WO2020103939A1 - Triazolo cycle compound, preparation method therefor, intermediate thereof and application thereof - Google Patents

Triazolo cycle compound, preparation method therefor, intermediate thereof and application thereof

Info

Publication number
WO2020103939A1
WO2020103939A1 PCT/CN2019/120284 CN2019120284W WO2020103939A1 WO 2020103939 A1 WO2020103939 A1 WO 2020103939A1 CN 2019120284 W CN2019120284 W CN 2019120284W WO 2020103939 A1 WO2020103939 A1 WO 2020103939A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
unsubstituted
alkylene
heteroalkylene
Prior art date
Application number
PCT/CN2019/120284
Other languages
French (fr)
Chinese (zh)
Inventor
程建军
闫文仲
Original Assignee
上海科技大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海科技大学 filed Critical 上海科技大学
Publication of WO2020103939A1 publication Critical patent/WO2020103939A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings

Definitions

  • the invention relates to a triazolo ring compound, its preparation method, intermediate and application.
  • Adenosine is an endogenous purine nucleoside substance, which mainly exerts its physiological regulation function by combining with adenosine receptors (AR) on the cell membrane.
  • Adenosine receptors belong to G protein-coupled receptors (GPCR, or seven transmembrane receptors, 7TMR), and are divided into 4 subtypes: A1, A2A, A2B, and A3.
  • A2A receptors are located in the central nervous system and the periphery There are widely distributed.
  • A2A receptors are distributed at a high density in the central nervous system and are closely related to the pathogenesis of various degenerative central nervous system diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease (Gomes) ., Biochimica Biophysica Acta, 2011, 1808, 1380-1399).
  • Parkinson's disease the A2A receptor is highly expressed in the nigrostriatal and can co-localize with the dopamine D2 receptor and form a heterodimer.
  • the A2A receptor is activated by adenosine and inhibits the dopamine D2 receptor. Signal transduction of the body (Shook and Jackson, ACS Chemical Science, 2011, 2, 555-567).
  • A2A receptor antagonists can enhance the downstream signal of D2 receptors as a drug for the treatment of Parkinson's disease.
  • A2A receptor antagonists, as therapeutic drugs for Parkinson's disease can also reduce the side effects of dyskinesia induced by levodopa (L-DOPA).
  • L-DOPA levodopa
  • small molecule antagonists of A2A receptors such as ZM-241385, SCH58261, preladenant (SCH-420814), tozadenant (SYN-115), vipadenant (BIIB-014), etc. have been reported and used for treatment Research on Parkinson's disease (Pinna, CNS Drugs, 2014, 28, 455-474).
  • Itratheline (istradefylline, KW-6002) was approved for marketing in Japan in 2013 and is used as an adjunct drug in combination with levodopa to treat Parkinson's disease. Although most A2A inhibitors are not effective as single agents in the clinical trials of Parkinson's disease, the potential of A2A receptor antagonists for the treatment of degenerative central nervous system diseases has been initially confirmed.
  • Adenosine and adenosine A1, A2A, A2B and A3 receptors can activate the receptors and play different regulatory functions. Among them, A2A receptors play a major role in the tumor immunosuppression process.
  • Adenosine and immune cell surface The binding of A2A receptor can suppress the immune function of these cells. Therefore, inhibiting the A2A receptor can significantly enhance the function of immune cells and promote the infiltration of immune cells into tumor tissue, which is beneficial to exert its anti-tumor effect.
  • Some known A2A receptor antagonists such as vipadenant, CPI-444, PBF-509, and AZD4635 have entered clinical research as tumor immunotherapy drugs. Most of these drugs are used in combination with other tumor immune drugs or anti-tumor drugs.
  • HDACs histone deacetylases
  • HATs histone acetyltransferases
  • HAT can catalyze the acetylation of lysine residues at the N-terminus of histones, leaving chromatin in a relatively loose and open state, which facilitates the transcription factor close to DNA and promotes the expression of specific genes; HDAC's function is to catalyze the removal of the histone The acetyl group on the lysine residue puts chromatin in a compact conformation, thereby blocking the transcription of DNA and the expression of specific genes (Kazantsev and Thompson, Nature Reviews Drug Discovery, 2008, 7,854-868). At present, there are 18 subtypes of human HDACs, which can be divided into four subfamilies of Class I-IV.
  • Class I includes HDAC 1, 2, 3 and 8; Class II is divided into Class IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10); Class IV has only one member, HDAC 11.
  • the above three subfamilies are all Zn 2+ dependent HDACs, also known as classic HDAC.
  • Class III also known as sirtuins, including SIRT 1-7, relies on NAD + to exert catalytic activity.
  • HDAC anti-tumor
  • Over-expression of HDAC will inhibit the expression of a series of tumor suppressor genes and promote the growth of tumor cells.
  • abnormal HDAC function can lead to a decrease in the expression of the cell cycle inhibitor p21 and block the cell cycle; Acetylation blocks its binding to DNA and blocks the transcription of apoptotic genes.
  • HDAC is also related to tumor blood vessel formation and regulating immune cell function (Falkenberg and Johnstone, Nature ReviewsDrug Discovery, 2014, 13,673-691).
  • HDAC inhibitors in inhibiting tumor proliferation, their research and application as anti-tumor drugs have received extensive attention (Zagni et al., Medicinal Research Reviews, 2017, 37, 1373-1428),
  • HDAC inhibitors vorinostat / SAHA, romidepsin / FK228, belinostat / PDX-101, panobinostat / LBH-589
  • vorinostat / SAHA romidepsin / FK228, belinostat / PDX-101, panobinostat / LBH-589
  • Another HDAC inhibitor Chidamid is also approved in China for the treatment of peripheral T-cell lymphoma.
  • HDAC inhibitors such as abexinostat / PCI024781, givinostat / ITF2375, entinostat / MS-275, etc. which are in different stages of clinical research.
  • HDAC2 can regulate brain function, nervous system development and deterioration; overexpression of HDAC2 can negatively regulate the plasticity and number of synapses and dendritic spine density, which in turn leads to the deterioration of learning and cognitive function , 2009,459,55-60).
  • HDAC6 can regulate the phosphorylation level of tau protein, which in turn affects the development of tau protein-driven neurological diseases (Selenica et al., Alzheimer's Research & Therapy, 2014, 6, 12). HDAC6 can also regulate the degradation of misfolded proteins by regulating protein aggregation and HSP90 function, and the accumulation of misfolded proteins is a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease Pathological features. At present, there are literatures confirming that HDAC inhibitors can have a therapeutic effect on neurological diseases.
  • SAHA can significantly improve cognition in animal models (Guan et al., Nature, 2009, 459, 55-60), LBH-589 in In animal models, the symptoms of Huntington's chorea can be reversed by inhibiting HDAC function (Siebzehnrübl et al., PNAS, 2018, doi / 10.1073 / pnas.1807962115).
  • A2A receptors and HDAC are closely related to tumors and various central nervous system diseases, the synergistic use of the two is likely to play a more powerful therapeutic effect in the treatment of related diseases.
  • dual-target small molecule drugs based on A2A receptor antagonists and HDAC inhibitors have been reported, for example, dual-target compounds of A2A receptor and dopamine D2 receptor et al., J Med Chem, 2015, 58, 718-738), dual target compounds of HDAC and cyclin-dependent kinase 4/9 (CDK4 / 9) (Li et al., J Med Chem, 2018, 61,3166- 3192), dual-target compounds of HDAC and nicotinamide phosphoribosyltransferase (NAMPT) (Dong et al., J Med Chem, 2017, 60, 7965-7983), but also dual-target small molecule compounds targeting HDAC and A2A receptor No reports.
  • the technical problem to be solved by the present invention is to provide a triazolocyclic compound, its preparation method, intermediate and application.
  • the triazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylation HDAC inhibitor. Further, the triazolocyclic compounds of the present invention can have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity, and thus can be used to treat tumors and central nervous system diseases and other related diseases.
  • the present invention provides a compound represented by formula I or I ', pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, and solvates , Metabolites or prodrugs:
  • R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
  • R 3 is a substituted or unsubstituted C 6 -C 12 aryl group (such as phenyl) or a substituted or unsubstituted 5-12 membered heteroaryl group (such as 5, 6 or 7 membered heteroaryl group, such as furanyl, Again );
  • the substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl means that it is substituted with one or more R 19 , each R 19 is independently halogen (for example, fluorine), C 1 -C 6 alkyl (such as C 1 -C 4 alkyl or methyl), C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
  • X is N or CR 4 ;
  • R 4 is hydrogen, fluorine or C 1 -C 3 alkyl
  • Y is Or substituted or unsubstituted The nitrogen atom in Connected); said Is a 3-10 membered heterocycloalkylene (eg 3-8 membered heterocycloalkylene); the substituted Means it is replaced by one or more R 20 ;
  • R 5 is hydrogen, C 1 -C 6 alkyl (such as C 1 -C 4 alkyl, such as methyl or ethyl), C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene )-(C 3 -C 6 cycloalkyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • Each L is independently the following case (i), (ii), (iii), (iv) or (v):
  • L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene (for example, C 1 -C 7 alkylene Groups, such as C 5 alkylene, C 6 alkylene or C 7 alkylene), C 2 -C 10 alkenylene (eg C 2 -C 7 alkenylene, such as C 5 , C 6 or C 7 alkenylene), C 2 -C 10 alkynylene (e.g. C 5 -C 7 alkynylene), heteroalkylene having 2-10 chain atoms (e.g.
  • heteroalkyl groups such as heteroalkylene groups having 5, 6 or 7 chain atoms
  • heteroalkenylene groups having 2-10 chain atoms eg, heteroalkenylene groups having 2-7 chain atoms, and Such as heteroalkenylene having 5, 6 or 7 atoms) or heteroalkynylene having 3-10 chain atoms (eg heteroalkynylene having 5, 6 or 7 chain atoms);
  • -M 1 -means that it is substituted by one or more R 21 ;
  • L is substituted or unsubstituted -M 2 -M 3-
  • M 2 is -NH-, -O-, -S-, single bond
  • C 1 -C 6 alkylene eg C 1 -C 4 alkylene, such as methylene, ethylene or propylene
  • heteroalkylene having 2-6 chain atoms eg heteroalkylene having 2 or 3 chain atoms, for example Another example E.g
  • L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene (e.g.
  • M 5 is a C 6 -C 12 arylene group (for example, phenylene, such as 1,4-phenylene) or a 5-12 membered heteroarylene group ( For example, 5, 6 or 7-membered heteroarylene, as in 1,4- (6-membered heteroarylene), and then );
  • M 6 is C 1 -C 9 alkylene (eg C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or C 6 alkylene), having 2-9 Heteroalkylene groups of chain atoms (for example, heteroalkylene groups having 2, 3, 4, 5 or 6 atoms; another example is -U 1 -U 2 -where U 1 is -NH-, -O- or
  • L is substituted or unsubstituted -M 7 -M 8 -M 9-
  • M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene (eg methylene or Ethylene, such as ethylene) or a heteroalkylene group having 2-4 chain atoms (for example, a heteroalkylene group having 2 chain atoms)
  • M 8 is C 3 -C 12 cycloalkylene ( For example, C 3 -C 8 cycloalkylene, like ) Or 3-12 membered heterocycloalkylene (eg 3-8 membered heterocycloalkylene )
  • M 9 is C 6 -C 12 arylene (eg phenylene, such as 1,4-phenylene) or 5-12 membered heteroarylene (eg 5, 6 or 7 membered heteroarylene) , As in 1,4- (6-membered heteroarylene), as in );
  • Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are independently halogen (for example fluorine or chlorine, such as fluorine), hydroxy, C 1 -C 6 alkyl (for example C 1 -C 3 alkyl) or C 1 -C 6 alkoxy (such as C 1 -C 3 alkoxy);
  • halogen for example fluorine or chlorine, such as fluorine
  • hydroxy for example C 1 -C 6 alkyl
  • C 1 -C 3 alkyl for example C 1 -C 3 alkyl
  • C 1 -C 6 alkoxy such as C 1 -C 3 alkoxy
  • hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
  • R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen (e.g. fluorine), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl (eg 5, 6 or 7 membered heteroaryl, like thienyl, and then Thiophen-2-yl);
  • halogen e.g. fluorine
  • C 1 -C 6 alkyl C 1 -C 6 alkoxy
  • C 1 -C 6 haloalkyl C 3 -C 6 cycloalkyl
  • 3-6 membered heterocycloalkyl C 6 -C 12 aryl or 5-12 membered heteroaryl (eg 5, 6 or 7 membered heteroaryl, like thienyl, and then Thiophen-2
  • hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
  • the compound represented by Formula I or I 'as described above has the following structure:
  • R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
  • R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
  • X is N or CR 4 ;
  • R 4 is hydrogen, fluorine or C 1 -C 3 alkyl
  • Y is Or substituted or unsubstituted Said Is a 3-10 membered heterocycloalkylene; the substituted Means it is replaced by one or more R 20 ;
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), C 2 -C 6 Alkenyl or C 2 -C 6 alkynyl;
  • L is the following case (i), (ii), (iii) or (iv):
  • L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene , C 2 -C 10 alkynylene, heteroalkylene having 2-10 chain atoms, heteroalkenylene having 2-10 chain atoms or heteroalkynylene having 3-10 chain atoms;
  • the substituted -M 1 - refers to its substitution by one or more R 21 ;
  • L is substituted or unsubstituted -M 2 -M 3-
  • M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene; the substituted -M 2 -M 3 -means that it is replaced by one or more R 22 ;
  • L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene or has 2-4 Heteroalkylene group of chain atom, M 8 is C 3 -C 12 cycloalkylene group or 3-12 membered heterocycloalkylene group, M 9 is C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical; the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
  • Each R 20 , R 21 , R 22 , R 23 and R 24 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
  • R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
  • hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
  • R 1 and R 2 are hydrogen.
  • R 4 is hydrogen
  • X is N or CH, preferably N.
  • R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5 -12 membered heteroaryl; the substituent in the substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl is independently C 1 -C 6 alkyl.
  • R 3 is substituted or unsubstituted
  • R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted
  • the substituents are independently C 1 -C 6 alkyl.
  • R 3 is phenyl
  • Y is R 5 is hydrogen or C 1 -C 6 alkyl.
  • Y is R 5 is hydrogen, methyl or ethyl, for example hydrogen.
  • ZBG is R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 6 -C 12 aryl or 5-12 membered heteroaryl.
  • R 12 is halogen, such as fluorine.
  • R 11 is a 5-12 membered heteroaryl, such as thiophen-2-yl.
  • ZBG is E.g
  • ZBG is
  • ZBG is
  • each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently C 1 -C 6 alkyl.
  • the number of R 20 , R 21 , R 22 , R 23 , R 24 or R 25 may each be independently 1, 2, 3, 4, 5, 6, or 7, such as 1, 2, or 3, and then another one.
  • M 1 is a C 1 -C 10 alkylene group or a heteroalkylene group having 2 to 10 chain atoms.
  • M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene, or heteroalkylene having 5, 6 or 7 atoms.
  • M 1 is C 5 alkylene, C 6 alkylene, or C 7 alkylene.
  • M 2 is a C 1 -C 6 alkylene group or a heteroalkylene group having 2 to 6 chain atoms
  • M 3 is a C 6 -C 12 subgroup Aryl or 5-12 membered heteroarylene.
  • M 2 is methylene, ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms
  • M 3 is 1,4 -Phenylene or 1,4- (6-membered heteroarylene).
  • M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms
  • M 3 is 1,4-phenylene .
  • M 2 when Y is When L is substituted or unsubstituted -M 2 -M 3- , the definition of M 2 is as described in any of the aspects of the present invention, and M 3 is 1,4-phenylene.
  • M 2 is methylene, ethylene, propylene or M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms
  • M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 2 is ethylene and M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
  • M 2 is propylene or a heteroalkylene group having 3 chain atoms
  • M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms
  • M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene
  • M 6 is
  • M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms
  • M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene)
  • M 6 is
  • M 4 is as described in any scheme of the present invention.
  • M 5 is 1,4-phenylene; M 6 is
  • M 4 and M 6 are as described in any of the aspects of the present invention, and M 5 is 1,4-phenylene.
  • M 4 is methylene or ethylene
  • M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl)
  • M 6 is
  • M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms
  • M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene
  • M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene or has 2 , 3, 4, 5 or 6 chain atoms of heteroalkylene.
  • M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms
  • M 5 is 1,4-phenylene Radical or 1,4-6 membered heteroarylene
  • M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene or “-U 1 -U 2- , wherein U 1 is -NH-, -O-, or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, or has 2 , A heteroalkylene group of 3, 4 or 5 chain atoms ".
  • M 4 is methylene or ethylene
  • M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl)
  • M 6 is
  • M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms
  • M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene
  • M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms
  • M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene)
  • M 6 is
  • M 4 is ethylene and M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene); M 6 is
  • M 7 is a C 1 -C 4 alkylene group or a heteroalkylene group having 2-4 chain atoms
  • M 8 is M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 7 is ethylene or heteroalkylene having two chain atoms
  • M 8 is M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 10 is ethylene
  • Z 1 , Z 2 and Z 3 are CH.
  • L is substituted or unsubstituted -M 1- , substituted or unsubstituted -M 2 -M 3- , substituted or unsubstituted -M 4 -M 5 -M 6- , substituted or unsubstituted- M 7 -M 8 -M 9 -or substituted or unsubstituted -M 10 -M 11- .
  • R 1 and R 2 are hydrogen
  • R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
  • X is N or CR 4 ;
  • R 4 is hydrogen, fluorine or C 1 -C 3 alkyl
  • Y is Or substituted or unsubstituted The substituted Means it is replaced by one or more R 20 ;
  • R 5 is hydrogen or C 1 -C 6 alkyl
  • Each L is independently the following case (i), (ii), (iii), (iv) or (v):
  • L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms;
  • the substituted -M 1 - refers to its substitution by one or more R 21 ;
  • L is substituted or unsubstituted -M 2 -M 3- ;
  • M 2 is ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms (the heteroalkylene group is, for example, E.g And M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); alternatively, M 2 is ethylene, propylene or heteroalkylene having 2 or 3 chain atoms , And M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene), the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
  • L is a substituted or unsubstituted -M 4 -M 5 -M 6- , is a methylene group, an ethylene group or a heteroalkylene group having 2 chain atoms, and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene), M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, “-U 1 -U 2- , where U 1 is -NH-, -O- Or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or heteroalkylene having 2, 3, 4 or 5 chain atoms ",
  • the substituted -M 4 -M 5 -M 6 - refers to its substitution by one or more R 23 ;
  • L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
  • Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
  • R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
  • hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
  • the compound represented by Formula I is selected from any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • each L is independently the following case (i), (ii), (iii) or (iv):
  • L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 chain atoms ;
  • L is substituted or unsubstituted -M 2 -M 3-
  • M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example or E.g ), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 2 -M 3 -means that it is substituted by one or more R 22 ;
  • L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene, M 5 is 1,4-phenylene or 1,4- (6 member Heteroarylene), M 6 is Alternatively, M 4 is ethylene, M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene), M 6 is The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
  • L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is or M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
  • the compound represented by Formula I has any of the following structures:
  • each L is independently the following situation (ii) or (iii):
  • L is substituted or unsubstituted -M 2 -M 3-
  • M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example or E.g )
  • M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
  • L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene (for example, M 4 is methylene), and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene) (eg M 5 is 1,4-phenylene), M 6 is The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
  • the compound represented by Formula I has the following structure:
  • L is substituted or unsubstituted -M 2 -M 3- ; the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
  • the compound represented by Formula I has the following structure:
  • L is substituted or unsubstituted -M 2 -M 3- ; the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
  • the compound represented by Formula I has any of the following structures:
  • Each L is independently the following case (i) or (ii):
  • L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms ( For example, M 1 is C 6 alkylene); the substituted -M 1 -means that it is substituted with one or more R 21 ;
  • L is substituted or unsubstituted -M 2 -M 3-
  • M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example or E.g )
  • M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
  • the compound represented by Formula I ' has the following structure:
  • L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms (eg M 1 Is C 6 alkylene); the substituted -M 1 -means that it is substituted with one or more R 21 ;
  • the compound represented by Formula I ' has the following structure:
  • L is substituted or unsubstituted -M 2 -M 3- , M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (the Heteroalkyl for example or E.g ), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
  • the compound represented by Formula I or I ' is selected from any of the following structures:
  • the present invention also provides a method for preparing the compound shown in Formula I as described above, which is at least one of the following schemes:
  • Scheme one includes the following steps: in an organic solvent (such as methanol), the compound shown in formula II and NH 2 -OH in the presence of a base (such as potassium hydroxide) in the presence of a substitution reaction to obtain formula I Is sufficient;
  • ZBG is R 1, R 2, R 3 , X, Y and L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl);
  • Scheme two includes the following steps: In an organic solvent (such as DMF), the compound shown in formula III and The condensation reaction can be carried out in the presence of a condensing agent (such as HATU) and a base (such as DIPEA) to obtain the compound represented by Formula I; wherein, ZBG is R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , X, Y, and L are as defined above.
  • a condensing agent such as HATU
  • DIPEA a base
  • the preparation method of the compound shown in formula III may include the following steps: In an organic solvent (such as a mixed solvent of tetrahydrofuran and water), the compound shown in formula II is present in a base (such as lithium hydroxide) The hydrolysis reaction is carried out under the conditions to obtain the compound represented by formula III; wherein, R 1 , R 2 , R 3 , X, Y and L are as defined above, and R a is C 1 -C 6 alkyl ( (Such as methyl or ethyl);
  • the preparation method of the compound shown in Formula II may include the following steps: In an organic solvent (such as acetonitrile), the compound shown in Formula IV and the compound shown in Formula V are subjected to a condensation reaction to obtain a compound shown in Formula the compound represented by II; wherein, R 1, R 2, R 3, X, Y and L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl), LG Is a leaving group (e.g. Where R 30 is C 1 -C 4 alkyl, such as methyl);
  • the present invention also provides a compound, which has any of the following structures:
  • R 1 , R 2 , R 3 , X, Y and L are as defined above, and R a is C 1 -C 6 alkyl (such as methyl or ethyl).
  • the compound of formula II has any of the following structures:
  • the compound of formula III has any of the following structures:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer Constructors, tautomers, solvates, metabolites or prodrugs, and at least one pharmaceutical excipient.
  • the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
  • a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
  • the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation Structurants, solvates, metabolites or prodrugs, or the pharmaceutical composition is prepared for the treatment and / or prevention of diseases related to adenosine A2A receptor and / or histone deacetylase HDAC Application.
  • the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
  • a pharmaceutically acceptable salt thereof an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
  • the use of structurants, solvates, metabolites or prodrugs, or said pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of cancer or diseases of the central nervous system.
  • the compound represented by formula I or I ' its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites Or the dose of prodrug may be a therapeutically effective amount.
  • the present invention also provides a method of treating and / or preventing "disease related to adenosine A2A receptor and / or histone deacetylase HDAC", which method comprises administering to a subject in need of such treatment effective Amount of a compound represented by formula I or I ', its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or Prodrugs.
  • the present invention also provides a method of treating and / or preventing cancer or central nervous system diseases, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound represented by Formula I or I ', and its pharmacy Acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or prodrugs.
  • the "diseases associated with adenosine A2A receptor and / or histone deacetylase HDAC" as described above may be cancer or central nervous system diseases.
  • Cancers as described above may be head and neck cancers (such as thyroid cancer, nasopharyngeal cancer, meningeal cancer, or intracranial metastases), cancers of the respiratory system (such as small cell lung cancer or non-small cell lung cancer), cancers of the digestive system (such as liver cancer , Gastric cancer, esophageal cancer, rectal cancer, colon cancer or pancreatic cancer), urinary system cancer (such as kidney cancer, bladder cancer, prostate cancer or testicular cancer), bone cancer, gynecological cancer (such as breast cancer, cervical cancer or ovarian cancer) , Hematological cancer (such as leukemia, lymphoma or myeloma or other types of cancer (such as melanoma, glioma or skin cancer).
  • head and neck cancers such as thyroid cancer, nasopharyngeal cancer, meningeal cancer, or intracranial metastases
  • cancers of the respiratory system such as small cell lung cancer or non-small cell lung cancer
  • the central nervous system disease as described above may be Parkinson's disease, Alzheimer's disease, or Huntington's disease.
  • the product or prodrug, or the pharmaceutical composition may also be used in any disease process characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis , Glomerulonephritis, restenosis after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxin shock and fungal infection.
  • the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
  • a construct, solvate, metabolite, or prodrug, or the pharmaceutical composition described in the preparation of a product for modulating the activity of adenosine A2A receptor and / or histone deacetylase HDAC The use of a construct, solvate, metabolite, or prodrug, or the pharmaceutical composition described in the preparation of a product for modulating the activity of adenosine A2A receptor and / or histone deacetylase HDAC.
  • the choice of the medicinal adjuvant varies according to the route of administration and the characteristics of the action, and can generally be conventional fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending aids Agent.
  • the pharmaceutical composition can be administered by oral, injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, transbuccal, transrectal, transurethral, transvaginal, nasal, inhalation or topical routes. oral.
  • substituted or “substituent” means that one or more hydrogen atoms are replaced with the specified group.
  • substitution position is not specified, the substitution can be in any position, but only the formation of a stable or chemically feasible chemical substance is allowed.
  • the term “optional” or “optionally” means that the subsequently described event or condition may, but need not necessarily occur, and the description includes the situation in which the event or condition occurs and the event or Situations where no situation occurs.
  • the term “optionally substituted” means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis that they are chemically achievable.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • the group can be optionally substituted with up to two Rs, and R in each case has independent options.
  • combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.
  • alkyl refers to a saturated monovalent hydrocarbon radical straight or branched chain having the indicated number of carbon atoms, for example C 1 -C 10 alkyl means an alkyl group having 1 to 10 carbon atoms, .
  • alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl) and pentyl (eg n-pentyl, isopentyl, neopentyl).
  • alkoxy refers to an alkyl group (as defined in the present invention) connected to the rest of the molecule through an oxygen bridge.
  • alkenyl refers to a linear or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, for example C 2 -C 6 alkenyl refers to alkenyl groups having 2 to 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, and hexadienyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located at any position within the alkynyl group, for example C 2 -C 6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms.
  • alkynyl groups include, but are not limited to ethynyl and propynyl.
  • alkylene refers to a saturated linear divalent hydrocarbon group having the specified number of carbon atoms.
  • C 1 alkylene ie, methylene
  • C 2 alkylene ie, ethylene
  • C 3 alkylene refers to -CH 2- CH 2 -CH 2- .
  • alkenylene refers to a linear divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, where the carbon-carbon double bond may be located at any position within the alkenylene group.
  • C 2 alkenylene ie vinylene
  • -CH 2 CH-CH 2 -CH 2-
  • -CH 2 -CH-CH 2 CH 2- .
  • alkynylene refers to a straight-chain divalent hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond, where the carbon-carbon triple bond may be located at any position within the alkynylene group.
  • C 2 alkynylene (ethynylene) refers to C 3 alkynylene means
  • heteroalkyl refers to a saturated linear or branched monovalent hydrocarbon group having the specified number of carbon atoms and at least one heteroatom selected from N, O, and S. Heteroalkyl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein.
  • the heteroatom may be located at any internal position of the heteroalkyl group (including the position where the heteroalkyl group is connected to other parts of the molecule), that is, the heteroalkyl group does not include a hydroxyalkyl group (for example, -CH 2 OH, -CH (CH 3 ) OH) , Aminoalkyl (for example, -CH 2 NH 2 , -CH (CH 3 ) NH 2 ), etc.
  • heteroalkyl groups include, but are not limited to, -O-CH 3 , -CH 2 -NH-CH 3 , -NH-CH (CH 3 ) -CH 3 , -CH 2 -O-CH 3, and -CH 2 -S -CH 3 .
  • heteroalkylene refers to a saturated straight-chain divalent hydrocarbon group having a specified number of chain atoms, at least one of which is a hetero atom selected from N, O, and S, and the remaining chains The atom is carbon. Heteroalkylene groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. Heteroalkylene groups having 2 chain atoms such as —O-CH 2 —, —NH—CH 2 —, etc.
  • Heteroalkylene groups having 3 chain atoms such as —CH 2 —NH—CH 2 —, —O— CH 2 -CH 2- , -CH 2 -O-CH 2- , etc., a heteroalkylene group having 4 chain atoms such as -O-CH 2 -CH 2 -NH-.
  • heteroalkenylene refers to a straight-chain divalent hydrocarbon group having a specified number of chain atoms and at least one double bond, wherein at least one chain atom is a hetero atom selected from N, O, and S .
  • the heteroalkenylene group may be connected to other parts of the molecule through a hetero atom or a carbon atom therein.
  • Heteroalkenylene having 2 chain atoms such as —N ⁇ CH 2 —, etc.
  • Heteroalkenylene having 3 chain atoms such as —N ⁇ CH—CH 2 —, —CH ⁇ N-CH 2 —, etc.
  • heteroalkynylene refers to a straight-chain divalent hydrocarbon group having a specified number of chain atoms and at least one triple bond, wherein at least one chain atom is a hetero atom selected from N, O, and S .
  • the heteroalkynylene group may be connected to other parts of the molecule through a hetero atom or a carbon atom therein.
  • Examples of heteroalkynylene include, but are not limited to (4 chain atoms) and (5 chain atoms).
  • cycloalkyl refers to a non-aromatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having a specified number of ring carbon atoms.
  • the cycloalkyl group may be monocyclic or polycyclic (for example, bicyclic And tricyclic), can be a parallel ring, spiro ring and bridge ring structure.
  • the cycloalkyl group optionally contains one or more double bonds or triple bonds.
  • Monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-ene Group, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclo Nonyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Cycloalkyl also includes polycyclic cycloalkyl structures, where the polycyclic structure optionally includes saturated or partially fused to saturated or partially unsaturated cycloalkyl or heterocyclic groups or aryl or heteroaryl rings Unsaturated cycloalkyl.
  • Bicyclic carbocycles with 7 to 12 atoms can be arranged as, for example, bicyclic [4,5], [5,5], [5,6] or [6,6] systems, or as bridged ring systems such as bi [2.2 .1] Heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.
  • heterocycloalkyl refers to a non-aromatic saturation formed by replacing at least one ring carbon atom in a cycloalkyl group (as defined in the present invention) with a heteroatom selected from N, O and S Or a partially unsaturated monovalent cyclic hydrocarbon group.
  • Heterocycloalkyl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein.
  • heterocycloalkyl examples include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrothiophene -2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • Bridged ring heterocycloalkyl for example
  • cycloalkylene refers to a non-aromatic saturated or partially unsaturated divalent cyclic hydrocarbon group having the specified number of ring carbon atoms.
  • the cycloalkylene group may be monocyclic or polycyclic, may For the ring, spiral ring and bridge ring structure.
  • Examples of cycloalkylene include, but are not limited to (I.e. 1,3-cyclobutylene), (I.e. 1,3-cyclopentylene), (I.e. 1,4-cyclohexylene) or
  • heterocycloalkylene refers to a non-aromatic group formed by replacing at least one ring carbon atom in a cycloalkylene group (as defined in the present invention) with a hetero atom selected from N, O, and S Group of saturated or partially unsaturated divalent cyclic hydrocarbon groups.
  • Heterocycloalkylene can be connected to other parts of the molecule through heteroatoms or carbon atoms therein.
  • Examples of heterocyclic heterocycloalkylene include, but are not limited to Bridged ring heterocycloalkylene groups include, but are not limited to Spirocyclic heterocycloalkylene groups include, but are not limited to with
  • aryl refers to any stable monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, at least one of which is an aromatic ring.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthrenyl, anthracenyl, or acenaphthyl. It can be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
  • arylene refers to a divalent aryl group. 1,4-phenylene
  • heteroaryl refers to a stable monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains at least one selected Heteroatoms from O, N and S. Heteroaryl groups can be attached to other parts of the molecule through heteroatoms or carbon atoms therein.
  • heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnoline, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl , Benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl (eg, pyrrole-1 -Base Pyrrol-2-yl ), Tetrahydroquinolinyl. It can be understood that in the case where the heteroaryl substituent is a bicyclic substituent, and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
  • heteroarylene refers to a divalent heteroaryl group.
  • the 6-membered heteroarylene group in 1,4- (6-membered heteroarylene) is monocyclic, where 1 and 4 do not refer to the original number of the ring atoms in the 6-membered heteroarylene group, but refer to the 6-membered subarylene group The relative position of the two connection sites of the heteroaryl group is para.
  • 1,4- (6-membered heteroarylene) include but are not limited to
  • the linking direction is connected in the same direction as the reading order from left to right.
  • the linking group L 1 is -CD-, and then -CD- is connected to ring A and ring B in the same direction as the reading order from left to right
  • the structure formed is Instead of when enumerating L is , The structure formed is Instead of
  • halogen refers to F, Cl, Br, I.
  • the term "pharmaceutically acceptable salt” means a salt formed of a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base and a compound represented by Formula I or I ', which retains the formula The biological activity of the compound represented by I or I '.
  • the organic acid may be various organic acids that can form salts in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , Propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalene sulfonic acid and one or more of salicylic acid.
  • the inorganic acid may be various conventional inorganic acids capable of forming salts in the art, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic base may be a variety of conventional organic bases capable of forming salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines Species.
  • the tertiary amine organic base is preferably triethylamine and / or N, N-diisopropylethylamine.
  • the aniline organic base is preferably N, N-dimethylaniline.
  • the pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
  • the inorganic base may be various inorganic bases conventionally capable of forming salts in the art, preferably alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate , One or more of potassium bicarbonate and sodium bicarbonate.
  • the alkali metal hydride is preferably sodium hydride and / or potassium hydride.
  • the alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide.
  • the pharmaceutically acceptable salt is the hydrochloride salt.
  • solvate means a substance formed by a compound represented by formula I or I 'and a suitable solvent.
  • the solvent is preferably water or an organic solvent.
  • the compounds of the present invention and their structures are also meant to include all isomers (e.g. enantiomers, diastereomers, geometric isomers and conformational isomers), which can be based on the absolute stereochemistry for amino acids Chemistry is defined as (R)-/ (S)-or (D)-/ (L)-or (R, R)-/ (R, S)-/ (S, S)-.
  • the present invention includes all these possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms.
  • Optical rotation (+) and (-), (R)-and (S)-and (R, R)-/ (R, S)-/ (S, S)-or (D)-and (L) -iso Constructs can be prepared using chiral synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid phase (HPLC) using chiral columns.
