型的有机或无机酸包括但不限于盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、羟乙基磺酸、苯磺酸、草酸、扑酸、2-萘磺酸、对甲苯磺酸、环己胺磺酸、水杨酸、糖精酸或三氟乙酸。药学上可接受的碱/阳离子盐包括但不限于铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐。
本发明化合物的“前体药物”包含在本发明的保护范围内。通常，所述“前体药物”是很容易在体内转化成所需要的化合物的功能性衍生物。因此，本发明提供的治疗方法涉及的术语“给药”包括施用本发明公开的化合物，或虽未明确公开但对主体给药后能够在体内转化为本发明公开的化合物治疗所述的各种疾病。有关选择和制备合适药物前体衍生物的常规方法，已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
显然的，一个分子中任何取代基或特定位置的变量的定义，与其他分子中的任何取代基或特定位置的变量的定义是无关的。很容易理解，本发明中的化合物可以根据本学科现有技术选择合适的取代基或取代形式，以提供化学上稳定且容易用本学科现有技术或本发明中所述的方法进行制备合成。
当式(Ⅰ)所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限 定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰、钾、钠、锌之类的盐。特别地，优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙烯二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N－乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。较优地，柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地，甲酸和盐酸。由于式(Ⅰ)所示化合物将作为药物应用，所以优选使用基本上纯的形式，例如，至少60％纯度，更适当至少75％的纯度，特别适当至少98％的纯度(％是重量比)。
本发明提供的药物组合物包括作为活性组分的式(Ⅰ)所示化合物(或其药学上可接受的盐)及一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度，但是本发明的药物组合物包括适于口腔、直肠、局部和肠外(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
实际上，根据常规的药物混合技术，本发明式(Ⅰ)所示化合物，或药物前体，或代谢物，或药学上可接受的盐，可以合并用药作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，取决于想采用的给药方式， 例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立单位的形式，如包含预先确定剂量的活性组分的胶囊剂，扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液或油包水型乳液形式。另外，除了上述提到的常见的剂型，式(Ⅰ)所示化合物或其药学上可接受的盐，也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和构成一个或多个必要组分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的的密切混合制得。另外，该产品可以方便地制备成所需要的外观。
因此，本发明的药物组合物包括药学上可接受的载体和式(Ⅰ)所示化合物，或其药学上可接受的盐。式(Ⅰ)所示化合物，或其药学上可接受的盐，与其他一种或多种具有治疗活性联合用药的化合物的也包括在本发明的药物组合物中。
本发明采用的药物载体可以是，例如，固体载体、液体载体或气体载体。固体载体的例子，包括，乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体的例子包括，糖浆、花生油、橄榄油和水。气体载体的例子；包括二氧化碳和氮气。制备药物口服制剂时，可以使用任何方便的制药学上的介质。例如，水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂；而载体，如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用，口服制剂首选片剂和胶囊。可选地，片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过，可选地，可以与一种或多种辅助组分或辅药一起压制或成型制备。活性组分以可以自由流动的形式如粉末或颗粒，与润滑剂、惰性稀释剂、表面活性或分散剂混合，在适当的机器中，通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物，然后在适当的机器中，通过成型可以制得模制片。较优地，每个片剂含有大约0.05mg到5g的活性组分，每个扁襄剂或胶囊剂含有大约0.05mg到5g的活性组分。例如，拟用于人类口服给药的剂型包含约0.5mg到约5g的活性组分，与合适且方便计量的辅助材料复合，该辅助材料约占药物组合物总量的5％至95％。单位剂型一般包含约 1mg到约2g的有效组分，典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇，及其在油中的混合物，也可以制得分散体系。进一步地，防腐剂也可以，包含在本发明的药物组合物中用于防止有害的微生物生长。
本发明提供适用于注射使用的药物组合物，包括无菌水溶液或分散体系。进一步地，上述药物组合物可以制备成可用于即时配制无菌注射液的无菌粉末的形式。无论如何，最终的注射形式必须是无菌的，且为了易于注射，必须是易于流动的。此外，所述药物组合物在制备和储存过程中必须稳定。因此，优选抗微生物如细菌和真菌的污染的保存。载体可以是溶剂或分散介质，例如，水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油，及其适当的混合物。
本发明提供的药物组合，可以是适于局部用药的形式，例如，气溶胶、乳剂、软膏、洗液、撒粉，或其他类似的剂型。进一步地，本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式(Ⅰ)所示化合物，或其药学上可接受的盐，通过常规的加工方法，可以制备这些制剂。作为一个例子，乳剂或软膏剂的制备是通过在上述化合物中加入亲水性材料和水(二者总量约为化合物的5wt％到10wt％)，制得具有预期一致性的乳剂或软膏。
本发明提供的药物组合物，可以制成以固体为载体、适用于直肠给药的形式。混合物形成单位剂量的栓剂是最优选的剂型。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备，首先药物组合物与软化或熔化的辅料混合，然后冷却和模具成型而制得。
除了上述提到的载体组分外，上述药学制剂还可以包括，适当的，一种或多种附加的辅料组分，如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等。进一步地，其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含有式(Ⅰ)所示化合物，或其药学上可接受的盐的药物组合物，也可以制备成粉剂或浓缩液的形式。
具体实施方式
本发明将用以下实施例来进一步阐述本发明所述的式(Ⅰ)的化合物的制备，但对本发明没有限制。
以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。
实施例中使用了下列缩略语：
DCM：二氯甲烷
DMF：N,N-二甲基甲酰胺
DIEA：N,N-二异丙基乙胺
PE：石油醚
EA：乙酸乙酯
NIS：N-碘代丁二酰亚胺
LCMS或者LC-MS：液质联用
THF：四氢呋喃
DMSO：二甲基亚砜
Et 3N或者TEA：三乙胺
HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
Hex：正己烷
h、hr或hrs：小时
LiHMDS：双(三甲基硅基)氨基锂
[PdCl 2(dppf)]CH 2Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物
Boc：叔丁氧羰基
min：分钟
rt or RT：室温。
通用路线：
式(Ⅵ)化合物可以由如下路线制备而成：
Figure PCTCN2020126359-appb-000055
中间体M-5的制备：
步骤1：化合物M-2的合成
取1000mL单口瓶加入4-溴-2-羟基苯甲醛(40g)和MeOH(400mL)，冰浴搅拌下滴加氨水(136.50g)，35℃油浴中加热反应。LC-MS监测至反应结束后，浓缩反应液，加水稀释，采用EA萃取四遍，合并有机相，干燥，浓缩，柱层析纯化(PE:EA＝3:1)，浓缩得34.55g化合物M-2。
LC-MS[M+H +]：239。
步骤2：化合物M-3的合成
取1000mL单口瓶加入化合物M-2(34.55g)，Cs 2CO 3(133g)和DMF(300mL)，常温搅拌20min后滴加1,2-二溴乙烷(54.30g)，滴加完毕后放入80℃油浴中回流反应，LC-MS监测至反应完全。浓缩反应液，加水稀释，采用EA萃取三遍，合并有机相，干燥，减压浓缩，柱层析纯化(PE:EA＝70:30)，浓缩得21.37g化合物M-3。
LC-MS[M+H +]：265。
1H NMR(500MHz,氯仿-d)δ8.38(d,J＝8.5Hz,1H),7.30-7.15(m,3H),6.99(s,1H),4.47-4.43(m,2H),4.41-4.35(m,2H)。
步骤3：化合物M-4的合成
取1000mL单口瓶加入化合物M-3(21.37g)和DMF(100mL)，搅拌溶解，向其中滴加NIS(50.78g)溶于DMF(100mL)的溶液，滴加完毕后放入60℃油浴中反应过夜，LC-MS监测至反应完毕后，向反应液中加水，析出固体，抽滤，干燥，得35g化合物M-4。
LC-MS[M+H +]：517。
1H NMR(500MHz,Chloroform-d)δ8.30(d,J＝8.6Hz,1H),7.25-7.16(m,2H),4.46-4.41(m,2H),4.36-4.32(m,2H)。
步骤4：化合物M-5的合成
向500mL三口瓶中加入化合物M-4(35g)和THF(150mL)，氮气保护，-40℃下向反应体系中滴加100mL乙基溴化镁(1M的THF溶液)，滴加完毕后-40℃搅拌反应。LC-MS监测至反应完全，在冰浴条件下加饱和氯化铵溶液淬灭反应，加EA萃取三遍，合并有机相，干燥，浓缩，加甲基叔丁基醚打浆，抽滤后干燥，得19.8g化合物M-5。
LC-MS[M+H +]：391。
1H NMR(500MHz,DMSO-d6)δ8.22(d,J＝8.6Hz,1H),7.55(s,1H),7.31-7.23(m,2H),4.47-4.39(m,4H)。
实施例1(2S)-1-(2-(5-异丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000056
-9-基)吡咯烷-2-甲酰胺(化合物1)的合成
Figure PCTCN2020126359-appb-000057
步骤1：化合物1-3的合成
向500mL三口瓶中加入化合物1-1(9g)，化合物1-2(16.8g)，DCM(200mL)和HATU(31.25g)，冰浴条件下向三口瓶中滴加TEA(50.21g)，滴加完毕后，室温反应。LC-MS监测至反应完毕后加水淬灭，分离有机相，有机相水洗，无水Na 2SO 4干燥，浓缩，柱层析纯化(PE:EA＝50:50)，得到9.2g化合物1-3。
LC-MS[M-Boc+H] +：131。
步骤2：化合物1-4的合成
向化合物1-3(1.3g)的二氯甲烷(10mL)溶液中加入HCl/二氧六环溶液(10mL，4.0mol/L)，室温下搅拌3小时。反应完毕后，浓缩得0.9g化合物1-4。化合物未进一步纯化直接用于下一步反应。
LC-MS[M+H] +：131。
步骤3：化合物1-5的合成
将化合物1-4(900mg)和TEA(4.19g)溶解于THF(50mL)中。冰水浴下，将三光气(802mg)的THF(10mL)溶液缓慢滴加到反应体系中，自然升温到室温反应搅拌12h。LCMS监测至反应完毕后加5mL水淬灭反应，浓缩，加入二氯甲烷/水萃取分液。有机相用无水Na 2SO 4干燥，浓缩，柱层析纯化(PE:EA＝1:1)后得732mg化合物1-5。
LC-MS[M+H] +：157。
步骤4：化合物1-6的合成
将化合物1-5(177mg)，化合物M-5(443mg)，CuI(64.75mg)，反式-N,N’-二甲基环己烷-1,2-二胺(48.36mg)和K 3PO 4(721.68mg)溶解于DMF(5mL)中，氮气置换三次，升温至110℃反应2h。LCMS监测至反应完毕后，加EA(100mL)稀释反应液，反应液水洗，合并有机相，有机相用无水Na 2SO 4干燥，浓缩，柱层析纯化(PE:EA＝70:30)，得350mg化合物1-6。
LC-MS[M+H] +：419。
步骤5：化合物1-7的合成
向100mL单口瓶中加入化合物1-6(350mg)，L-脯氨酸(290mg)，K 3PO 4(848mg)，CuI(79.8mg)和DMSO(5mL)，氮气保护，120℃搅拌反应3h。LCMS监测至反应完毕后，过滤反应液，滤饼用DMSO(3mL)洗涤，滤液直接用于下一步。
LC-MS[M+H] +：454。
步骤6：化合物1的合成
氮气保护下，向步骤5所得的滤液中加入DCM(12mL)，NH 4Cl(445mg)和DIEA(2.17g)，降温至0℃，冰浴条件下向反应体系中加入HATU(1.27g)，0℃下搅拌反应20min。LCMS监测至反应完毕后，加DCM稀释反应液，水洗，有机相用无水Na 2SO 4干燥，浓缩，所得粗品经柱层析纯化(PE:EA＝100:0-0:100)得300mg化合物1。
LC-MS[M+H] +：453。
1H NMR(500MHz,DMSO-d6)δ8.04(d,J＝8.9Hz,1H),7.41(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.7Hz,1H),6.03(s,1H),4.62-4.51(m,1H),4.45-4.30(m,4H),3.94(d,J＝8.7Hz,1H),3.55(t,J＝7.3Hz,1H),3.23(q,J＝7.2Hz,1H),2.92(s,3H),2.68(m,1H),2.26-2.12(m,1H),1.96(m,3H),1.16(d,J＝7.0Hz,3H),0.74(d,J＝6.8Hz,3H)。
实施例2(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000058
-9-基)吡咯烷-2-甲酰胺(化合物2)的合成
Figure PCTCN2020126359-appb-000059
步骤1：化合物2-2的合成
向250mL单口瓶中加入化合物1-1(5.0g)，DCM(100mL)和HATU(9.55g)，氮气保护，冰浴条件下加入TEA(8.15g)和化合物2-1(1.45g)，室温反应2h。LCMS监测反应完毕后，浓缩反应液，加EA稀释，水洗，无水硫酸钠干燥，浓缩，得5.0g化合物2-2，直接用于下一步。
LC-MS[M-Boc+H] +：157。
1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),6.54(d,J＝9.0Hz,1H),3.69-3.58(m,1H),2.65-2.55(m,1H),1.88-1.80(m,1H),1.37(s,9H),0.79(d,J＝6.0Hz,6H),0.62-0.58(m,2H),0.42-0.30(m,2H)。
步骤2：化合物2-3的合成
向250mL单口瓶中加入化合物2-2(5g)，DCM(20mL)和HCl/二氧六环(20mL，4.0mol/L)，室温反应2h。LCMS监测反应完毕后，浓缩反应液，得3.75g化合物2-3。
LC-MS[M+H] +：157。
步骤3：化合物2-4的合成
向250mL三口瓶中加入化合物2-3(2.0g)，DCM(50mL)和TEA(4.20g)，氮气保护，冰浴条件下向反应体系中滴加三光气(1.54g)溶于DCM(50mL)的溶液，冰浴条件下搅拌反应2h，LCMS监测反应完毕后，冰浴下用冰水淬灭反应， 浓缩反应液，EA萃取，无水Na 2SO 4干燥，浓缩，粗品经柱层析纯化(PE:EA＝100:0-50:50)，得810mg化合物2-4。
LC-MS[M+H] +：183/185。
1H NMR(500MHz,氯仿-d)δ6.28(s,1H),3.85(d,J＝3.6Hz,1H),2.66-2.48(m,J＝3.7Hz,1H),2.25-2.15(m,1H),1.03(d,J＝6.5Hz,3H),0.98-0.91(m,4H),0.88(d,J＝7.0Hz,3H)。
步骤4：化合物2-5的合成