  • HPLC high performance liquid phase
  • stereoisomer refers to a compound composed of the same atoms bonded with the same chemical bond but having different three-dimensional structures, and they are not interchangeable.
  • the present invention covers various stereoisomers and mixtures thereof and includes “enantiomers” and “diastereomers”.
  • Enantiomers refer to two stereoisomers whose molecules are non-overlapping mirror images of each other Conformator; diastereomer is a stereoisomer with two or more chiral centers and a non-mirror relationship between the molecules.
  • tautomer refers to the movement of a proton from one atom of a molecule to another position of the same molecule.
  • the invention includes tautomers of any of the compounds.
  • the term "prodrug” refers to a derivative of a compound containing a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide The compound.
  • the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until it is cleaved from the bioreactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • the prodrug may contain biohydrolyzable groups.
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Acyl urea.
  • the term "isotopic derivative” refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • having the structure of the present invention in addition to replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with an 18 F-fluorine label ( 18 F isotope), or using 11 C-, 13 C-, or 14 C-rich Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present invention.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • Deuterated compounds can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased half-life in vivo or reduced dose requirements) ). Therefore, in the present invention, the isotopic derivative is preferably a deuterium.
  • the term “therapeutically effective amount” refers to a sufficient amount of a drug or medicament that is non-toxic but achieves the desired effect.
  • the “therapeutically effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine experiments.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive progress effect of the present invention is to provide a triazolocyclic compound, its preparation method, intermediate and application.
  • the triazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylation HDAC inhibitor. Further, the triazolocyclic compounds of the present invention can have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity, and thus can be used to treat tumors and central nervous system diseases and other related diseases.
  • Step 1 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) methyl) -N-hydroxybenzoic acid methyl ester (Intermediate Int-1)
  • Step 2 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Amino) methyl) -N-hydroxybenzamide (Compound I-1)
  • reaction solution was neutralized with 1,4-dioxane solution (4M) of hydrogen chloride to pH 7.4, the solvent was evaporated under reduced pressure, water was added to the solid residue, stirred at room temperature for 1 hour, and filtered to obtain white solid compound 1 (0.056g, 70% yield).
  • Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with “Methyl 4- (3-aminopropyl) benzoate” (for the preparation method, see WO2012117421), the remaining required raw materials, reagents and preparation methods As in Example 1, a white solid compound (I-3) can be obtained.
  • Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with “Methyl 4- (2-aminoethoxy) benzoate” (see WO2001000206 for the preparation method), the remaining required raw materials, reagents and preparation The method is the same as in Example 1, to obtain a white solid compound (I-4).
  • Example 1 Replace "methyl 4-aminomethylbenzoate” in Example 1 with "(E) -3- (4- (aminomethyl) phenyl) acrylic acid methyl ester” (for the preparation method, see WO2011021209)
  • the raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-5).
  • Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with "(E) -3- (4- (2-aminoethyl) phenyl) acrylic acid methyl ester” (for preparation methods, see MedChemComm, 2013 , 4,1562-1570), the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-6).
  • Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with “Methyl 4- (2- (methylamino) ethyl) benzoate” (see WO2008156820 for the preparation method), and the remaining required raw materials and reagents
  • the preparation method is the same as that in Example 1, to obtain a white solid compound (I-7).
  • Step 1 Preparation of methyl 4- (2- (ethylamino) ethyl) benzoate (intermediate Int-2)
  • Methyl 4- (2-aminoethyl) benzoate (see WO2017133521 for preparation method) (0.50g, 2.78mmol), acetaldehyde (0.122g, 2.78mmol) and triethylamine (0.78mL) are dissolved in methanol (2.5 mL), add sodium borohydride acetate (0.91 g, 4.17 mmol), and stir at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain yellow solid intermediate Int-2 (0.43 g, yield 74%).
  • HRMS (ESI) C 12 H 18 NO 2 + [M + H] + calculated value: 208.1332, found value: 208.1341.
  • Step 2 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) (ethyl) amino) ethyl-N-hydroxybenzamide (Compound I-8)
  • Example 1 The "methyl 4-aminomethylbenzoate" in Example 1 was replaced with the intermediate Int-2, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1, to obtain a white solid compound (I-8).
  • Step 1 Preparation of methyl 4- (2-((tert-butoxycarbonyl) (methyl) amino) ethoxy) benzoate (intermediate Int-3)
  • Step 2 Preparation of methyl 4- (2- (methylamino) ethoxy) benzoate (Intermediate Int-4)
  • Step 3 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) (methyl) amino) ethoxy) -N-hydroxybenzamide (compound I-9)
  • Example 1 Replace “Methyl 6-aminocaproate” in Example 1 with “Methyl 7-aminoheptanoate”, the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-10) .
  • Example 11-12 According to the listed methods provided in Example 1, the compounds listed in Examples 11-12 can be prepared in the same way by changing the corresponding raw materials, as shown in Table 1.
  • Step 1 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) amino) amino) ethyl) -benzoic acid (Compound Int-5)
  • ester intermediate 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl) amino) amino) ethyl) -benzoic acid methyl ester (0.19g, 0.50mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), Lithium hydroxide (0.060 g, 2.5 mmol) was added and stirred at room temperature overnight.
  • reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-5, which was directly used in the next reaction.
  • Step 2 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) amino) amino) ethyl) -N- (2-aminophenyl) benzamide (Compound I-13)
  • Example 13 According to the method provided in Example 13, by changing the corresponding raw materials, the compounds listed in Examples 15 and 16 can also be prepared by the same method, see Table 2 for details.
  • Step 1 Preparation of 4- (4- (cyanomethyl) phenoxy) butyric acid methyl ester (Intermediate Int-6)
  • Step 2 Preparation of methyl 4- (4- (2-aminoethyl) phenoxy) butanoate (Intermediate Int-7)
  • the intermediate Int-6 (1.13g, 4.8mmol) was dissolved in a mixed solution of dichloromethane (20mL) and methanol (20mL), concentrated hydrochloric acid (1.5mL) and palladium / carbon (10% palladium, 500mg) were added, Stir at room temperature overnight under a hydrogen atmosphere. The solvent was distilled off under reduced pressure to obtain the hydrochloride salt of intermediate Int-7 (1.32 g, crude yield 100%).
  • Step 3 4- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] tri Preparation of oxazin-5-yl) amino) ethyl) phenoxy) -N-hydroxybutyramide (Compound I-17)
  • Example 1 The "methyl 6-aminocaproate" in Example 1 was replaced with the intermediate Int-7, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-17).
  • Step 1 Preparation of 8-((4- (cyanomethyl) phenyll) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-8)
  • Step 2 Preparation of 8-((4- (2-aminoethyl) phenyl) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-9)
  • Step 3 N 1- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenyl) -N 8 -hydroxy suberamide (Compound I-22)
  • Example 1 The "methyl 6-aminocaproate" in Example 1 was replaced with the intermediate Int-9, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-22).
  • Example 22 According to the method provided in Example 22, by changing the corresponding raw materials, the compounds listed in Examples 23-25 can be prepared by the same method, see Table 3.
  • Step 1 Preparation of 4- (4- (methoxycarbonyl) phenethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate Int-10)
  • Step 2 Preparation of methyl 4- (2- (piperazin-1-yl) ethyl) benzoate (Intermediate Int-11)
  • Step 3 4- (2- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3, 5] Preparation of triazin-5-yl) piperazin-1-yl) ethyl) -N-hydroxybenzamide (compound I-26)
  • Example 1 The methyl 6-aminocaproate in Example 1 was replaced with the intermediate Int-11, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1, to obtain a white solid compound (I-26).
  • Example 26 by changing the corresponding raw materials, the compounds shown in Examples 27-29 can be prepared by the same method, see Table 4 for details.
  • Example 1 According to the method described in Example 1, by changing the corresponding raw materials, the compounds listed in Examples 30-36 can be prepared in a similar manner, see Table 5 for details.
  • Step 1 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) methyl) benzoic acid (Intermediate Int-12)
  • Step 2 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Amino) methyl) -N- (2-aminophenyl) benzamide (Compound I-37)
  • Example 38 4- (3-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-38)
  • Step 1 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) methyl benzoate (intermediate Int-13)
  • reaction can also separate Int-14, another isomer of intermediate Int-13.
  • the details will be described in Embodiment 41.
  • Step 2 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of -7-yl) ethyl) benzoic acid (Intermediate Int-15)
  • Step 3 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) -N- (2-aminophenyl) benzamide (Compound I-40)
  • Step 1 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of methyl-8-yl) ethyl) benzoate (Intermediate Int-14)
  • Step 2 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of -8-yl) ethyl) benzoic acid (Intermediate Int-16)
  • Step 3 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) ethyl) -N- (2-aminophenyl) benzamide (compound I'-41)
  • Step 1 (2- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] Pyrimidin-7-yl) ethyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-17)
  • Example 40 Replace o-phenylenediamine in Step 3 of Example 40 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 40 to obtain a foamy intermediate (Int-17).
  • Step 2 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (compound I-42)
  • Step 1 The intermediate Int-17 (0.06 g, 0.1 mmol) obtained in Step 1 was dissolved in methanol (5 mL), 4M hydrochloric acid dioxane solution (5 mL) was added, and the mixture was stirred overnight at room temperature.
  • Step 1 (2- (4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] Pyrimidin-8-yl) ethyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-18)
  • Example 41 Replace o-phenylenediamine in step 3 of Example 41 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 41 to obtain a foamy intermediate (Int-18).
  • Step 2 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (compound I'-43)
  • Step 1 The intermediate Int-18 (0.06 g, 0.1 mmol) obtained in Step 1 was dissolved in methanol (5 mL), 4M hydrochloric acid dioxane solution (5 mL) was added, and the mixture was stirred overnight at room temperature.
  • Step 1 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) ethyl) methyl benzoate (intermediate Int-19)
  • reaction can also separate Int-20, another isomer of intermediate Int-19. The details will be described in Example 46.
  • Step 2 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) methyl) -N- (2-aminophenyl) benzamide (Compound I-45)
  • Step 1 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) methyl) methyl benzoate (intermediate Int-20)
  • Step 2 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) methyl) -N- (2-aminophenyl) benzamide (Compound I'-46)
  • Example 48 4- (3- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I-48)
  • Step 1 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of methyl -7-yl) propyl) benzoate (Intermediate Int-21)
  • Step 2 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I-48)
  • Step 1 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of Methyl-8-yl) propyl) benzoate (Intermediate Int-22)
  • Step 2 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) propyl) -N- (2-aminophenyl) benzamide (compound I'-49)
  • Example 50 4- (3- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-50)
  • Step 1 (2- (4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) propyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-23)
  • Example 48 Replace o-phenylenediamine in Step 2 of Example 48 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 48 to obtain a foamy intermediate (Int-23).
  • Step 2 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-50)
  • Step 1 7- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7- Of methyl) heptanoate (intermediate Int-24)
  • Step 1 of Example 40 Replace the methyl 4- (2-bromoethyl) benzoate in Step 1 of Example 40 with methyl 7-bromoheptanoate.
  • the remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40 to obtain a white solid Intermediate (Int-24).
  • reaction can also isolate Int-25, another isomer of intermediate Int-24. The details will be described in Example 52.
  • Step 2 7- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7- ) -N-hydroxyheptanamide (Compound I-51)
  • Step 1 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8- Preparation of Methyl) heptanoate (Intermediate Int-25)
  • Step 2 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8- ) -N-hydroxyheptanamide (Compound I'-52)
  • Step 1 Preparation of 6- (4- (2-hydroxyethyl) phenoxy) hexanoic acid methyl ester (Intermediate Int-26)
  • Step 2 Preparation of 6- (4- (2-bromoethyl) phenoxy) hexanoic acid methyl ester (Intermediate Int-27)
  • Step 3 6- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of methyl pyrimidin-7-yl) ethyl) phenoxy) hexanoate (intermediate Int-28)
  • Step 1 of Example 40 Replace methyl 4- (2-bromoethyl) benzoate in step 1 of Example 40 with intermediate Int-27.
  • the remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40 to obtain a white solid intermediate (Int-27).
  • Step 4 6- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of pyrimidin-7-yl) ethyl) phenoxy) -N-hydroxyhexanamide (compound I-53)
  • Step 1 Preparation of 8-((4- (2-hydroxyethyl) phenyl) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-29)
  • Step 2 N 1- (4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) ethyl) phenyl) -N 8 -hydroxyoctanediamide (Compound I-54)
  • Step 1 4- (1- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of methyl pyrimidin-7-yl) ethyl) piperidin-4-yl) benzoate (intermediate Int-30)
  • Step 2 4- (1- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of pyrimidin-7-yl) ethyl) piperidin-4-yl) -N-hydroxybenzamide (compound I-55)
  • Example 56 2- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N-hydroxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Compound I-56)
  • Example 58 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-58)
  • Step 1 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of Methyl Amino) propyl) benzoate (Intermediate Int-31)
  • Step 2 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of Methyl Amino) propyl) benzoate (Intermediate Int-32)
  • Step 3 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-58)
  • Example 60 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) amino) propane ) -N- (2-aminophenyl) benzamide (Compound I-60)
  • Example 58 Replace methyl 4- (3- (methylamino) propyl) benzoate in step 1 of Example 58 with methyl 4- (3-aminopropyl) benzoate (for the preparation method, see WO2012117421)
  • the raw materials, reagents and preparation methods are the same as in Example 58, to obtain a yellow solid compound (I-60).
  • Example 61 4- (3-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-61)
  • Step 1 (2- (4- (3-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) Preparation of (methyl) amino) propyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-33)
  • Step 3 of Example 58 Replace o-phenylenediamine in Step 3 of Example 58 with tert-butyl (2-amino-5-fluorophenyl) carbamate, the remaining required raw materials, reagents and preparation methods are the same as Step 3 of Example 58 to obtain a foam Intermediate (Int-33).
  • Step 2 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-61)
  • Example 62 4- (2-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) ethoxy) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-62)
  • Step 1 (2- (4- (2-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) Preparation of (methyl) amino) ethoxy) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-34)
  • Example 59 Replace o-phenylenediamine in Example 59 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 59 to obtain a foamy intermediate (Int -34).
  • Step 2 4- (2-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) ethoxy) -N- (2-amino-4-fluorophenyl) benzamide (compound I-62)
  • Example 63 Determination of the inhibitory activity of the compound on histone deacetylase HDAC.
  • the specific operation method is as follows:
  • the compound to be tested is formulated into a corresponding DMSO solution at a concentration of 10 mM, and then diluted with DMSO to 1 mM, followed by a 3-fold gradient dilution at 10 concentration points;
  • LGK (Ac) -AMC Gill Biochemical
  • HDAC6 activity the final concentration of LGK (Ac) -AMC is 11 ⁇ M, and the final concentration of Trypsin is 0.01 ⁇ M;
  • step (6) Add 15 ⁇ L of the enzyme solution prepared in step (4) to each well of the test 384-well plate, add 15 ⁇ L of the buffer in step (1) to the low control group, centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 15 minutes;
  • Example 64 Determination of the A2A receptor binding activity of the compounds of the invention.
  • the compounds were tested for human A2A receptor binding activity using competitive binding experiments based on radioisotope ligands.
  • the specific operation method is as follows:
  • test compound is formulated into a DMSO solution with a corresponding concentration of 10 mM. Then dilute with buffer to 10 ⁇ M, then dilute with buffer 3 times, 10 concentration points;
  • Example 65 Determination of the functional activity of the compounds of the invention on the A2A receptor.
  • the activity of the compound on the human A2A receptor function test was measured using the cAMP test (Perkin Elmer) based on HTRF.
  • the specific operation method is as follows:
  • Example 66 Test of compounds of the present invention for inhibiting tumor cell proliferation activity.
  • the compound's activity in inhibiting the proliferation of tumor cells was determined using HCT-116, HL-60, and B16F10 cells.
  • HCT-116 and B16F10 cells were discarded from the culture medium and digested with trypsin. After digestion, they were neutralized with serum-containing medium, and the cells were pipetted to make the cells fall off. Pipette the cell suspension into a centrifuge tube and centrifuge at 800-1000rmp for 3-5 minutes. HL-60 cells were pipetted into the centrifuge tube, and centrifuged at 800-1000rmp for 3-5 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are a triazolo cycle compound, a preparation method therefor, an intermediate thereof and an application thereof. Furthermore, the triazolo cycle compound in the present invention can simultaneously have the antagonistic activity of an A2A adenosine receptor and the inhibitory activity of a histone deacetylase (HDAC), and therefore can be used for treating diseases such as tumor and central nervous system diseases.

Description

三唑并环类化合物、其制备方法、中间体和应用Triazolo ring compound, its preparation method, intermediate and application
本申请要求申请日为2018/11/22的中国专利申请201811397796.3的优先权。本申请引用上述中国专利申请的全文。This application requires the priority of Chinese patent application 201811397796.3 with an application date of 2018/11/22. This application cites the entire text of the aforementioned Chinese patent application.
技术领域Technical field
本发明涉及一种三唑并环类化合物，其制备方法、中间体和应用。The invention relates to a triazolo ring compound, its preparation method, intermediate and application.
背景技术Background technique
腺苷是一种内源性的嘌呤核苷类物质，它主要通过与细胞膜上的腺苷受体(adenosine receptors，AR)结合而发挥其生理调节功能。腺苷受体属于G蛋白偶联受体(GPCR，或七次跨膜受体，7TMR)，分为A1、A2A、A2B和A3共4个亚型，其中A2A受体在中枢神经及外周均有广泛分布。A2A受体在中枢神经呈高密度分布并与多种退行性中枢神经系统疾病如帕金森氏症、阿尔茨海默氏病和亨廷顿氏舞蹈病等的发病过程均有着密切的联系(Gomes et al.,Biochimica et Biophysica Acta,2011,1808,1380-1399)。例如在帕金森氏症中，A2A受体在黑质纹状体中高度表达并可以与多巴胺D2受体共定位并形成异源二聚体，A2A受体被腺苷激活后会抑制多巴胺D2受体的信号传导(Shook and Jackson,ACS Chemical Neuroscience,2011,2,555-567)。因此，A2A受体拮抗剂可增强D2受体的下游信号，作为治疗帕金森症的药物。A2A受体拮抗剂作为帕金森氏症的治疗药物还能够减轻由左旋多巴(L-DOPA)诱导的运动障碍副作用。目前已有多种不同结构类型的A2A受体的小分子拮抗剂如ZM-241385,SCH58261,preladenant(SCH-420814),tozadenant(SYN-115),vipadenant(BIIB-014)等被报导并用于治疗帕金森氏症的研究(Pinna,CNS Drugs,2014,28,455-474)。伊曲茶碱(istradefylline，KW-6002)于2013年在日本获批上市，作为辅助药物与左旋多巴联用治疗帕金森氏症。虽然大部分的A2A抑制剂作为单药治疗帕金森氏症的临床试验效果不佳，但A2A受体拮抗剂治疗相关退行性中枢中枢神经系统疾病药物的潜力已经得到初步证实。Adenosine is an endogenous purine nucleoside substance, which mainly exerts its physiological regulation function by combining with adenosine receptors (AR) on the cell membrane. Adenosine receptors belong to G protein-coupled receptors (GPCR, or seven transmembrane receptors, 7TMR), and are divided into 4 subtypes: A1, A2A, A2B, and A3. A2A receptors are located in the central nervous system and the periphery There are widely distributed. A2A receptors are distributed at a high density in the central nervous system and are closely related to the pathogenesis of various degenerative central nervous system diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease (Gomes) ., Biochimica Biophysica Acta, 2011, 1808, 1380-1399). For example, in Parkinson's disease, the A2A receptor is highly expressed in the nigrostriatal and can co-localize with the dopamine D2 receptor and form a heterodimer. The A2A receptor is activated by adenosine and inhibits the dopamine D2 receptor. Signal transduction of the body (Shook and Jackson, ACS Chemical Science, 2011, 2, 555-567). Therefore, A2A receptor antagonists can enhance the downstream signal of D2 receptors as a drug for the treatment of Parkinson's disease. A2A receptor antagonists, as therapeutic drugs for Parkinson's disease, can also reduce the side effects of dyskinesia induced by levodopa (L-DOPA). There are many different types of small molecule antagonists of A2A receptors such as ZM-241385, SCH58261, preladenant (SCH-420814), tozadenant (SYN-115), vipadenant (BIIB-014), etc. have been reported and used for treatment Research on Parkinson's disease (Pinna, CNS Drugs, 2014, 28, 455-474). Itratheline (istradefylline, KW-6002) was approved for marketing in Japan in 2013 and is used as an adjunct drug in combination with levodopa to treat Parkinson's disease. Although most A2A inhibitors are not effective as single agents in the clinical trials of Parkinson's disease, the potential of A2A receptor antagonists for the treatment of degenerative central nervous system diseases has been initially confirmed.
Figure PCTCN2019120284-appb-000001
Figure PCTCN2019120284-appb-000001
2006年，Sitkovsky研究组报道了腺苷通过激动A2A受体，能够抑制肿瘤微环境中T细胞对于肿瘤细胞的攻击(Ohta et al.,PNAS,2006,103,13132-13137)。因此，A2A受体作为一个肿瘤免疫治疗的靶点近年受到了很多关注。虽然目前的肿瘤免疫疗法对于特定癌症类型的治疗取得了非常好的效果，多个药物如靶向PD-1或PD-L1的抗体药物Keytruda,Opdivo和Tecentriq，靶向CTLA4的抗体药物Yervoy等均已获批在美国上市(Hoos,Nature Reviews Drug Discovery,2016,15,235-247)，但由于肿瘤微环境中存在着多种免疫抑制机制，这些药物的有效率仍然较低，开发新的肿瘤免疫药物仍然迫在眉睫。嘌呤能信号通路在肿瘤的多种免疫抑制机制中发挥着重要的作用(Vijayan et al.,Nature Reviews Cancer,2017,17,709-724)，肿瘤微环境中腺苷对于机体免疫功能的抑制使得干预这一信号通路成为肿瘤免疫治疗的一种新方案。作用机制上，肿瘤缺氧的微环境限制了能量的利用并诱导了胞外ATP的聚集，ATP可由核苷酸酶CD39和CD73水解转化为腺苷，从而使肿瘤外围的腺苷水平显著增高。腺苷与腺苷A1、A2A、A2B和A3受体结合可激活受体进而并发挥不同的调节功能，其中A2A受体在肿瘤的免疫抑制过程中发挥着主要的作用，腺苷与免疫细胞表面的A2A受体结合可抑制这些细胞的免疫功能。因此，抑制A2A受体可显著增强免疫细胞的功能并促进免疫细胞向肿瘤组织的浸润，有利于发挥其抗肿瘤作用。已知的一些A2A受体拮抗剂如vipadenant,CPI-444,PBF-509和AZD4635等已作为肿瘤免疫治疗的药物已经进入临床研究。这些药物大部分是与其它肿瘤免疫药物或抗肿瘤药物联用以发挥作用。In 2006, the Sitkovsky research group reported that adenosine can inhibit the attack of T cells on tumor cells in the tumor microenvironment by activating the A2A receptor (Ohta et al., PNAS, 2006, 103, 13132-13137). Therefore, A2A receptors have received much attention as a target for tumor immunotherapy in recent years. Although the current tumor immunotherapy has achieved very good results for the treatment of specific cancer types, multiple drugs such as the antibody drugs Keytruda, Opdivo and Tecentriq targeting PD-1 or PD-L1, and the antibody drug Yervoy targeting CTLA4 are all Has been approved for listing in the United States (Hoos, Nature Reviews Drug Discovery, 2016, 15, 235-247), but due to the existence of multiple immunosuppressive mechanisms in the tumor microenvironment, the effectiveness of these drugs is still low, and new tumor immune drugs are being developed Still imminent. The purinergic signaling pathway plays an important role in various immunosuppressive mechanisms of tumors (Vijayan et al., Nature Reviews Cancer, 2017, 17, 709-724). The suppression of the body's immune function by adenosine in the tumor microenvironment makes the intervention of this A signaling pathway has become a new approach to tumor immunotherapy. In terms of mechanism of action, the tumor's hypoxic microenvironment limits the use of energy and induces the accumulation of extracellular ATP. ATP can be hydrolyzed and converted into adenosine by nucleotidase CD39 and CD73, thereby significantly increasing the level of adenosine around the tumor. Adenosine and adenosine A1, A2A, A2B and A3 receptors can activate the receptors and play different regulatory functions. Among them, A2A receptors play a major role in the tumor immunosuppression process. Adenosine and immune cell surface The binding of A2A receptor can suppress the immune function of these cells. Therefore, inhibiting the A2A receptor can significantly enhance the function of immune cells and promote the infiltration of immune cells into tumor tissue, which is beneficial to exert its anti-tumor effect. Some known A2A receptor antagonists such as vipadenant, CPI-444, PBF-509, and AZD4635 have entered clinical research as tumor immunotherapy drugs. Most of these drugs are used in combination with other tumor immune drugs or anti-tumor drugs.
另一方面，组蛋白去乙酰化酶(histone deacetylases,HDACs)是另一个与肿瘤和退行性中枢神经系统疾病均密切相关的药物靶点。HDAC与组蛋白乙酰基转移酶(histone acetyltransferases,HATs)是两个调控表观遗传学的关键酶，它们共同调节染色体组蛋白的乙酰化状态，并在这个过程中发挥着相反的作用。HAT可以催化组蛋白N端的赖氨酸残基乙酰化，使染色质处于一个相对松散开放的状态，利于转录因子接近DNA而促进特定基因的表达；而HDAC的功能则是催化脱去该组蛋白赖氨酸残基上的乙酰基，使染色 质处于一个紧致的构象，从而阻断DNA的转录和特定基因的表达(Kazantsev and Thompson,Nature Reviews Drug Discovery,2008,7,854-868)。目前已发现的人源HDAC共有18个亚型，可分为Class I-IV四个亚家族。Class I包括HDAC 1、2、3和8；Class II又分为Class IIa(HDAC 4、5、7和9)和Class IIb(HDAC 6和10)；Class IV只有一个成员HDAC 11。以上三个亚族均是Zn 2+依赖性的HDACs，又被称为经典的HDAC。而Class III又被称为sirtuins，包括SIRT 1-7，依赖NAD +发挥催化活性。 On the other hand, histone deacetylases (HDACs) are another drug targets closely related to tumors and degenerative central nervous system diseases. HDAC and histone acetyltransferases (HATs) are two key enzymes that regulate epigenetics. They jointly regulate the acetylation status of chromosomal histones, and play the opposite role in this process. HAT can catalyze the acetylation of lysine residues at the N-terminus of histones, leaving chromatin in a relatively loose and open state, which facilitates the transcription factor close to DNA and promotes the expression of specific genes; HDAC's function is to catalyze the removal of the histone The acetyl group on the lysine residue puts chromatin in a compact conformation, thereby blocking the transcription of DNA and the expression of specific genes (Kazantsev and Thompson, Nature Reviews Drug Discovery, 2008, 7,854-868). At present, there are 18 subtypes of human HDACs, which can be divided into four subfamilies of Class I-IV. Class I includes HDAC 1, 2, 3 and 8; Class II is divided into Class IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10); Class IV has only one member, HDAC 11. The above three subfamilies are all Zn 2+ dependent HDACs, also known as classic HDAC. Class III, also known as sirtuins, including SIRT 1-7, relies on NAD + to exert catalytic activity.
目前，抗肿瘤是HDAC抑制剂最为重要和广泛的应用。HDAC的过度表达会抑制一系列抑癌基因的表达进而促进肿瘤细胞的生长，如HDAC功能异常可导致细胞周期抑制因子p21的表达下降，而使细胞周期阻滞；还会通过调节p53蛋白的去乙酰化而阻断其与DNA的结合进而阻断凋亡基因的转录，此外，HDAC与肿瘤组织的血管形成、调节免疫细胞功能等也均有关系(Falkenberg and Johnstone,Nature Reviews Drug Discovery,2014,13,673-691)。鉴于HDAC抑制剂在抑制肿瘤增殖方面所展现出来的巨大潜力，使其作为抗肿瘤药物的研究和应用受到了广泛的关注(Zagni et al.,Medicinal Research Reviews,2017,37,1373-1428)，目前已有四个HDAC抑制剂(vorinostat/SAHA、romidepsin/FK228、belinostat/PDX-101、panobinostat/LBH-589)被美国FDA批准上市用于T细胞淋巴瘤等肿瘤的治疗，另一个HDAC抑制剂西达本胺(Chidamid)也在中国获批上市用于治疗外周T细胞淋巴瘤。此外，还有数个HDAC抑制剂如abexinostat/PCI024781、givinostat/ITF2375、entinostat/MS-275等正处于不同阶段的临床研究中。At present, anti-tumor is the most important and widely used HDAC inhibitor. Over-expression of HDAC will inhibit the expression of a series of tumor suppressor genes and promote the growth of tumor cells. For example, abnormal HDAC function can lead to a decrease in the expression of the cell cycle inhibitor p21 and block the cell cycle; Acetylation blocks its binding to DNA and blocks the transcription of apoptotic genes. In addition, HDAC is also related to tumor blood vessel formation and regulating immune cell function (Falkenberg and Johnstone, Nature ReviewsDrug Discovery, 2014, 13,673-691). In view of the huge potential of HDAC inhibitors in inhibiting tumor proliferation, their research and application as anti-tumor drugs have received extensive attention (Zagni et al., Medicinal Research Reviews, 2017, 37, 1373-1428), There are currently four HDAC inhibitors (vorinostat / SAHA, romidepsin / FK228, belinostat / PDX-101, panobinostat / LBH-589) approved by the US FDA for the treatment of T cell lymphoma and other tumors, and another HDAC inhibitor Chidamid (Chidamid) is also approved in China for the treatment of peripheral T-cell lymphoma. In addition, there are several HDAC inhibitors such as abexinostat / PCI024781, givinostat / ITF2375, entinostat / MS-275, etc. which are in different stages of clinical research.
Figure PCTCN2019120284-appb-000002
Figure PCTCN2019120284-appb-000002
除了在抗肿瘤方面的应用，HDAC抑制剂在神经系统疾病领域如阿尔茨海默氏病、帕金森氏症、亨廷顿氏舞蹈病等中的应用同样也受到了越来越多的关注(Falkenberg and Johnstone,Nature Reviews Drug Discovery,2014,13,673-691)。例如，实验证明HDAC2可以调节脑功能、神经系统发展及恶化；HDAC2的过度表达可负调节突触的可塑性和数量以及树突棘密度，进而导致学习认知功能的退化(Guan et al.,Nature,2009,459,55-60)。又如，HDAC6可以调节tau蛋白的磷酸化水平，进而影响tau蛋白驱动的神经疾病的发展(Selenica et al.,Alzheimer's Research&Therapy,2014,6,12)。HDAC6还可以通过调控蛋白的聚集及HSP90的功能来调节错误折叠蛋白的降解，而错误折叠蛋白的积累则是阿尔茨海默氏病、帕金森氏症、亨廷顿氏舞蹈病等多种神经性疾病的病理特征。目前已有 文献证实HDAC抑制剂可以对神经系统疾病起到治疗效果，如SAHA在动物模型中可以显著改善认知(Guan et al.,Nature,2009,459,55-60)，LBH-589在动物模型中能够通过抑制HDAC功能逆转亨廷顿氏舞蹈症的症状(Siebzehnrübl et al.,PNAS,2018,doi/10.1073/pnas.1807962115)。In addition to its application in anti-tumor, the application of HDAC inhibitors in the field of nervous system diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease also received more and more attention (Falkenberg and Johnstone, Nature, Reviews, Discovery, 2014, 13, 673-691). For example, experiments show that HDAC2 can regulate brain function, nervous system development and deterioration; overexpression of HDAC2 can negatively regulate the plasticity and number of synapses and dendritic spine density, which in turn leads to the deterioration of learning and cognitive function , 2009,459,55-60). As another example, HDAC6 can regulate the phosphorylation level of tau protein, which in turn affects the development of tau protein-driven neurological diseases (Selenica et al., Alzheimer's Research & Therapy, 2014, 6, 12). HDAC6 can also regulate the degradation of misfolded proteins by regulating protein aggregation and HSP90 function, and the accumulation of misfolded proteins is a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease Pathological features. At present, there are literatures confirming that HDAC inhibitors can have a therapeutic effect on neurological diseases. For example, SAHA can significantly improve cognition in animal models (Guan et al., Nature, 2009, 459, 55-60), LBH-589 in In animal models, the symptoms of Huntington's chorea can be reversed by inhibiting HDAC function (Siebzehnrübl et al., PNAS, 2018, doi / 10.1073 / pnas.1807962115).
鉴于A2A受体和HDAC与肿瘤及多种中枢神经系统疾病均有着密切的联系，二者的协同使用极有可能在相关疾病的治疗中发挥出更强效的治疗效果。目前，虽然分别基于A2A受体拮抗剂和HDAC抑制剂的双靶点小分子药物均有报导，例如A2A受体与多巴胺D2受体的双靶点化合物(
Figure PCTCN2019120284-appb-000003
et al.,J Med Chem,2015,58,718-738)，HDAC与cyclin-dependent kinase 4/9(CDK4/9)的双靶点化合物(Li et al.,J Med Chem,2018,61,3166-3192)、HDAC与nicotinamide phosphoribosyltransferase(NAMPT)的双靶点化合物(Dong et al.,J Med Chem,2017,60,7965-7983)，但同时靶向HDAC与A2A受体的双靶点小分子化合物却未见报导。 Given that A2A receptors and HDAC are closely related to tumors and various central nervous system diseases, the synergistic use of the two is likely to play a more powerful therapeutic effect in the treatment of related diseases. At present, although dual-target small molecule drugs based on A2A receptor antagonists and HDAC inhibitors have been reported, for example, dual-target compounds of A2A receptor and dopamine D2 receptor
Figure PCTCN2019120284-appb-000003
et al., J Med Chem, 2015, 58, 718-738), dual target compounds of HDAC and cyclin-dependent kinase 4/9 (CDK4 / 9) (Li et al., J Med Chem, 2018, 61,3166- 3192), dual-target compounds of HDAC and nicotinamide phosphoribosyltransferase (NAMPT) (Dong et al., J Med Chem, 2017, 60, 7965-7983), but also dual-target small molecule compounds targeting HDAC and A2A receptor No reports.
发明内容Summary of the invention
本发明所要解决的技术问题是提供一种三唑并环类化合物、其制备方法、中间体和应用，本发明的三唑并环类化合物可以作为腺苷A2A受体拮抗剂或组蛋白去乙酰化酶HDAC抑制剂。进一步地，本发明的三唑并环类化合物可以同时具有腺苷A2A受体拮抗活性和组蛋白去乙酰化酶HDAC抑制活性，从而可以用于治疗肿瘤和中枢神经系统疾病等相关疾病。The technical problem to be solved by the present invention is to provide a triazolocyclic compound, its preparation method, intermediate and application. The triazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylation HDAC inhibitor. Further, the triazolocyclic compounds of the present invention can have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity, and thus can be used to treat tumors and central nervous system diseases and other related diseases.