向50mL单口瓶中加入化合物2-4(431mg)，化合物M-5(700mg)，DMF(10mL)，CuI(102mg)，反式-N,N’-二甲基环己烷-1,2-二胺(77mg)和K 3PO 4(760mg)，氮气保护，升温至120℃搅拌反应2h。LCMS监测反应完毕后，EA稀释，水洗，无水Na 2SO 4干燥，浓缩，粗品经柱层析纯化(PE:EA＝100:0-60:40)得642mg化合物2-5。
LC-MS[M+H] +：445/447。
1H NMR(500MHz,氯仿-d)δ8.23(d,J＝8.5Hz,1H),7.27(s,1H),7.22(d,J＝8.7Hz,1H),7.20(s,1H),4.63-4.59(m,1H),4.51-4.38(m,2H),4.36(t,J＝4.3Hz,2H),2.79-2.71(m,1H),2.68-2.60(m,1H),1.24(d,J＝7.1Hz,3H),1.02-0.94(m,4H),0.81(d,J＝6.9Hz,3H)。
步骤5：化合物2-6的合成
向30mL微波管中加入化合物2-5(642mg)，化合物M-12(415mg)，K 3PO 4(919mg)和DMSO(10mL)，氮气吹扫，向其中加入CuI(83mg)，升温至120℃微波反应1h。LCMS监测反应完毕后，反应液直接用于下一步。
LC-MS[M+H] +：480。
步骤6：化合物2的合成
向50mL单口瓶中加入步骤5所得的反应液，氮气置换，加入DCM(10mL)，NH 4Cl(462mg)和TEA(1.46g)，反应体系降温至0℃，冰浴条件下加入HATU(3.28g)，0℃下搅拌反应1h。LCMS监测反应完毕后，加DCM稀释反应液，水洗，有机相用无水Na 2SO 4干燥，浓缩，所得粗品经Pre-HPLC纯化(C18柱，H 2O:MeOH＝95:5-50:50)，得到85mg化合物2。
LC-MS[M+H] +：479。
1H NMR(500MHz,DMSO-d6)δ8.03(d,J＝9.0Hz,1H),7.40(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.9Hz,1H),6.03(d,J＝2.6Hz,1H),4.48(s,1H),4.41-4.29(m,4H),3.94(d,J＝8.8Hz,1H),3.55(t,J＝8.1Hz,1H),3.25-3.19(m,1H),2.74-2.55(m,2H),2.25-2.14(m,1H),2.07-1.85(m,3H),1.13(d,J＝7.0Hz,3H),0.88(d,J＝7.2Hz,2H),0.81(d,J＝3.9Hz,2H),0.71(d,J＝6.8Hz,3H)。
步骤7：化合物32和化合物33的制备
在本实施方案中，在如下条件手性柱上拆分化合物2，即可得到化合物32(前峰)和化合物33(后峰)。
手性HPLC条件：
Figure PCTCN2020126359-appb-000060
化合物32：LC-MS[M+H] +：479。
1H NMR(500MHz,DMSO-d6)δ8.03(d,J＝9.0Hz,1H),7.40(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.9Hz,1H),6.03(d,J＝2.6Hz,1H),4.48(s,1H),4.41–4.29(m,4H),3.94(d,J＝8.8Hz,1H),3.55(t,J＝8.1Hz,1H),3.25-3.19(m,1H),2.74–2.55(m,2H),2.25-2.14(m,1H),2.07-1.85(m,3H),1.13(d,J＝7.0Hz,3H),0.88(d,J＝7.2Hz,2H),0.81(d,J＝3.9Hz,2H),0.71(d,J＝6.8Hz,3H).
化合物33：LC-MS[M+H] +：479。
1H NMR(500MHz,DMSO-d6)δ8.03(d,J＝9.0Hz,1H),7.40(s,1H),7.24(s,1H),7.05(s,1H),6.32(d,J＝8.9Hz,1H),6.03(d,J＝2.6Hz,1H),4.48(s,1H),4.41–4.29(m,4H),3.94(d,J＝8.8Hz,1H),3.55(t,J＝8.1Hz,1H),3.25-3.19(m,1H),2.74–2.55(m,2H),2.25-2.14(m,1H),2.07-1.85(m,3H),1.13(d,J＝7.0Hz,3H),0.88(d,J＝7.2Hz,2H),0.81(d,J＝3.9Hz,2H),0.71(d,J＝6.8Hz,3H).
实施例3(2S)-1-(2-(5-异丙基-2,4-二氧代-3-(2,2,2-三氟乙基)咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1，2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000061
-9-基)吡咯烷-2-甲酰胺(化合物3)的合成
Figure PCTCN2020126359-appb-000062
步骤1：化合物3-2的合成
化合物3-0(2g)和化合物3-1(583mg)加入DCM(100ml)中，HATU(2.67g)和DIEA(2.28g)依次加入到反应体系中，反应在室温下搅拌12h。向反应液中加水，分液，浓缩得残余物。向残余物中加入乙酸乙酯(25mL)，水洗，饱和食盐水洗，有机相用无水Na 2SO 4干燥，浓缩，得到1.8g产品。
LC-MS[M+H] +：421。
步骤2：化合物3-3的合成
将二乙胺(10mL)加入到化合物3-2(1.8g)溶于DCM(10ml)的溶液中，室温下搅拌2h。减压浓缩得残余物，残余物经柱色谱纯化得到0.70g化合物3-3。
LC-MS[M+H] +：199。
步骤3：化合物3-4的合成
向50mL三口瓶中加入化合物3-3(200mg)，CH 3CN(10mL)，NaHCO 3(254mg)，氮气置换三次，向其中加入氯甲酸对硝基苯酯(203mg)，室温下搅拌反应2小时。然后向反应体系中加入6mL水，室温下搅拌反应3小时。反应完毕后，减压浓缩得残余物，向残余物中加EA稀释，有机相依次用水、碳酸钾水溶液和饱和食盐水洗涤，有机相用无水硫酸钠干燥，浓缩得粗品。粗品经柱层析(PE:EA＝60:40)纯化，得195mg化合物3-4。
LC-MS[M+H] +：225。
步骤4：化合物3-5的合成
将化合物3-4(138mg)，化合物M-5(200mg)，CuI(39mg)，反式-N,N’-二甲基环己烷-1,2-二胺(29mg)，K 3PO 4(326mg)溶解于DMF(5mL)中，氮气置换三次，反应升温至110℃反应2小时。反应完成后，向反应混合物中加入EA稀释，水洗一次，饱和食盐水洗三次，有机相用无水硫酸钠干燥，浓缩，柱层析纯化(PE:EA＝100:0-70:30)，得180mg化合物3-5。
LC-MS[M+H +]：487/489。
步骤5：化合物3-6的合成
向50mL单口瓶中加入化合物3-5(117mg)，化合物M-12(138mg)，K 3PO 4(356mg)，CuI(46mg)和DMSO(3mL)，氮气置换三次，升温至120℃搅拌反应3小时。反应完毕后，过滤反应液，滤饼用DMSO(3mL)洗涤，滤液直接用于下一步。
LC-MS[M+H] +：522。
步骤6：化合物3的合成
在氮气保护下，向步骤5所得的滤液中加入DCM(6mL)，NH 4Cl(127mg)，DIEA(613mg)，反应液降温至0℃，冰浴下分批向其中加入HATU(447mg)，0℃下搅拌反应20min。反应完毕后，加二氯甲烷稀释反应液，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，减压浓缩得粗品。所得粗品经Pre-HPLC纯化得到85mg化合物3。
LC-MS[M+H] +：521。
1H NMR(500MHz,DMSO-d6)δ8.05(d,J＝8.5Hz,1H),7.41(s,1H),7.29(s,1H),7.06(s,1H),6.33(d,J＝9Hz,1H),6.04(s,1H),4.71–4.70(m,1H),4.38–4.24(m,6H),3.95(d,J＝8.5Hz,1H),3.55(t,J＝7.3Hz,1H),3.28-3.20(m,1H),2.70(brs,1H),2.25-2.15(m,1H),2.00–1.94(m,3H),1.17(d,J＝7.0Hz,3H),0.75(d,J＝7Hz,3H)。
实施例4(2S)-1-(2-(3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000063
-9-基)吡咯烷-2-甲酰胺(化合物4)的合成
Figure PCTCN2020126359-appb-000064
步骤1：化合物4-1的合成
向化合物1-1(1.5g)和对氟苯胺(921mg)的DCM(50ml)溶液中加入HATU(3.39g)和DIEA(2.68g)。反应液在室温下搅拌12h。反应完成后向反应液中加水稀释，分液，有机相依次用1N HCl，NaHCO 3饱和水溶液和饱和食盐水洗涤，有机相无水Na 2SO 4干燥，浓缩得到粗产品。粗产品经柱色谱(EA/PE＝0-30％)纯化，得到2.1g化合物4-1。
LC-MS[M-Boc+H] +：211。
步骤2：化合物4-2的合成
将化合物4-1(2.1g)加入HCl/二氧六环(10mL，4M)溶液中，室温下搅拌12h。减压浓缩得1.64g化合物4-2，化合物未进一步纯化直接用于下一步反应。
LC-MS[M+H] +：211。
步骤3：化合物4-3的合成
向50mL三口瓶中加入化合物4-2(500mg)，CH 3CN(30mL)，NaHCO 3(681mg)，氮气置换三次，然后向其中加入氯甲酸对硝基苯酯(449mg)，室温下搅拌反应2小时。向反应液中加入18mL水，室温下搅拌反应3小时。
反应完毕后，减压浓缩得残余物，残余物用乙酸乙酯(100mL)稀释，有机相分别用水(50mL)，5％K 2CO 3水溶液(50mL)和饱和食盐水洗涤，分液，有机相用无水硫酸钠干燥，浓缩得粗品。粗品经柱色谱(EA/PE＝0-40％)纯化，得447mg化合物4-3。
LC-MS[M+H] +：237。
步骤4：化合物4-4的合成
将化合物4-3(144mg)，化合物M-5(200mg)，CuI(39mg)，反式-N,N’-二甲基环己烷-1,2-二胺(29mg)，K 3PO 4(326mg)溶解于DMF(5mL)中，氮气置换三次，升温至110C反应2小时。反应完毕后，加乙酸乙酯(100mL)稀释反应液，有机相依次用水洗(60mL)和饱和食盐水(60mL)洗涤，有机相无水硫酸钠干燥，浓缩，柱层析(PE:EA＝100:0-70:30)纯化，得215mg化合物4-4。
LC-MS[M+H] +：499。
步骤5：化合物4-5的合成
向100mL单口瓶中加入4-4(120mg)，化合物M-12(138mg)，K 3PO 4(356mg)，CuI(46mg)和DMSO(3mL)，氮气置换三次，升温至120℃搅拌反应3小时。反应完毕后，过滤反应液，滤饼用3mL DMSO洗涤，滤液直接用于下一步。
LC-MS[M+H +]：534。
步骤6：化合物4的合成
氮气保护下，向步骤5得到的滤液中加入DCM(12mL)，NH 4Cl(445mg)和DIEA(2.17g)，反应液降温至0℃，冰浴下分批向其中加入HATU(1.27g)，然后0℃下搅拌反应20min。反应完毕后，用DCM(50mL)稀释反应液，有机相分别水(40mL)洗和饱和食盐水(40mL)洗，无水硫酸钠干燥，浓缩得粗品。粗品经柱层析纯化(PE:EA＝100:0-0:100)得89mg化合物4。
LC-MS[M+H] +：533。
1H NMR(500MHz,DMSO-d 6)δ8.08(d,J＝8.9Hz,1H),7.45-7.41(m,3H),7.38-7.35(m,2H),7.28(s,1H),7.06(s,1H),6.34(d,J＝8.9Hz,1H),6.04(s,1H),4.76(s,1H),4.40-4.37(m,4H),3.95(d,J＝8.8Hz,1H),3.60-3.52(m,1H),3.24(q,J＝8.5,7.7Hz,1H),2.75(s,1H),2.26–2.14(m,1H),2.00-1.93(m,3H),1.22(d,J＝7.1Hz,3H),0.88(d,J＝6.8Hz,3H).
采用与实施例2步骤7相似的拆分方法，可以制备得到化合物30和化合物31。
实施例5(2S)-1-(2-(5-环丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000065
-9-基)吡咯烷-2-甲酰胺(化合物5)的合成
Figure PCTCN2020126359-appb-000066
将化合物1-1替换为化合物5-0，将对氟苯胺替换为甲胺盐酸盐，使用与实施例4相近似的制备方法即可得到化合物5。
LC-MS[M+H] +：451。
实施例6(2S)-1-(2-(3-环丁基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000067
-9-基)吡咯烷-2-甲酰胺(化合物6)的合成
Figure PCTCN2020126359-appb-000068
将对氟苯胺替换为环丁胺，使用与实施例4相近似的制备方法即可得到化合物6。
LC-MS[M+H] +：493。
1H NMR(500MHz,DMSO-d6)δ8.04(d,J＝9Hz,1H),7.41(s,1H),7.25(s,1H),7.05(s,1H),6.32(d,J＝9Hz,1H),6.03(s,1H),4.52–4.48(m,1H),4.37–4.35(m,4H), 3.94(d,J＝8.5Hz,1H),3.55(t,J＝7Hz,1H),3.23(q,J＝7.2Hz,1H),2.80-2.65(m,3H),2.14–2.12(m,3H),1.96-1.94(m,3H),1.79-1.71(m,3H),1.15(d,J＝7Hz,3H)0.74(d,J＝6.5Hz,3H)。
实施例7(2S)-1-(2-(3-乙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
Figure PCTCN2020126359-appb-000069
-9-基)吡咯烷-2-甲酰胺(化合物7)的合成
Figure PCTCN2020126359-appb-000070
将化合物3-1替换为化合物7-1，使用与实施例3相近似的制备方法即可得到化合物7。LC-MS[M+H] +：467。
经由不同的反应起始原料和合适的试剂，采用与实施例1-7类似的方法制备表1实施例化合物。
表1
Figure PCTCN2020126359-appb-000071
Figure PCTCN2020126359-appb-000072
Figure PCTCN2020126359-appb-000073
Figure PCTCN2020126359-appb-000074
Figure PCTCN2020126359-appb-000075
Figure PCTCN2020126359-appb-000076
Figure PCTCN2020126359-appb-000077
表1中的所有消旋体化合物均可使用相应手性原料合成制备而得相应对映异构体，或者基本按照实施例2步骤7所述方法，在手性柱上分离得到对映异构体。
对照例
表2
Figure PCTCN2020126359-appb-000078
Figure PCTCN2020126359-appb-000079
参考WO2017001658中实施例102的制备方法，应用相应的起始原料、中间体及合适的试剂，即可得到表2中的对照例1(WO2017001658中实施例102)和对照例2化合物；对照例3化合物的制备方法如下所示。
对照例3的制备
Figure PCTCN2020126359-appb-000080
步骤1：化合物D3-2的合成
将化合物D3-1(2000g)和草酰氯(2019g)溶解于二氯甲烷(8L)中，将DMF(5mL)缓慢滴加入反应体系，回流反应6个小时。将反应物浓缩得到2245g含黄色固体的悬浊液，直接用于下一步反应。
步骤2：化合物D3-3的合成
将4-甲氧基-3-丁烯-2-酮(642g)溶于无水THF(16L)溶液中，并在-78℃条件下将6.42L溶于THF中的LiHMDS(1mol/L)溶液逐滴加入反应体系中。在-78℃搅拌2小时，向体系中缓慢滴加将步骤1得到的悬浊液溶于无水THF(1L)的溶液，-78℃下搅拌1-2小时后升至室温搅拌16小时，得到反应液直接进行下一步反应。
LC-MS[M+H] +：239。
步骤3：化合物D3-4的合成
将步骤2所得的反应液在冰水浴条件下加入水(500mL)淬灭，然后加入三氟乙酸(50mL)，室温继续搅拌3小时。反应结束后，将体系浓缩后用EA萃取。有机相用盐水洗涤，无水Na 2SO 4干燥，浓缩，柱层析纯化(Hex/EA 100:1-10:1)得到棕色固体，用HEX与EA混合溶液(体积比50:1)将固体洗涤，抽滤，收集滤液并浓缩，得到395g化合物D3-4。
LC-MS[M+H] +：207。
1H NMR(MeOD-d6):1.59(s,6H),6.39-6.41(m,1H),6.53-6.54(m,1H),8.12-8.14(m,1H)。
步骤4：化合物D3-5的合成