本发明提供了一种如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体：The present invention provides a compound represented by formula I or I ', pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, and solvates , Metabolites or prodrugs:
Figure PCTCN2019120284-appb-000004
Figure PCTCN2019120284-appb-000004
Figure PCTCN2019120284-appb-000005
Figure PCTCN2019120284-appb-000005
其中，among them,
R 1和R 2各自独立地为氢、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 10环烷基(例如C 3-C 6环烷基)、C 6-C 12芳基、5-12元杂芳基或-C(＝O)-R 7；或者，R 1、R 2和与其相连的氮原子一起共同形成3-10元杂环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl (eg, C 3 -C 6 cycloalkyl), C 6 -C 12 aryl, 5-12 membered heteroaryl or -C (= O) -R 7 ; alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl;
R 7为C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(6-12元芳基)或-(C 1-C 3亚烷基)-(5-12元杂芳基)； R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
R 3为取代或未取代的C 6-C 12芳基(如苯基)或取代或未取代的5-12元杂芳基(如5、6或7元杂芳基，又如呋喃基，再如
Figure PCTCN2019120284-appb-000006
)；所述的取代的C 6-C 12芳基或取代的5-12元杂芳基是指其被一个或多个R 19取代，每个R 19独立地为卤素(例如氟)、C 1-C 6烷基(如C 1-C 4烷基，又如甲基)、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 3-C 6环烷基； R 3 is a substituted or unsubstituted C 6 -C 12 aryl group (such as phenyl) or a substituted or unsubstituted 5-12 membered heteroaryl group (such as 5, 6 or 7 membered heteroaryl group, such as furanyl, Again
Figure PCTCN2019120284-appb-000006
); The substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl means that it is substituted with one or more R 19 , each R 19 is independently halogen (for example, fluorine), C 1 -C 6 alkyl (such as C 1 -C 4 alkyl or methyl), C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
X为N或CR 4； X is N or CR 4 ;
R 4为氢、氟或C 1-C 3烷基； R 4 is hydrogen, fluorine or C 1 -C 3 alkyl;
Y为
Figure PCTCN2019120284-appb-000007
或取代或未取代的
Figure PCTCN2019120284-appb-000008
中的氮原子与
Figure PCTCN2019120284-appb-000009
相连)；所述的
Figure PCTCN2019120284-appb-000010
为3-10元亚杂环烷基(如3-8元亚杂环烷基)；所述的取代的
Figure PCTCN2019120284-appb-000011
是指其被一个或多个R 20取代； Y is
Figure PCTCN2019120284-appb-000007
Or substituted or unsubstituted
Figure PCTCN2019120284-appb-000008
The nitrogen atom in
Figure PCTCN2019120284-appb-000009
Connected); said
Figure PCTCN2019120284-appb-000010
Is a 3-10 membered heterocycloalkylene (eg 3-8 membered heterocycloalkylene); the substituted
Figure PCTCN2019120284-appb-000011
Means it is replaced by one or more R 20 ;
R 5为氢、C 1-C 6烷基(如C 1-C 4烷基，又如甲基或乙基)、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(C 3-C 6环烷基)、C 2-C 6烯基或C 2-C 6炔基； R 5 is hydrogen, C 1 -C 6 alkyl (such as C 1 -C 4 alkyl, such as methyl or ethyl), C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene )-(C 3 -C 6 cycloalkyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
或者，R 5与R 4以及它们连接的原子一起共同形成
Figure PCTCN2019120284-appb-000012
Or, R 5 and R 4 together with the atoms to which they are attached together form
Figure PCTCN2019120284-appb-000012
每个L独立地为如下情形(i)、(ii)、(iii)、(iv)或(v)：Each L is independently the following case (i), (ii), (iii), (iv) or (v):
(i)L为取代或未取代的-M 1-，M 1为-NH-、-O-、-S-、单键、C 1-C 10亚烷基(例如C 1-C 7亚烷基，又如C 5亚烷基、C 6亚烷基或C 7亚烷基)、C 2-C 10亚烯基(例如C 2-C 7亚烯基，又如C 5、C 6或C 7亚烯基)、C 2-C 10亚炔基(例如C 5-C 7亚炔基)、具有2-10个链原子的亚杂烷基(例如具有2-7个链原子的亚杂烷基，又如具有5、6或7个链原子的亚杂烷基)、具有2-10个链原子的亚杂烯基(例如具有2-7个链原子的亚杂烯基，又如具有5、6或7个原子的亚杂烯基)或具有3-10个链原子的亚杂炔基(例如具有5、6或7个链原子的亚杂炔基)；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene (for example, C 1 -C 7 alkylene Groups, such as C 5 alkylene, C 6 alkylene or C 7 alkylene), C 2 -C 10 alkenylene (eg C 2 -C 7 alkenylene, such as C 5 , C 6 or C 7 alkenylene), C 2 -C 10 alkynylene (e.g. C 5 -C 7 alkynylene), heteroalkylene having 2-10 chain atoms (e.g. having 2-7 chain atoms Heteroalkyl groups, such as heteroalkylene groups having 5, 6 or 7 chain atoms), heteroalkenylene groups having 2-10 chain atoms (eg, heteroalkenylene groups having 2-7 chain atoms, and Such as heteroalkenylene having 5, 6 or 7 atoms) or heteroalkynylene having 3-10 chain atoms (eg heteroalkynylene having 5, 6 or 7 chain atoms); -M 1 -means that it is substituted by one or more R 21 ;
(ii)L为取代或未取代的-M 2-M 3-，M 2为-NH-、-O-、-S-、单键、C 1-C 6亚烷基(例如C 1-C 4亚烷基，又如亚甲基、亚乙基或亚丙基)、具有2-6个链原子的亚杂烷基(例如具有2或3个链原子的亚杂烷基，例如
Figure PCTCN2019120284-appb-000013
又如
Figure PCTCN2019120284-appb-000014
例如
Figure PCTCN2019120284-appb-000015
)、“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”(所述的“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”中的C 1-C 6亚烷基可以为C 2-C 3亚烷基；例如
Figure PCTCN2019120284-appb-000016
又如
Figure PCTCN2019120284-appb-000017
)；M 3为C 6-C 12亚芳基(例如亚苯基，又如1,4-亚苯基)或5-12元亚杂芳基(例如5、6或7元亚杂芳基，又如1,4-(6元亚杂芳基)，再如
Figure PCTCN2019120284-appb-000018
)；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene (eg C 1 -C 4 alkylene, such as methylene, ethylene or propylene), heteroalkylene having 2-6 chain atoms (eg heteroalkylene having 2 or 3 chain atoms, for example
Figure PCTCN2019120284-appb-000013
Another example
Figure PCTCN2019120284-appb-000014
E.g
Figure PCTCN2019120284-appb-000015
), " 1 carbon atom in the C 1 -C 6 alkylene group is independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC ( = O)-group replaced after the formation of the group "(the" C 1 -C 6 alkylene group 1 carbon atom is independently selected -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups replace the group formed later ", the C 1 -C 6 alkylene group may be C 2 -C 3 alkylene group ;E.g
Figure PCTCN2019120284-appb-000016
Another example
Figure PCTCN2019120284-appb-000017
); M 3 is C 6 -C 12 arylene (eg phenylene, such as 1,4-phenylene) or 5-12 membered heteroarylene (eg 5, 6 or 7 membered heteroarylene) , As in 1,4- (6-membered heteroarylene), as in
Figure PCTCN2019120284-appb-000018
); The substituted -M 2 -M 3 -means that it is substituted by one or more R 22 ;
(iii)L为取代或未取代的-M 4-M 5-M 6-，M 4为-NH-、-O-、-S-、单键、C 1-C 6亚烷基(例如亚甲基、亚乙基或亚丙基，又如亚甲基或亚乙基)或具有2-6个链原子的亚杂烷基(例如具有2、3或4个原子的亚杂烷基，又如具有2个原子的亚杂烷基)；M 5为C 6-C 12亚芳基(例如亚苯基，又如1,4-亚苯基)或5-12元亚杂芳基(例如5、6或7元亚杂芳 基，又如1,4-(6元亚杂芳基)，再如
Figure PCTCN2019120284-appb-000019
)；M 6为C 1-C 9亚烷基(例如C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或C 6亚烷基)、具有2-9个链原子的亚杂烷基(例如具有2、3、4、5或6个原子的亚杂烷基；又如-U 1-U 2-，其中U 1为-NH-、-O-或-S-，U 2为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或具有2、3、4或5个链原子的亚杂烷基；再如
Figure PCTCN2019120284-appb-000020
“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团后代替形成的基团”(例如-W 1-W 2-，其中W 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，W 2为C 4亚烷基、C 5亚烷基、C 6亚烷基或C 7亚烷基；又如
Figure PCTCN2019120284-appb-000021
Figure PCTCN2019120284-appb-000022
)、“具有2-9个链原子的亚杂烷基中的1或2个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”(例如-V 1-V 2-，其中V 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，V 2为具有4、5、6或7个链原子的亚杂烷基)、C 2-C 9亚烯基(例如亚乙烯基，优选
Figure PCTCN2019120284-appb-000023
即反式构型的亚乙烯基)、C 2-C 9亚炔基或具有2-9个链原子的亚杂烯基；所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene (e.g. Methyl, ethylene or propylene, such as methylene or ethylene) or heteroalkylene having 2-6 chain atoms (eg heteroalkylene having 2, 3 or 4 atoms, Another example is a heteroalkylene group having 2 atoms); M 5 is a C 6 -C 12 arylene group (for example, phenylene, such as 1,4-phenylene) or a 5-12 membered heteroarylene group ( For example, 5, 6 or 7-membered heteroarylene, as in 1,4- (6-membered heteroarylene), and then
Figure PCTCN2019120284-appb-000019
); M 6 is C 1 -C 9 alkylene (eg C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or C 6 alkylene), having 2-9 Heteroalkylene groups of chain atoms (for example, heteroalkylene groups having 2, 3, 4, 5 or 6 atoms; another example is -U 1 -U 2 -where U 1 is -NH-, -O- or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or heteroalkylene having 2, 3, 4 or 5 chain atoms;
Figure PCTCN2019120284-appb-000020
" 1 , 2 or 3 carbon atoms in the C 1 -C 9 alkylene group are independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and- The NHC (= O)-group replaces the formed group "(e.g. -W 1 -W 2- , where W 1 is -C (= O) O-, -OC (= O)-, -C ( = O) NH- or -NHC (= O)-, W 2 is C 4 alkylene, C 5 alkylene, C 6 alkylene or C 7 alkylene;
Figure PCTCN2019120284-appb-000021
Figure PCTCN2019120284-appb-000022
), "1 or 2 carbon atoms in the heteroalkylene group having 2-9 chain atoms are independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups replace the groups formed later "(for example -V 1 -V 2- , where V 1 is -C (= O) O-, -OC (= O)- , -C (= O) NH- or -NHC (= O)-, V 2 is a heteroalkylene group having 4, 5, 6 or 7 chain atoms), C 2 -C 9 alkenylene (such as Vinyl, preferably
Figure PCTCN2019120284-appb-000023
Ie trans-vinylidene), C 2 -C 9 alkynylene or heteroalkenylene having 2-9 chain atoms; the substituted -M 4 -M 5 -M 6 -means It is replaced by one or more R 23 ;
(iv)L为取代或未取代的-M 7-M 8-M 9-，M 7为-NH-、-O-、-S-、C 1-C 4亚烷基(例如亚甲基或亚乙基，又如亚乙基)或具有2-4个链原子的亚杂烷基(例如具有2个链原子的亚杂烷基)，M 8为C 3-C 12亚环烷基(例如C 3-C 8亚环烷基，又如
Figure PCTCN2019120284-appb-000024
Figure PCTCN2019120284-appb-000025
)或3-12元亚杂环烷基(例如3-8元亚杂环烷基，又如
Figure PCTCN2019120284-appb-000026
Figure PCTCN2019120284-appb-000027
)，M 9为C 6-C 12亚芳基(例如亚苯基，又如1,4-亚苯基)或5-12元亚杂芳基(例如5、6或7元亚杂芳基，又如1,4-(6元亚杂芳基)，再如
Figure PCTCN2019120284-appb-000028
)；所述的取代的-M 7-M 8-M 9-是指 其被一个或多个R 24取代； (iv) L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene (eg methylene or Ethylene, such as ethylene) or a heteroalkylene group having 2-4 chain atoms (for example, a heteroalkylene group having 2 chain atoms), M 8 is C 3 -C 12 cycloalkylene ( For example, C 3 -C 8 cycloalkylene, like
Figure PCTCN2019120284-appb-000024
Figure PCTCN2019120284-appb-000025
) Or 3-12 membered heterocycloalkylene (eg 3-8 membered heterocycloalkylene
Figure PCTCN2019120284-appb-000026
Figure PCTCN2019120284-appb-000027
), M 9 is C 6 -C 12 arylene (eg phenylene, such as 1,4-phenylene) or 5-12 membered heteroarylene (eg 5, 6 or 7 membered heteroarylene) , As in 1,4- (6-membered heteroarylene), as in
Figure PCTCN2019120284-appb-000028
); The substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
(v)取代或未取代的-M 10-M 11-，其中M 10为亚甲基、亚乙基或亚丙基，M 11为
Figure PCTCN2019120284-appb-000029
Z 1、Z 2和Z 3各自独立地为CH或N；所述的取代的-M 10-M 11-是指其被一个或多个R 25取代； (v) substituted or unsubstituted -M 10 -M 11- , wherein M 10 is methylene, ethylene or propylene, and M 11 is
Figure PCTCN2019120284-appb-000029
Z 1 , Z 2 and Z 3 are each independently CH or N; the substituted -M 10 -M 11 -means that it is substituted with one or more R 25 ;
每个R 20、R 21、R 22、R 23、R 24和R 25各自独立地为卤素(例如氟或氯，又如氟)、羟基、C 1-C 6烷基(如C 1-C 3烷基)或C 1-C 6烷氧基(如C 1-C 3烷氧基)； Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are independently halogen (for example fluorine or chlorine, such as fluorine), hydroxy, C 1 -C 6 alkyl (for example C 1 -C 3 alkyl) or C 1 -C 6 alkoxy (such as C 1 -C 3 alkoxy);
所述的亚杂烷基、亚杂烯基、亚杂炔基、亚杂环烷基和亚杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个；The hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
ZBG为
Figure PCTCN2019120284-appb-000030
ZBG is
Figure PCTCN2019120284-appb-000030
R 10、R 11、R 12和R 13各自独立地为氢、卤素(例如氟)、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 12芳基或5-12元杂芳基(例如5、6或7元杂芳基，又如噻吩基，再如噻吩-2-基)； R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen (e.g. fluorine), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl (eg 5, 6 or 7 membered heteroaryl, like thienyl, and then Thiophen-2-yl);
所述的杂烷基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个。The hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
在一些实施方案中，如前所述的如式I或I’所示的化合物为如下结构：In some embodiments, the compound represented by Formula I or I 'as described above has the following structure:
Figure PCTCN2019120284-appb-000031
Figure PCTCN2019120284-appb-000031
其中，R 1和R 2各自独立地为氢、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 10环烷基、C 6-C 12芳基、5-12元杂芳基或-C(＝O)-R 7；或者，R 1、R 2和与其相连的氮原子一起共同形成3-10元杂环烷基； Wherein R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 6 -C 12 aryl, 5-12 Member heteroaryl or -C (= O) -R 7 ; or, R 1 and R 2 together with the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl;
R 7为C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(6-12元芳基)或-(C 1-C 3亚烷基)-(5-12元杂芳基)； R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
R 3为取代或未取代的C 6-C 12芳基或取代或未取代的5-12元杂芳基；所述的取代的 C 6-C 12芳基或取代的5-12元杂芳基是指其被一个或多个R 19取代，每个R 19独立地为卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 3-C 6环烷基； R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
X为N或CR 4； X is N or CR 4 ;
R 4为氢、氟或C 1-C 3烷基； R 4 is hydrogen, fluorine or C 1 -C 3 alkyl;
Y为
Figure PCTCN2019120284-appb-000032
或取代或未取代的
Figure PCTCN2019120284-appb-000033
所述的
Figure PCTCN2019120284-appb-000034
为3-10元亚杂环烷基；所述的取代的
Figure PCTCN2019120284-appb-000035
是指其被一个或多个R 20取代； Y is
Figure PCTCN2019120284-appb-000032
Or substituted or unsubstituted
Figure PCTCN2019120284-appb-000033
Said
Figure PCTCN2019120284-appb-000034
Is a 3-10 membered heterocycloalkylene; the substituted
Figure PCTCN2019120284-appb-000035
Means it is replaced by one or more R 20 ;
R 5为氢、C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(C 3-C 6环烷基)、C 2-C 6烯基或C 2-C 6炔基； R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), C 2 -C 6 Alkenyl or C 2 -C 6 alkynyl;
L为如下情形(i)、(ii)、(iii)或(iv)：L is the following case (i), (ii), (iii) or (iv):
(i)L为取代或未取代的-M 1-，M 1为-NH-、-O-、-S-、单键、C 1-C 10亚烷基、C 2-C 10亚烯基、C 2-C 10亚炔基、具有2-10个链原子的亚杂烷基、具有2-10个链原子的亚杂烯基或具有3-10个链原子的亚杂炔基；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene , C 2 -C 10 alkynylene, heteroalkylene having 2-10 chain atoms, heteroalkenylene having 2-10 chain atoms or heteroalkynylene having 3-10 chain atoms; The substituted -M 1 -refers to its substitution by one or more R 21 ;
(ii)L为取代或未取代的-M 2-M 3-，M 2为-NH-、-O-、-S-、单键、C 1-C 6亚烷基、具有2-6个链原子的亚杂烷基、“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”；M 3为C 6-C 12亚芳基或5-12元亚杂芳基；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene, having 2-6 heteroalkylene chain atoms, "C 1 -C 6 alkylene in which one carbon atom is independently selected from -C (= O) O -, - OC (= O) -, - C (= O) NH- and -NHC (= O)-groups replace the group formed "; M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene; the substituted -M 2 -M 3 -means that it is replaced by one or more R 22 ;
(iii)L为取代或未取代的-M 4-M 5-M 6-，M 4为-NH-、-O-、-S-、单键、C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基；M 5为C 6-C 12亚芳基或5-12元亚杂芳基；M 6为C 1-C 9亚烷基、具有2-9个链原子的亚杂烷基、“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-的基团后代替形成的基团”、“具有2-9个链原子的亚杂烷基中的1或2个链原子被独立选自-C(＝O)-、-C(＝O)O-和-C(＝O)NH-的基团代替后形成的基团”、C 2-C 9亚炔基或具有2-9个链原子的亚杂烯基；所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene group or having 2 -6 chain atoms of heteroalkylene; M 5 is C 6 -C 12 arylene or 5-12 membered heteroarylene; M 6 is C 1 -C 9 alkylene with 2-9 chains heteroalkylene atoms, "C 1 -C 9 alkylene group of 2 or 3 carbon atoms are independently selected from -C (= O) O -, - OC (= O) -, - C ( = O) NH- or -NHC (= O)-group after replacing the formed group "," 1 or 2 chain atoms in the heteroalkylene group having 2-9 chain atoms are independently selected from C (= O)-, -C (= O) O- and -C (= O) NH- groups replace the group formed later ", C 2 -C 9 alkynylene group or have 2-9 chains Atomic heteroalkenylene; said substituted -M 4 -M 5 -M 6 -means that it is substituted with one or more R 23 ;
(iv)L为取代或未取代的-M 7-M 8-M 9-，M 7为-NH-、-O-、-S-、C 1-C 4亚烷基或具有2-4个链原子的亚杂烷基，M 8为C 3-C 12亚环烷基或3-12元亚杂环烷基，M 9为C 6-C 12亚芳基或5-12元亚杂芳基；所述的取代的-M 7-M 8-M 9-是指其被一个或多个R 24取代； (iv) L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene or has 2-4 Heteroalkylene group of chain atom, M 8 is C 3 -C 12 cycloalkylene group or 3-12 membered heterocycloalkylene group, M 9 is C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical; the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
每个R 20、R 21、R 22、R 23和R 24各自独立地为卤素、羟基、C 1-C 6烷基或C 1-C 6烷氧基； Each R 20 , R 21 , R 22 , R 23 and R 24 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
所述的亚杂烷基、亚杂烯基、亚杂炔基、亚杂环烷基和亚杂芳基中的杂原子各自独 立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个；The hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
ZBG为
Figure PCTCN2019120284-appb-000036
ZBG is
Figure PCTCN2019120284-appb-000036
R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 12芳基或5-12元杂芳基； R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
所述的杂烷基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个。The hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
在一些实施方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000037
时，所述的
Figure PCTCN2019120284-appb-000038
可以为
Figure PCTCN2019120284-appb-000039
Figure PCTCN2019120284-appb-000040
In some embodiments, in the compound represented by formula I or I ′ as described in any of the preceding schemes, when Y is
Figure PCTCN2019120284-appb-000037
At the time
Figure PCTCN2019120284-appb-000038
Can be
Figure PCTCN2019120284-appb-000039
Figure PCTCN2019120284-appb-000040
在一些实施方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000041
时，所述的
Figure PCTCN2019120284-appb-000042
为
Figure PCTCN2019120284-appb-000043
Figure PCTCN2019120284-appb-000044
In some embodiments, in the compound represented by formula I or I ′ as described in any of the preceding schemes, when Y is
Figure PCTCN2019120284-appb-000041
At the time
Figure PCTCN2019120284-appb-000042
for
Figure PCTCN2019120284-appb-000043
Figure PCTCN2019120284-appb-000044
在一些实施方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000045
时，所述的
Figure PCTCN2019120284-appb-000046
为
Figure PCTCN2019120284-appb-000047
In some embodiments, in the compound represented by formula I or I ′ as described in any of the preceding schemes, when Y is
Figure PCTCN2019120284-appb-000045
At the time
Figure PCTCN2019120284-appb-000046
for
Figure PCTCN2019120284-appb-000047
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 1和R 2为氢。 In some embodiments of the present invention, in the compound represented by Formula I or I ′ as described in any of the foregoing embodiments, R 1 and R 2 are hydrogen.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 4为氢。 In some embodiments of the present invention, in the compound represented by Formula I or I ′ as described in any one of the preceding embodiments, R 4 is hydrogen.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，X为 N或CH，优选为N。In some embodiments of the present invention, in the compound represented by formula I or I 'as described in any one of the preceding embodiments, X is N or CH, preferably N.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 3为取代或未取代的C 6-C 12芳基或取代或未取代的5-12元杂芳基；所述的取代的C 6-C 12芳基或取代的5-12元杂芳基中的取代基独立地为C 1-C 6烷基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any one of the foregoing embodiments, R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5 -12 membered heteroaryl; the substituent in the substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl is independently C 1 -C 6 alkyl.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 3为取代或未取代的
Figure PCTCN2019120284-appb-000048
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, R 3 is substituted or unsubstituted
Figure PCTCN2019120284-appb-000048
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 3为取代或未取代的苯基或取代或未取代的
Figure PCTCN2019120284-appb-000049
取代基独立地为C 1-C 6烷基。 In some aspects of the present invention, in the compound represented by formula I or I ′ as described in any of the foregoing aspects, R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted
Figure PCTCN2019120284-appb-000049
The substituents are independently C 1 -C 6 alkyl.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 3为苯基、
Figure PCTCN2019120284-appb-000050
例如
Figure PCTCN2019120284-appb-000051
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the foregoing embodiments, R 3 is phenyl,
Figure PCTCN2019120284-appb-000050
E.g
Figure PCTCN2019120284-appb-000051
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，Y为
Figure PCTCN2019120284-appb-000052
R 5为氢或C 1-C 6烷基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, Y is
Figure PCTCN2019120284-appb-000052
R 5 is hydrogen or C 1 -C 6 alkyl.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，Y为
Figure PCTCN2019120284-appb-000053
R 5为氢、甲基或乙基，例如氢。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, Y is
Figure PCTCN2019120284-appb-000053
R 5 is hydrogen, methyl or ethyl, for example hydrogen.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，ZBG为
Figure PCTCN2019120284-appb-000054
R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 6-C 12芳基或5-12元杂芳基。在本发明的一些方案中，R 12为卤素，例如氟。在本发明的一些方案中，R 11为5-12元杂芳基，例如噻吩-2-基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any one of the preceding embodiments, ZBG is
Figure PCTCN2019120284-appb-000054
R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 6 -C 12 aryl or 5-12 membered heteroaryl. In some aspects of the invention, R 12 is halogen, such as fluorine. In some embodiments of the invention, R 11 is a 5-12 membered heteroaryl, such as thiophen-2-yl.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，ZBG 为
Figure PCTCN2019120284-appb-000055
例如
Figure PCTCN2019120284-appb-000056
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, ZBG is
Figure PCTCN2019120284-appb-000055
E.g
Figure PCTCN2019120284-appb-000056
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，ZBG为
Figure PCTCN2019120284-appb-000057
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any one of the preceding embodiments, ZBG is
Figure PCTCN2019120284-appb-000057
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，ZBG为
Figure PCTCN2019120284-appb-000058
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any one of the preceding embodiments, ZBG is
Figure PCTCN2019120284-appb-000058
在一些实施方案中，如前述任一方案所述的如式I或I’所示的化合物中，每个R 20、R 21、R 22、R 23、R 24和R 25各自独立地为C 1-C 6烷基。 In some embodiments, in the compound represented by formula I or I ′ as described in any one of the preceding schemes, each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently C 1 -C 6 alkyl.
在一些实施方案中，如前述任一方案所述的如式I或I’所示的化合物中，R 20、R 21、R 22、R 23、R 24或R 25的个数可以各自独立地为1、2、3、4、5、6或7个，例如1、2或3个，再如1个。 In some embodiments, in the compound represented by formula I or I ′ as described in any one of the preceding schemes, the number of R 20 , R 21 , R 22 , R 23 , R 24 or R 25 may each be independently 1, 2, 3, 4, 5, 6, or 7, such as 1, 2, or 3, and then another one.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000059
L为取代或未取代的-M 1-时，M 1为C 1-C 10亚烷基或具有2-10个链原子的亚杂烷基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000059
When L is a substituted or unsubstituted -M 1- , M 1 is a C 1 -C 10 alkylene group or a heteroalkylene group having 2 to 10 chain atoms.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000060
L为取代或未取代的-M 1-时，M 1为C 5亚烷基、C 6亚烷基、C 7亚烷基或具有5、6或7个原子的亚杂烷基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000060
When L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene, or heteroalkylene having 5, 6 or 7 atoms.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000061
L为取代或未取代的-M 1-时，M 1为C 5亚烷基、C 6亚烷基或C 7亚烷基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000061
When L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, or C 7 alkylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000062
L为取代或未取代的-M 2-M 3-时，M 2为C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基，M 3为C 6-C 12亚芳基或5-12元亚杂芳基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000062
When L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a C 1 -C 6 alkylene group or a heteroalkylene group having 2 to 6 chain atoms, and M 3 is a C 6 -C 12 subgroup Aryl or 5-12 membered heteroarylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000063
L为取代或未取代的-M 2-M 3-时，M 2为亚甲基、亚乙基、亚丙基或具有2或3个链原子的亚杂烷基，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y
Figure PCTCN2019120284-appb-000063
When L is substituted or unsubstituted -M 2 -M 3- , M 2 is methylene, ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms, and M 3 is 1,4 -Phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000064
L为取代或未取代的-M 2-M 3-时，M 2为亚乙基、亚丙基或具有2或3个链原子的亚杂烷基，M 3为1,4-亚苯基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000064
When L is a substituted or unsubstituted -M 2 -M 3- , M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms, and M 3 is 1,4-phenylene .
在本发明的一些方案中，当Y为
Figure PCTCN2019120284-appb-000065
L为取代或未取代的-M 2-M 3-时，M 2的定义如本发明中任一方案中所述，M 3为1,4-亚苯基。 In some aspects of the invention, when Y is
Figure PCTCN2019120284-appb-000065
When L is substituted or unsubstituted -M 2 -M 3- , the definition of M 2 is as described in any of the aspects of the present invention, and M 3 is 1,4-phenylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000066
L为取代或未取代的-M 2-M 3-时，M 2为亚甲基、亚乙基、亚丙基或
Figure PCTCN2019120284-appb-000067
M 3为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000066
When L is substituted or unsubstituted -M 2 -M 3- , M 2 is methylene, ethylene, propylene or
Figure PCTCN2019120284-appb-000067
M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000068
L为取代或未取代的-M 2-M 3-时，-M 2-M 3-为
Figure PCTCN2019120284-appb-000069
Figure PCTCN2019120284-appb-000070
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y
Figure PCTCN2019120284-appb-000068
When L is substituted or unsubstituted -M 2 -M 3- , -M 2 -M 3 -is
Figure PCTCN2019120284-appb-000069
Figure PCTCN2019120284-appb-000070
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000071
L为取代或未取代的-M 2-M 3-时，L为
Figure PCTCN2019120284-appb-000072
Figure PCTCN2019120284-appb-000073
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000071
When L is substituted or unsubstituted -M 2 -M 3- , L is
Figure PCTCN2019120284-appb-000072
Figure PCTCN2019120284-appb-000073
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为取代或未取代的
Figure PCTCN2019120284-appb-000074
L为取代或未取代的-M 2-M 3-时，M 2为C 1-C 6亚烷基、具有2-6个链原子的亚杂烷基或“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”；M 3为C 6-C 12亚芳基或5-12元亚杂芳基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is substituted
Figure PCTCN2019120284-appb-000074
When L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a C 1 -C 6 alkylene group, a heteroalkylene group having 2 to 6 chain atoms, or “C 1 -C 6 alkylene group Formed by replacing one carbon atom in a group independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)- "Group"; M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为取代或未取代的
Figure PCTCN2019120284-appb-000075
L为取代或未取代的-M 2-M 3-时，M 2为亚乙基、亚丙基或具有2或3个链原子的亚杂烷基、
Figure PCTCN2019120284-appb-000076
M 3为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is substituted or unsubstituted
Figure PCTCN2019120284-appb-000075
When L is substituted or unsubstituted -M 2 -M 3- , M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms,
Figure PCTCN2019120284-appb-000076
M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为取代或未取代的
Figure PCTCN2019120284-appb-000077
L为取代或未取代的-M 2-M 3-时，
Figure PCTCN2019120284-appb-000078
为
Figure PCTCN2019120284-appb-000079
Figure PCTCN2019120284-appb-000080
M 2为
Figure PCTCN2019120284-appb-000081
M 3为1,4-亚苯基或1,4-(6元亚杂芳基)； In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is substituted or unsubstituted
Figure PCTCN2019120284-appb-000077
When L is substituted or unsubstituted -M 2 -M 3- ,
Figure PCTCN2019120284-appb-000078
for
Figure PCTCN2019120284-appb-000079
Figure PCTCN2019120284-appb-000080
M 2 is
Figure PCTCN2019120284-appb-000081
M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
或者，
Figure PCTCN2019120284-appb-000082
为
Figure PCTCN2019120284-appb-000083
Figure PCTCN2019120284-appb-000084
M 2为亚乙基，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)； or,
Figure PCTCN2019120284-appb-000082
for
Figure PCTCN2019120284-appb-000083
Figure PCTCN2019120284-appb-000084
M 2 is ethylene and M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
或者，
Figure PCTCN2019120284-appb-000085
为
Figure PCTCN2019120284-appb-000086
M 2为亚丙基或具有3个链原子的亚杂烷基，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)。 or,
Figure PCTCN2019120284-appb-000085
for
Figure PCTCN2019120284-appb-000086
M 2 is propylene or a heteroalkylene group having 3 chain atoms, and M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为取代或未取代的
Figure PCTCN2019120284-appb-000087
L为取代或未取代的-M 2-M 3-时，
Figure PCTCN2019120284-appb-000088
为
Figure PCTCN2019120284-appb-000089
Figure PCTCN2019120284-appb-000090
-M 2-M 3-为
Figure PCTCN2019120284-appb-000091
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is substituted or unsubstituted
Figure PCTCN2019120284-appb-000087
When L is substituted or unsubstituted -M 2 -M 3- ,
Figure PCTCN2019120284-appb-000088
for
Figure PCTCN2019120284-appb-000089
Figure PCTCN2019120284-appb-000090
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000091
或者，
Figure PCTCN2019120284-appb-000092
为
Figure PCTCN2019120284-appb-000093
-M 2-M 3-为
Figure PCTCN2019120284-appb-000094
or,
Figure PCTCN2019120284-appb-000092
for
Figure PCTCN2019120284-appb-000093
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000094
或者，
Figure PCTCN2019120284-appb-000095
为
Figure PCTCN2019120284-appb-000096
-M 2-M 3-为
Figure PCTCN2019120284-appb-000097
or,
Figure PCTCN2019120284-appb-000095
for
Figure PCTCN2019120284-appb-000096
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000097
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为取代或未取代的
Figure PCTCN2019120284-appb-000098
L为取代或未取代的-M 2-M 3-时，Y为
Figure PCTCN2019120284-appb-000099
或
Figure PCTCN2019120284-appb-000100
L为
Figure PCTCN2019120284-appb-000101
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is substituted or unsubstituted
Figure PCTCN2019120284-appb-000098
When L is substituted or unsubstituted -M 2 -M 3- , Y is
Figure PCTCN2019120284-appb-000099
or
Figure PCTCN2019120284-appb-000100
L is
Figure PCTCN2019120284-appb-000101
或者，Y为
Figure PCTCN2019120284-appb-000102
L为
Figure PCTCN2019120284-appb-000103
Or, Y is
Figure PCTCN2019120284-appb-000102
L is
Figure PCTCN2019120284-appb-000103
或者，Y为
Figure PCTCN2019120284-appb-000104
L为
Figure PCTCN2019120284-appb-000105
Or, Y is
Figure PCTCN2019120284-appb-000104
L is
Figure PCTCN2019120284-appb-000105
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000106
L为取代或未取代的-M 4-M 5-M 6-时，M 4为C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基；M 5为C 6-C 12亚芳基或5-12元亚杂芳基；M 6为
Figure PCTCN2019120284-appb-000107
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000106
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms; M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene; M 6 is
Figure PCTCN2019120284-appb-000107
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y 为
Figure PCTCN2019120284-appb-000108
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基、亚乙基或具有2个链原子的亚杂烷基；M 5为1,4-亚苯基或1,4-(6元亚杂芳基)；M 6为
Figure PCTCN2019120284-appb-000109
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000108
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms; M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene); M 6 is
Figure PCTCN2019120284-appb-000109
在本发明的一些方案中，当Y为
Figure PCTCN2019120284-appb-000110
L为取代或未取代的-M 4-M 5-M 6-时，M 4的定义如本发明中任一方案所述；M 5为1,4-亚苯基；M 6为
Figure PCTCN2019120284-appb-000111
In some aspects of the invention, when Y is
Figure PCTCN2019120284-appb-000110
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , the definition of M 4 is as described in any scheme of the present invention; M 5 is 1,4-phenylene; M 6 is
Figure PCTCN2019120284-appb-000111
在本发明的一些方案中，当Y为
Figure PCTCN2019120284-appb-000112
L为取代或未取代的-M 4-M 5-M 6-时，M 4和M 6的定义如本发明中任一方案所述，M 5为1,4-亚苯基。 In some aspects of the invention, when Y is
Figure PCTCN2019120284-appb-000112
When L is a substituted or unsubstituted -M 4 -M 5 -M 6- , the definitions of M 4 and M 6 are as described in any of the aspects of the present invention, and M 5 is 1,4-phenylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000113
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基或亚乙基；M 5为1,4-亚苯基或1,4-(6元亚杂芳基)；M 6为
Figure PCTCN2019120284-appb-000114
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000113
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene; M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl); M 6 is
Figure PCTCN2019120284-appb-000114
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000115
L为取代或未取代的-M 4-M 5-M 6-时，-M 4-M 5-M 6-为
Figure PCTCN2019120284-appb-000116
Figure PCTCN2019120284-appb-000117
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y
Figure PCTCN2019120284-appb-000115
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , -M 4 -M 5 -M 6 -is
Figure PCTCN2019120284-appb-000116
Figure PCTCN2019120284-appb-000117
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000118
L为取代或未取代的-M 4-M 5-M 6-时，L为
Figure PCTCN2019120284-appb-000119
Figure PCTCN2019120284-appb-000120
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000118
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , L is
Figure PCTCN2019120284-appb-000119
Figure PCTCN2019120284-appb-000120
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000121
L为取代或未取代的-M 4-M 5-M 6-时，M 4为C 1-C 6亚烷基或具有2-6个链原子 的亚杂烷基；M 5为C 6-C 12亚芳基或5-12元亚杂芳基；M 6为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基或具有2、3、4、5或6个链原子的亚杂烷基。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000121
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms; M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene; M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene or has 2 , 3, 4, 5 or 6 chain atoms of heteroalkylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000122
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基、亚乙基或具有2个链原子的亚杂烷基；M 5为1,4-亚苯基或1,4-6元亚杂芳基；M 6为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基或“-U 1-U 2-，其中U 1为-NH-、-O-或-S-，U 2为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或具有2、3、4或5个链原子的亚杂烷基”。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y
Figure PCTCN2019120284-appb-000122
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms; M 5 is 1,4-phenylene Radical or 1,4-6 membered heteroarylene; M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene or “-U 1 -U 2- , wherein U 1 is -NH-, -O-, or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, or has 2 , A heteroalkylene group of 3, 4 or 5 chain atoms ".
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000123
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基或亚乙基；M 5为1,4-亚苯基或1,4-(6元亚杂芳基)；M 6为
Figure PCTCN2019120284-appb-000124
Figure PCTCN2019120284-appb-000125
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000123
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene; M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl); M 6 is
Figure PCTCN2019120284-appb-000124
Figure PCTCN2019120284-appb-000125
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000126
L为取代或未取代的-M 4-M 5-M 6-时，-M 4-M 5-M 6-为
Figure PCTCN2019120284-appb-000127
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y
Figure PCTCN2019120284-appb-000126
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , -M 4 -M 5 -M 6 -is
Figure PCTCN2019120284-appb-000127
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000128
L为取代或未取代的-M 4-M 5-M 6-时，L为
Figure PCTCN2019120284-appb-000129
Figure PCTCN2019120284-appb-000130
Figure PCTCN2019120284-appb-000131
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000128
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , L is
Figure PCTCN2019120284-appb-000129
Figure PCTCN2019120284-appb-000130
Figure PCTCN2019120284-appb-000131
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000132
L为取代或未取代的-M 4-M 5-M 6-时，M 4为C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基；M 5为C 6-C 12亚芳基或5-12元亚杂芳基；M 6为“-W 1-W 2-，其中W 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，W 2为C 4亚烷基、C 5亚烷基、C 6亚烷基或C 7亚烷基”或“-V 1-V 2-，其中V 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，V 2为具有4、5、6或7个链原子的亚杂烷基”。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000132
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms; M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene; M 6 is "-W 1 -W 2- , where W 1 is -C (= O) O-, -OC (= O)-, -C (= O) NH- or -NHC (= O)-, W 2 is C 4 alkylene, C 5 alkylene, C 6 alkylene or C 7 alkylene "or" -V 1 -V 2 -, Where V 1 is -C (= O) O-, -OC (= O)-, -C (= O) NH- or -NHC (= O)-, and V 2 is having 4, 5, 6 or 7 chain atoms of heteroalkylene ".
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000133
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基、亚乙基或具有2个链原子的亚杂烷基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)；M 6为
Figure PCTCN2019120284-appb-000134
Figure PCTCN2019120284-appb-000135
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000133
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms, and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene); M 6 is
Figure PCTCN2019120284-appb-000134
Figure PCTCN2019120284-appb-000135
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000136
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基或亚乙基，M 5为1,4-亚苯基；M 6为
Figure PCTCN2019120284-appb-000137
Figure PCTCN2019120284-appb-000138
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000136
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene, M 5 is 1,4-phenylene; M 6 is
Figure PCTCN2019120284-appb-000137
Figure PCTCN2019120284-appb-000138
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000139
L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚乙基，M 5为1,4-亚苯基或1,4-(6 元亚杂芳基)；M 6为
Figure PCTCN2019120284-appb-000140
Figure PCTCN2019120284-appb-000141
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y
Figure PCTCN2019120284-appb-000139
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is ethylene and M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene); M 6 is
Figure PCTCN2019120284-appb-000140
Figure PCTCN2019120284-appb-000141
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000142
L为取代或未取代的-M 4-M 5-M 6-时，-M 4-M 5-M 6-为
Figure PCTCN2019120284-appb-000143
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000142
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , -M 4 -M 5 -M 6 -is
Figure PCTCN2019120284-appb-000143
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000144
L为取代或未取代的-M 4-M 5-M 6-时，L为
Figure PCTCN2019120284-appb-000145
Figure PCTCN2019120284-appb-000146
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000144
When L is substituted or unsubstituted -M 4 -M 5 -M 6- , L is
Figure PCTCN2019120284-appb-000145
Figure PCTCN2019120284-appb-000146
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000147
L为取代或未取代的-M 7-M 8-M 9-时，M 7为C 1-C 4亚烷基或具有2-4个链原子的亚杂烷基，M 8为
Figure PCTCN2019120284-appb-000148
Figure PCTCN2019120284-appb-000149
Figure PCTCN2019120284-appb-000150
M 9为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000147
When L is a substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is a C 1 -C 4 alkylene group or a heteroalkylene group having 2-4 chain atoms, and M 8 is
Figure PCTCN2019120284-appb-000148
Figure PCTCN2019120284-appb-000149
Figure PCTCN2019120284-appb-000150
M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000151
L为取代或未取代的-M 7-M 8-M 9-时，M 7为亚乙基或具有两个链原子的亚杂烷基，M 8为
Figure PCTCN2019120284-appb-000152
Figure PCTCN2019120284-appb-000153
Figure PCTCN2019120284-appb-000154
M 9为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000151
When L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene or heteroalkylene having two chain atoms, M 8 is
Figure PCTCN2019120284-appb-000152
Figure PCTCN2019120284-appb-000153
Figure PCTCN2019120284-appb-000154
M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000155
L为取代或未取代的-M 7-M 8-M 9-时，M 7为亚乙基，M 8为
Figure PCTCN2019120284-appb-000156
Figure PCTCN2019120284-appb-000157
Figure PCTCN2019120284-appb-000158
M 9为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000155
When L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is
Figure PCTCN2019120284-appb-000156
Figure PCTCN2019120284-appb-000157
Figure PCTCN2019120284-appb-000158
M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000159
L为取代或未取代的-M 7-M 8-M 9-时，M 7为亚乙基，M 8为
Figure PCTCN2019120284-appb-000160
或
Figure PCTCN2019120284-appb-000161
M 9为1,4-亚苯基或1,4-(6元亚杂芳基)。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000159
When L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is
Figure PCTCN2019120284-appb-000160
or
Figure PCTCN2019120284-appb-000161
M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000162
L为取代或未取代的-M 7-M 8-M 9-时，-M 7-M 8-M 9-为
Figure PCTCN2019120284-appb-000163
Figure PCTCN2019120284-appb-000164
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000162
When L is substituted or unsubstituted -M 7 -M 8 -M 9- , -M 7 -M 8 -M 9 -is
Figure PCTCN2019120284-appb-000163
Figure PCTCN2019120284-appb-000164
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y 为
Figure PCTCN2019120284-appb-000165
L为取代或未取代的-M 7-M 8-M 9-时，L为
Figure PCTCN2019120284-appb-000166
Figure PCTCN2019120284-appb-000167
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000165
When L is substituted or unsubstituted -M 7 -M 8 -M 9- , L is
Figure PCTCN2019120284-appb-000166
Figure PCTCN2019120284-appb-000167
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，M 10为亚乙基。 In some embodiments of the present invention, in the compound represented by Formula I or I ′ as described in any of the foregoing embodiments, M 10 is ethylene.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，Z 1、Z 2和Z 3为CH。 In some embodiments of the present invention, in the compound represented by Formula I or I ′ as described in any one of the foregoing embodiments, Z 1 , Z 2 and Z 3 are CH.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，M 11为
Figure PCTCN2019120284-appb-000168
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any one of the preceding embodiments, M 11 is
Figure PCTCN2019120284-appb-000168
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当L为取代或未取代的-M 10-M 11-时，M 10为亚乙基，M 11为
Figure PCTCN2019120284-appb-000169
Figure PCTCN2019120284-appb-000170
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when L is substituted or unsubstituted -M 10 -M 11- , M 10 is ethylene Base, M 11 is
Figure PCTCN2019120284-appb-000169
Figure PCTCN2019120284-appb-000170
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当L为取代或未取代的-M 10-M 11-时，L为
Figure PCTCN2019120284-appb-000171
In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when L is substituted or unsubstituted -M 10 -M 11- , L is
Figure PCTCN2019120284-appb-000171
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为
Figure PCTCN2019120284-appb-000172
时，L为取代或未取代的-M 1-、取代或未取代的-M 2-M 3-、为取代或未取代的-M 4-M 5-M 6-、取代或未取代的-M 7-M 8-M 9-或取代或未取代的-M 10-M 11-。在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中，当Y为取代或未取代的
Figure PCTCN2019120284-appb-000173
时，L为取代或未取代的-M 2-M 3-。在本发明的一些方案中，如前述任一方案 所述的如式I或I’所示的化合物中，当ZBG为
Figure PCTCN2019120284-appb-000174
时，Y为
Figure PCTCN2019120284-appb-000175
L为取代或未取代的-M 2-M 3-、或取代或未取代的-M 4-M 5-M 6-；M 6为
Figure PCTCN2019120284-appb-000176
其他变量的定义如前述任一方案中所述。 In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is
Figure PCTCN2019120284-appb-000172
, L is substituted or unsubstituted -M 1- , substituted or unsubstituted -M 2 -M 3- , substituted or unsubstituted -M 4 -M 5 -M 6- , substituted or unsubstituted- M 7 -M 8 -M 9 -or substituted or unsubstituted -M 10 -M 11- . In some embodiments of the present invention, in the compound represented by formula I or I ′ as described in any of the preceding embodiments, when Y is substituted or unsubstituted
Figure PCTCN2019120284-appb-000173
, L is substituted or unsubstituted -M 2 -M 3- . In some aspects of the present invention, in the compound represented by formula I or I ′ as described in any of the foregoing aspects, when ZBG is
Figure PCTCN2019120284-appb-000174
, Y is
Figure PCTCN2019120284-appb-000175
L is substituted or unsubstituted -M 2 -M 3- , or substituted or unsubstituted -M 4 -M 5 -M 6- ; M 6 is
Figure PCTCN2019120284-appb-000176
The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，如前述任一方案所述的如式I或I’所示的化合物中：In some embodiments of the present invention, in the compound represented by formula I or I 'as described in any of the preceding embodiments:
R 1和R 2为氢； R 1 and R 2 are hydrogen;
R 3为取代或未取代的C 6-C 12芳基或取代或未取代的5-12元杂芳基；所述的取代的C 6-C 12芳基或取代的5-12元杂芳基是指其被一个或多个R 19取代，每个R 19独立地为卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 3-C 6环烷基； R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
X为N或CR 4； X is N or CR 4 ;
R 4为氢、氟或C 1-C 3烷基； R 4 is hydrogen, fluorine or C 1 -C 3 alkyl;
Y为
Figure PCTCN2019120284-appb-000177
或取代或未取代的
Figure PCTCN2019120284-appb-000178
所述的取代的
Figure PCTCN2019120284-appb-000179
是指其被一个或多个R 20取代； Y is
Figure PCTCN2019120284-appb-000177
Or substituted or unsubstituted
Figure PCTCN2019120284-appb-000178
The substituted
Figure PCTCN2019120284-appb-000179
Means it is replaced by one or more R 20 ;
所述的
Figure PCTCN2019120284-appb-000180
为
Figure PCTCN2019120284-appb-000181
Figure PCTCN2019120284-appb-000182
(例如所述的
Figure PCTCN2019120284-appb-000183
为
Figure PCTCN2019120284-appb-000184
)； Said
Figure PCTCN2019120284-appb-000180
for
Figure PCTCN2019120284-appb-000181
Figure PCTCN2019120284-appb-000182
(For example
Figure PCTCN2019120284-appb-000183
for
Figure PCTCN2019120284-appb-000184
);
R 5为氢或C 1-C 6烷基； R 5 is hydrogen or C 1 -C 6 alkyl;
或者，R 5与R 4以及它们连接的原子一起共同形成
Figure PCTCN2019120284-appb-000185
Or, R 5 and R 4 together with the atoms to which they are attached together form
Figure PCTCN2019120284-appb-000185
每个L独立地为如下情形(i)、(ii)、(iii)、(iv)或(v)：Each L is independently the following case (i), (ii), (iii), (iv) or (v):
(i)L为取代或未取代的-M 1-，M 1为C 5亚烷基、C 6亚烷基、C 7亚烷基或具有5、6或7个原子的亚杂烷基；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms; The substituted -M 1 -refers to its substitution by one or more R 21 ;
(ii)L为取代或未取代的-M 2-M 3-；M 2为亚乙基、亚丙基或具有2或3个链原子的亚杂烷基(所述的亚杂烷基例如
Figure PCTCN2019120284-appb-000186
例如
Figure PCTCN2019120284-appb-000187
Figure PCTCN2019120284-appb-000188
且M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；或者，M 2为亚乙基、亚丙基或具有2或3个链原子的亚杂烷基、
Figure PCTCN2019120284-appb-000189
Figure PCTCN2019120284-appb-000190
且M 3为1,4-亚苯基或1,4-(6元亚杂芳基)所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- ; M 2 is ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms (the heteroalkylene group is, for example,
Figure PCTCN2019120284-appb-000186
E.g
Figure PCTCN2019120284-appb-000187
Figure PCTCN2019120284-appb-000188
And M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); alternatively, M 2 is ethylene, propylene or heteroalkylene having 2 or 3 chain atoms ,
Figure PCTCN2019120284-appb-000189
Figure PCTCN2019120284-appb-000190
And M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene), the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
(iii)L为取代或未取代的-M 4-M 5-M 6-，为亚甲基、亚乙基或具有2个链原子的亚杂烷基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)，M 6为
Figure PCTCN2019120284-appb-000191
C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基、“-U 1-U 2-，其中U 1为-NH-、-O-或-S-，U 2为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或具有2、3、4或5个链原子的亚杂烷基”、
Figure PCTCN2019120284-appb-000192
Figure PCTCN2019120284-appb-000193
所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is a substituted or unsubstituted -M 4 -M 5 -M 6- , is a methylene group, an ethylene group or a heteroalkylene group having 2 chain atoms, and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene), M 6 is
Figure PCTCN2019120284-appb-000191
C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, “-U 1 -U 2- , where U 1 is -NH-, -O- Or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or heteroalkylene having 2, 3, 4 or 5 chain atoms ",
Figure PCTCN2019120284-appb-000192
Figure PCTCN2019120284-appb-000193
The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
(iv)L为取代或未取代的-M 7-M 8-M 9-，M 7为亚乙基，M 8为
Figure PCTCN2019120284-appb-000194
Figure PCTCN2019120284-appb-000195
Figure PCTCN2019120284-appb-000196
M 9为1,4-亚苯基或1,4-(6元亚杂芳基)；所述的取代的-M 7-M 8-M 9-是指其被一个或多个R 24取代； (iv) L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is
Figure PCTCN2019120284-appb-000194
Figure PCTCN2019120284-appb-000195
Figure PCTCN2019120284-appb-000196
M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
(v)取代或未取代的-M 10-M 11，其中M 10为亚甲基、亚乙基或亚丙基，M 11为
Figure PCTCN2019120284-appb-000197
Z 1、Z 2和Z 3各自独立地为CH或N；所述的取代的-M 10-M 11-是指其被一个或多个R 25取代； (v) substituted or unsubstituted -M 10 -M 11 , wherein M 10 is methylene, ethylene or propylene, and M 11 is
Figure PCTCN2019120284-appb-000197
Z 1 , Z 2 and Z 3 are each independently CH or N; the substituted -M 10 -M 11 -means that it is substituted with one or more R 25 ;
每个R 20、R 21、R 22、R 23、R 24和R 25各自独立地为卤素、羟基、C 1-C 6烷基或C 1-C 6 烷氧基； Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
所述的亚杂烷基、亚杂烯基、亚杂炔基、亚杂环烷基和亚杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个；The hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
ZBG为
Figure PCTCN2019120284-appb-000198
ZBG is
Figure PCTCN2019120284-appb-000198
R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 12芳基或5-12元杂芳基； R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
所述的杂烷基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个。The hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
在本发明的一些方案中，所述的如式I所示的化合物选自以下任一结构：In some aspects of the invention, the compound represented by Formula I is selected from any of the following structures:
Figure PCTCN2019120284-appb-000199
Figure PCTCN2019120284-appb-000199
Figure PCTCN2019120284-appb-000200
Figure PCTCN2019120284-appb-000200
各变量的定义如前述任一方案所述。The definition of each variable is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I’所示的化合物为如下任一结构：In some aspects of the invention, the compound represented by Formula I 'has any of the following structures:
Figure PCTCN2019120284-appb-000201
Figure PCTCN2019120284-appb-000201
各变量的定义如前述任一方案所述。The definition of each variable is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I所示的化合物为如下任一结构：In some aspects of the present invention, the compound represented by Formula I has any of the following structures:
Figure PCTCN2019120284-appb-000202
Figure PCTCN2019120284-appb-000202
其中，每个L独立地为如下情形(i)、(ii)、(iii)或(iv)：Where each L is independently the following case (i), (ii), (iii) or (iv):
(i)L为取代或未取代的-M 1-，M 1为C 5亚烷基、C 6亚烷基、C 7亚烷基或具有5、6或7个链原子的亚杂烷基；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 chain atoms ; The substituted -M 1 -means that it is substituted by one or more R 21 ;
(ii)L为取代或未取代的-M 2-M 3-，M 2为M 2为亚甲基、亚乙基、亚丙基或具有2或 3个链原子的亚杂烷基(所述的亚杂烷基例如
Figure PCTCN2019120284-appb-000203
或
Figure PCTCN2019120284-appb-000204
例如
Figure PCTCN2019120284-appb-000205
)，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example
Figure PCTCN2019120284-appb-000203
or
Figure PCTCN2019120284-appb-000204
E.g
Figure PCTCN2019120284-appb-000205
), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 2 -M 3 -means that it is substituted by one or more R 22 ;
(iii)L为取代或未取代的-M 4-M 5-M 6-，M 4为亚甲基或亚乙基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)，M 6为
Figure PCTCN2019120284-appb-000206
Figure PCTCN2019120284-appb-000207
或者，M 4为亚乙基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)，M 6为
Figure PCTCN2019120284-appb-000208
Figure PCTCN2019120284-appb-000209
所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene, M 5 is 1,4-phenylene or 1,4- (6 member Heteroarylene), M 6 is
Figure PCTCN2019120284-appb-000206
Figure PCTCN2019120284-appb-000207
Alternatively, M 4 is ethylene, M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene), M 6 is
Figure PCTCN2019120284-appb-000208
Figure PCTCN2019120284-appb-000209
The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
(iv)L为取代或未取代的-M 7-M 8-M 9-，M 7为亚乙基，M 8为
Figure PCTCN2019120284-appb-000210
或
Figure PCTCN2019120284-appb-000211
M 9为1,4-亚苯基或1,4-(6元亚杂芳基)；所述的取代的-M 7-M 8-M 9-是指其被一个或多个R 24取代； (iv) L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is
Figure PCTCN2019120284-appb-000210
or
Figure PCTCN2019120284-appb-000211
M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
(v)取代或未取代的-M 10-M 11，其中M 10为亚甲基、亚乙基或亚丙基，M 11为
Figure PCTCN2019120284-appb-000212
Z 1、Z 2和Z 3各自独立地为CH或N；所述的取代的-M 10-M 11-是指其被一个或多个R 25取代； (v) substituted or unsubstituted -M 10 -M 11 , wherein M 10 is methylene, ethylene or propylene, and M 11 is
Figure PCTCN2019120284-appb-000212
Z 1 , Z 2 and Z 3 are each independently CH or N; the substituted -M 10 -M 11 -means that it is substituted with one or more R 25 ;
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I所示的化合物为如下任一结构：In some aspects of the present invention, the compound represented by Formula I has any of the following structures:
Figure PCTCN2019120284-appb-000213
Figure PCTCN2019120284-appb-000213
Figure PCTCN2019120284-appb-000214
Figure PCTCN2019120284-appb-000214
其中，每个L独立地为如下情形(ii)或(iii)：Wherein, each L is independently the following situation (ii) or (iii):
(ii)L为取代或未取代的-M 2-M 3-，M 2为M 2为亚甲基、亚乙基、亚丙基或具有2或3个链原子的亚杂烷基(所述的亚杂烷基例如
Figure PCTCN2019120284-appb-000215
或
Figure PCTCN2019120284-appb-000216
例如
Figure PCTCN2019120284-appb-000217
)，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)(例如M 3为1,4-亚苯基)；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example
Figure PCTCN2019120284-appb-000215
or
Figure PCTCN2019120284-appb-000216
E.g
Figure PCTCN2019120284-appb-000217
), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
(iii)L为取代或未取代的-M 4-M 5-M 6-，M 4为亚甲基或亚乙基(例如M 4为亚甲基)，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)(例如M 5为1,4-亚苯基)，M 6为
Figure PCTCN2019120284-appb-000218
所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene (for example, M 4 is methylene), and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene) (eg M 5 is 1,4-phenylene), M 6 is
Figure PCTCN2019120284-appb-000218
The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I所示的化合物为如下结构：In some embodiments of the present invention, the compound represented by Formula I has the following structure:
Figure PCTCN2019120284-appb-000219
Figure PCTCN2019120284-appb-000219
其中，L为取代或未取代的-M 2-M 3-；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； Wherein, L is substituted or unsubstituted -M 2 -M 3- ; the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
Figure PCTCN2019120284-appb-000220
和-M 2-M 3-的定义选自以下任一组：
Figure PCTCN2019120284-appb-000220
The definition of and -M 2 -M 3 -is selected from any of the following groups:
(i)
Figure PCTCN2019120284-appb-000221
为
Figure PCTCN2019120284-appb-000222
-M 2-M 3-为
Figure PCTCN2019120284-appb-000223
(i)
Figure PCTCN2019120284-appb-000221
for
Figure PCTCN2019120284-appb-000222
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000223
(ii)
Figure PCTCN2019120284-appb-000224
为
Figure PCTCN2019120284-appb-000225
-M 2-M 3-为
Figure PCTCN2019120284-appb-000226
(ii)
Figure PCTCN2019120284-appb-000224
for
Figure PCTCN2019120284-appb-000225
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000226
(iii)
Figure PCTCN2019120284-appb-000227
为
Figure PCTCN2019120284-appb-000228
-M 2-M 3-为
Figure PCTCN2019120284-appb-000229
(iii)
Figure PCTCN2019120284-appb-000227
for
Figure PCTCN2019120284-appb-000228
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000229
Figure PCTCN2019120284-appb-000230
任选被一个或多个R 20取代；
Figure PCTCN2019120284-appb-000230
Optionally substituted by one or more R 20 ;
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I所示的化合物为如下结构：In some embodiments of the present invention, the compound represented by Formula I has the following structure:
Figure PCTCN2019120284-appb-000231
Figure PCTCN2019120284-appb-000231
其中，L为取代或未取代的-M 2-M 3-；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； Wherein, L is substituted or unsubstituted -M 2 -M 3- ; the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
Figure PCTCN2019120284-appb-000232
为
Figure PCTCN2019120284-appb-000233
其任选被一个或多个R 20取代；
Figure PCTCN2019120284-appb-000232
for
Figure PCTCN2019120284-appb-000233
It is optionally substituted with one or more R 20 ;
-M 2-M 3-为
Figure PCTCN2019120284-appb-000234
-M 2 -M 3 -is
Figure PCTCN2019120284-appb-000234
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I’所示的化合物为如下任一结构：In some aspects of the invention, the compound represented by Formula I 'has any of the following structures:
Figure PCTCN2019120284-appb-000235
Figure PCTCN2019120284-appb-000235
每个L独立地为如下情形(i)或(ii)：Each L is independently the following case (i) or (ii):
(i)L为取代或未取代的-M 1-，M 1为C 5亚烷基、C 6亚烷基、C 7亚烷基或具有5、6 或7个原子的亚杂烷基(例如M 1为C 6亚烷基)；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms ( For example, M 1 is C 6 alkylene); the substituted -M 1 -means that it is substituted with one or more R 21 ;
(ii)L为取代或未取代的-M 2-M 3-，M 2为M 2为亚甲基、亚乙基、亚丙基或具有2或3个链原子的亚杂烷基(所述的亚杂烷基例如
Figure PCTCN2019120284-appb-000236
或
Figure PCTCN2019120284-appb-000237
例如
Figure PCTCN2019120284-appb-000238
)，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)(例如M 3为1,4-亚苯基)；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example
Figure PCTCN2019120284-appb-000236
or
Figure PCTCN2019120284-appb-000237
E.g
Figure PCTCN2019120284-appb-000238
), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I’所示的化合物为如下结构：In some embodiments of the present invention, the compound represented by Formula I 'has the following structure:
Figure PCTCN2019120284-appb-000239
Figure PCTCN2019120284-appb-000239
L为取代或未取代的-M 1-，M 1为C 5亚烷基、C 6亚烷基、C 7亚烷基或具有5、6或7个原子的亚杂烷基(例如M 1为C 6亚烷基)；所述的取代的-M 1-是指其被一个或多个R 21取代； L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms (eg M 1 Is C 6 alkylene); the substituted -M 1 -means that it is substituted with one or more R 21 ;
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I’所示的化合物为如下结构：In some embodiments of the present invention, the compound represented by Formula I 'has the following structure:
Figure PCTCN2019120284-appb-000240
Figure PCTCN2019120284-appb-000240
L为取代或未取代的-M 2-M 3-，M 2为M 2为亚甲基、亚乙基、亚丙基或具有2或3个链原子的亚杂烷基(所述的亚杂烷基例如
Figure PCTCN2019120284-appb-000241
或
Figure PCTCN2019120284-appb-000242
例如
Figure PCTCN2019120284-appb-000243
)，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)(例如M 3为1,4-亚苯基)；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； L is substituted or unsubstituted -M 2 -M 3- , M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (the Heteroalkyl for example
Figure PCTCN2019120284-appb-000241
or
Figure PCTCN2019120284-appb-000242
E.g
Figure PCTCN2019120284-appb-000243
), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
其他变量的定义如前述任一方案中所述。The definition of other variables is as described in any of the preceding schemes.
在本发明的一些方案中，所述的如式I或I’所示的化合物选自以下任一结构：In some aspects of the invention, the compound represented by Formula I or I 'is selected from any of the following structures:
Figure PCTCN2019120284-appb-000244
Figure PCTCN2019120284-appb-000244
Figure PCTCN2019120284-appb-000245
Figure PCTCN2019120284-appb-000245
Figure PCTCN2019120284-appb-000246
Figure PCTCN2019120284-appb-000246
Figure PCTCN2019120284-appb-000247
Figure PCTCN2019120284-appb-000247
Figure PCTCN2019120284-appb-000248
Figure PCTCN2019120284-appb-000248
本发明还提供了一种如上所述的如式I所示的化合物的制备方法，其为如下至少一 种方案：The present invention also provides a method for preparing the compound shown in Formula I as described above, which is at least one of the following schemes:
方案一Option One
Figure PCTCN2019120284-appb-000249
Figure PCTCN2019120284-appb-000249
方案一包括如下步骤：在有机溶剂(如甲醇)中，将如式II所示的化合物和NH 2-OH在碱(如氢氧化钾)存在的条件下进行取代反应，得到如式I所示的化合物即可；其中，ZBG为
Figure PCTCN2019120284-appb-000250
R 1、R 2、R 3、X、Y和L的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)； Scheme one includes the following steps: in an organic solvent (such as methanol), the compound shown in formula II and NH 2 -OH in the presence of a base (such as potassium hydroxide) in the presence of a substitution reaction to obtain formula I Is sufficient; ZBG is
Figure PCTCN2019120284-appb-000250
R 1, R 2, R 3 , X, Y and L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl);
方案二Option II
Figure PCTCN2019120284-appb-000251
Figure PCTCN2019120284-appb-000251
方案二包括如下步骤：在有机溶剂(如DMF)中，将如式III所示的化合物和
Figure PCTCN2019120284-appb-000252
在缩合剂(如HATU)和碱(如DIPEA)存在的条件下进行缩合反应，得到如式I所示的化合物即可；其中，ZBG为
Figure PCTCN2019120284-appb-000253
R 1、R 2、R 3、R 10、R 11、R 12、R 13、X、Y和L的定义如上所述。 Scheme two includes the following steps: In an organic solvent (such as DMF), the compound shown in formula III and
Figure PCTCN2019120284-appb-000252
The condensation reaction can be carried out in the presence of a condensing agent (such as HATU) and a base (such as DIPEA) to obtain the compound represented by Formula I; wherein, ZBG is
Figure PCTCN2019120284-appb-000253
R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , X, Y, and L are as defined above.
所述的如式III所示的化合物的制备方法可以包括如下步骤：在有机溶剂(如四氢呋喃和水的混合溶剂)中，将如式II所示的化合物在碱(如氢氧化锂)存在的条件下进行 水解反应，得到如式III所示的化合物即可；其中，R 1、R 2、R 3、X、Y和L的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)； The preparation method of the compound shown in formula III may include the following steps: In an organic solvent (such as a mixed solvent of tetrahydrofuran and water), the compound shown in formula II is present in a base (such as lithium hydroxide) The hydrolysis reaction is carried out under the conditions to obtain the compound represented by formula III; wherein, R 1 , R 2 , R 3 , X, Y and L are as defined above, and R a is C 1 -C 6 alkyl ( (Such as methyl or ethyl);
Figure PCTCN2019120284-appb-000254
Figure PCTCN2019120284-appb-000254
所述的如式II所示的化合物的制备方法可以包括如下步骤：在有机溶剂(例如乙腈)中，将如式IV所示的化合物和如式V所示的化合物进行缩合反应，得到如式II所示的化合物即可；其中，R 1、R 2、R 3、X、Y和L的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)，LG为离去基团(例如
Figure PCTCN2019120284-appb-000255
其中R 30为C 1-C 4烷基，例如甲基)； The preparation method of the compound shown in Formula II may include the following steps: In an organic solvent (such as acetonitrile), the compound shown in Formula IV and the compound shown in Formula V are subjected to a condensation reaction to obtain a compound shown in Formula the compound represented by II; wherein, R 1, R 2, R 3, X, Y and L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl), LG Is a leaving group (e.g.
Figure PCTCN2019120284-appb-000255
Where R 30 is C 1 -C 4 alkyl, such as methyl);
Figure PCTCN2019120284-appb-000256
Figure PCTCN2019120284-appb-000256
本发明还提供了一种化合物，其为如下任一结构：The present invention also provides a compound, which has any of the following structures:
Figure PCTCN2019120284-appb-000257
Figure PCTCN2019120284-appb-000257
其中，R 1、R 2、R 3、X、Y和L的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)。 Wherein, R 1 , R 2 , R 3 , X, Y and L are as defined above, and R a is C 1 -C 6 alkyl (such as methyl or ethyl).
在本发明的一些方案中，所述的如式II所述的化合物为如下任一结构：In some aspects of the invention, the compound of formula II has any of the following structures:
Figure PCTCN2019120284-appb-000258
Figure PCTCN2019120284-appb-000258
Figure PCTCN2019120284-appb-000259
Figure PCTCN2019120284-appb-000259
Figure PCTCN2019120284-appb-000260
Figure PCTCN2019120284-appb-000260
Figure PCTCN2019120284-appb-000261
Figure PCTCN2019120284-appb-000261
在本发明的一些方案中，所述的如式III所述的化合物为如下任一结构：In some aspects of the invention, the compound of formula III has any of the following structures:
Figure PCTCN2019120284-appb-000262
Figure PCTCN2019120284-appb-000262
Figure PCTCN2019120284-appb-000263
Figure PCTCN2019120284-appb-000263
Figure PCTCN2019120284-appb-000264
Figure PCTCN2019120284-appb-000264
Figure PCTCN2019120284-appb-000265
Figure PCTCN2019120284-appb-000265
本发明还提供了一种药物组合物，其包含如上所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，以及至少一种药用辅料。The present invention also provides a pharmaceutical composition comprising a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer Constructors, tautomers, solvates, metabolites or prodrugs, and at least one pharmaceutical excipient.
本发明还提供了一种如上所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，或所述的药物组合物在制备腺苷A2A受体拮抗剂和/或组蛋白去乙酰化酶HDAC抑制剂中的应用。The present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation The use of the structure, solvate, metabolite or prodrug, or the pharmaceutical composition in the preparation of adenosine A2A receptor antagonist and / or histone deacetylase HDAC inhibitor.