将化合物D3-4(395g)加入到2L氨水溶液(30％)中，回流搅拌反应2小时。将反应液冷却，浓缩，得到343.00g化合物D3-5，直接用于下一步。
LC-MS[M+H] +：206。
步骤5：化合物D3-6的合成
将化合物D3-5(343g)和三溴氧磷(966.68g)的混合物于120℃下加热搅拌1小时。趁热将反应液倒入冰水中，加入碳酸氢钠，将PH调至中性，用EA萃取，将有机相干燥并浓缩，柱层析纯化(Hex/EA＝100:1)得到305g化合物D3-6。
LC-MS[M+H] +：269。
1H NMR(MeOD-d6):1.59(s,6H),7.52-7.54(m,1H),7.78(s,1H),8.41-8.42(m,1H)。
步骤6：化合物D3-7的合成
取单口瓶加入联硼酸频那醇酯(710.45mg)，化合物D3-6(500mg)，醋酸钾(1.88g)，[PdCl 2(dppf)]CH 2Cl 2(152.32mg)和二氧六环(20mL)，氮气保护，90℃油浴反应4h，浓缩反应液，柱层析纯化(Hex/EA＝3:1)得到450mg化合物D3-7。
LC-MS[M+H] +：316。
步骤7：化合物D3-8的合成
取单口瓶加入[PdCl 2(dppf)]CH 2Cl 2(233.22mg)，碳酸钾(394.70mg)，化合物D3-7(450mg)，化合物M-5(586.25mg)，二氧六环(3mL)和H 2O(0.5mL)，氮气保护，70℃油浴中回流反应15h，浓缩反应液，柱层析纯化(PE:EA＝50:50)得到130mg化合物D3-8。
LC-MS[M+H] +：452。
步骤8：化合物D3-9的合成
参照实施例2步骤5的方法得到化合物D3-9。
LC-MS[M+H] +：487。
步骤9：对照例3的合成
参照实施例2步骤6的方法得到对照例3化合物。
LC-MS[M+H] +：486。
药理试验
以下试验表明，本发明的优选化合物在体外可有效的抑制PI3Kα激酶的活性。本发明的优选化合物的抗PI3Kα突变肿瘤细胞增殖活性以及药代动力学实验结果均优于对照例，具有显著的进步。
实施例A：激酶试验
PI3Kα、PI3Kβ、PI3Kγ激酶与其底物ATP、PIP2:3PS进行酶学反应，利用ADP-Glo试剂和发光的方法检测产物的量用以反映PI3Kα、PI3Kβ、PI3Kγ酶学活性(ATP终浓度10μM)。采用上述方法测试本发明一些化合物对PI3Kα、PI3Kβ和PI3Kγ激酶的抑制活性。
检测方法：
试剂：基础激酶缓冲液(pH 7.5)；PI3Kα、PI3Kβ、PI3Kγ酶溶液；PIP2:3PS和ATP溶液；ADP-Glo试剂盒(含有10mM MgCl 2)。
其中，缓冲液成分：50mM Hepes(pH7.2-7.5)，3mM MgCl 2，1mM EGTA,0.03％CHAPS，100mM NaCl，2mM DTT；
准备化合物：利用100％DMSO将测试化合物稀释到特定的浓度。
反应过程：1)向384反应板(6008280,PerkinElmer)中加入PI3Kα、PI3Kβ、PI3Kγ蛋白溶液，1000rpm离心1分钟备用。
2)向上述加有酶的384反应板中加入待测试化合物，阴性对照物DMSO或阳性对照物BYL719，1000rpm离心1分钟，25℃孵育15分钟。
3)向上述384反应板中加入PIP2:3PS&ATP溶液，1000rpm离心1分钟，25℃孵育60分钟。
4)转移5μL的ADP-Glo试剂(含有10mM MgCl 2)到384反应板中，1000rpm离心1分钟，25℃孵育40分钟。
5)转移10μL的Detection试剂到384反应板中，1000rpm离心1分钟，25℃孵育40分钟。
6)使用Envision多功能读板机读取RLU(相对光单位，relative luminescence unit)值。RLU值大小用于表征酶与底物反应程度，并计算IC 50值。
7)实验数据处理过程：
化合物抑制率(％inh)＝(阴性对照RLU-待测试化合物RLU)/(阴性对照RLU-阳性对照RLU)*100％
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)：
Y＝最小抑制率+(最大抑制率-最小抑制率)/(1+10^((LogIC 50-X)*斜率))；其中，X为待测试化合物浓度log值，Y为待测试化合物抑制率(％inh)。
本发明的一些实施例的实验结果如表3所示。其中，A代表IC 50值≤5nM；B代表IC 50值为5～20nM；C代表IC 50值为300～600nM；D代表IC 50值>600nM。
表3
Figure PCTCN2020126359-appb-000081
Figure PCTCN2020126359-appb-000082
注：“/”表示未测试。
由表3可见，本发明所提供的化合物具有较好的PI3Kα激酶抑制活性，并且具有较好的PI3Kβ和PI3Kγ激酶亚型选择性，可以避免多靶点抑制带来的潜在副作用。
实施例B：细胞增殖试验
方法：采用CellTiter Glo assay方法，观察本发明的一些化合物对体外培养的人肿瘤细胞MCF-7和HGC27的生长抑制作用。
检测方法：将MCF-7细胞悬浮于DMEM培养基中形成细胞悬浮液，调整细胞浓度至25000cells/mL；将HGC27细胞悬浮于RPMI-1640培养基中形成细胞悬浮液，调整细胞浓度至5000cells/mL。加100μL细胞悬浮液至96孔板，置CO 2培养箱过夜。将待测试化合物溶于DMSO中，进行3倍梯度稀释，共计得到10个浓度。分别将10个浓度的待测试化合物或DMSO阴性对照品转移至含有100μL培养基的孔中，37℃，5％CO 2条件下孵育，HGC27细胞孵育96小时，MCF-7细胞孵育120小时。然后加入100μL CellTiter-Glo试剂至上述96孔板中，置于室温下孵育10分钟稳定发光信号。使用VICTOR TM X5仪器记录RLU(relative luminescence unit)值，然后计算IC 50值。
化合物抑制率(％inh)＝100％-(待测试化合物RLU-空白对照RLU)/(阴性对照品RLU-空白对照品RLU)*100％
阴性对照：DMSO孔；
空白对照：空白培养基孔，无化合物无细胞；
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)：
Y＝最小抑制率+(最大抑制率-最小抑制率)/(1+10^((LogIC 50-X)*斜率))；其中，X:待测试化合物浓度log值；Y:待测试化合物抑制率(％inh)。
实验数据如表4和表5所示。
表4实施例化合物对MCF细胞IC 50检测结果
实施例 化合物对MCF细胞IC 50(μM)
对照例1 0.444
对照例2 0.549
对照例3 0.519
实施例1 0.176
实施例2 0.070
实施例5 0.373
实施例9 0.142
实施例23 0.074
实施例28 0.468
实施例32 0.107
实施例33 0.047
表5实施例化合物对HGC-27细胞IC 50检测结果
实施例 化合物对HGC-27细胞IC 50(μM)
对照例1 1.579
对照例3 2.067
实施例2 0.361
实施例5 4.071
实施例28 3.921
实施例32 0.415
实施例33 0.267
由上表可见，本发明的所提供的化合物对于具有PI3Kα点突变的细胞系具有比对照化合物更好的细胞增殖抑制活性，在同等浓度下具有更好的抗肿瘤效果。因此，本发明所提供的化合物有望成为一种抗肿瘤效果更好的PI3Kα激酶抑制剂。
实施例C：药代动力学试验
检测方法：雄性SD大鼠42只，体重：150-300g。随机分为7组，每组6只大鼠。每组的6只大鼠中，3只单次静脉注射2mg/mL的实施例化合物，另外3只单次灌胃给药10mg/mL的实施例化合物，分别在指定的时间点通过眼眶静脉丛采血，分离血浆，放入-80℃冰箱保存备用。
将上述血浆样品，通过乙腈沉淀蛋白后，提取上清液，并与水1:1混合，取10μL至LC-MS/MS检测，计算平均值，实验数据如表6所示。
表6实施例化合物的药代动力学试验结果
Figure PCTCN2020126359-appb-000083
根据相关统计(Kola I,Landis J.Nat Rev Drug Discov.2004Aug；3(8):711-5.)，上世纪90年代初，约有40％的候选药物临床开发失败的原因是PK/生物利用度较差，由此可见PK/生物利用度对候选药物临床开发的成败起着非常关键的作用。
由上表可见，本发明所提供的化合物对较对照实施例化合物而言，具有预料不到的更高的口服暴露量，且同时具有更低的体内清除率；可在同等剂量下具有更高的体内循环系统药物浓度。在抗肿瘤效果相当的前提下，本发明化合物的给药剂量更低，从而可以降低可能的毒性反应和安全性风险概率，有效增加化合物的成药性。