本发明还提供了一种如上所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，或所述的药物组合物在制备用于治疗和/或预防与腺苷A2A受体和/或组蛋白去乙酰化酶HDAC相关的疾病的药物中的应用。The present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation Structurants, solvates, metabolites or prodrugs, or the pharmaceutical composition is prepared for the treatment and / or prevention of diseases related to adenosine A2A receptor and / or histone deacetylase HDAC Application.
本发明还提供了一种如上所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，或所述的药物组合物在制备用于治疗和/或预防癌症或中枢神经系统疾病的药物中的应用。The present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation The use of structurants, solvates, metabolites or prodrugs, or said pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of cancer or diseases of the central nervous system.
所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体的剂量可以为治疗有效量。The compound represented by formula I or I ', its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites Or the dose of prodrug may be a therapeutically effective amount.
本发明还提供了一种治疗和/或预防“与腺苷A2A受体和/或组蛋白去乙酰化酶HDAC相关的疾病”的方法，该方法包括向需要此治疗的受试者给予治疗有效量的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体。The present invention also provides a method of treating and / or preventing "disease related to adenosine A2A receptor and / or histone deacetylase HDAC", which method comprises administering to a subject in need of such treatment effective Amount of a compound represented by formula I or I ', its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or Prodrugs.
本发明还提供了一种治疗和/或预防癌症或中枢神经系统疾病的方法，该方法包括向需要此治疗的受试者给予治疗有效量的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体。The present invention also provides a method of treating and / or preventing cancer or central nervous system diseases, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound represented by Formula I or I ', and its pharmacy Acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or prodrugs.
如上所述的“与腺苷A2A受体和/或组蛋白去乙酰化酶HDAC相关的疾病”可以为癌症或中枢神经系统疾病。The "diseases associated with adenosine A2A receptor and / or histone deacetylase HDAC" as described above may be cancer or central nervous system diseases.
如上所述的癌症可以为头颈部癌症(如甲状腺癌、鼻咽癌、脑膜癌或颅内转移瘤)、呼吸系统癌症(如小细胞肺癌或非小细胞肺癌)、消化系统癌症(如肝癌、胃癌、食管癌、直肠癌、结肠癌或胰腺癌)、泌尿系统癌症(如肾癌、膀胱癌、前列腺癌或睾丸癌)、骨癌、妇科癌症(如乳腺癌、宫颈癌或卵巢癌)、血液系统癌症(如白血病、淋巴瘤或骨髓瘤或其他类型癌症(如黑色素瘤、神经胶质瘤或皮肤癌)。Cancers as described above may be head and neck cancers (such as thyroid cancer, nasopharyngeal cancer, meningeal cancer, or intracranial metastases), cancers of the respiratory system (such as small cell lung cancer or non-small cell lung cancer), cancers of the digestive system (such as liver cancer , Gastric cancer, esophageal cancer, rectal cancer, colon cancer or pancreatic cancer), urinary system cancer (such as kidney cancer, bladder cancer, prostate cancer or testicular cancer), bone cancer, gynecological cancer (such as breast cancer, cervical cancer or ovarian cancer) , Hematological cancer (such as leukemia, lymphoma or myeloma or other types of cancer (such as melanoma, glioma or skin cancer).
如上所述的中枢神经系统疾病可以为帕金森氏症、阿尔茨海默氏病或亨廷顿氏舞蹈病。The central nervous system disease as described above may be Parkinson's disease, Alzheimer's disease, or Huntington's disease.
如上所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，或所述的药物组合物还可以用于特征为细胞异常增殖的任意疾病过程，例如良性前列腺增生、神经纤维瘤病、动脉粥样硬化、肺纤维化、关节炎、牛皮癣、肾小球肾炎、血管成形术或脉管手术之后出现的再狭窄、炎性肠病、移植排斥反应、内毒素性休克和真菌感染。The compound represented by formula I or I 'as described above, its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolism The product or prodrug, or the pharmaceutical composition may also be used in any disease process characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis , Glomerulonephritis, restenosis after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxin shock and fungal infection.
本发明还提供了一种如上所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，或所述的药物组合物在制备用于调节腺苷A2A受体和/或组蛋白去乙酰化酶HDAC活性的制品中的应用。The present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation The use of a construct, solvate, metabolite, or prodrug, or the pharmaceutical composition described in the preparation of a product for modulating the activity of adenosine A2A receptor and / or histone deacetylase HDAC.
所述的药用辅料的选择因施用途径和作用特点而异，通常可为本领域常规的填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂、助悬剂等。The choice of the medicinal adjuvant varies according to the route of administration and the characteristics of the action, and can generally be conventional fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending aids Agent.
所述的药物组合物可以通过口服、注射(静脉、肌肉、皮下和冠状动脉内)、舌下、经颊、经直肠、经尿道、经阴道、经鼻、吸入或局部途径施用，优选途径是口服。The pharmaceutical composition can be administered by oral, injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, transbuccal, transrectal, transurethral, transvaginal, nasal, inhalation or topical routes. oral.
在本发明中，除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：In the present invention, unless otherwise stated, the following terms appearing in the description and claims of the present invention have the following meanings:
在本发明中，术语“取代”或“取代基”是指一个或多个氢原子被指定的基团所代替。当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。In the present invention, the term "substituted" or "substituent" means that one or more hydrogen atoms are replaced with the specified group. When the substitution position is not specified, the substitution can be in any position, but only the formation of a stable or chemically feasible chemical substance is allowed.
在本发明中，术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。例如，术语“任选被取代”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。In the present invention, the term "optional" or "optionally" means that the subsequently described event or condition may, but need not necessarily occur, and the description includes the situation in which the event or condition occurs and the event or Situations where no situation occurs. For example, the term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis that they are chemically achievable.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任 选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can be optionally substituted with up to two Rs, and R in each case has independent options. In addition, combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.
在本发明中，术语“烷基”是指具有指定数目碳原子的饱和的直链或支链的一价烃基，例如C 1-C 10烷基是指具有1-10个碳原子的烷基。烷基的例子包括但不限于甲基(Me)、乙基(Et)、丙基(如正丙基、异丙基)、丁基(如正丁基、异丁基、s-丁基、t-丁基)和戊基(如n-戊基、异戊基、新戊基)。 In the present invention, the term "alkyl" refers to a saturated monovalent hydrocarbon radical straight or branched chain having the indicated number of carbon atoms, for example C 1 -C 10 alkyl means an alkyl group having 1 to 10 carbon atoms, . Examples of alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl) and pentyl (eg n-pentyl, isopentyl, neopentyl).
在本发明中，术语“烷氧基”是指通过氧桥连接到分子其他部分的烷基(如本发明中所定义)。In the present invention, the term "alkoxy" refers to an alkyl group (as defined in the present invention) connected to the rest of the molecule through an oxygen bridge.
在本发明中，术语“烯基”是指具有指定数目碳原子和至少一个碳碳双键的直链或支链的一价烃基，其中碳碳双键可以位于烯基内的任何位置，例如C 2-C 6烯基是指具有2-6个碳原子的烯基。烯基的例子包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基。 In the present invention, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, for example C 2 -C 6 alkenyl refers to alkenyl groups having 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, and hexadienyl.
在本发明中，术语“炔基”是指具有指定数目碳原子并且至少一个碳碳三键的直链或支链的一价烃基，其中碳碳三键可以位于炔基内的任何位置，例如C 2-C 6炔基是指具有2-6个碳原子的炔基。炔基的例子包括但不限于乙炔基和丙炔基。 In the present invention, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located at any position within the alkynyl group, for example C 2 -C 6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to ethynyl and propynyl.
在本发明中，术语“亚烷基”是指具有指定数目碳原子的饱和的直链的二价烃基。由此，C 1亚烷基(即亚甲基)指-CH 2-，C 2亚烷基(即亚乙基)指-CH 2-CH 2-，C 3亚烷基指-CH 2-CH 2-CH 2-。 In the present invention, the term "alkylene" refers to a saturated linear divalent hydrocarbon group having the specified number of carbon atoms. Thus, C 1 alkylene (ie, methylene) refers to -CH 2- , C 2 alkylene (ie, ethylene) refers to -CH 2 -CH 2- , and C 3 alkylene refers to -CH 2- CH 2 -CH 2- .
在本发明中，术语“亚烯基”是指具有指定数目碳原子和至少一个碳碳双键的直链的二价烃基，其中碳碳双键可以位于亚烯基内的任何位置。由此，C 2亚烯基(即亚乙烯基)指-CH＝CH-，C 3亚烯基指-CH 2-CH＝CH-和-CH 2＝CH-CH 2-，C 4亚烯基指-CH 2-CH＝CH-CH 2-、-CH 2＝CH-CH 2-CH 2-和-CH 2-CH-CH 2＝CH 2-。 In the present invention, the term "alkenylene" refers to a linear divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, where the carbon-carbon double bond may be located at any position within the alkenylene group. Thus, C 2 alkenylene (ie vinylene) refers to —CH═CH—, C 3 alkenylene refers to —CH 2 —CH═CH— and —CH 2 = CH—CH 2 —, C 4 alkenylene The base refers to -CH 2 -CH = CH-CH 2- , -CH 2 = CH-CH 2 -CH 2- , and -CH 2 -CH-CH 2 = CH 2- .
在本发明中，术语“亚炔基”是指具有指定数目碳原子和至少一个碳碳三键的直链的二价烃基，其中碳碳三键可以位于亚炔基内的任何位置。由此，C 2亚炔基(亚乙炔基)指
Figure PCTCN2019120284-appb-000266
C 3亚炔基指
Figure PCTCN2019120284-appb-000267
In the present invention, the term "alkynylene" refers to a straight-chain divalent hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond, where the carbon-carbon triple bond may be located at any position within the alkynylene group. Thus, C 2 alkynylene (ethynylene) refers to
Figure PCTCN2019120284-appb-000266
C 3 alkynylene means
Figure PCTCN2019120284-appb-000267
在本发明中，术语“杂烷基”是指具有指定数目碳原子和至少一个选自N、O和S的杂原子的饱和的直链或支链的一价烃基。杂烷基可以通过其中的杂原子或碳原子连接到分子中的其他部分。杂原子可以位于杂烷基的任何内部位置(包括杂烷基连接到分子其他部分的位置)，也即杂烷基不包括羟基烷基(例如-CH 2OH、-CH(CH 3)OH)、氨基烷基(例如-CH 2NH 2、-CH(CH 3)NH 2)等。杂烷基的例子包括但不限于-O-CH 3、-CH 2-NH-CH 3、 -NH-CH(CH 3)-CH 3、-CH 2-O-CH 3和-CH 2-S-CH 3。 In the present invention, the term "heteroalkyl" refers to a saturated linear or branched monovalent hydrocarbon group having the specified number of carbon atoms and at least one heteroatom selected from N, O, and S. Heteroalkyl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. The heteroatom may be located at any internal position of the heteroalkyl group (including the position where the heteroalkyl group is connected to other parts of the molecule), that is, the heteroalkyl group does not include a hydroxyalkyl group (for example, -CH 2 OH, -CH (CH 3 ) OH) , Aminoalkyl (for example, -CH 2 NH 2 , -CH (CH 3 ) NH 2 ), etc. Examples of heteroalkyl groups include, but are not limited to, -O-CH 3 , -CH 2 -NH-CH 3 , -NH-CH (CH 3 ) -CH 3 , -CH 2 -O-CH 3, and -CH 2 -S -CH 3 .
在本发明中，术语“亚杂烷基”是指具有指定数目链原子数的饱和的直链的二价烃基，其中至少有一个链原子为选自N、O和S的杂原子，其余链原子为碳。亚杂烷基可以通过其中的杂原子或碳原子连接到分子中的其他部分。具有2个链原子的亚杂烷基例如-O-CH 2-、-NH-CH 2-等，具有3个链原子的亚杂烷基例如-CH 2-NH-CH 2-、-O-CH 2-CH 2-、-CH 2-O-CH 2-等，具有4个链原子的亚杂烷基例如-O-CH 2-CH 2-NH-。 In the present invention, the term "heteroalkylene" refers to a saturated straight-chain divalent hydrocarbon group having a specified number of chain atoms, at least one of which is a hetero atom selected from N, O, and S, and the remaining chains The atom is carbon. Heteroalkylene groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. Heteroalkylene groups having 2 chain atoms such as —O-CH 2 —, —NH—CH 2 —, etc. Heteroalkylene groups having 3 chain atoms such as —CH 2 —NH—CH 2 —, —O— CH 2 -CH 2- , -CH 2 -O-CH 2- , etc., a heteroalkylene group having 4 chain atoms such as -O-CH 2 -CH 2 -NH-.
在本发明中，术语“亚杂烯基”是指具有指定数目链原子数和至少一个双键的直链的二价烃基，其中至少有一个链原子为选自N、O和S的杂原子。亚杂烯基可以通过其中的杂原子或碳原子连接到分子中的其他部分。具有2个链原子的亚杂烯基例如-N＝CH 2-等，具有3个链原子的亚杂烯基例如-N＝CH-CH 2-、-CH＝N-CH 2-等，具有4个链原子的亚杂烯基例如-CH 2＝CH-CH 2-O-、-CH 2＝CH-CH 2-NH-等，具有5个链原子的亚杂烯基例如-CH 2-CH＝CH-CH 2-NH-等。 In the present invention, the term "heteroalkenylene" refers to a straight-chain divalent hydrocarbon group having a specified number of chain atoms and at least one double bond, wherein at least one chain atom is a hetero atom selected from N, O, and S . The heteroalkenylene group may be connected to other parts of the molecule through a hetero atom or a carbon atom therein. Heteroalkenylene having 2 chain atoms such as —N═CH 2 —, etc. Heteroalkenylene having 3 chain atoms such as —N═CH—CH 2 —, —CH═N-CH 2 —, etc. having A heteroalkenylene group having 4 chain atoms, for example, -CH 2 = CH-CH 2 -O-, -CH 2 = CH-CH 2 -NH-, etc., and a heteroalkenylene group having 5 chain atoms, for example, -CH 2- CH = CH-CH 2 -NH- and so on.
在本发明中，术语“亚杂炔基”是指具有指定数目链原子数和至少一个三键的直链的二价烃基，其中至少有一个链原子为选自N、O和S的杂原子。亚杂炔基可以通过其中的杂原子或碳原子连接到分子中的其他部分。亚杂炔基的例子包括但不限于
Figure PCTCN2019120284-appb-000268
(4个链原子)和
Figure PCTCN2019120284-appb-000269
(5个链原子)。 In the present invention, the term "heteroalkynylene" refers to a straight-chain divalent hydrocarbon group having a specified number of chain atoms and at least one triple bond, wherein at least one chain atom is a hetero atom selected from N, O, and S . The heteroalkynylene group may be connected to other parts of the molecule through a hetero atom or a carbon atom therein. Examples of heteroalkynylene include, but are not limited to
Figure PCTCN2019120284-appb-000268
(4 chain atoms) and
Figure PCTCN2019120284-appb-000269
(5 chain atoms).
在本发明中，术语“环烷基”是指具有指定数目环碳原子数的非芳香族的饱和或部分不饱和的一价环烃基，环烷基可以为单环或多环(例如二环和三环)，可以为并环、螺环和桥环结构。环烷基内任选包含一个或多个双键或三键。单环的环烷基包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。环烷基还包括多环的环烷基结构，其中多环的结构任选地包括与饱和或部分不饱和的环烷基或杂环基或芳基或杂芳基环稠合的饱和或部分不饱和的环烷基。具有7到12个原子的双环碳环可以布置为例如双环[4,5]、[5,5]、[5,6]或[6,6]系统，或布置为桥接环系统例如双[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.2]壬烷。In the present invention, the term "cycloalkyl" refers to a non-aromatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having a specified number of ring carbon atoms. The cycloalkyl group may be monocyclic or polycyclic (for example, bicyclic And tricyclic), can be a parallel ring, spiro ring and bridge ring structure. The cycloalkyl group optionally contains one or more double bonds or triple bonds. Monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-ene Group, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclo Nonyl, cyclodecyl, cycloundecyl and cyclododecyl. Cycloalkyl also includes polycyclic cycloalkyl structures, where the polycyclic structure optionally includes saturated or partially fused to saturated or partially unsaturated cycloalkyl or heterocyclic groups or aryl or heteroaryl rings Unsaturated cycloalkyl. Bicyclic carbocycles with 7 to 12 atoms can be arranged as, for example, bicyclic [4,5], [5,5], [5,6] or [6,6] systems, or as bridged ring systems such as bi [2.2 .1] Heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.
在本发明中，术语“杂环烷基”是指环烷基(如本发明中所定义)内的至少一个环碳原子被选自N、O和S的杂原子代替形成的非芳香族的饱和或部分不饱和的一价环烃基。杂环烷基可以通过其中的杂原子或碳原子连接到分子中的其他部分。杂环烷基的的例子包括但不限于1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基和2-哌嗪基。桥环的杂环烷基例如
Figure PCTCN2019120284-appb-000270
Figure PCTCN2019120284-appb-000271
In the present invention, the term "heterocycloalkyl" refers to a non-aromatic saturation formed by replacing at least one ring carbon atom in a cycloalkyl group (as defined in the present invention) with a heteroatom selected from N, O and S Or a partially unsaturated monovalent cyclic hydrocarbon group. Heterocycloalkyl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. Examples of heterocycloalkyl include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrothiophene -2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl. Bridged ring heterocycloalkyl for example
Figure PCTCN2019120284-appb-000270
Figure PCTCN2019120284-appb-000271
在本发明中，术语“亚环烷基”是指具有指定数目环碳原子数的非芳香族的饱和或部分不饱和的二价环烃基，亚环烷基可以为单环或多环，可以为并环、螺环和桥环结构。亚环烷基的例子包括但不限于
Figure PCTCN2019120284-appb-000272
(即1,3-亚环丁基)、
Figure PCTCN2019120284-appb-000273
(即1,3-亚环戊基)、
Figure PCTCN2019120284-appb-000274
(即1,4-亚环己基)或
Figure PCTCN2019120284-appb-000275
In the present invention, the term "cycloalkylene" refers to a non-aromatic saturated or partially unsaturated divalent cyclic hydrocarbon group having the specified number of ring carbon atoms. The cycloalkylene group may be monocyclic or polycyclic, may For the ring, spiral ring and bridge ring structure. Examples of cycloalkylene include, but are not limited to
Figure PCTCN2019120284-appb-000272
(I.e. 1,3-cyclobutylene),
Figure PCTCN2019120284-appb-000273
(I.e. 1,3-cyclopentylene),
Figure PCTCN2019120284-appb-000274
(I.e. 1,4-cyclohexylene) or
Figure PCTCN2019120284-appb-000275
在本发明中，术语“亚杂环烷基”是指亚环烷基(如本发明中所定义)中的至少一个环碳原子被选自N、O和S的杂原子代替形成的非芳香族的饱和或部分不饱和的二价环烃基。亚杂环烷基可以通过其中的杂原子或碳原子连接到分子中的其他部分。并环的亚杂环烷基的例子包括但不限于
Figure PCTCN2019120284-appb-000276
Figure PCTCN2019120284-appb-000277
桥环的亚杂环烷基包括但不限于
Figure PCTCN2019120284-appb-000278
Figure PCTCN2019120284-appb-000279
螺环的亚杂环烷基包括但不限于
Figure PCTCN2019120284-appb-000280
和
Figure PCTCN2019120284-appb-000281
In the present invention, the term "heterocycloalkylene" refers to a non-aromatic group formed by replacing at least one ring carbon atom in a cycloalkylene group (as defined in the present invention) with a hetero atom selected from N, O, and S Group of saturated or partially unsaturated divalent cyclic hydrocarbon groups. Heterocycloalkylene can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. Examples of heterocyclic heterocycloalkylene include, but are not limited to
Figure PCTCN2019120284-appb-000276
Figure PCTCN2019120284-appb-000277
Bridged ring heterocycloalkylene groups include, but are not limited to
Figure PCTCN2019120284-appb-000278
Figure PCTCN2019120284-appb-000279
Spirocyclic heterocycloalkylene groups include, but are not limited to
Figure PCTCN2019120284-appb-000280
with
Figure PCTCN2019120284-appb-000281
在本发明中，术语“芳基”是指任何稳定的在各环中可高达7个原子的单环或者多环(例如双环或三环)碳环，其中至少一个环是芳香环。芳基的实例包括不限于苯基、萘基、四氢萘基、2,3-二氢化茚基、菲基、蒽基或者苊基(acenaphthyl)。可以理解，在芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳环进行的。In the present invention, the term "aryl" refers to any stable monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, at least one of which is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthrenyl, anthracenyl, or acenaphthyl. It can be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
在本发明中，术语“亚芳基”是指二价的的芳基。1,4-亚苯基即
Figure PCTCN2019120284-appb-000282
In the present invention, the term "arylene" refers to a divalent aryl group. 1,4-phenylene
Figure PCTCN2019120284-appb-000282
在本发明中，术语“杂芳基”是指各环中可高达7个原子的稳定单环或者多环(例如双环或三环)碳环，其中至少一个环是芳香环并且含有至少一个选自O、N和S的杂原子。杂芳基可以通过其中的杂原子或碳原子连接到分子中的其他部分。杂芳基的例子包括但不限于吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡 嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基(例如，吡咯-1-基即
Figure PCTCN2019120284-appb-000283
吡咯-2-基即
Figure PCTCN2019120284-appb-000284
)、四氢喹啉基。可以理解，在杂芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳香环进行的。 In the present invention, the term "heteroaryl" refers to a stable monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains at least one selected Heteroatoms from O, N and S. Heteroaryl groups can be attached to other parts of the molecule through heteroatoms or carbon atoms therein. Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnoline, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl , Benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl (eg, pyrrole-1 -Base
Figure PCTCN2019120284-appb-000283
Pyrrol-2-yl
Figure PCTCN2019120284-appb-000284
), Tetrahydroquinolinyl. It can be understood that in the case where the heteroaryl substituent is a bicyclic substituent, and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
在本发明中，术语“亚杂芳基”是指二价的杂芳基。1,4-(6元亚杂芳基)中的6元亚杂芳基是单环的，其中1和4并不指6元亚杂芳基中环原子本来的编号，而是指6元亚杂芳基的两个连接位点的相对位置为对位，1,4-(6元亚杂芳基)的例子包括但不限于
Figure PCTCN2019120284-appb-000285
In the present invention, the term "heteroarylene" refers to a divalent heteroaryl group. The 6-membered heteroarylene group in 1,4- (6-membered heteroarylene) is monocyclic, where 1 and 4 do not refer to the original number of the ring atoms in the 6-membered heteroarylene group, but refer to the 6-membered subarylene group The relative position of the two connection sites of the heteroaryl group is para. Examples of 1,4- (6-membered heteroarylene) include but are not limited to
Figure PCTCN2019120284-appb-000285
本发明所列举的连接基团没有指明其连接方向时，其连接方向是按与从左往右的读取顺序相同的方向进行连接的，举例说明如下，
Figure PCTCN2019120284-appb-000286
中连接基团L 1为-C-D-，此时-C-D-按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019120284-appb-000287
而不构成
Figure PCTCN2019120284-appb-000288
具体到本发明中，如式I所示的化合物中的
Figure PCTCN2019120284-appb-000289
中，当L为-M 2-M 3-M 4-时，形成的结构为
Figure PCTCN2019120284-appb-000290
而不为
Figure PCTCN2019120284-appb-000291
当列举L为
Figure PCTCN2019120284-appb-000292
时，形成的结构为
Figure PCTCN2019120284-appb-000293
而不为
Figure PCTCN2019120284-appb-000294
When the linking groups listed in the present invention do not indicate the linking direction, the linking direction is connected in the same direction as the reading order from left to right. Examples are as follows,
Figure PCTCN2019120284-appb-000286
The linking group L 1 is -CD-, and then -CD- is connected to ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2019120284-appb-000287
Not constitute
Figure PCTCN2019120284-appb-000288
Specifically in the present invention, among the compounds represented by formula I
Figure PCTCN2019120284-appb-000289
In the case where L is -M 2 -M 3 -M 4- , the structure formed is
Figure PCTCN2019120284-appb-000290
Instead of
Figure PCTCN2019120284-appb-000291
When enumerating L is
Figure PCTCN2019120284-appb-000292
, The structure formed is
Figure PCTCN2019120284-appb-000293
Instead of
Figure PCTCN2019120284-appb-000294
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。Combinations of the linking groups, substituents, and / or variants thereof are only allowed if such combinations will produce stable compounds.
在本发明中，除非另有说明，术语“卤素”是指F、Cl、Br、I。In the present invention, unless otherwise stated, the term "halogen" refers to F, Cl, Br, I.
在本发明中，术语“药学上可接受的盐”表示由适宜的非毒性有机酸、无机酸、有机碱或无机碱与如式I或I’所示的化合物形成的盐，其保留如式I或I’所示的化合物的生物活性。所述的有机酸可为本领域常规的能成盐的各种有机酸，优选甲磺酸、对甲苯磺酸、马 来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、羟乙基磺酸、萘磺酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸，优选盐酸、硫酸和磷酸中的一种或多种。所述的有机碱可为本领域常规的能成盐的各种有机碱，优选吡啶类、咪唑类、吡嗪类、吲哚类、嘌啉类、叔胺类和苯胺类中的一种或多种。所述的叔胺类有机碱优选三乙胺和/或N,N-二异丙基乙胺。所述的苯胺类有机碱优选N,N-二甲基苯胺。所述的吡啶类有机碱优选吡啶、甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡啶中的一种或多种。所述的无机碱可为本领域常规的能成盐的各种无机碱，优选碱金属氢化物、碱金属的氢氧化物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钾和碳酸氢钠中的一种或多种。所述的碱金属氢化物优选氢化钠和/或氢化钾。所述的碱金属的氢氧化物优选氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。所述的碱金属的烷氧化物优选甲醇钠、乙醇钠、叔丁醇钾和叔丁醇钠中的一种或多种。在本发明的一些实施方案中，药学上可接受的盐为盐酸盐。In the present invention, the term "pharmaceutically acceptable salt" means a salt formed of a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base and a compound represented by Formula I or I ', which retains the formula The biological activity of the compound represented by I or I '. The organic acid may be various organic acids that can form salts in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , Propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalene sulfonic acid and one or more of salicylic acid. The inorganic acid may be various conventional inorganic acids capable of forming salts in the art, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base may be a variety of conventional organic bases capable of forming salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines Species. The tertiary amine organic base is preferably triethylamine and / or N, N-diisopropylethylamine. The aniline organic base is preferably N, N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic base may be various inorganic bases conventionally capable of forming salts in the art, preferably alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate , One or more of potassium bicarbonate and sodium bicarbonate. The alkali metal hydride is preferably sodium hydride and / or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide. In some embodiments of the invention, the pharmaceutically acceptable salt is the hydrochloride salt.
术语“溶剂化物”表示如式I或I’所示的化合物与适宜的溶剂形成的物质。所述的溶剂较佳地为水或有机溶剂。The term "solvate" means a substance formed by a compound represented by formula I or I 'and a suitable solvent. The solvent is preferably water or an organic solvent.
本发明的化合物和它们的结构还表示包括所有异构体(例如对映异构体、非对映异构体、几何异构体和构象异构体)形式，它们可以根据对于氨基酸的绝对立体化学定义为(R)-/(S)-或者(D)-/(L)-或者(R,R)-/(R,S)-/(S,S)-。本发明包括所有这些可能的异构体，以及它们的外消旋的、对映体富集的和任选的纯的形式。旋光(+)和(-)，(R)-和(S)-以及(R,R)-/(R,S)-/(S,S)-或(D)-和(L)-异构体可以使用手性合成、手性拆分制备，或者可以使用常规技术例如但不限于使用手性柱的高效液相(HPLC)拆分。当本文所述的化合物包含烯基双键或其他几何不对称中心时，除非另有说明，所述化合物包括E和Z几何异构体两者。同样，还包括所有互变异构体形式。The compounds of the present invention and their structures are also meant to include all isomers (e.g. enantiomers, diastereomers, geometric isomers and conformational isomers), which can be based on the absolute stereochemistry for amino acids Chemistry is defined as (R)-/ (S)-or (D)-/ (L)-or (R, R)-/ (R, S)-/ (S, S)-. The present invention includes all these possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms. Optical rotation (+) and (-), (R)-and (S)-and (R, R)-/ (R, S)-/ (S, S)-or (D)-and (L) -iso Constructs can be prepared using chiral synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid phase (HPLC) using chiral columns. When the compounds described herein contain alkenyl double bonds or other centers of geometric asymmetry, unless otherwise stated, the compounds include both E and Z geometric isomers. Similarly, all tautomeric forms are also included.
在本发明中，术语“立体异构体”指由相同的原子以相同的化学键键合构成但具有不同三维结构的化合物，它们不可互换。本发明涵盖各种立体异构体及其混合物并包括“对映异构体”和“非对映异构体”，对映异构体指其分子互为不可重叠的镜像的两种立体异构体；非对映异构体是指分子具有两个或多个手性中心，并且分子间为非镜像关系的立体异构体。In the present invention, the term "stereoisomer" refers to a compound composed of the same atoms bonded with the same chemical bond but having different three-dimensional structures, and they are not interchangeable. The present invention covers various stereoisomers and mixtures thereof and includes "enantiomers" and "diastereomers". Enantiomers refer to two stereoisomers whose molecules are non-overlapping mirror images of each other Conformator; diastereomer is a stereoisomer with two or more chiral centers and a non-mirror relationship between the molecules.
在本发明中，术语“互变异构体”指质子从分子的一个原子从原位置移动到同一分子的另一个位置上。本发明包括任何所述化合物的互变异构体。In the present invention, the term "tautomer" refers to the movement of a proton from one atom of a molecule to another position of the same molecule. The invention includes tautomers of any of the compounds.
在本发明中，术语“药物前体”是指包含生物反应官能团的化合物的衍生物，使得在生 物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。In the present invention, the term "prodrug" refers to a derivative of a compound containing a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide The compound. Generally, the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until it is cleaved from the bioreactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound. For example, the prodrug may contain biohydrolyzable groups. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Acyl urea.
在本发明中，术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本发明的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素)代替碳原子的化合物处于本发明的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势(如体内半衰期增加或剂量需求减少)。因此，在本发明中，所述的同位素衍生物优选为氘代物。 In the present invention, the term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the present invention, in addition to replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with an 18 F-fluorine label ( 18 F isotope), or using 11 C-, 13 C-, or 14 C-rich Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present invention. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased half-life in vivo or reduced dose requirements) ). Therefore, in the present invention, the isotopic derivative is preferably a deuterium.
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“治疗有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or medicament that is non-toxic but achieves the desired effect. For the oral dosage form of the present invention, the "therapeutically effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine experiments.
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of meeting the common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.
本发明的积极进步效果在于：提供一种三唑并环类化合物、其制备方法、中间体和应用，本发明的三唑并环类化合物可以作为腺苷A2A受体拮抗剂或组蛋白去乙酰化酶HDAC抑制剂。进一步地，本发明的三唑并环类化合物可以同时具有腺苷A2A受体拮抗活性和组蛋白去乙酰化酶HDAC抑制活性，从而可以用于治疗肿瘤和中枢神经系统疾病等相关疾病。The positive progress effect of the present invention is to provide a triazolocyclic compound, its preparation method, intermediate and application. The triazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylation HDAC inhibitor. Further, the triazolocyclic compounds of the present invention can have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity, and thus can be used to treat tumors and central nervous system diseases and other related diseases.
具体实施方式detailed description
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不 以任何方式限制本发明的保护范围。在化学制备实施例中，目标产物和中间体以核磁共振氢谱( 1H NMR)和质谱(MS，ESI)的方式进行表征。 The invention will be further exemplified in the following examples. These examples are only for illustrating the present invention, but do not limit the protection scope of the present invention in any way. In the chemical preparation examples, the target products and intermediates were characterized by nuclear magnetic resonance hydrogen spectroscopy ( 1 H NMR) and mass spectrometry (MS, ESI).
实施例1：4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)-N-羟基苯甲酰胺(化合物I-1)的制备Example 1: 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5- Yl) amino) methyl) -N-hydroxybenzamide (Compound I-1)
步骤1：4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)-N-羟基苯甲酸甲酯的制备(中间体Int-1)的制备Step 1: 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) methyl) -N-hydroxybenzoic acid methyl ester (Intermediate Int-1)
Figure PCTCN2019120284-appb-000295
Figure PCTCN2019120284-appb-000295
将2-(呋喃-2-基)-5-甲砜基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-7-胺(0.10g,0.36mmol)(制备方法参见J Med Chem,2015,58,718-738)和4-氨甲基苯甲酸甲酯(0.248g,1.5mmol)溶于乙腈(10mL)中，室温搅拌过夜。减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得白色固体中间体Int-1(0.124g，收率95％)。 1H NMR(500MHz,DMSO-d 6)δ8.25(s,2H),8.11–8.02(m,1H),7.92(d,J＝8.1Hz,2H),7.86(s,1H),7.46(d,J＝7.9Hz,2H),7.10–6.99(m,1H),6.67(s,1H),4.64–4.52(m,2H),3.83(s,3H)。HRMS(ESI)C 17H 16N 7O 3 +[M+H] +计算值：366.1315，实测值：366.1318。 2- (furan-2-yl) -5-methylsulfonyl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-7-amine (0.10g, 0.36 mmol) (for the preparation method, see J Med Chem, 2015, 58, 718-738) and methyl 4-aminomethylbenzoate (0.248 g, 1.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain white solid intermediate Int-1 (0.124 g, yield 95%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.25 (s, 2H), 8.11–8.02 (m, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.86 (s, 1H), 7.46 ( d, J = 7.9 Hz, 2H), 7.10–6.99 (m, 1H), 6.67 (s, 1H), 4.64–4.52 (m, 2H), 3.83 (s, 3H). HRMS (ESI) C 17 H 16 N 7 O 3 + [M + H] + calculated value: 366.1315, found value: 366.1318.
步骤2：4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)-N-羟基苯甲酰胺(化合物I-1)的制备Step 2: 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Amino) methyl) -N-hydroxybenzamide (Compound I-1)
Figure PCTCN2019120284-appb-000296
Figure PCTCN2019120284-appb-000296
将氢氧化钾(1.29g,23mmol)的无水甲醇溶液(3.22mL)于0℃下缓慢滴加至盐酸羟胺(1.07g,15.4mmol)的无水甲醇溶液(5.52mL)中。加毕缓慢升温至室温搅拌0.5小时，过滤除去固体得羟胺的甲醇溶液。将步骤1中得到的中间体Int-1(0.080g，0.22mmol)加入该羟胺的甲醇溶液中，室温搅拌1小时。用氯化氢的1,4-二氧六环溶液(4M)中和反应液至pH7.4，减压蒸干溶剂，向固体残留物中加入水，室温搅拌1小时，过滤得白色固体化合物I-1(0.056g，收率70％)。 1H NMR(500MHz,DMSO-d 6)δ8.23(s,2H),8.09–7.97(m,1H),7.86(s,1H),7.69(d,J＝7.7Hz,2H),7.37(d,J＝7.5Hz,2H),7.09–6.98(m,1H),6.67(s,1H),4.62–4.41(m,2H)；HRMS(ESI)C 16H 15N 8O 3 +[M+H] +计算值：367.1267，实 测值：367.1274。 Anhydrous methanol solution (3.22 mL) of potassium hydroxide (1.29 g, 23 mmol) was slowly added dropwise to an anhydrous methanol solution (5.52 mL) of hydroxylamine hydrochloride (1.07 g, 15.4 mmol) at 0 ° C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 0.5 hour, and the solid was removed by filtration to obtain a methanol solution of hydroxylamine. The intermediate Int-1 (0.080 g, 0.22 mmol) obtained in step 1 was added to the hydroxylamine methanol solution, and stirred at room temperature for 1 hour. The reaction solution was neutralized with 1,4-dioxane solution (4M) of hydrogen chloride to pH 7.4, the solvent was evaporated under reduced pressure, water was added to the solid residue, stirred at room temperature for 1 hour, and filtered to obtain white solid compound 1 (0.056g, 70% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.23 (s, 2H), 8.09–7.97 (m, 1H), 7.86 (s, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.37 ( d, J = 7.5Hz, 2H), 7.09–6.98 (m, 1H), 6.67 (s, 1H), 4.62–4.41 (m, 2H); HRMS (ESI) C 16 H 15 N 8 O 3 + [M + H] + Calculated value: 367.1267, found value: 367.1274.
实施例2：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)-N-羟基苯甲酰胺(化合物I-2)的制备Example 2: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) ethyl) -N-hydroxybenzamide (Compound I-2)
Figure PCTCN2019120284-appb-000297
Figure PCTCN2019120284-appb-000297
将实施例1步骤1中的“4-氨甲基苯甲酸甲酯”替换成“4-(2-氨乙基)苯甲酸甲酯”(制备方法参见WO2017133521)，其余所需原料，试剂及制备方法同实施例1，可得白色固体化合物(I-2)。 1H NMR(500MHz,DMSO-d 6)δ11.15(s,1H),8.99(s,1H),8.21(s,2H),7.87(s,1H),7.69(d,J＝7.8Hz,2H),7.62–7.49(m,1H),7.37–7.29(m,2H),7.06(d,J＝3.2Hz,1H),6.68(s,1H),3.55–3.44(m,2H),2.95–2.83(m,2H)；HRMS(ESI)C 17H 17N 8O 3 +[M+H] +计算值：381.1424；实测值：381.1428。 Replace "Methyl 4-aminomethylbenzoate" in Step 1 of Example 1 with "Methyl 4- (2-aminoethyl) benzoate" (for the preparation method, see WO2017133521), the remaining required raw materials, reagents and The preparation method is the same as that in Example 1, and a white solid compound (I-2) can be obtained. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 8.99 (s, 1H), 8.21 (s, 2H), 7.87 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.62–7.49 (m, 1H), 7.37–7.29 (m, 2H), 7.06 (d, J = 3.2 Hz, 1H), 6.68 (s, 1H), 3.55–3.44 (m, 2H), 2.95 – 2.83 (m, 2H); HRMS (ESI) C 17 H 17 N 8 O 3 + [M + H] + calculated value: 381.1424; measured value: 381.1428.
实施例3：4-(3-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)丙基)-N-羟基苯甲酰胺(化合物I-3)的制备Example 3: 4- (3-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) propyl) -N-hydroxybenzamide (Compound I-3)
Figure PCTCN2019120284-appb-000298
Figure PCTCN2019120284-appb-000298
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成“4-(3-氨丙基)苯甲酸甲酯”(制备方法参见WO2012117421)，其余所需原料，试剂及制备方法同实施例1，可得白色固体化合物(I-3)。 1H NMR(800MHz,DMSO-d 6)δ11.13(s,1H),8.96(s,1H),8.50–7.91(m,2H),7.87(s,1H),7.68(d,J＝8.0Hz,2H),7.61–7.49(m,1H),7.31(d,J＝7.9Hz,2H),7.07–7.03(m,1H),6.68(s,1H),3.32–3.25(m,2H),2.68(t,J＝7.7Hz,2H),1.89–1.81(m,2H)；HRMS(ESI)C 18H 19N 8O 3 +[M+H] +计算值：395.1580，实测值：395.1561。 Replace "Methyl 4-aminomethylbenzoate" in Example 1 with "Methyl 4- (3-aminopropyl) benzoate" (for the preparation method, see WO2012117421), the remaining required raw materials, reagents and preparation methods As in Example 1, a white solid compound (I-3) can be obtained. 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.13 (s, 1H), 8.96 (s, 1H), 8.50–7.91 (m, 2H), 7.87 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.61–7.49 (m, 1H), 7.31 (d, J = 7.9Hz, 2H), 7.07–7.03 (m, 1H), 6.68 (s, 1H), 3.32–3.25 (m, 2H) , 2.68 (t, J = 7.7 Hz, 2H), 1.89–1.81 (m, 2H); HRMS (ESI) C 18 H 19 N 8 O 3 + [M + H] + calculated value: 395.1580, measured value: 395.1561 .
实施例4：4-(2-((7-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙氧基)-N-羟基苯甲酰胺(化合物I-4)的制备Example 4: 4- (2-((7-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-a] [1,3,5] triazine -5-yl) amino) ethoxy) -N-hydroxybenzamide (compound I-4)
Figure PCTCN2019120284-appb-000299
Figure PCTCN2019120284-appb-000299
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成“4-(2-氨基乙氧基)苯甲酸甲酯”(制备方法参见WO2001000206)，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-4)。 1H NMR(500MHz,DMSO-d 6)δ11.07(s,1H),8.90(s,1H),8.58–7.99(m,3H),7.87(s,1H),7.72(d,J＝8.5Hz,2H),7.68–7.59(m,1H),7.10–6.93(m,3H),6.68(s,1H),4.23–4.11(m,2H),3.71–3.59(m,2H)；HRMS(ESI)C 17H 17N 8O 4 +[M+H] +计算值：397.1373，实测值：397.1378。 Replace "Methyl 4-aminomethylbenzoate" in Example 1 with "Methyl 4- (2-aminoethoxy) benzoate" (see WO2001000206 for the preparation method), the remaining required raw materials, reagents and preparation The method is the same as in Example 1, to obtain a white solid compound (I-4). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.58–7.99 (m, 3H), 7.87 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.68–7.59 (m, 1H), 7.10–6.93 (m, 3H), 6.68 (s, 1H), 4.23–4.11 (m, 2H), 3.71–3.59 (m, 2H); HRMS ( ESI) C 17 H 17 N 8 O 4 + [M + H] + Calculated value: 397.1373, found value: 397.1378.
实施例5：(E)-3-(4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)苯基)-N-羟基丙烯酰胺(化合物I-5)的制备Example 5: (E) -3- (4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3, 5] Preparation of triazin-5-yl) amino) methyl) phenyl) -N-hydroxyacrylamide (Compound I-5)
Figure PCTCN2019120284-appb-000300
Figure PCTCN2019120284-appb-000300
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成“(E)-3-(4-(氨甲基)苯基)丙烯酸甲酯”(制备方法参见WO2011021209)，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-5)。 1H NMR(800MHz,DMSO-d 6)δ10.72(s,1H),10.08(s,1H),8.54-8.10(m,2H),8.10–7.98(m,1H),7.90–7.83(m,1H),7.50(d,J＝7.5Hz,2H),7.42(d,J＝15.7Hz,1H),7.35(d,J＝7.7Hz,2H),7.08–7.00(m,1H),6.67(s,1H),6.42(d,J＝15.7Hz,1H),4.57–4.45(m,2H)；HRMS(ESI)C 18H 17N 8O 3 +[M+H] +计算值：393.1424,实测值：393.1434。 Replace "methyl 4-aminomethylbenzoate" in Example 1 with "(E) -3- (4- (aminomethyl) phenyl) acrylic acid methyl ester" (for the preparation method, see WO2011021209) The raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-5). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.72 (s, 1H), 10.08 (s, 1H), 8.54-8.10 (m, 2H), 8.10–7.98 (m, 1H), 7.90–7.83 (m , 1H), 7.50 (d, J = 7.5 Hz, 2H), 7.42 (d, J = 15.7 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 7.08–7.00 (m, 1H), 6.67 (s, 1H), 6.42 (d, J = 15.7 Hz, 1H), 4.57–4.45 (m, 2H); HRMS (ESI) C 18 H 17 N 8 O 3 + [M + H] + calculated value: 393.1424 , Measured value: 393.1434.
实施例6：(E)-3-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯基)-N-羟基丙烯酰胺(化合物I-6)的制备Example 6: (E) -3- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1, Preparation of 3,5] triazin-5-yl) amino) ethyl) phenyl) -N-hydroxyacrylamide (Compound I-6)
Figure PCTCN2019120284-appb-000301
Figure PCTCN2019120284-appb-000301
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成“(E)-3-(4-(2-氨乙基)苯基)丙烯酸甲酯”(制备方法参见MedChemComm,2013,4,1562-1570)，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-6)。 1H NMR(800MHz,DMSO-d 6)δ10.71(s,1H),8.62–7.96(m,2H),7.89–7.85(m,1H),7.56–7.52(m,1H),7.49(d,J＝7.7Hz,2H),7.42(d,J＝15.7Hz,1H),7.29(d,J＝7.9Hz,2H),7.10–7.05(m,1H),6.70–6.66(m,1H),6.42(d,J＝15.9Hz,1H),3.52–3.48(m,2H),2.90–2.85(m,2H)；HRMS(ESI)C 19H 19N 8O 3 +[M+H] +计算值：407.1575,实测值：407.1580。 Replace "Methyl 4-aminomethylbenzoate" in Example 1 with "(E) -3- (4- (2-aminoethyl) phenyl) acrylic acid methyl ester" (for preparation methods, see MedChemComm, 2013 , 4,1562-1570), the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-6). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 8.62–7.96 (m, 2H), 7.89–7.85 (m, 1H), 7.56–7.52 (m, 1H), 7.49 (d , J = 7.7 Hz, 2H), 7.42 (d, J = 15.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.10–7.05 (m, 1H), 6.70–6.66 (m, 1H) , 6.42 (d, J = 15.9 Hz, 1H), 3.52–3.48 (m, 2H), 2.90–2.85 (m, 2H); HRMS (ESI) C 19 H 19 N 8 O 3 + [M + H] + Calculated value: 407.1575, measured value: 407.1580.
实施例7：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)(甲基)氨基)乙基-N-羟基苯甲酰胺(化合物I-7)的制备Example 7: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) (methyl) amino) ethyl-N-hydroxybenzamide (Compound I-7)
Figure PCTCN2019120284-appb-000302
Figure PCTCN2019120284-appb-000302
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成“4-(2-(甲氨基)乙基)苯甲酸甲酯”(制备方法参见WO2008156820)，其余所需原料，试剂及制备方法同实施例1，可得白色固体化合物(I-7)。 1H NMR(800MHz,DMSO-d 6)δ11.16(s,1H),8.34(brs,2H),7.89(s,1H),7.70(t,J＝8.0Hz,2H),7.37(dd,J＝26.0,7.8Hz,2H),7.12–7.04(m,1H),6.69(s,1H),3.83–3.76(m,2H),3.06(d,J＝8.6Hz,3H),2.96–2.89(m,2H)；HRMS(ESI)C 18H 19N 8O 3[M+H] +计算值：395.1580,实测值：395.1584。 Replace "Methyl 4-aminomethylbenzoate" in Example 1 with "Methyl 4- (2- (methylamino) ethyl) benzoate" (see WO2008156820 for the preparation method), and the remaining required raw materials and reagents The preparation method is the same as that in Example 1, to obtain a white solid compound (I-7). 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.16 (s, 1H), 8.34 (brs, 2H), 7.89 (s, 1H), 7.70 (t, J = 8.0 Hz, 2H), 7.37 (dd, J = 26.0, 7.8Hz, 2H), 7.12–7.04 (m, 1H), 6.69 (s, 1H), 3.83–3.76 (m, 2H), 3.06 (d, J = 8.6Hz, 3H), 2.96–2.89 (m, 2H); HRMS (ESI) C 18 H 19 N 8 O 3 [M + H] + calculated value: 395.1580, found value: 395.1584.
实施例8：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)(乙基)氨基)乙基-N-羟基苯甲酰胺(化合物I-8)的制备Example 8: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) (ethyl) amino) ethyl-N-hydroxybenzamide (Compound I-8)
步骤1：4-(2-(乙胺基)乙基)苯甲酸甲酯(中间Int-2)的制备Step 1: Preparation of methyl 4- (2- (ethylamino) ethyl) benzoate (intermediate Int-2)
Figure PCTCN2019120284-appb-000303
Figure PCTCN2019120284-appb-000303
4-(2-氨乙基)苯甲酸甲酯(制备方法参见WO2017133521)(0.50g,2.78mmol)、乙醛(0.122g,2.78mmol)与三乙胺(0.78mL)共同溶解于甲醇(2.5mL)中，加入醋酸硼氢化钠(0.91g,4.17mmol)，室温搅拌12小时。减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得黄色固体中间体Int-2(0.43g,收率74％)。HRMS(ESI)C 12H 18NO 2 +[M+H] +计算值：208.1332,实测值：208.1341。 Methyl 4- (2-aminoethyl) benzoate (see WO2017133521 for preparation method) (0.50g, 2.78mmol), acetaldehyde (0.122g, 2.78mmol) and triethylamine (0.78mL) are dissolved in methanol (2.5 mL), add sodium borohydride acetate (0.91 g, 4.17 mmol), and stir at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain yellow solid intermediate Int-2 (0.43 g, yield 74%). HRMS (ESI) C 12 H 18 NO 2 + [M + H] + calculated value: 208.1332, found value: 208.1341.
步骤2：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)(乙基)氨基)乙基-N-羟基苯甲酰胺(化合物I-8)的制备Step 2: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) (ethyl) amino) ethyl-N-hydroxybenzamide (Compound I-8)
Figure PCTCN2019120284-appb-000304
Figure PCTCN2019120284-appb-000304
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成中间体Int-2，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-8)。 1H NMR(800MHz,DMSO-d 6)δ11.16(s,1H),8.54–8.13(m,2H),7.89(s,1H),7.74–7.66(m,2H),7.45–7.32(m,2H),7.14–7.04(m,1H),6.69(s,1H),3.76–3.69(m,2H),3.53(q,J＝7.0Hz,2H),2.99–2.91(m,2H),1.11(dt,J ＝13.7,7.0Hz,3H)；HRMS(ESI)C 19H 21N 8O 3 +[M+H] +计算值：409.1731,实测值：409.1744。 The "methyl 4-aminomethylbenzoate" in Example 1 was replaced with the intermediate Int-2, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1, to obtain a white solid compound (I-8). 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.16 (s, 1H), 8.54–8.13 (m, 2H), 7.89 (s, 1H), 7.74–7.66 (m, 2H), 7.45–7.32 (m , 2H), 7.14–7.04 (m, 1H), 6.69 (s, 1H), 3.76–3.69 (m, 2H), 3.53 (q, J = 7.0Hz, 2H), 2.99–2.91 (m, 2H), 1.11 (dt, J = 13.7, 7.0 Hz, 3H); HRMS (ESI) C 19 H 21 N 8 O 3 + [M + H] + calculated value: 409.1731, measured value: 409.1744.
实施例9：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)(甲基)氨基)乙氧基)-N-羟基苯甲酰胺(化合物I-9)的制备Example 9: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) (methyl) amino) ethoxy) -N-hydroxybenzamide (Compound I-9)
步骤1：4-(2-((叔丁氧羰基)(甲基)氨基)乙氧基)苯甲酸甲酯(中间体Int-3)的制备Step 1: Preparation of methyl 4- (2-((tert-butoxycarbonyl) (methyl) amino) ethoxy) benzoate (intermediate Int-3)
Figure PCTCN2019120284-appb-000305
Figure PCTCN2019120284-appb-000305
将DIAD(2.03g,15mmol)的无水四氢呋喃溶液(15mL)滴加至4-羟基苯甲酸甲酯(1.52g，10mmol)、(1.92g，11mmol)及三苯基膦(3.93g，15mmol)的无水四氢呋喃溶液(45mL)中，氮气保护下室温搅拌过夜。减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得白色固体中间体Int-3(1.86g，收率60％)。 1H NMR(500MHz,CDCl 3)δ7.95–7.88(m,2H),6.88–6.80(m,2H),4.12–4.04(m,2H),3.81(d,J＝4.7Hz,3H),3.55(t,J＝5.5Hz,2H),2.91(s,3H),1.39(s,9H)。 A solution of DIAD (2.03g, 15mmol) in anhydrous tetrahydrofuran (15mL) was added dropwise to methyl 4-hydroxybenzoate (1.52g, 10mmol), (1.92g, 11mmol) and triphenylphosphine (3.93g, 15mmol) In anhydrous tetrahydrofuran solution (45mL), stir at room temperature overnight under nitrogen. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain white solid intermediate Int-3 (1.86 g, yield 60%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.95–7.88 (m, 2H), 6.88–6.80 (m, 2H), 4.12–4.04 (m, 2H), 3.81 (d, J = 4.7Hz, 3H), 3.55 (t, J = 5.5 Hz, 2H), 2.91 (s, 3H), 1.39 (s, 9H).
步骤2：4-(2-(甲氨基)乙氧基)苯甲酸甲酯(中间体Int-4)的制备Step 2: Preparation of methyl 4- (2- (methylamino) ethoxy) benzoate (Intermediate Int-4)
Figure PCTCN2019120284-appb-000306
Figure PCTCN2019120284-appb-000306
将步骤1得到的中间体Int-3(1.8g，5.8mmol)溶于二氯甲烷(20mL)中，加入4M的氯化氢/1，4-二氧六环溶液(10mL)，室温搅拌过夜。减压蒸除溶剂得中间体Int-4的盐酸盐(1.2g，粗品收率100％)。 1H NMR(500MHz,DMSO-d 6)δ9.25(s,2H),7.95(d,J＝8.8Hz,2H),7.11(d,J＝8.8Hz,2H),4.36(t,J＝5.0Hz,2H),3.82(s,3H),3.37–3.30(m,2H),2.61(s,3H)。 The intermediate Int-3 (1.8 g, 5.8 mmol) obtained in Step 1 was dissolved in dichloromethane (20 mL), 4M hydrogen chloride / 1,4-dioxane solution (10 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain the hydrochloride salt of intermediate Int-4 (1.2 g, crude yield 100%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.25 (s, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 4.36 (t, J = 5.0Hz, 2H), 3.82 (s, 3H), 3.37–3.30 (m, 2H), 2.61 (s, 3H).
步骤3：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)(甲基)氨基)乙氧基)-N-羟基苯甲酰胺(化合物I-9)的制备Step 3: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) (methyl) amino) ethoxy) -N-hydroxybenzamide (compound I-9)
Figure PCTCN2019120284-appb-000307
Figure PCTCN2019120284-appb-000307
将实施例1中的“4-氨甲基苯甲酸甲酯”替换成中间体Int-4，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-9)。 1H NMR(800MHz,DMSO-d 6)δ11.06(s, 1H),8.66–8.06(m,2H),7.88(s,1H),7.72(s,2H),7.17–6.91(m,3H),6.68(s,1H),4.27(d,J＝24.6Hz,2H),3.98(d,J＝26.8Hz,2H),3.23(d,J＝37.2Hz,3H)；HRMS(ESI)C 18H 19N 8O 4 +[M+H] +计算值：411.1529,实测值：411.1524。 Substitute the "methyl 4-aminomethylbenzoate" in Example 1 with the intermediate Int-4, and the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-9). 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 8.66–8.06 (m, 2H), 7.88 (s, 1H), 7.72 (s, 2H), 7.17–6.91 (m, 3H ), 6.68 (s, 1H), 4.27 (d, J = 24.6 Hz, 2H), 3.98 (d, J = 26.8 Hz, 2H), 3.23 (d, J = 37.2 Hz, 3H); HRMS (ESI) C 18 H 19 N 8 O 4 + [M + H] + calculated value: 411.1529, actual value: 411.1524.
实施例10：7-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)-N-羟基庚酰胺(化合物I-10)的制备Example 10: 7-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) -N-hydroxyheptanamide (Compound I-10)
Figure PCTCN2019120284-appb-000308
Figure PCTCN2019120284-appb-000308
将实施例1中的“6-氨基己酸甲酯”替换为“7-氨基庚酸甲酯”，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-10)。 1H NMR(800MHz,DMSO-d 6)δ10.32(s,1H),8.64(s,1H),8.46–7.89(m,2H),7.86(s,1H),7.51–7.36(m,1H),7.09–7.00(m,1H),6.70–6.62(m,1H),3.28–3.21(m,2H),1.99–1.91(m,2H),1.56–1.45(m,4H),1.31–1.24(m,4H)；HRMS(ESI)C 15H 21N 8O 3 +[M+H] +计算值：61.1737,实测值：361.1731。 Replace "Methyl 6-aminocaproate" in Example 1 with "Methyl 7-aminoheptanoate", the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-10) . 1 H NMR (800MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.64 (s, 1H), 8.46-7.89 (m, 2H), 7.86 (s, 1H), 7.51-7.36 (m, 1H) ), 7.09–7.00 (m, 1H), 6.70–6.62 (m, 1H), 3.28–3.21 (m, 2H), 1.99–1.91 (m, 2H), 1.56–1.45 (m, 4H), 1.31–1.24 (m, 4H); HRMS (ESI) C 15 H 21 N 8 O 3 + [M + H] + calculated value: 61.1737, found value: 361.1731.
根据实施例1所提供列举的方法，通过变换相对应的原料，用相同的方法可制备实施例11-12所列的化合物，详见表1。According to the listed methods provided in Example 1, the compounds listed in Examples 11-12 can be prepared in the same way by changing the corresponding raw materials, as shown in Table 1.
表1Table 1
Figure PCTCN2019120284-appb-000309
Figure PCTCN2019120284-appb-000309
实施例13：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)氨基)乙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-13)的制备Example 13: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) amino) ethyl) -N- (2-aminophenyl) benzamide (Compound I-13)
步骤1：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)氨基)乙基)-苯甲酸(化合物Int-5)的制备Step 1: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) amino) amino) ethyl) -benzoic acid (Compound Int-5)
Figure PCTCN2019120284-appb-000310
Figure PCTCN2019120284-appb-000310
将实施例2、步骤1中得到的酯类中间体4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)氨基)乙基)-苯甲酸甲酯(0.19g，0.50mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶剂中，加入氢氧化锂(0.060g，2.5mmol)，室温下搅拌过夜。用氯化氢的1，4-二氧六环溶液(4M)中和反应液至pH7.4，减压蒸干溶剂，得相应羧酸中间体Int-5粗品，直接用于下一步反应。 1H NMR(800MHz,DMSO-d 6)δ12.74(s,1H),8.51–7.96(m,2H),7.90–7.84(m,3H),7.61–7.48(m,1H),7.41–7.35(m,2H),7.07–7.03(m,1H),6.69–6.64(m,1H),3.56–3.48(m,2H),2.97–2.90(m,2H)；HRMS(ESI)C 17H 16N 7O 3 +[M+H] +计算值：366.1315,实测值：366.1314。 The ester intermediate 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl) amino) amino) ethyl) -benzoic acid methyl ester (0.19g, 0.50mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), Lithium hydroxide (0.060 g, 2.5 mmol) was added and stirred at room temperature overnight. The reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-5, which was directly used in the next reaction. 1 H NMR (800 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 8.51–7.96 (m, 2H), 7.90–7.84 (m, 3H), 7.61–7.48 (m, 1H), 7.41–7.35 (m, 2H), 7.07–7.03 (m, 1H), 6.69–6.64 (m, 1H), 3.56–3.48 (m, 2H), 2.97–2.90 (m, 2H); HRMS (ESI) C 17 H 16 N 7 O 3 + [M + H] + calculated value: 366.1315, measured value: 366.1314.
步骤2：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)氨基)乙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-13)的制备Step 2: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) amino) amino) ethyl) -N- (2-aminophenyl) benzamide (Compound I-13)
Figure PCTCN2019120284-appb-000311
Figure PCTCN2019120284-appb-000311
将步骤1得到的全部中间体Int-5粗品溶于无水DMF(5mL)中，加入HATU(0.38g，1.0mmol),室温搅拌20分钟，再加入邻苯二胺(0.108g，1.0mmol)及DIPEA(0.387g，3.0mmol)，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得化合物I-13(0.104g，收率45％)。 1H NMR(800MHz,Methanol-d 4)δ7.92(d,J＝7.8Hz,2H),7.69(d,J＝1.7Hz,1H),7.43(d,J＝7.9Hz,2H),7.18(d,J＝7.8Hz,1H),7.13(d,J＝3.4Hz,1H),7.08(t,J＝7.7Hz,1H),6.93–6.88(m,1H),6.77(t,J＝7.6Hz,1H),6.61(d,J＝2.9Hz,1H),3.72–3.62(m,2H),3.02(dt,J＝14.3,6.8Hz,2H)；HRMS(ESI)C 23H 22N 9O 2 +[M+H] +计算值：456.1891,实测值：456.1876。 Dissolve all crude intermediate Int-5 obtained in Step 1 in anhydrous DMF (5mL), add HATU (0.38g, 1.0mmol), stir at room temperature for 20 minutes, then add o-phenylenediamine (0.108g, 1.0mmol) And DIPEA (0.387g, 3.0mmol), stirred at room temperature overnight. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure. The remaining solid was separated and purified by silica gel column chromatography to obtain compound I-13 (0.104 g, yield 45%). 1 H NMR (800 MHz, Methanol-d 4 ) δ 7.92 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.8Hz, 1H), 7.13 (d, J = 3.4Hz, 1H), 7.08 (t, J = 7.7Hz, 1H), 6.93–6.88 (m, 1H), 6.77 (t, J = 7.6Hz, 1H), 6.61 (d, J = 2.9Hz, 1H), 3.72–3.62 (m, 2H), 3.02 (dt, J = 14.3, 6.8Hz, 2H); HRMS (ESI) C 23 H 22 N 9 O 2 + [M + H] + calculated value: 456.1891, measured value: 456.1876.
实施例14：4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)氨基)乙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-14)的制备Example 14: 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) amino) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-14)
Figure PCTCN2019120284-appb-000312
Figure PCTCN2019120284-appb-000312
将实施例13步骤2中的邻苯二胺替换为4-氟-1,2-苯二胺，其余所需原料，试剂及制备方法同实施例13，得白色固体化合物(I-14)。 1H NMR(800MHz,DMSO-d 6)δ9.54(s,1H),8.54–7.96(m,2H),7.92(d,J＝7.7Hz,2H),7.89–7.83(m,1H),7.61–7.47(m,1H),7.39(t,J＝10.6Hz,2H),7.13–7.07(m,1H),7.06(dd,J＝3.4,0.6Hz,1H),6.71–6.62(m,1H),6.53(dd,J＝11.2,2.9Hz,1H),6.35(td,J＝8.4,2.6Hz,1H),5.20(s,2H),3.61–3.46(m,2H),3.00–2.89(m,2H).HRMS(ESI)C 23H 21FN 9O 2 +[M+H] +计算值:474.1802,实测值:474.1794. The o-phenylenediamine in Step 2 of Example 13 was replaced with 4-fluoro-1,2-phenylenediamine, and the remaining required raw materials, reagents and preparation methods were the same as in Example 13 to obtain a white solid compound (I-14). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 8.54–7.96 (m, 2H), 7.92 (d, J = 7.7 Hz, 2H), 7.89–7.83 (m, 1H), 7.61–7.47 (m, 1H), 7.39 (t, J = 10.6Hz, 2H), 7.13–7.07 (m, 1H), 7.06 (dd, J = 3.4, 0.6Hz, 1H), 6.71–6.62 (m, 1H), 6.53 (dd, J = 11.2, 2.9 Hz, 1H), 6.35 (td, J = 8.4, 2.6 Hz, 1H), 5.20 (s, 2H), 3.61–3.46 (m, 2H), 3.00–2.89 (m, 2H). HRMS (ESI) C 23 H 21 FN 9 O 2 + [M + H] + calculated value: 474.1802, actual value: 474.1794.
根据实施例13所提供列举的方法，通过变换相对应的原料，用相同的方法还可制备实施例15和16所列的化合物，详见表2。According to the method provided in Example 13, by changing the corresponding raw materials, the compounds listed in Examples 15 and 16 can also be prepared by the same method, see Table 2 for details.
表2Table 2
Figure PCTCN2019120284-appb-000313
Figure PCTCN2019120284-appb-000313
实施例17：4-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯氧基)-N-羟基丁酰胺(化合物I-17)的制备Example 17: 4- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenoxy) -N-hydroxybutyramide (Compound I-17)
步骤1：4-(4-(氰基甲基)苯氧基)丁酸甲酯(中间体Int-6)的制备Step 1: Preparation of 4- (4- (cyanomethyl) phenoxy) butyric acid methyl ester (Intermediate Int-6)
Figure PCTCN2019120284-appb-000314
Figure PCTCN2019120284-appb-000314
将4-羟基苯乙腈(1.35g,10mmol)和4-溴丁酸甲酯(1.81g,10mmol)溶解于DMF(20 mL)中，加入碳酸铯(4.48g,20mmol)，室温搅拌过夜。减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得白色固体中间体Int-6(1.13g，收率49％)。 1H NMR(500MHz,CDCl 3)δ7.24(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,1H),4.02(t,J＝6.1Hz,2H),3.74–3.67(m,5H),2.60–2.51(m,2H),2.18–2.07(m,2H)。 4-Hydroxyphenylacetonitrile (1.35 g, 10 mmol) and methyl 4-bromobutyrate (1.81 g, 10 mmol) were dissolved in DMF (20 mL), cesium carbonate (4.48 g, 20 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain white solid intermediate Int-6 (1.13 g, yield 49%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.24 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 4.02 (t, J = 6.1 Hz, 2H), 3.74–3.67 (m, 5H), 2.60–2.51 (m, 2H), 2.18–2.07 (m, 2H).
步骤2：4-(4-(2-氨乙基)苯氧基)丁酸甲酯(中间体Int-7)的制备Step 2: Preparation of methyl 4- (4- (2-aminoethyl) phenoxy) butanoate (Intermediate Int-7)
Figure PCTCN2019120284-appb-000315
Figure PCTCN2019120284-appb-000315
将中间体Int-6(1.13g,4.8mmol)溶于二氯甲烷(20mL)与甲醇(20mL)的混合溶液中，加入浓盐酸(1.5mL)及钯/碳(10％钯，500mg)，在氢气环境下室温搅拌过夜。减压蒸除溶剂得中间体Int-7的盐酸盐(1.32g，粗品收率100％)。 1H NMR(500MHz,DMSO-d 6)δ7.94(s,3H),7.16(d,J＝8.2Hz,2H),6.88(d,J＝8.2Hz,2H),3.95(t,J＝6.2Hz,2H),3.60(s,3H),3.01–2.93(m,2H),2.83–2.75(m,2H),2.46(t,J＝7.3Hz,2H),2.01–1.89(m,2H)。 The intermediate Int-6 (1.13g, 4.8mmol) was dissolved in a mixed solution of dichloromethane (20mL) and methanol (20mL), concentrated hydrochloric acid (1.5mL) and palladium / carbon (10% palladium, 500mg) were added, Stir at room temperature overnight under a hydrogen atmosphere. The solvent was distilled off under reduced pressure to obtain the hydrochloride salt of intermediate Int-7 (1.32 g, crude yield 100%). 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.94 (s, 3H), 7.16 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 3.95 (t, J = 6.2Hz, 2H), 3.60 (s, 3H), 3.01-2.93 (m, 2H), 2.83-2.75 (m, 2H), 2.46 (t, J = 7.3Hz, 2H), 2.01-1.89 (m, 2H ).
步骤3：4-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯氧基)-N-羟基丁酰胺(化合物I-17)的制备Step 3: 4- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] tri Preparation of oxazin-5-yl) amino) ethyl) phenoxy) -N-hydroxybutyramide (Compound I-17)
Figure PCTCN2019120284-appb-000316
Figure PCTCN2019120284-appb-000316
将实施例1中的“6-氨基己酸甲酯”替换为中间体Int-7，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-17)。 1H NMR(800MHz,DMSO-d 6)δ10.41(s,1H),8.54–7.97(m,2H),7.87(s,1H),7.59–7.41(m,1H),7.21–7.12(m,2H),7.09–7.04(m,1H),6.86(d,J＝7.4Hz,2H),6.68(s,1H),3.97–3.88(m,2H),3.51–3.40(m,2H),2.86–2.72(m,2H),2.12(t,J＝7.2Hz,2H),1.98–1.86(m,2H)；HRMS(ESI)C 20H 23N 8O 4 +[M+H] +计算值:439.1842,实测值:439.1838。 The "methyl 6-aminocaproate" in Example 1 was replaced with the intermediate Int-7, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-17). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.54–7.97 (m, 2H), 7.87 (s, 1H), 7.59–7.41 (m, 1H), 7.21–7.12 (m , 2H), 7.09–7.04 (m, 1H), 6.86 (d, J = 7.4 Hz, 2H), 6.68 (s, 1H), 3.97–3.88 (m, 2H), 3.51–3.40 (m, 2H), 2.86–2.72 (m, 2H), 2.12 (t, J = 7.2 Hz, 2H), 1.98–1.86 (m, 2H); HRMS (ESI) C 20 H 23 N 8 O 4 + [M + H] + calculation Value: 439.1842, measured value: 439.1838.