Claims (41)

  1. 一种式(Ⅰ)所示的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，
    Figure PCTCN2020126359-appb-100001
    其中，
    X选自O或S；
    R 1选自H、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基、OR a或-NR aR b；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环烷基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个选自卤素、CN、OR a、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或C 3-6杂环基的取代基所取代；
    R 2选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个选自卤素、CN、-OH、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2- 6烯基、C 2-6卤代烯基、C 2-6炔基、C 2-6卤代炔基、C 3-6环烷基、C 3-6卤代环烷基、C 3-6杂环基、C 3-6卤代杂环基、C 6-8芳基、C 6-8卤代芳基、C 5-8杂芳基、C 5-8卤代杂芳基、氧代基、-OR a、-NR aR b、-C(O)R a、-C(O)O R a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a的取代基所取代；
    R 3选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-OR a或-NR aR b；所述C 1-6烷基、C 2-6烯基、C 2-6炔基可任选地被1个或多个选自卤素、CN、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a的取代基所取代；
    R 4选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、氧代基、C 1-6卤代烷基、C 2-6卤代烯基、C 2-6卤代炔基、C 1-6烷氧基、C 1-6卤代烷氧基、-OR a、-NR aR b、-C(O)R a、-C(O)OR a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a；
    R 5选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 2-6卤代烯基、C 2-6卤代炔基、C 1-6烷氧基、C 1-6卤代烷氧基、-OR a、-NR aR b、-S(O)R a或-S(O) 2R a；
    R 6选自H、卤素、CN、氧代基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基、-OR a、-NR aR b、-C(O)R a、-C(O)O R a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个选自卤素、CN、氧代基、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、-OR a、-NR aR b、-C(O)R a、-C(O)O R a、-C(O)NR aR b、-S(O)R a或-S(O) 2R a的基团所取代；或者，
    两个R 6与其相连接的C原子共同形成C 3-6环烷基或C 3-6杂环基；
    R a和R b分别独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基；所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基、C 5-8杂芳基可任选地被卤素、CN、-OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基所取代；
    m选自0、1、2、3或4；
    n选自0、1、2或3；
    y选自0、1、2、3、4、5或6。
  2. 根据权利要求1所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 1为C 1-6烷基或C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基可独立任选地经卤素所取代。
  3. 根据权利要求1-2任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基或C 5-8杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个卤素、-CN、-OH、-NR aR b、C 1-6烷基或C 1-6卤代烷基所取代；所述R a和R b分别独立地选自H或C 1-6烷基。
  4. 根据权利要求1-3任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 3选自H、卤素、CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 2-6卤代烯基或C 2-6卤代炔基。
  5. 根据权利要求1-4任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 6选自H、卤素、CN、-NH 2、氧代基、-OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6 烷氧基、C 1-6卤代烷基、C 2-6卤代烯基、C 2-6卤代炔基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基或C 5-8杂芳基。
  6. 根据权利要求1-5任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(Ⅱ)所示：
    Figure PCTCN2020126359-appb-100002
  7. 根据权利要求1-6任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(Ⅲ-1)所示：
    Figure PCTCN2020126359-appb-100003
    其中，所述R 1为C 1-6烷基或C 1-6卤代烷基。
  8. 根据权利要求1-6任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(Ⅲ-2)所示：
    Figure PCTCN2020126359-appb-100004
  9. 根据权利要求1-8任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 3选自H、卤素、C 1-6烷基或C 2-6烯基。
  10. 根据权利要求1-9任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，R 4和R 5均为H。
  11. 根据权利要求1-6任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(Ⅳ)所示：
    Figure PCTCN2020126359-appb-100005
    其中：
    R 1为C 1-6烷基或C 1-6卤代烷基；
    R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基或C 5-8杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6-8芳基和C 5-8杂芳基可任选地被1个或多个卤素、-CN、-OH、-NR aR b、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基所取代；
    R 3选自选自H、卤素、C 1-6烷基或C 2-6烯基；
    R 6选自H、卤素、-NH 2、氧代基、-OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 3-6环烷基或C 6-8芳基；
    R a和R b分别独立地选自H或C 1-6烷基；
    y选自0、1、2、3、4、5或6。
  12. 根据权利要求11所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述X为O。
  13. 根据权利要求1-7任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(V)所示：
    Figure PCTCN2020126359-appb-100006
  14. 根据权利要求1-13任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基和C 5-6杂芳基可任选地被1个或多个卤素、-CN、-OH、-N-(CH 3) 2、C 1-6烷基或C 1-6卤代烷基所取代。
  15. 根据权利要求1-14任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 6选自H、卤素、-NH 2、氧代基、-OH、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或C 6芳基。
  16. 根据权利要求1-7任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(Ⅵ)所示：
    Figure PCTCN2020126359-appb-100007
    其中，
    R 1选自C 1-6烷基或C 1-6卤代烷基；
    R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基和C 5-6杂芳基可任选地被1个或多个卤素、-CN、-OH、-N-(CH 3) 2、C 1-6烷基或C 1-6卤代烷基所取代。
  17. 根据权利要求1-16任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，R 1为C 1-4烷基，所述R 1任选地经卤素取代。
  18. 根据权利要求1-17任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述R 1选自-CH(CH 3) 2、-C(CH 3) 3、-CF 3或-CHF 2。
  19. 根据权利要求1-18任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-C 6杂芳基，所述R 2任选地经卤素取代。
  20. 根据权利要求1-19任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，R 2选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 3-6卤代环烷基、苯基或卤代苯基。
  21. 根据权利要求1-7任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，进一步如式(Ⅶ)所示：
    Figure PCTCN2020126359-appb-100008
    其中，所述R 2选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环基、C 6芳基或C 5-6杂芳基；所述R 2任选地经卤素取代。
  22. 根据权利要求1-21任一所述化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，R 2选自-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2CF 3、环丙基、环丁基、苯基或吡啶基；所述-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2CF 3、环丙基、环丁基、苯基或吡啶基任选的经卤素取代。
  23. 根据权利要求1-22任一所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，R 2选自-CH 3、-CH(CH 3) 2、环丙基、苯基或卤素取代的苯基。
  24. 权利要求1所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，所述化合物或其立体异构体、几何异构体或互变异构体选自：
    1)(2S)-1-(2-(5-异丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100009
    -9-基)吡咯烷-2-甲酰胺；
    2)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100010
    -9-基)吡咯烷-2-甲酰胺；
    3)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-(2,2,2-三氟乙基)咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1，2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100011
    -9-基)吡咯烷-2-甲酰胺；
    4)(2S)-1-(2-(3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100012
    -9-基)吡咯烷-2-甲酰胺；
    5)(2S)-1-(2-(5-环丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100013
    -9-基)吡咯烷-2-甲酰胺；
    6)(2S)-1-(2-(3-环丁基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100014
    -9-基)吡咯烷-2-甲酰胺；
    7)(2S)-1-(2-(3-乙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100015
    -9-基)吡咯烷-2-甲酰胺；
    8)(2S)-1-(2-(5-二氟甲基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100016
    -9-基)吡咯烷-2-甲酰胺；
    9)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100017
    -9-基)吡咯烷-2-甲酰胺；
    10)(S)-1-(2-((S)-5-异丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100018
    -9-基)吡咯烷-2-甲酰胺；
    11)(S)-1-(2-((R)-5-异丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100019
    -9-基)吡咯烷-2-甲酰胺；
    12)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-(4-(三氟甲基)苯基)咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100020
    -9-基)吡咯烷-2-甲酰胺；
    13)(2S)-1-(2-(5-异丙基-2,4-二氧代-3-丙基咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100021
    -9-基)吡咯烷-2-甲酰胺；
    14)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100022
    -9-基)-2-甲基吡咯烷-2-甲酰胺；
    15)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)-4,4-二氟吡咯烷-2-甲酰胺；
    16)(2S)-1-(2-(5-异丙基-3-(1-甲基-1H-1,2,4-三唑-5-基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100023
    -9-基)吡咯烷-2-甲酰胺；
    17)(2S,4S)-4-氨基-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100024
    -9-基)吡咯烷-2-甲酰胺；
    18)(2S)-1-(2-(3-(2-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100025
    -9-基)吡咯烷-2-甲酰胺；
    19)(2S)-1-(2-(3-(4-氯苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100026
    -9-基)吡咯烷-2-甲酰胺；
    20)(2S)-4-(叔丁氧基)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2]-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100027
    -9-基)吡咯烷-2-甲酰胺；
    21)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100028
    -9-基)-4,4-二甲基吡咯烷-2-甲酰胺；
    22)(2S)-1-(2-(3-(2,2-二氟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100029
    -9-基)吡咯烷-2-甲酰胺；
    23)(2S)-1-(2-(3,5-二异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100030
    -9-基)吡咯烷-2-甲酰胺；
    24)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100031
    -9-基)-4-苯基吡咯烷-2-甲酰胺；
    25)(2S)-1-(2-(3-(3-氯5-氰基苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
    26)(2S)-1-(2-(3,5-二异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
    27)(2S)-1-(2-(3-氮杂环丁烷-3-基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100032
    -9-基)吡咯烷-2-甲酰胺；
    28)(2S)-1-(2-(3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100033
    -9-基)吡咯烷-2-甲酰胺；
    29)(2S)-1-(2-(5-叔丁基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100034
    -9-基)吡咯烷-2-甲酰胺；
    30)(S)-1-(2-((R)-3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2]-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100035
    -9-基)吡咯烷-2-甲酰胺；
    31)(S)-1-(2-((S)-3-(4-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2]-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100036
    -9-基)吡咯烷-2-甲酰胺；
    32)(2S)-1-(2-((5R)-3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100037
    -9-基)吡咯烷-2-甲酰胺；
    33)(2S)-1-(2-((5S)-3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100038
    -9-基)吡咯烷-2-甲酰胺；
    34)(2S)-1-(2-(3-(2-羟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100039
    -9-基)吡咯烷-2-甲酰胺；
    35)(2S)-1-(2-(3-(2-氟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100040
    -9-基)吡咯烷-2-甲酰胺；
    36)(2S)-1-(2-(3-(2-(二甲基氨基)乙基)-5-)异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100041
    -9-基)吡咯烷-2-甲酰胺；
    37)(2S)-1-(2-(3-环丙基-5-异丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
    38)(2S)-1-(2-(3-(6-氟吡啶-3-基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100042
    -9-基)吡咯烷-2-甲酰胺；
    39)(2S)-1-(2-(3-(5-氟吡啶-3-基)-5-异丙基-2,4-二氧代咪唑烷1-基)-5,6-二氢苯并[f]咪唑并[1,2]-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100043
    -9-基)吡咯烷-2-甲酰胺；
    40)(2S)-1-(2-(3-(3-氰基-5-氟苯基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100044
    -9-基)-4-氟吡咯烷-2-甲酰胺；
    41)(2S)-1-(2-(3-(3-氯嘧啶-2-基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100045
    -9-基)吡咯烷-2-甲酰胺；
    42)(2S)-1-(2-(3-环戊基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100046
    -9-基)吡咯烷-2-甲酰胺；
    43)(2S)-1-(2-(3-(氰基甲基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100047
    -9-基)吡咯烷-2-甲酰胺；
    44)(2S)-1-(2-(5-异丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
    45)(2S)-1-(2-(3-(2,2-二氟乙基)-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
    46)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-3-乙烯基-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100048
    -9-基)吡咯烷-2-甲酰胺；
    47)(2S)-1-(3-氯-2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100049
    -9-基)吡咯烷-2-甲酰胺；
    48)(2S)-1-(2-(3-环丙基-5-(二氟甲基)-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)吡咯烷-2-甲酰胺；
    49)(2S,3S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100050
    -9-基)-3-羟基吡咯烷-2-甲酰胺；
    50)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-3-甲基-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100051
    -9-基)-4-氧代吡咯烷-2-甲酰胺；
    51)(2S)-4-环己基-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂
    Figure PCTCN2020126359-appb-100052
    -9-基)吡咯烷-2-甲酰胺；
    52)(2S)-1-(2-(3-环丙基-5-异丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]噻唑啉-9-基)-5-氧代吡咯烷-2-甲酰胺。
  25. 一种药物组合物，其特征在于，包含治疗有效量的至少一种权利要求1-24任一项所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物和至少一种药学上可接受的辅料。
  26. 根据权利要求25所述的药物组合物，其特征在于，所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物和药学上可接受的辅料的重量比为0.0001-10。
  27. 权利要求1-24任一项所述的化合物或其立体异构体、几何异构体或互变异构体，或其药学上可接受的盐、溶剂化物、螯合物、非共价复合物或前体药物或权利要求25或26所述的组合物在制备药物中的应用。
  28. 根据权利要求27所述的应用，其特征在于，所述药物用于治疗、预防、延迟或阻止癌症或癌症转移的发生或进展。
  29. 根据权利要求28所述的应用，其特征在于，所述药物用作PI3K抑制剂。
  30. 根据权利要求27所述的应用，其特征在于，所述药物用于治疗PI3K介导的疾病。
  31. 根据权利要求29或30所述的应用，其特征在于，所述PI3K为PI3Kα、PI3Kβ、PI3Kδ和/或PI3Kγ。
  32. 根据权利要求31所述的应用，其特征在于，所述PI3K为PI3Kα。
  33. 根据权利要求30所述的应用，其特征在于，所述PI3K介导的疾病是癌症。
  34. 根据权利要求33所述的应用，其特征在于，所述癌症选自肉瘤、前列腺癌、乳腺癌、胰腺癌、胃肠癌、结肠直肠癌、甲状腺癌、肝癌、肾上腺癌、神经胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、子宫癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、脑癌、口腔和咽癌、喉癌、淋巴瘤、基底细胞癌、真性红细胞增多症、原发性血小板增多症。
  35. 一种治疗和/或预防患有PI3K介导的疾病患者的方法，其特征在于，向需要的患者施用治疗有效量的权利要求1-24任一项所述的化合物或权利要求25或26所述的药物组合物。
  36. 根据权利要求35所述的方法，其特征在于，所述PI3K包括PI3Kα、PI3Kβ、PI3Kδ和/或PI3Kγ。
  37. 根据权利要求35所述的方法，其特征在于，所述PI3K是PI3Kα。
  38. 根据权利要求35-37任一项所述的方法，其特征在于，所述PI3K介导的疾病是癌症。
  39. 根据权利要求38所述的方法，其特征在于，所述癌症是肉瘤、前列腺癌、乳腺癌、胰腺癌、胃肠癌、结肠直肠癌、甲状腺癌、肝癌、肾上腺癌、神经胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、子宫癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、脑癌、口腔和咽癌、喉癌、淋巴瘤、基底细胞癌、真性红细胞增多症、原发性血小板增多症。
  40. 一种治疗癌症的方法，包括向治疗对象施用治疗有效量的权利要求1-24任一项所述的化合物或权利要求25或26所述的药物组合物，其特征在于，所述癌症是肉瘤、前列腺癌、乳腺癌、胰腺癌、胃肠癌、结肠直肠癌、甲状腺癌、肝癌、肾上腺癌、神经胶质瘤、子宫内膜癌、黑色素瘤、肾癌、膀胱癌、子宫癌、阴道癌、卵巢癌、多发性骨髓瘤、食管癌、白血病、脑癌、口腔和咽癌、喉癌、淋巴瘤、基底细胞癌、真性红细胞增多症、原发性血小板增多症。
  41. 根据权利要求40所述的方法，其特征在于，所述治疗对象为人类。
PCT/CN2020/126359 2019-11-04 2020-11-04 咪唑烷酮类化合物及其制备方法与应用 WO2021088839A1 (zh)