实施例18：5-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯氧基)-N-羟基戊酰胺(化合物I-18)的制备Example 18: 5- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenoxy) -N-hydroxyvaleramide (Compound I-18)
Figure PCTCN2019120284-appb-000317
Figure PCTCN2019120284-appb-000317
将实施例17步骤1中的“4-溴丁酸甲酯”替换为“5-溴戊酸甲酯”，其余所需原料，试剂及制备方法同实施例17，可得白色固体化合物(I-18)。 1H NMR(800MHz,DMSO-d 6)δ10.36(s,1H),8.68(s,1H),8.50–7.90(m,2H),7.86(s,1H),7.55–7.39(m,1H),7.19–7.11(m,2H),7.05(d,J＝3.0Hz,1H),6.85(d,J＝7.8Hz,2H),6.72–6.61(m,1H),3.92(t,J＝6.0Hz,2H),3.51–3.39(m,2H),2.84–2.72(m,2H),2.00(t,J＝7.1Hz,2H),1.72–1.58(m,4H)；HRMS(ESI)C 21H 25N 8O 4 +[M+H] +计算值:453.1999,实测值:453.1998。 Replace "methyl 4-bromobutyrate" in step 1 of Example 17 with "methyl 5-bromovalerate", the remaining required raw materials, reagents and preparation methods are the same as in Example 17 to obtain a white solid compound (I -18). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.68 (s, 1H), 8.50–7.90 (m, 2H), 7.86 (s, 1H), 7.55–7.39 (m, 1H ), 7.19–7.11 (m, 2H), 7.05 (d, J = 3.0 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 6.72–6.61 (m, 1H), 3.92 (t, J = 6.0Hz, 2H), 3.51–3.39 (m, 2H), 2.84–2.72 (m, 2H), 2.00 (t, J = 7.1Hz, 2H), 1.72–1.58 (m, 4H); HRMS (ESI) C 21 H 25 N 8 O 4 + [M + H] + calculated value: 453.1999, measured value: 453.1998.
实施例19：6-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯氧基)-N-羟基己酰胺(化合物I-19)的制备Example 19: 6- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenoxy) -N-hydroxyhexanamide (Compound I-19)
Figure PCTCN2019120284-appb-000318
Figure PCTCN2019120284-appb-000318
将实施例17步骤1中的“4-溴丁酸甲酯”替换为“6-溴己酸甲酯”，其余所需原料，试剂及制备方法同实施例17，得白色固体化合物(I-19)。 1H NMR(800MHz,DMSO-d 6)δ8.87–7.89(m,2H),7.86(s,1H),7.54–7.41(m,1H),7.18–7.12(m,2H),7.05(d,J＝3.3Hz,1H),6.84(d,J＝8.2Hz,2H),6.69–6.65(m,1H),3.90(t,J＝6.4Hz,2H),3.49–3.39(m,2H),2.82–2.72(m,2H),1.96(t,J＝7.3Hz,2H),1.72–1.64(m,2H),1.57–1.50(m,2H),1.41–1.33(m,2H)；HRMS(ESI)C 22H 27N 8O 4 +[M+H] +计算值：467.2155,实测值：467.2157。 Replace "4-bromobutyric acid methyl ester" in step 1 of Example 17 with "6-bromohexanoic acid methyl ester", the remaining required raw materials, reagents and preparation methods are the same as in Example 17, to obtain a white solid compound (I- 19). 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.87–7.89 (m, 2H), 7.86 (s, 1H), 7.54–7.41 (m, 1H), 7.18–7.12 (m, 2H), 7.05 (d , J = 3.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.69–6.65 (m, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.49–3.39 (m, 2H) , 2.82–2.72 (m, 2H), 1.96 (t, J = 7.3 Hz, 2H), 1.72–1.64 (m, 2H), 1.57–1.50 (m, 2H), 1.41–1.33 (m, 2H); HRMS (ESI) C 22 H 27 N 8 O 4 + [M + H] + calculated value: 467.2155, found value: 467.2157.
实施例20：5-(4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)苯氧基)-N-羟基戊酰胺(化合物I-20)的制备Example 20: 5- (4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine Preparation of 5-yl) amino) methyl) phenoxy) -N-hydroxyvaleramide (Compound I-20)
Figure PCTCN2019120284-appb-000319
Figure PCTCN2019120284-appb-000319
将实施例17步骤1中的“4-溴丁酸甲酯”替换为“5-溴戊酸甲酯”，将“4-羟基苯乙腈”替换为“4-羟基苯腈”，其余所需原料，试剂及制备方法同实施例17，得白色固体化合物(I-20)。 1H NMR(800MHz,DMSO-d 6)δ10.35(s,1H),8.67(s,1H),8.50–7.97(m,2H),7.95–7.87(m,1H),7.86(s,1H),7.24(d,J＝8.3Hz,2H),7.08–7.01(m,1H),6.86(d,J＝8.4Hz,2H),6.69–6.63(m,1H),4.48–4.36(m,2H),3.92(t,J＝6.1Hz,2H),1.99(t,J＝7.1Hz,2H),1.73–1.57(m,4H)；HRMS(ESI)C 20H 23N 8O 4 +[M+H] +计算值：439.1842,实测值：439.1846。 Replace "methyl 4-bromobutyrate" with "methyl 5-bromovalerate" in step 1 of Example 17 and replace "4-hydroxyphenylacetonitrile" with "4-hydroxybenzonitrile" The raw materials, reagents and preparation methods are the same as in Example 17, to obtain a white solid compound (I-20). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.67 (s, 1H), 8.50–7.97 (m, 2H), 7.95–7.87 (m, 1H), 7.86 (s, 1H ), 7.24 (d, J = 8.3 Hz, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.69-6.63 (m, 1H), 4.48-4.36 (m, 2H), 3.92 (t, J = 6.1 Hz, 2H), 1.99 (t, J = 7.1 Hz, 2H), 1.73–1.57 (m, 4H); HRMS (ESI) C 20 H 23 N 8 O 4 + [ M + H] + Calculated value: 439.1842, found value: 439.1846.
实施例21：2-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯氧基)-N-羟基乙酰胺(化合物I-21)的制备Example 21: 2- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenoxy) -N-hydroxyacetamide (Compound I-21)
Figure PCTCN2019120284-appb-000320
Figure PCTCN2019120284-appb-000320
将实施例17步骤1中的“4-溴丁酸甲酯”替换为溴乙酸甲酯，其余所需原料，试剂及制备方法同实施例17，得白色固体化合物(I-21)。 1H NMR(800MHz,DMSO-d 6)δ10.79(s,1H),8.95(s,1H),8.50–7.94(m,2H),7.89–7.83(m,1H),7.56–7.41(m,1H),7.21–7.13(m,2H),7.05(d,J＝3.2Hz,1H),6.89(d,J＝8.3Hz,2H),6.68–6.65(m,1H),4.42(s,1H),3.48–3.41(m,2H),2.83–2.73(m,2H)；HRMS(ESI)C 18H 19N 8O 4 +[M+H] +计算值：411.1529,实测值：411.1530。 The "methyl 4-bromobutyrate" in Step 1 of Example 17 was replaced with methyl bromoacetate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 17 to obtain a white solid compound (I-21). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 8.95 (s, 1H), 8.50–7.94 (m, 2H), 7.89–7.83 (m, 1H), 7.56–7.41 (m , 1H), 7.21–7.13 (m, 2H), 7.05 (d, J = 3.2Hz, 1H), 6.89 (d, J = 8.3Hz, 2H), 6.68–6.65 (m, 1H), 4.42 (s, 1H), 3.48–3.41 (m, 2H), 2.83–2.73 (m, 2H); HRMS (ESI) C 18 H 19 N 8 O 4 + [M + H] + calculated value: 411.1529, measured value: 411.1530.
实施例22:N 1-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯基)-N 8-羟基辛二酰胺(化合物I-22)的制备 Example 22: N 1- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5 ] Triazine-5-yl) amino) ethyl) phenyl) -N 8 -hydroxy suberamide (compound I-22)
步骤1：8-((4-(氰基甲基)苯基l)氨基)-8-氧代辛酸甲酯(中间体Int-8)的制备Step 1: Preparation of 8-((4- (cyanomethyl) phenyll) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-8)
Figure PCTCN2019120284-appb-000321
Figure PCTCN2019120284-appb-000321
将辛二酸单甲酯(0.188g,1mmol)溶于无水DMF(10mL)中，加入HATU(0.76g，2.0mmol),室温搅拌20分钟，再加入4-氨基苯乙腈(0.132g，1mmol)及DIPEA(0.774g，6.0mmol)，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得中间体Int-8(0.136g，收率45％)。HRMS(ESI)C 17H 23N 2O 3 +[M+H] +计算值:303.1709,实测值:303.1711。 Dissolve monomethyl suberate (0.188g, 1mmol) in anhydrous DMF (10mL), add HATU (0.76g, 2.0mmol), stir at room temperature for 20 minutes, then add 4-aminobenzeneacetonitrile (0.132g, 1mmol) ) And DIPEA (0.774 g, 6.0 mmol), stirred at room temperature overnight. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure. The remaining solid was separated and purified by silica gel column chromatography to obtain intermediate Int-8 (0.136 g, yield 45%). HRMS (ESI) C 17 H 23 N 2 O 3 + [M + H] + calculated value: 303.1709, found value: 303.1711.
步骤2：8-((4-(2-氨乙基)苯基)氨基)-8-氧代辛酸甲酯(中间体Int-9)的制备Step 2: Preparation of 8-((4- (2-aminoethyl) phenyl) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-9)
Figure PCTCN2019120284-appb-000322
Figure PCTCN2019120284-appb-000322
将实施例17步骤2中的中间体Int-6替换成中间体Int-8，其余所需原料，试剂及制备方法同实施例17步骤2，可得白色固体化合物Int-9的盐酸盐。HRMS(ESI)C 17H 27N 2O 3 +[M+H] +计算值:307.2022,实测值:307.2020。 The intermediate Int-6 in Step 2 of Example 17 was replaced with the intermediate Int-8, and the remaining required raw materials, reagents and preparation methods were the same as those in Step 2 of Example 17 to obtain the hydrochloride salt of the white solid compound Int-9. HRMS (ESI) C 17 H 27 N 2 O 3 + [M + H] + calculated value: 307.2022, found value: 307.2020.
步骤3：N 1-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙基)苯基)-N 8-羟基辛二酰胺(化合物I-22)的制备 Step 3: N 1- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenyl) -N 8 -hydroxy suberamide (Compound I-22)
Figure PCTCN2019120284-appb-000323
Figure PCTCN2019120284-appb-000323
将实施例1中的“6-氨基己酸甲酯”替换为中间体Int-9，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-22)。 1H NMR(800MHz,DMSO-d 6)δ10.32(s,1H),9.78(s,1H),8.64(s,1H),8.51–7.93(m,2H),7.87(s,1H),7.59–7.37(m,3H),7.16(d,J＝7.7Hz,2H),7.09–7.02(m,1H),6.73–6.63(m,1H),3.53–3.40(m,2H),2.86–2.74(m,2H),2.33–2.22(m,2H),1.94(t,J＝6.8Hz,2H),1.63–1.53(m,2H),1.53–1.43(m,2H),1.30–1.24(m,4H)；HRMS(ESI)C 24H 30N 9O 4 +[M+H] +计算值：508.2421,实测值：508.2422。 The "methyl 6-aminocaproate" in Example 1 was replaced with the intermediate Int-9, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-22). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 9.78 (s, 1H), 8.64 (s, 1H), 8.51–7.93 (m, 2H), 7.87 (s, 1H), 7.59–7.37 (m, 3H), 7.16 (d, J = 7.7Hz, 2H), 7.09–7.02 (m, 1H), 6.73–6.63 (m, 1H), 3.53–3.40 (m, 2H), 2.86– 2.74 (m, 2H), 2.33–2.22 (m, 2H), 1.94 (t, J = 6.8Hz, 2H), 1.63–1.53 (m, 2H), 1.53–1.43 (m, 2H), 1.30–1.24 ( m, 4H); HRMS (ESI) C 24 H 30 N 9 O 4 + [M + H] + calculated value: 508.2421, measured value: 508.2422.
根据实施例22所提供的方法，通过变换相对应的原料，用相同的方法可制备实施例23-25所列的化合物，详见表3.According to the method provided in Example 22, by changing the corresponding raw materials, the compounds listed in Examples 23-25 can be prepared by the same method, see Table 3.
表3table 3
Figure PCTCN2019120284-appb-000324
Figure PCTCN2019120284-appb-000324
实施例26：4-(2-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)哌嗪-1-基)乙基)-N-羟基苯甲酰胺(化合物I-26)的制备Example 26: 4- (2- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3 , 5] Triazine-5-yl) piperazin-1-yl) ethyl) -N-hydroxybenzamide (Compound I-26)
步骤1：4-(4-(甲氧基羰基)苯乙基)哌嗪-1-甲酸叔丁酯(中间体Int-10)的制备Step 1: Preparation of 4- (4- (methoxycarbonyl) phenethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate Int-10)
Figure PCTCN2019120284-appb-000325
Figure PCTCN2019120284-appb-000325
将4-(2-溴乙基)苯甲酸甲酯(0.243g，1.0mmol)、1-叔丁氧羰基哌嗪(0.372g，2.0mmol)及二异丙基乙胺(0.58g，4.5mmol)溶于DMF(5mL)中，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得中间体Int-10(0.26g，收率75％)。 1H NMR(800MHz,CDCl 3)δ7.98(d,J＝7.9Hz,2H),7.29(t,J＝7.7Hz,2H),3.92(s,3H),3.76–3.25(m,4H),3.24–2.16(m,8H),1.48(s,9H)。 Combine methyl 4- (2-bromoethyl) benzoate (0.243g, 1.0mmol), 1-tert-butoxycarbonylpiperazine (0.372g, 2.0mmol) and diisopropylethylamine (0.58g, 4.5mmol) ) Dissolved in DMF (5mL), stirred at room temperature overnight. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure. The remaining solid was separated and purified by silica gel column chromatography to obtain intermediate Int-10 (0.26 g, yield 75%). 1 H NMR (800 MHz, CDCl 3 ) δ 7.98 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 3.92 (s, 3H), 3.76–3.25 (m, 4H) , 3.24–2.16 (m, 8H), 1.48 (s, 9H).
步骤2：4-(2-(哌嗪-1-基)乙基)苯甲酸甲酯(中间体Int-11)的制备Step 2: Preparation of methyl 4- (2- (piperazin-1-yl) ethyl) benzoate (Intermediate Int-11)
Figure PCTCN2019120284-appb-000326
Figure PCTCN2019120284-appb-000326
将实施例9步骤2中的中间体Int-3替换为中间体Int-10，其余所需原料，试剂及制备方法同实施例9步骤2，得白色固体化合物(中间体Int-3)的盐酸盐。HRMS(ESI)C 14H 21N 2O 2 +[M+H] +计算值:249.1603,实测值:249.1602。 The intermediate Int-3 in Step 2 of Example 9 was replaced with Intermediate Int-10, and the remaining required raw materials, reagents and preparation methods were the same as in Step 2 of Example 9 to obtain the salt of the white solid compound (Intermediate Int-3) Acid salt. HRMS (ESI) C 14 H 21 N 2 O 2 + [M + H] + calculated value: 249.1603, found value: 249.1602.
步骤3：4-(2-(4-(2-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)哌嗪-1-基)乙基)-N-羟基苯甲酰胺(化合物I-26)的制备Step 3: 4- (2- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3, 5] Preparation of triazin-5-yl) piperazin-1-yl) ethyl) -N-hydroxybenzamide (compound I-26)
Figure PCTCN2019120284-appb-000327
Figure PCTCN2019120284-appb-000327
将实施例1中的6-氨基己酸甲酯替换为中间体Int-11，其余所需原料，试剂及制备方法同实施例1，得白色固体化合物(I-26)。 1H NMR(800MHz,DMSO-d 6)δ11.13(s,1H),8.96(s,1H),8.51–8.11(m,2H),7.91–7.83(m,1H),7.67(d,J＝8.1Hz,2H),7.32(d,J＝8.0Hz,2H),7.05(d,J＝3.2Hz,1H),6.70–6.64(m,1H),3.85–3.69(m,4H),3.34–3.30(m,4H),2.87–2.78(m,2H),2.63–2.55(m,2H)；HRMS(ESI)C 21H 24N 9O 3 +[M+H] +计算值：450.2002,实测值：450.2001。 The methyl 6-aminocaproate in Example 1 was replaced with the intermediate Int-11, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1, to obtain a white solid compound (I-26). 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.13 (s, 1H), 8.96 (s, 1H), 8.51–8.11 (m, 2H), 7.91–7.83 (m, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 3.2 Hz, 1H), 6.70–6.64 (m, 1H), 3.85–3.69 (m, 4H), 3.34 –3.30 (m, 4H), 2.87–2.78 (m, 2H), 2.63–2.55 (m, 2H); HRMS (ESI) C 21 H 24 N 9 O 3 + [M + H] + calculated value: 450.2002, Found value: 450.2001.
根据实施例26所提供的方法，通过变换相对应的原料，用相同的方法可制备实施例 27-29所示的化合物，详见表4。According to the method provided in Example 26, by changing the corresponding raw materials, the compounds shown in Examples 27-29 can be prepared by the same method, see Table 4 for details.
表4Table 4
Figure PCTCN2019120284-appb-000328
Figure PCTCN2019120284-appb-000328
根据实施例1所述的方法，通过变换相对应的原料，用类似的方法可制备实施例30-36所列的化合物，详见表5。According to the method described in Example 1, by changing the corresponding raw materials, the compounds listed in Examples 30-36 can be prepared in a similar manner, see Table 5 for details.
表5table 5
Figure PCTCN2019120284-appb-000329
Figure PCTCN2019120284-appb-000329
Figure PCTCN2019120284-appb-000330
Figure PCTCN2019120284-appb-000330
实施例37：4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)-N-(2-氨基苯基)苯甲酰胺(化合物I-37)的制备Example 37: 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5- Yl) amino) methyl) -N- (2-aminophenyl) benzamide (Compound I-37)
步骤1：4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)苯甲酸的制备(中间体Int-12)的制备Step 1: 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) methyl) benzoic acid (Intermediate Int-12)
Figure PCTCN2019120284-appb-000331
Figure PCTCN2019120284-appb-000331
将实施例1步骤1得到的酯类中间体Int-1(0.18g，0.50mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶剂中，加入氢氧化锂(0.060g，2.5mmol)，室温下搅拌过夜。用氯 化氢的1,4-二氧六环溶液(4M)中和反应液至pH7.4，减压蒸干溶剂，得相应羧酸中间体Int-12粗品，直接用于下一步反应。HRMS(ESI)C 16H 14N 7O 3 +[M+H] +计算值:352.1158,实测值:352.1125. The ester intermediate Int-1 (0.18 g, 0.50 mmol) obtained in Step 1 of Example 1 was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2.5 mL), and lithium hydroxide (0.060 g, 2.5 mmol) was added , Stir overnight at room temperature. The reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-12, which was directly used in the next reaction. HRMS (ESI) C 16 H 14 N 7 O 3 + [M + H] + calculated value: 352.1158, measured value: 352.1125.
步骤2：4-(((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)甲基)-N-(2-氨基苯基)苯甲酰胺(化合物I-37)的制备Step 2: 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Amino) methyl) -N- (2-aminophenyl) benzamide (Compound I-37)
Figure PCTCN2019120284-appb-000332
Figure PCTCN2019120284-appb-000332
将步骤1得到的全部中间体Int-12粗品溶于无水DMF(5mL)中，加入HATU(0.38g，1.0mmol),室温搅拌20分钟，再加入邻苯二胺(0.108g，1.0mmol)及DIPEA(0.387g，3.0mmol)，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得化合物I-37(0.095g，收率43％)。 1H NMR(800MHz,DMSO-d 6)δ9.60(s,1H),8.50–8.12(m,2H),8.11–8.01(m,1H),7.92(d,J＝7.5Hz,2H),7.86(s,1H),7.44(d,J＝8.1Hz,2H),7.16(d,J＝7.6Hz,1H),7.09–7.01(m,1H),6.96(t,J＝7.5Hz,1H),6.77(d,J＝7.9Hz,1H),6.67(d,J＝1.5Hz,1H),6.59(t,J＝7.4Hz,1H),4.87(s,2H),4.63–4.53(m,2H).HRMS(ESI)C 22H 20N 9O 2 +[M+H] +计算值:442.1740,实测值:442.1723. Dissolve all crude intermediate Int-12 obtained in Step 1 in anhydrous DMF (5mL), add HATU (0.38g, 1.0mmol), stir at room temperature for 20 minutes, then add o-phenylenediamine (0.108g, 1.0mmol) And DIPEA (0.387g, 3.0mmol), stirred at room temperature overnight. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain compound I-37 (0.095 g, yield 43%). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 8.50–8.12 (m, 2H), 8.11–8.01 (m, 1H), 7.92 (d, J = 7.5 Hz, 2H), 7.86 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.09–7.01 (m, 1H), 6.96 (t, J = 7.5 Hz, 1H) ), 6.77 (d, J = 7.9Hz, 1H), 6.67 (d, J = 1.5Hz, 1H), 6.59 (t, J = 7.4Hz, 1H), 4.87 (s, 2H), 4.63-4.53 (m , 2H). HRMS (ESI) C 22 H 20 N 9 O 2 + [M + H] + calculated value: 442.1740, measured value: 442.1723.
实施例38：4-(3-((7-氨基-2-(呋喃-2-基-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-38)的制备Example 38: 4- (3-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-38)
Figure PCTCN2019120284-appb-000333
Figure PCTCN2019120284-appb-000333
将实施例37步骤1中的酯类中间体Int-1替换成实施例3中得到的酯类中间体，其余所需原料，试剂及制备方法同实施例37，得黄褐色固体化合物(I-38)。 1H NMR(800MHz,DMSO-d 6)δ9.62(s,1H),8.52–7.97(m,2H),7.92(d,J＝7.7Hz,2H),7.87(s,1H),7.65–7.49(m,1H),7.38(d,J＝7.9Hz,2H),7.18(d,J＝7.5Hz,1H),7.09–7.04(m,1H),6.98(t,J＝7.6Hz,1H),6.80(d,J＝8.0Hz,1H),6.70–6.65(m,1H),6.62(t,J＝7.4Hz,1H),4.99(br,2H),3.31–3.28(m,2H),2.73(t,J＝7.6Hz,2H),1.92–1.84(m,2H).HRMS(ESI)C 24H 24N 9O 2 +[M+H] +计算值:470.2053,实测值:470.2047. Replace the ester intermediate Int-1 in Step 1 of Example 37 with the ester intermediate obtained in Example 3, and the remaining required raw materials, reagents and preparation methods are the same as in Example 37 to obtain a yellow-brown solid compound (I- 38). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.62 (s, 1H), 8.52–7.97 (m, 2H), 7.92 (d, J = 7.7 Hz, 2H), 7.87 (s, 1H), 7.65– 7.49 (m, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H), 7.09–7.04 (m, 1H), 6.98 (t, J = 7.6 Hz, 1H) ), 6.80 (d, J = 8.0Hz, 1H), 6.70-6.65 (m, 1H), 6.62 (t, J = 7.4Hz, 1H), 4.99 (br, 2H), 3.31-3.28 (m, 2H) , 2.73 (t, J = 7.6 Hz, 2H), 1.92–1.84 (m, 2H). HRMS (ESI) C 24 H 24 N 9 O 2 + [M + H] + calculated value: 470.22053, actual value: 470.2047 .
实施例39：4-(2-((7-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-a][1,3,5]三嗪-5-基)氨基)乙氧基)-N-(2-氨基苯基)苯甲酰胺(化合物I-39)的制备Example 39: 4- (2-((7-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-a] [1,3,5] triazine -5-yl) amino) ethoxy) -N- (2-aminophenyl) benzamide (compound I-39)
Figure PCTCN2019120284-appb-000334
Figure PCTCN2019120284-appb-000334
将实施例37步骤1中的酯类中间体Int-1替换成实施例4中得到的酯类中间体，其余所需原料，试剂及制备方法同实施例37，得黄褐色固体化合物(I-38)。 1H NMR(800MHz,DMSO-d 6)δ9.54(s,1H),8.57–8.02(m,2H),7.96(d,J＝8.4Hz,2H),7.87(s,1H),7.70–7.57(m,1H),7.14(d,J＝7.6Hz,1H),7.10–7.02(m,3H),6.95(t,J＝7.6Hz,1H),6.77(d,J＝7.9Hz,1H),6.67(s,1H),6.59(t,J＝7.4Hz,1H),4.86(s,2H),4.26–4.16(m,2H),3.73–3.63(m,2H).HRMS(ESI)C 23H 22N 9O 3 +[M+H] +计算值:472.1846,实测值:472.1818. Replace the ester intermediate Int-1 in Step 1 of Example 37 with the ester intermediate obtained in Example 4, the remaining required raw materials, reagents and preparation methods are the same as in Example 37 to obtain a yellow-brown solid compound (I- 38). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 8.57–8.02 (m, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.87 (s, 1H), 7.70– 7.57 (m, 1H), 7.14 (d, J = 7.6Hz, 1H), 7.10–7.02 (m, 3H), 6.95 (t, J = 7.6Hz, 1H), 6.77 (d, J = 7.9Hz, 1H) ), 6.67 (s, 1H), 6.59 (t, J = 7.4Hz, 1H), 4.86 (s, 2H), 4.26-4.16 (m, 2H), 3.73-3.63 (m, 2H). HRMS (ESI) C 23 H 22 N 9 O 3 + [M + H] + calculated value: 472.1846, measured value: 472.1818.
实施例40：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-40)的制备Example 40: 4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N- (2-aminophenyl) benzamide (Compound I-40)
步骤1：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯甲酸甲酯的制备(中间体Int-13)的制备Step 1: 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) methyl benzoate (intermediate Int-13)
Figure PCTCN2019120284-appb-000335
Figure PCTCN2019120284-appb-000335
将2-(呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-5-胺(1.0g,4.1mmol)(制备方法参见J Med Chem,,1996,39,1164-1171)与碳酸钾(0.62g,4.5mmol)溶于DMF(100mL)中，再加入4-(2-溴乙基)苯甲酸甲酯(1.08g,4.5mmol)，100℃搅拌过夜。减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得白色固体中间体Int-13(0.75g，收率45％)。 1H NMR(800MHz,CDCl 3)δ8.34(s,1H),7.93(d,J＝8.2Hz,2H),7.68(dd,J＝1.5,0.6Hz,1H),7.46(s,1H),7.25(d,J＝8.2Hz,2H),6.64(dd,J＝3.4,1.7Hz,1H),6.01(s,2H),4.65–4.62(m,2H),3.90(s,3H),3.33(t,J＝7.4Hz,2H).HRMS(ESI)C 20H 18N 7O 3 +[M+H] +计算值:404.1471,实测值:404.1464. 2- (furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidin-5-amine (1.0 g, 4.1 mmol) (preparation For the method, see J Med Chem, 1996, 39, 1164-1171) and potassium carbonate (0.62g, 4.5mmol) dissolved in DMF (100mL), and then add methyl 4- (2-bromoethyl) benzoate (1.08 g, 4.5 mmol), and stirred at 100 ° C. overnight. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain white solid intermediate Int-13 (0.75 g, yield 45%). 1 H NMR (800 MHz, CDCl 3 ) δ 8.34 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 1.5, 0.6 Hz, 1H), 7.46 (s, 1H) , 7.25 (d, J = 8.2 Hz, 2H), 6.64 (dd, J = 3.4, 1.7 Hz, 1H), 6.01 (s, 2H), 4.65–4.62 (m, 2H), 3.90 (s, 3H), 3.33 (t, J = 7.4 Hz, 2H). HRMS (ESI) C 20 H 18 N 7 O 3 + [M + H] + calculated value: 404.1471, measured value: 404.1464.
另外，该反应还可同时分离得到中间体Int-13的另一同分异构体Int-14。具体将在实施例41中进行描述。In addition, the reaction can also separate Int-14, another isomer of intermediate Int-13. The details will be described in Embodiment 41.
步骤2：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯甲酸的制备(中间体Int-15)的制备Step 2: 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of -7-yl) ethyl) benzoic acid (Intermediate Int-15)
Figure PCTCN2019120284-appb-000336
Figure PCTCN2019120284-appb-000336
将步骤1得到的酯类中间体Int-13(0.202g，0.50mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶剂中，加入氢氧化锂(0.060g，2.5mmol)，室温下搅拌过夜。用氯化氢的1,4-二氧六环溶液(4M)中和反应液至pH7.4，减压蒸干溶剂，得相应羧酸中间体Int-15粗品，直接用于下一步反应。HRMS(ESI)C 19H 16N 7O 3 +[M+H] +计算值:390.1315,实测值:390.1302. Dissolve the ester intermediate Int-13 (0.202g, 0.50mmol) obtained in Step 1 in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), add lithium hydroxide (0.060g, 2.5mmol) at room temperature Stir overnight. The reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-15, which was directly used in the next reaction. HRMS (ESI) C 19 H 16 N 7 O 3 + [M + H] + calculated value: 390.1315, measured value: 390.1302.
步骤3：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-40)的制备Step 3: 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) -N- (2-aminophenyl) benzamide (Compound I-40)
Figure PCTCN2019120284-appb-000337
Figure PCTCN2019120284-appb-000337
将步骤2得到的全部中间体Int-15粗品溶于无水DMF(5mL)中，加入HATU(0.38g，1.0mmol),室温搅拌20分钟，再加入邻苯二胺(0.108g，1.0mmol)及DIPEA(0.387g，3.0mmol)，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得化合物(I-40)(0.139g，收率58％)。 1H NMR(800MHz,DMSO-d 6)δ9.58(s,1H),8.17(s,1H),8.08(s,2H),7.96–7.93(m,1H),7.87(d,J＝7.9Hz,2H),7.31(d,J＝8.1Hz,2H),7.23(dd,J＝3.4,0.6Hz,1H),7.13(d,J＝7.5Hz,1H),6.97–6.93(m,1H),6.76(dd,J＝8.0,1.2Hz,1H),6.73(dd,J＝3.4,1.7Hz,1H),6.58(t,J＝7.3Hz,1H),4.86(s,2H),4.55(t,J＝7.2Hz,2H),3.29(t,J＝7.2Hz,2H).HRMS(ESI)C 25H 22N 9O 2 +[M+H] +计算值:480.1896,实测值:480.1867. Dissolve all crude intermediate Int-15 obtained in Step 2 in anhydrous DMF (5mL), add HATU (0.38g, 1.0mmol), stir at room temperature for 20 minutes, then add o-phenylenediamine (0.108g, 1.0mmol) And DIPEA (0.387g, 3.0mmol), stirred at room temperature overnight. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain compound (I-40) (0.139 g, yield 58%). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 8.17 (s, 1H), 8.08 (s, 2H), 7.96–7.93 (m, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.23 (dd, J = 3.4, 0.6 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.97–6.93 (m, 1H ), 6.76 (dd, J = 8.0, 1.2 Hz, 1H), 6.73 (dd, J = 3.4, 1.7 Hz, 1H), 6.58 (t, J = 7.3 Hz, 1H), 4.86 (s, 2H), 4.55 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H). HRMS (ESI) C 25 H 22 N 9 O 2 + [M + H] + calculated value: 480.1896, measured value: 480.1867.
实施例41：4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-41)的制备Example 41: 4- (2- (5-amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-8-yl) ethyl) -N- (2-aminophenyl) benzamide (Compound I-41)
步骤1：4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)苯甲酸甲酯的制备(中间体Int-14)的制备Step 1: 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of methyl-8-yl) ethyl) benzoate (Intermediate Int-14)
Figure PCTCN2019120284-appb-000338
Figure PCTCN2019120284-appb-000338
按照实施例40步骤1的方法可同时分离得到中间体Int-13的另一同分异构体(Int-14)(0.42g，收率25％)。 1H NMR(800MHz,DMSO-d 6)δ8.44(s,1H),7.95–7.91(m,1H),7.85(d,J＝8.2Hz,2H),7.62(s,2H),7.33(d,J＝8.2Hz,2H),7.21–7.15(m,1H),6.72(dd,J＝3.3,1.7Hz,1H),4.58(t,J＝7.0Hz,2H),3.82(s,3H),3.31(t,J＝7.0Hz,2H).HRMS(ESI)C 20H 18N 7O 3 +[M+H] +计算值:404.1471,实测值:404.14062. According to the method of Step 1 in Example 40, another isomer of the intermediate Int-13 (Int-14) (0.42 g, yield 25%) can be simultaneously isolated. 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 7.95–7.91 (m, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.62 (s, 2H), 7.33 ( d, J = 8.2Hz, 2H), 7.21–7.15 (m, 1H), 6.72 (dd, J = 3.3, 1.7Hz, 1H), 4.58 (t, J = 7.0Hz, 2H), 3.82 (s, 3H ), 3.31 (t, J = 7.0 Hz, 2H). HRMS (ESI) C 20 H 18 N 7 O 3 + [M + H] + calculated value: 404.1471, measured value: 404.14062.
步骤2：4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)苯甲酸的制备(中间体Int-16)的制备Step 2: 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of -8-yl) ethyl) benzoic acid (Intermediate Int-16)
Figure PCTCN2019120284-appb-000339
Figure PCTCN2019120284-appb-000339
将步骤1得到的酯类中间体Int-14(0.202g，0.50mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶剂中，加入氢氧化锂(0.060g，2.5mmol)，室温下搅拌过夜。用氯化氢的1，4-二氧六环溶液(4M)中和反应液至pH7.4，减压蒸干溶剂，得相应羧酸中间体Int-16粗品，直接用于下一步反应。HRMS(ESI)C 19H 16N 7O 3 +[M+H] +计算值:390.1315,实测值:390.1309. Dissolve the ester intermediate Int-14 (0.202g, 0.50mmol) obtained in Step 1 in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), add lithium hydroxide (0.060g, 2.5mmol) at room temperature Stir overnight. The reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-16, which was directly used in the next reaction. HRMS (ESI) C 19 H 16 N 7 O 3 + [M + H] + calculated value: 390.1315, measured value: 390.1309.