Priority Applications (11)

Application Number Priority Date Filing Date Title
CN202410229432.3A CN118084935A (zh) 2019-11-04 2020-11-04 咪唑烷酮类化合物及其制备方法与应用
CA3156625A CA3156625A1 (en) 2019-11-04 2020-11-04 Imidazolidinone compound, preparation method therefor and use thereof
MX2022005415A MX2022005415A (es) 2019-11-04 2020-11-04 Compuesto de imidazolidinona, metodo de preparacion del mismo y uso del mismo.
BR112022008647A BR112022008647A2 (pt) 2019-11-04 2020-11-04 Composto de imidazolidinona, método de preparação do mesmo e uso do mesmo
IL292592A IL292592A (en) 2019-11-04 2020-11-04 Imidazoline compound, process for its preparation and use
CN202080074622.2A CN114599655B (zh) 2019-11-04 2020-11-04 咪唑烷酮类化合物及其制备方法与应用
AU2020379709A AU2020379709A1 (en) 2019-11-04 2020-11-04 Imidazolidinone compound, preparation method therefor and use thereof
KR1020227018861A KR20220097466A (ko) 2019-11-04 2020-11-04 이미다졸리디논류 화합물 및 이들의 제조방법과 용도
JP2022525930A JP2023501324A (ja) 2019-11-04 2020-11-04 イミダゾリジノン類化合物、並びにその調製方法及び使用
EP20885710.2A EP4056575A4 (en) 2019-11-04 2020-11-04 IMIDAZOLIDINONE COMPOUND, PROCESS THEREOF AND USE THEREOF
US17/773,771 US20230053342A1 (en) 2019-11-04 2020-11-04 Imidazolidinone compound, preparation method therefor and use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201911066776 2019-11-04
CN201911066776.2 2019-11-04
CN202011167875 2020-10-28
CN202011167875.2 2020-10-28

Publications (1)

Publication Number Publication Date
WO2021088839A1 true WO2021088839A1 (zh) 2021-05-14

Family

ID=75848348

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/126359 WO2021088839A1 (zh) 2019-11-04 2020-11-04 咪唑烷酮类化合物及其制备方法与应用

Country Status (12)

Country Link
US (1) US20230053342A1 (zh)
EP (1) EP4056575A4 (zh)
JP (1) JP2023501324A (zh)
KR (1) KR20220097466A (zh)
CN (2) CN114599655B (zh)
AU (1) AU2020379709A1 (zh)
BR (1) BR112022008647A2 (zh)
CA (1) CA3156625A1 (zh)
IL (1) IL292592A (zh)
MX (1) MX2022005415A (zh)
TW (1) TW202132313A (zh)
WO (1) WO2021088839A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022237871A1 (zh) * 2021-05-13 2022-11-17 贝达药业股份有限公司 咪唑烷酮类化合物的多晶型物、制备方法及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102762576A (zh) * 2009-09-28 2012-10-31 霍夫曼-拉罗奇有限公司 苯并氧杂氮杂*pi3k抑制剂化合物和使用方法
CN103562210A (zh) * 2011-03-21 2014-02-05 弗·哈夫曼-拉罗切有限公司 对pI3K 110δ具有选择性的苯并氧氮杂*化合物及使用方法
WO2017001658A1 (en) 2015-07-02 2017-01-05 F. Hoffmann-La Roche Ag Benzoxazepin oxazolidinone compounds and methods of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102762576A (zh) * 2009-09-28 2012-10-31 霍夫曼-拉罗奇有限公司 苯并氧杂氮杂*pi3k抑制剂化合物和使用方法
CN103562210A (zh) * 2011-03-21 2014-02-05 弗·哈夫曼-拉罗切有限公司 对pI3K 110δ具有选择性的苯并氧氮杂*化合物及使用方法
WO2017001658A1 (en) 2015-07-02 2017-01-05 F. Hoffmann-La Roche Ag Benzoxazepin oxazolidinone compounds and methods of use
CN107995911A (zh) * 2015-07-02 2018-05-04 豪夫迈·罗氏有限公司 苯并氧氮杂*噁唑烷酮化合物及其使用方法

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
DEJAN JURIC, CANCER RES, vol. 72, 2012, pages 1
FALASCA MT. MUFFUCCI, BIOCHEM SOC TRANS, vol. 35, 2007, pages 211 - 214
KOLA ILANDIS J, NAT REV DRUG DISCOV., vol. 3, no. 8, August 2004 (2004-08-01), pages 711 - 5
KONG DYAMORI T, CANCER SCI, vol. 99, 2008, pages 1734 - 1740
MA KCHEUNG SMMARSHALL AJ, CELL SIGNAL, vol. 20, 2008, pages 684 - 694
SCHU PTAKEGAWA. KFRY. M, SCIENCE, vol. 260, 1993, pages 88 - 91
See also references of EP4056575A4
STEELMAN. LSCHAPPELL. WHABRAMS. SL ET AL., AGING, vol. 3, 2011, pages 192 - 222
VANHAESEBROECK BWATERFIELD MD, EXP CELL RES, vol. 253, 1999, pages 239 - 254
WU PLIU THU Y, CURR MED CHEM, vol. 16, 2009, pages 916 - 930

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022237871A1 (zh) * 2021-05-13 2022-11-17 贝达药业股份有限公司 咪唑烷酮类化合物的多晶型物、制备方法及其用途

Also Published As

Publication number Publication date
CN118084935A (zh) 2024-05-28
US20230053342A1 (en) 2023-02-23
JP2023501324A (ja) 2023-01-18
CA3156625A1 (en) 2021-05-14
CN114599655B (zh) 2024-02-27
EP4056575A1 (en) 2022-09-14
BR112022008647A2 (pt) 2022-07-19
MX2022005415A (es) 2022-05-26
TW202132313A (zh) 2021-09-01
KR20220097466A (ko) 2022-07-07
IL292592A (en) 2022-07-01
EP4056575A4 (en) 2023-11-08
CN114599655A (zh) 2022-06-07
AU2020379709A1 (en) 2022-06-09

Similar Documents

Publication Publication Date Title
AU2014267723B2 (en) Arylquinazolines
WO2021169990A1 (zh) 用于癌症治疗的kras抑制剂
WO2021088945A1 (zh) 作为shp2抑制剂的化合物及其应用
KR20210013145A (ko) 키나아제 억제제로서 헤테로시클릭 화합물, 헤테로시클릭 화합물을 포함하는 조성물 및 그 사용 방법
HUE030519T2 (en) Pyridazinone derivatives
KR102480074B1 (ko) 설폰아마이드 화합물 및 이의 용도
TW202104223A (zh) 磷脂醯肌醇3-激酶抑制劑
CN110950876B (zh) 一类呋喃并内酰胺类化合物、制备方法和用途
TW202033526A (zh) 用作酪胺酸激酶抑制劑的化合物、包含其的藥物組合物及其用途
EP3741752A1 (en) Tam family kinase /and csf1r kinase inhibitor and use thereof
WO2019228404A1 (zh) 一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途
JP2022523477A (ja) ピロロピリミジン誘導体及びこれを有効成分として含有するタンパク質キナーゼ関連疾患の予防又は治療用薬学的組成物
CN114230524A (zh) (5-氟-2-苯胺嘧啶-4-基)氨基-n-羟基苯甲酰胺衍生物及其制备方法与应用
CN112979655A (zh) 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途
CA3191829A1 (en) Cd73 inhibitor and application thereof in medicine
TW202204351A (zh) 具有大環結構的化合物及其用途
WO2021088839A1 (zh) 咪唑烷酮类化合物及其制备方法与应用
WO2021088845A1 (zh) 咪唑烷酮类化合物及其制备方法与应用
JP2023538137A (ja) 芳香環ラクタム系化合物、その製造方法及び使用
TW202214634A (zh) 雜環化合物及其衍生物
EP4204093A1 (en) 1h-imidazo [4,5-h] quinazoline compound as novel selective flt3 inhibitors
CN116082307A (zh) Hpk1抑制剂及其在医药上的应用
TWI841376B (zh) 吡唑并嘧啶衍生物治療PI3Kδ相關病症之用途
WO2023169170A1 (zh) 作为shp2抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法
CN117164571A (zh) Hpk1抑制剂及其在医药上的应用

Legal Events

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

Ref document number: 20885710

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3156625

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 292592

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2022525930

Country of ref document: JP

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112022008647

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 788553

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 20227018861

Country of ref document: KR

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020379709

Country of ref document: AU

Date of ref document: 20201104

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020885710

Country of ref document: EP

Effective date: 20220607

ENP Entry into the national phase

Ref document number: 112022008647

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20220504