步骤3：4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)-N-(2-氨基苯基)苯甲酰胺(化合物I’-41)的制备Step 3: 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) ethyl) -N- (2-aminophenyl) benzamide (compound I'-41)
Figure PCTCN2019120284-appb-000340
Figure PCTCN2019120284-appb-000340
将步骤2得到的全部中间体Int-16粗品溶于无水DMF(5mL)中，加入HATU(0.38 g，1.0mmol),室温搅拌20分钟，再加入邻苯二胺(0.108g，1.0mmol)及DIPEA(0.387g，3.0mmol)，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得化合物(I’-41)(0.129g，收率54％)。 1H NMR(800MHz,DMSO-d 6)δ9.58(s,1H),8.49(s,1H),7.93(dd,J＝1.6,0.7Hz,1H),7.88(d,J＝7.9Hz,2H),7.62(s,2H),7.32(d,J＝8.1Hz,2H),7.19(dd,J＝3.4,0.7Hz,1H),7.14(d,J＝7.6Hz,1H),6.98–6.93(m,1H),6.76(dd,J＝8.0,1.3Hz,1H),6.72(dd,J＝3.3,1.7Hz,1H),6.58(t,J＝7.1Hz,1H),4.86(s,2H),4.61(t,J＝7.0Hz,2H),3.32–3.30(m,2H).HRMS(ESI)C 25H 22N 9O 2 +[M+H] +计算值:480.1896,实测值:480.1867. Dissolve all crude intermediate Int-16 obtained in Step 2 in anhydrous DMF (5 mL), add HATU (0.38 g, 1.0 mmol), stir at room temperature for 20 minutes, then add o-phenylenediamine (0.108 g, 1.0 mmol) And DIPEA (0.387g, 3.0mmol), stirred at room temperature overnight. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined and the solvent was distilled off under reduced pressure. The remaining solid was separated and purified by silica gel column chromatography to obtain compound (I'-41) (0.129 g, yield 54%). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 8.49 (s, 1H), 7.93 (dd, J = 1.6, 0.7 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.62 (s, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 3.4, 0.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.98- 6.93 (m, 1H), 6.76 (dd, J = 8.0, 1.3 Hz, 1H), 6.72 (dd, J = 3.3, 1.7 Hz, 1H), 6.58 (t, J = 7.1 Hz, 1H), 4.86 (s , 2H), 4.61 (t, J = 7.0 Hz, 2H), 3.32–3.30 (m, 2H). HRMS (ESI) C 25 H 22 N 9 O 2 + [M + H] + calculated value: 480.1896, measured Value: 480.1867.
实施例42：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-42)的制备Example 42: 4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-42)
步骤1：(2-(4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯甲酰胺基)-5-氟苯基)氨基甲酸叔丁酯(中间体Int-17)的制备Step 1: (2- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] Pyrimidin-7-yl) ethyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-17)
Figure PCTCN2019120284-appb-000341
Figure PCTCN2019120284-appb-000341
将实施例40步骤3中的邻苯二胺替换成(2-氨基-5-氟苯基)氨基甲酸叔丁酯，其余所需原料，试剂及制备方法同实施例40，得泡沫状中间体(Int-17)。 1H NMR(800MHz,CDCl 3)δ8.72(s,1H),8.21(s,1H),7.80(d,J＝7.7Hz,2H),7.64–7.62(m,1H),7.55–7.49(m,1H),7.28–7.26(m,1H),7.24(d,J＝7.9Hz,2H),7.22–7.20(m,1H),6.99(s,1H),6.89–6.84(m,1H),6.62–6.58(m,1H),6.07(s,2H),4.61(t,J＝7.3Hz,2H),3.31(t,J＝7.3Hz,2H),1.48(s,9H).HRMS(ESI)C 30H 29FN 9O 4 +[M+H] +计算值:598.2327,实测值:598.2319. Replace o-phenylenediamine in Step 3 of Example 40 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 40 to obtain a foamy intermediate (Int-17). 1 H NMR (800 MHz, CDCl 3 ) δ 8.72 (s, 1H), 8.21 (s, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.64–7.62 (m, 1H), 7.55–7.49 ( m, 1H), 7.28–7.26 (m, 1H), 7.24 (d, J = 7.9Hz, 2H), 7.22–7.20 (m, 1H), 6.99 (s, 1H), 6.89–6.84 (m, 1H) , 6.62–6.58 (m, 1H), 6.07 (s, 2H), 4.61 (t, J = 7.3Hz, 2H), 3.31 (t, J = 7.3Hz, 2H), 1.48 (s, 9H). HRMS ( ESI) C 30 H 29 FN 9 O 4 + [M + H] + calculated value: 598.2327, measured value: 598.2319.
步骤2：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-42)的制备Step 2: 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (compound I-42)
Figure PCTCN2019120284-appb-000342
Figure PCTCN2019120284-appb-000342
将步骤1中得到的中间体Int-17(0.06g，0.1mmol)溶于甲醇(5mL)中，加入4M的盐酸二氧六环溶液(5mL)，室温搅拌过夜。用饱和碳酸氢钠水溶液中和反应液中的氯化氢，减压蒸干溶剂，剩余固体用硅胶柱层析分离纯化，得黄色固体化合物(I-42)(0.047g，收率95％) 1H NMR(800MHz,DMSO-d 6)δ9.51(s,1H),8.18(s,1H),8.06(s,2H),7.96– 7.94(m,1H),7.87(d,J＝8.0Hz,2H),7.31(d,J＝8.1Hz,2H),7.24–7.22(m,1H),7.11–7.07(m,1H),6.74(dd,J＝3.4,1.7Hz,1H),6.55–6.49(m,1H),6.38–6.30(m,1H),5.19(s,2H),4.56(t,J＝7.2Hz,2H),3.31–3.28(m,2H).HRMS(ESI)C 25H 21FN 9O 2 +[M+H] +计算值:498.1802,实测值:498.1800. The intermediate Int-17 (0.06 g, 0.1 mmol) obtained in Step 1 was dissolved in methanol (5 mL), 4M hydrochloric acid dioxane solution (5 mL) was added, and the mixture was stirred overnight at room temperature. Neutralize hydrogen chloride in the reaction solution with saturated aqueous sodium bicarbonate solution, evaporate the solvent under reduced pressure, and separate the remaining solid by silica gel column chromatography to obtain yellow solid compound (I-42) (0.047g, yield 95%) 1 H NMR (800MHz, DMSO-d 6 ) δ9.51 (s, 1H), 8.18 (s, 1H), 8.06 (s, 2H), 7.96- 7.94 (m, 1H), 7.87 (d, J = 8.0Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.24-7.22 (m, 1H), 7.11-7.07 (m, 1H), 6.74 (dd, J = 3.4, 1.7 Hz, 1H), 6.55-6.49 (m, 1H), 6.38–6.30 (m, 1H), 5.19 (s, 2H), 4.56 (t, J = 7.2Hz, 2H), 3.31–3.28 (m, 2H). HRMS (ESI) C 25 H 21 FN 9 O 2 + [M + H] + Calculated value: 498.1802, measured value: 498.1800.
实施例43：4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-43)的制备Example 43: 4- (2- (5-amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-8-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-43)
步骤1：(2-(4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)苯甲酰胺基)-5-氟苯基)氨基甲酸叔丁酯(中间体Int-18)的制备Step 1: (2- (4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] Pyrimidin-8-yl) ethyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-18)
Figure PCTCN2019120284-appb-000343
Figure PCTCN2019120284-appb-000343
将实施例41步骤3中的邻苯二胺替换成(2-氨基-5-氟苯基)氨基甲酸叔丁酯，其余所需原料，试剂及制备方法同实施例41，得泡沫状中间体(Int-18)。 1H NMR(800MHz,CDCl 3)δ8.78(s,1H),7.88(s,1H),7.84(d,J＝7.5Hz,2H),7.64(d,J＝0.9Hz,1H),7.61–7.53(m,1H),7.24–7.16(m,4H),7.01(s,1H),6.92–6.86(m,1H),6.61(dd,J＝3.3,1.7Hz,1H),6.29(s,2H),4.58(t,J＝6.8Hz,2H),3.44–3.36(m,2H),1.47(s,9H).HRMS(ESI)C 30H 29FN 9O 4 +[M+H] +计算值:598.2327,实测值:598.2318. Replace o-phenylenediamine in step 3 of Example 41 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 41 to obtain a foamy intermediate (Int-18). 1 H NMR (800 MHz, CDCl 3 ) δ 8.78 (s, 1H), 7.88 (s, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 0.9 Hz, 1H), 7.61 –7.53 (m, 1H), 7.24–7.16 (m, 4H), 7.01 (s, 1H), 6.92–6.86 (m, 1H), 6.61 (dd, J = 3.3,1.7Hz, 1H), 6.29 (s , 2H), 4.58 (t, J = 6.8Hz, 2H), 3.44–3.36 (m, 2H), 1.47 (s, 9H). HRMS (ESI) C 30 H 29 FN 9 O 4 + [M + H] + Calculated value: 598.2327, measured value: 598.2318.
步骤2：4-(2-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)乙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I’-43)的制备Step 2: 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (compound I'-43)
Figure PCTCN2019120284-appb-000344
Figure PCTCN2019120284-appb-000344
将步骤1中得到的中间体Int-18(0.06g，0.1mmol)溶于甲醇(5mL)中，加入4M的盐酸二氧六环溶液(5mL)，室温搅拌过夜。用饱和碳酸氢钠水溶液中和反应液中的氯化氢，减压蒸干溶剂，剩余固体用硅胶柱层析分离纯化，得黄色固体化合物(I’-43)(0.046g，收率93％) 1H NMR(800MHz,DMSO-d 6)δ9.51(s,1H),8.49(s,1H),7.95–7.91(m,1H),7.88(d,J＝8.0Hz,2H),7.63(s,2H),7.32(d,J＝8.1Hz,2H),7.20–7.16(m,1H),7.11–7.06 (m,1H),6.74–6.70(m,1H),6.52(dd,J＝11.2,2.8Hz,1H),6.34(td,J＝8.5,2.8Hz,1H),5.19(s,2H),4.61(t,J＝6.9Hz,2H),3.32–3.30(m,2H).HRMS(ESI)C 25H 21FN 9O 2 +[M+H] +计算值:498.1802,实测值:498.1801. The intermediate Int-18 (0.06 g, 0.1 mmol) obtained in Step 1 was dissolved in methanol (5 mL), 4M hydrochloric acid dioxane solution (5 mL) was added, and the mixture was stirred overnight at room temperature. Neutralize the hydrogen chloride in the reaction solution with saturated sodium bicarbonate aqueous solution, evaporate the solvent under reduced pressure, and separate and purify the remaining solid by silica gel column chromatography to obtain yellow solid compound (I'-43) (0.046g, yield 93%) 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.51 (s, 1H), 8.49 (s, 1H), 7.95–7.91 (m, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.63 (s , 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.20–7.16 (m, 1H), 7.11–7.06 (m, 1H), 6.74–6.70 (m, 1H), 6.52 (dd, J = 11.2 , 2.8Hz, 1H), 6.34 (td, J = 8.5, 2.8Hz, 1H), 5.19 (s, 2H), 4.61 (t, J = 6.9Hz, 2H), 3.32–3.30 (m, 2H). HRMS (ESI) C 25 H 21 FN 9 O 2 + [M + H] + calculated value: 498.1802, measured value: 498.1801.
实施例44：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)-N-羟基苯甲酰胺(化合物I-44)的制备Example 44: 4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N-hydroxybenzamide (Compound I-44)
Figure PCTCN2019120284-appb-000345
Figure PCTCN2019120284-appb-000345
将实施例1步骤2中的中间体Int-1替换成中间体Int-13，其余所需原料，试剂及制备方法同实施例1步骤2，得白色固体化合物(I-44)。 1H NMR(800MHz,DMSO-d 6)δ11.11(s,1H),8.95(s,1H),8.16(s,1H),8.06(s,2H),7.94(s,1H),7.63(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),7.22(d,J＝3.2Hz,1H),6.75–6.71(m,1H),4.52(t,J＝7.3Hz,2H),3.24(t,J＝7.2Hz,2H).HRMS(ESI)C 19H 17N 8O 3 +[M+H] +计算值:405.1424,实测值:405.1430. The intermediate Int-1 in Step 2 of Example 1 was replaced with the intermediate Int-13, and the remaining required raw materials, reagents and preparation methods were the same as those in Step 2 of Example 1, to obtain a white solid compound (I-44). 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 8.95 (s, 1H), 8.16 (s, 1H), 8.06 (s, 2H), 7.94 (s, 1H), 7.63 ( d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 3.2 Hz, 1H), 6.75–6.71 (m, 1H), 4.52 (t, J = 7.3 Hz, 2H), 3.24 (t, J = 7.2Hz, 2H). HRMS (ESI) C 19 H 17 N 8 O 3 + [M + H] + calculated value: 405.1424, measured value: 405.1430.
实施例45：4-((5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)甲基)-N-(2-氨基苯基)苯甲酰胺(化合物I-45)的制备Example 45: 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine- Preparation of 7-yl) methyl) -N- (2-aminophenyl) benzamide (Compound I-45)
步骤1：4-((5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯甲酸甲酯的制备(中间体Int-19)的制备Step 1: 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) ethyl) methyl benzoate (intermediate Int-19)
Figure PCTCN2019120284-appb-000346
Figure PCTCN2019120284-appb-000346
将实施例40步骤1中的4-(2-溴乙基)苯甲酸甲酯替换成4-溴甲基苯甲酸甲酯，其余所需原料，试剂及制备方法同实施例40步骤1，得白色固体中间体(Int-19)。 1H NMR(800MHz,DMSO-d 6)δ8.25(s,1H),8.15(s,2H),7.97–7.94(m,1H),7.94–7.90(m,2H),7.32(d,J＝8.5Hz,2H),7.25(dd,J＝3.4,0.7Hz,1H),6.76–6.72(m,1H),5.60(s,2H),3.84(s,3H).HRMS(ESI)C 19H 16N 7O 3 +[M+H] +计算值:390.1315,实测值:390.1311. Replace methyl 4- (2-bromoethyl) benzoate in Step 1 of Example 40 with methyl 4-bromomethylbenzoate, and the remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40. White solid intermediate (Int-19). 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.25 (s, 1H), 8.15 (s, 2H), 7.97–7.94 (m, 1H), 7.94–7.90 (m, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.25 (dd, J = 3.4, 0.7 Hz, 1H), 6.76–6.72 (m, 1H), 5.60 (s, 2H), 3.84 (s, 3H). HRMS (ESI) C 19 H 16 N 7 O 3 + [M + H] + Calculated value: 390.1315, found value: 390.1311.
另外，该反应还可同时分离得到中间体Int-19的另一同分异构体Int-20。具体将在实施例46中进行描述。In addition, the reaction can also separate Int-20, another isomer of intermediate Int-19. The details will be described in Example 46.
步骤2：4-((5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)甲基)-N-(2-氨基苯基)苯甲酰胺(化合物I-45)的制备Step 2: 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) methyl) -N- (2-aminophenyl) benzamide (Compound I-45)
Figure PCTCN2019120284-appb-000347
Figure PCTCN2019120284-appb-000347
将实施例40步骤2中的中间体Int-13替换成中间体Int-19，其余所需原料，试剂及制备方法同实施例40步骤2～3，得白色固体化合物(I-45)。 1H NMR(800MHz,DMSO-d 6)δ9.61(s,1H),8.25(s,1H),8.14(s,2H),7.96(dd,J＝1.7,0.7Hz,1H),7.93(d,J＝8.1Hz,2H),7.33(d,J＝8.2Hz,2H),7.25(dd,J＝3.4,0.7Hz,1H),7.15(d,J＝7.7Hz,1H),6.99–6.93(m,1H),6.77(dd,J＝8.0,1.2Hz,1H),6.75(dd,J＝3.4,1.8Hz,1H),6.59(t,J＝7.2Hz,1H),5.59(s,2H),4.88(s,2H).HRMS(ESI)C 24H 20N 9O 2 +[M+H] +计算值:466.1740,实测值:466.1727. The intermediate Int-13 in Step 2 of Example 40 was replaced with the intermediate Int-19, and the remaining required raw materials, reagents and preparation methods were the same as those in Steps 2 to 3 of Example 40 to obtain a white solid compound (I-45). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.61 (s, 1H), 8.25 (s, 1H), 8.14 (s, 2H), 7.96 (dd, J = 1.7, 0.7 Hz, 1H), 7.93 ( d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.25 (dd, J = 3.4, 0.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.99– 6.93 (m, 1H), 6.77 (dd, J = 8.0, 1.2 Hz, 1H), 6.75 (dd, J = 3.4, 1.8 Hz, 1H), 6.59 (t, J = 7.2 Hz, 1H), 5.59 (s , 2H), 4.88 (s, 2H). HRMS (ESI) C 24 H 20 N 9 O 2 + [M + H] + calculated value: 466.1740, measured value: 466.1727.
实施例46：4-((5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)甲基)-N-(2-氨基苯基)苯甲酰胺(化合物I’-46)的制备Example 46: 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine- Preparation of 8-yl) methyl) -N- (2-aminophenyl) benzamide (Compound I'-46)
步骤1：4-((5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)甲基)苯甲酸甲酯的制备(中间体Int-20)的制备Step 1: 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) methyl) methyl benzoate (intermediate Int-20)
Figure PCTCN2019120284-appb-000348
Figure PCTCN2019120284-appb-000348
按照实施例45步骤1的方法可同时分离得到中间体Int-19的另一同分异构体(Int-20)。 1H NMR(800MHz,DMSO-d 6)δ8.80(s,1H),7.97–7.92(m,3H),7.66(s,2H),7.41(d,J＝8.4Hz,2H),7.21(dd,J＝3.3,0.4Hz,1H),6.73(dd,J＝3.4,1.7Hz,1H),5.61(s,2H),3.84(s,3H).HRMS(ESI)C 19H 16N 7O 3 +[M+H] +计算值:390.1315,实测值:390.1311. According to the method of Step 1 in Example 45, another isomer of the intermediate Int-19 (Int-20) can be simultaneously isolated. 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 7.97–7.92 (m, 3H), 7.66 (s, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.21 ( dd, J = 3.3, 0.4 Hz, 1H), 6.73 (dd, J = 3.4, 1.7 Hz, 1H), 5.61 (s, 2H), 3.84 (s, 3H). HRMS (ESI) C 19 H 16 N 7 O 3 + [M + H] + calculated value: 390.1315, measured value: 390.1311.
步骤2：4-((5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)甲基)-N-(2-氨基苯基)苯甲酰胺(化合物I’-46)的制备Step 2: 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) methyl) -N- (2-aminophenyl) benzamide (Compound I'-46)
Figure PCTCN2019120284-appb-000349
Figure PCTCN2019120284-appb-000349
将实施例41步骤2中的中间体Int-14替换成中间体Int-20，其余所需原料，试剂及制备方法同实施例41步骤2～3，得白色固体化合物(I’-46)。 1H NMR(800MHz,DMSO-d 6)δ9.64(s,1H),8.81(s,1H),7.97(d,J＝8.0Hz,2H),7.95(dd,J＝1.6,0.7Hz,1H),7.66(s,2H),7.44(d,J＝8.1Hz,2H),7.21(d,J＝3.3Hz,1H),7.16(d,J＝7.7Hz,1H),6.99–6.94(m,1H),6.77(d,J＝7.9Hz,1H),6.74(dd,J＝3.4,1.8Hz,1H),6.59(t,J＝7.4Hz,1H),5.60(s,2H),4.89(s,2H).HRMS(ESI)C 24H 20N 9O 2 +[M+H] +计算值:466.1740,实测值:466.1725. The intermediate Int-14 in Step 2 of Example 41 was replaced with the intermediate Int-20, and the remaining required raw materials, reagents and preparation methods were the same as those in Steps 2 to 3 of Example 41 to obtain a white solid compound (I'-46). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.64 (s, 1H), 8.81 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.95 (dd, J = 1.6, 0.7 Hz, 1H), 7.66 (s, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.99-6.94 ( m, 1H), 6.77 (d, J = 7.9Hz, 1H), 6.74 (dd, J = 3.4, 1.8Hz, 1H), 6.59 (t, J = 7.4Hz, 1H), 5.60 (s, 2H), 4.89 (s, 2H). HRMS (ESI) C 24 H 20 N 9 O 2 + [M + H] + calculated value: 466.1740, measured value: 466.1725.
实施例47：4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙氧基)-N-(2-氨基苯基)苯甲酰胺(化合物I-47)的制备Example 47: 4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethoxy) -N- (2-aminophenyl) benzamide (Compound I-47)
Figure PCTCN2019120284-appb-000350
Figure PCTCN2019120284-appb-000350
将实施例40步骤1中的4-(2-溴乙基)苯甲酸甲酯替换成4-(2-溴乙氧基)苯甲酸甲酯(制备方法参见ACS Medicinal Chemistry Letters,2013,4,527-531)，其余所需原料，试剂及制备方法同实施例40步骤1～3，得白色固体化合物(I-47)。 1H NMR(800MHz,DMSO-d 6)δ9.52(s,1H),8.22(s,1H),8.14(s,2H),7.96(dd,J＝1.6,0.6Hz,1H),7.93(d,J＝8.7Hz,2H),7.24(dd,J＝3.3,0.6Hz,1H),7.13(d,J＝7.7Hz,1H),7.01(d,J＝8.9Hz,2H),6.98–6.94(m,1H),6.77(dd,J＝8.0,1.3Hz,1H),6.74(dd,J＝3.4,1.7Hz,1H),6.61–6.56(m,1H),4.85(s,2H),4.68(t,J＝5.5Hz,2H),4.56(t,J＝5.5Hz,2H).HRMS(ESI)C 25H 22N 9O 3 +[M+H] +计算值:496.1846,实测值:496.1839. Replace methyl 4- (2-bromoethyl) benzoate in Step 1 of Example 40 with methyl 4- (2-bromoethoxy) benzoate (for the preparation method, see ACS Medicinal Chemistry Letters, 2013, 4,527- 531), the remaining required raw materials, reagents and preparation methods are the same as steps 1 to 3 in Example 40 to obtain a white solid compound (I-47). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.52 (s, 1H), 8.22 (s, 1H), 8.14 (s, 2H), 7.96 (dd, J = 1.6, 0.6 Hz, 1H), 7.93 ( d, J = 8.7 Hz, 2H), 7.24 (dd, J = 3.3, 0.6 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.98– 6.94 (m, 1H), 6.77 (dd, J = 8.0, 1.3 Hz, 1H), 6.74 (dd, J = 3.4, 1.7 Hz, 1H), 6.61–6.56 (m, 1H), 4.85 (s, 2H) , 4.68 (t, J = 5.5 Hz, 2H), 4.56 (t, J = 5.5 Hz, 2H). HRMS (ESI) C 25 H 22 N 9 O 3 + [M + H] + calculated value: 496.1846, measured Value: 496.1839.
实施例48：4-(3-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-48)的制备Example 48: 4- (3- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I-48)
步骤1：4-(3-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)丙基)苯甲酸甲酯的制备(中间体Int-21)的制备Step 1: 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of methyl -7-yl) propyl) benzoate (Intermediate Int-21)
Figure PCTCN2019120284-appb-000351
Figure PCTCN2019120284-appb-000351
将实施例40步骤1中的4-(2-溴乙基)苯甲酸甲酯替换成4-(3-溴丙基)苯甲酸甲酯(制备方法参见WO 2002042268)，其余所需原料，试剂及制备方法同实施例40步骤1，得 中间体(Int-21)。 1H NMR(800MHz,DMSO-d 6)δ8.17(d,J＝5.3Hz,1H),8.07(s,2H),7.95(dd,J＝1.7,0.7Hz,1H),7.88–7.83(m,2H),7.36(d,J＝8.3Hz,2H),7.23(dd,J＝3.3,0.7Hz,1H),6.76–6.72(m,1H),4.29(t,J＝6.9Hz,2H),3.81(s,3H),2.69(t,J＝7.5Hz,2H),2.22–2.17(m,2H).HRMS(ESI)C 21H 20N 7O 3 +[M+H] +计算值:418.1628,实测值:418.1626. Replace methyl 4- (2-bromoethyl) benzoate in step 1 of Example 40 with methyl 4- (3-bromopropyl) benzoate (for the preparation method, see WO 2002042268), and the remaining required raw materials and reagents The preparation method is the same as that in Step 1 of Example 40 to obtain the intermediate (Int-21). 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.17 (d, J = 5.3 Hz, 1H), 8.07 (s, 2H), 7.95 (dd, J = 1.7, 0.7 Hz, 1H), 7.88-7.83 ( m, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.23 (dd, J = 3.3, 0.7 Hz, 1H), 6.76–6.72 (m, 1H), 4.29 (t, J = 6.9 Hz, 2H ), 3.81 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 2.22–2.17 (m, 2H). HRMS (ESI) C 21 H 20 N 7 O 3 + [M + H] + calculation Value: 418.1628, measured value: 418.1626.
另外，该反应还可同时分离得到中间体Int-21的另一同分异构体Int-22。具体将在实施例49中进行描述。In addition, this reaction can also separate Int-22, another isomer of intermediate Int-21. The details will be described in Example 49.
步骤2：4-(3-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-48)的制备Step 2: 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I-48)
Figure PCTCN2019120284-appb-000352
Figure PCTCN2019120284-appb-000352
将实施例40步骤2中的中间体Int-13替换成中间体Int-21，其余所需原料，试剂及制备方法同实施例40步骤2～3，得白色固体化合物(I-48)。 1H NMR(800MHz,DMSO-d 6)δ9.60(s,1H),8.20(s,1H),8.11(t,J＝35.6Hz,2H),7.97–7.94(m,1H),7.92(d,J＝7.9Hz,2H),7.38(d,J＝8.1Hz,2H),7.27–7.21(m,1H),7.15(t,J＝16.2Hz,1H),7.00–6.94(m,1H),6.79(dd,J＝8.0,1.1Hz,1H),6.74(dd,J＝3.3,1.7Hz,1H),6.60(t,J＝7.4Hz,1H),4.89(s,2H),4.31(t,J＝7.0Hz,2H),2.70(t,J＝7.6Hz,2H),2.25–2.15(m,2H).HRMS(ESI)C 26H 24N 9O 2 +[M+H] +计算值:494.2053,实测值:494.2043. The intermediate Int-13 in Step 2 of Example 40 was replaced with the intermediate Int-21, and the remaining required raw materials, reagents and preparation methods were the same as those in Steps 2 to 3 of Example 40 to obtain a white solid compound (I-48). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 8.20 (s, 1H), 8.11 (t, J = 35.6 Hz, 2H), 7.97–7.94 (m, 1H), 7.92 ( d, J = 7.9Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27-7.21 (m, 1H), 7.15 (t, J = 16.2 Hz, 1H), 7.00-6.94 (m, 1H ), 6.79 (dd, J = 8.0, 1.1 Hz, 1H), 6.74 (dd, J = 3.3, 1.7 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 4.89 (s, 2H), 4.31 (t, J = 7.0 Hz, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.25–2.15 (m, 2H). HRMS (ESI) C 26 H 24 N 9 O 2 + [M + H] + Calculated value: 494.2053, measured value: 494.2043.
实施例49：4-(3-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I’-49)的制备Example 49: 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-8-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I'-49)
步骤1：4-(3-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)丙基)苯甲酸甲酯(中间体Int-22)的制备Step 1: 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of Methyl-8-yl) propyl) benzoate (Intermediate Int-22)
Figure PCTCN2019120284-appb-000353
Figure PCTCN2019120284-appb-000353
按照实施例48步骤1的方法可同时分离得到中间体Int-21的另一同分异构体(Int-22)。 1H NMR(800MHz,DMSO-d 6)δ8.62(s,1H),7.95–7.93(m,1H),7.87(d,J＝8.2Hz, 2H),7.61(s,2H),7.37(d,J＝8.2Hz,2H),7.21–7.19(m,1H),6.74(dd,J＝3.3,1.7Hz,1H),4.31(t,J＝6.9Hz,2H),3.82(s,3H),2.71–2.65(m,2H),2.26–2.20(m,2H).HRMS(ESI)C 21H 20N 7O 3 +[M+H] +计算值:418.1628,实测值:418.1629. According to the method of Step 1 in Example 48, another isomer of the intermediate Int-21 (Int-22) can be simultaneously isolated. 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 7.95–7.93 (m, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.61 (s, 2H), 7.37 ( d, J = 8.2Hz, 2H), 7.21–7.19 (m, 1H), 6.74 (dd, J = 3.3, 1.7Hz, 1H), 4.31 (t, J = 6.9Hz, 2H), 3.82 (s, 3H ), 2.71–2.65 (m, 2H), 2.26–2.20 (m, 2H). HRMS (ESI) C 21 H 20 N 7 O 3 + [M + H] + calculated value: 418.1628, measured value: 418.1629.
步骤2：4-(3-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I’-49)的制备Step 2: 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) propyl) -N- (2-aminophenyl) benzamide (compound I'-49)
Figure PCTCN2019120284-appb-000354
Figure PCTCN2019120284-appb-000354
将实施例41步骤2中的中间体Int-14替换成中间体Int-22，其余所需原料，试剂及制备方法同实施例41步骤2～3，得固体化合物(I’-49)。 1H NMR(800MHz,DMSO-d 6)δ9.61(s,1H),8.66(s,1H),7.96–7.88(m,3H),7.62(s,2H),7.37(d,J＝8.1Hz,2H),7.21(dd,J＝3.4,0.7Hz,1H),7.16(d,J＝7.6Hz,1H),6.99–6.94(m,1H),6.78(dd,J＝8.0,1.3Hz,1H),6.74(dd,J＝3.4,1.7Hz,1H),6.62–6.56(m,1H),4.88(s,2H),4.33(t,J＝6.9Hz,2H),2.70–2.67(m,2H),2.28–2.20(m,2H).HRMS(ESI)C 26H 24N 9O 2 +[M+H] +计算值:494.2053,实测值:494.2060. The intermediate Int-14 in Step 2 of Example 41 was replaced with the intermediate Int-22, and the remaining required raw materials, reagents and preparation methods were the same as those in Steps 2 to 3 of Example 41 to obtain a solid compound (I'-49). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.61 (s, 1H), 8.66 (s, 1H), 7.96–7.88 (m, 3H), 7.62 (s, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.21 (dd, J = 3.4, 0.7Hz, 1H), 7.16 (d, J = 7.6Hz, 1H), 6.99–6.94 (m, 1H), 6.78 (dd, J = 8.0, 1.3Hz , 1H), 6.74 (dd, J = 3.4, 1.7Hz, 1H), 6.62–6.56 (m, 1H), 4.88 (s, 2H), 4.33 (t, J = 6.9Hz, 2H), 2.70–2.67 ( m, 2H), 2.28–2.20 (m, 2H). HRMS (ESI) C 26 H 24 N 9 O 2 + [M + H] + calculated value: 494.2053, measured value: 494.2060.
实施例50：4-(3-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)丙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-50)的制备Example 50: 4- (3- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-50)
步骤1：(2-(4-(3-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)丙基)苯甲酰胺基)-5-氟苯基)氨基甲酸叔丁酯(中间体Int-23)的制备Step 1: (2- (4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) propyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-23)
Figure PCTCN2019120284-appb-000355
Figure PCTCN2019120284-appb-000355
将实施例48步骤2中的邻苯二胺替换成(2-氨基-5-氟苯基)氨基甲酸叔丁酯，其余所需原料，试剂及制备方法同实施例48，得泡沫状中间体(Int-23)。 1H NMR(800MHz,CDCl 3)δ8.73(s,1H),8.22(s,1H),7.82(d,J＝7.8Hz,2H),7.65–7.62(m,1H),7.54(dd,J＝8.4,5.9Hz,1H),7.28–7.27(m,2H),7.26(d,J＝3.4Hz,1H),7.25–7.22(m,1H),7.15(s,1H),6.90–6.84(m,1H),6.61(dd,J＝3.3,1.7Hz,1H),6.11(s,2H),4.40(t,J＝6.8Hz,2H),2.75(t,J＝7.6Hz,2H),2.37–2.30(m,2H),1.52(s,9H).HRMS(ESI)C 31H 31FN 9O 4 +[M+H] +计算值: 612.2483,实测值:612.2473. Replace o-phenylenediamine in Step 2 of Example 48 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 48 to obtain a foamy intermediate (Int-23). 1 H NMR (800 MHz, CDCl 3 ) δ 8.73 (s, 1H), 8.22 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.65–7.62 (m, 1H), 7.54 (dd, J = 8.4, 5.9Hz, 1H), 7.28–7.27 (m, 2H), 7.26 (d, J = 3.4Hz, 1H), 7.25–7.22 (m, 1H), 7.15 (s, 1H), 6.90–6.84 (m, 1H), 6.61 (dd, J = 3.3, 1.7 Hz, 1H), 6.11 (s, 2H), 4.40 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H) , 2.37–2.30 (m, 2H), 1.52 (s, 9H). HRMS (ESI) C 31 H 31 FN 9 O 4 + [M + H] + calculated value: 612.2483, measured value: 612.2473.
步骤2：4-(3-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)丙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-50)的制备Step 2: 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-50)
Figure PCTCN2019120284-appb-000356
Figure PCTCN2019120284-appb-000356
将步骤1中得到的中间体Int-23按照实施例42步骤2所描述的方法脱去Boc保护基得固体化合物(I-50)。 1H NMR(800MHz,DMSO-d 6)δ9.52(s,1H),8.20(s,1H),8.07(s,2H),7.96–7.94(m,1H),7.92(d,J＝8.0Hz,2H),7.37(d,J＝8.1Hz,2H),7.26–7.22(m,1H),7.14–7.08(m,1H),6.76–6.71(m,1H),6.54(dd,J＝11.2,2.8Hz,1H),6.38–6.31(m,1H),5.20(s,2H),4.30(t,J＝7.0Hz,2H),2.70(t,J＝7.6Hz,2H),2.25–2.14(m,2H).C 26H 23FN 9O 2 +[M+H] +计算值:512.1959,实测值:512.1947. The intermediate Int-23 obtained in Step 1 is deprotected according to the method described in Step 2 of Example 42 to obtain a solid compound (I-50). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.52 (s, 1H), 8.20 (s, 1H), 8.07 (s, 2H), 7.96–7.94 (m, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.26-7.22 (m, 1H), 7.14-7.08 (m, 1H), 6.76-6.71 (m, 1H), 6.54 (dd, J = 11.2, 2.8Hz, 1H), 6.38–6.31 (m, 1H), 5.20 (s, 2H), 4.30 (t, J = 7.0Hz, 2H), 2.70 (t, J = 7.6Hz, 2H), 2.25– 2.14 (m, 2H). C 26 H 23 FN 9 O 2 + [M + H] + calculated value: 512.1959, measured value: 512.1947.
实施例51：7-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)-N-羟基庚酰胺(化合物I-51)的制备Example 51: 7- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) -N-hydroxyheptanamide (Compound I-51)
步骤1：7-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)庚酸甲酯(中间体Int-24)的制备Step 1: 7- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7- Of methyl) heptanoate (intermediate Int-24)
Figure PCTCN2019120284-appb-000357
Figure PCTCN2019120284-appb-000357
将实施例40步骤1中的4-(2-溴乙基)苯甲酸甲酯替换成7-溴庚酸甲酯，其余所需原料，试剂及制备方法同实施例40步骤1，得白色固体中间体(Int-24)。 1H NMR(800MHz,DMSO)δ8.15(s,1H),8.06(s,2H),7.96–7.93(m,1H),7.25–7.22(m,1H),6.74(dd,J＝3.4,1.7Hz,1H),4.25(t,J＝7.1Hz,2H),3.56(s,3H),2.26(t,J＝7.4Hz,2H),1.85–1.79(m,2H),1.52–1.46(m,2H),1.31–1.24(m,4H).HRMS(ESI)C 18H 22N 7O 3 +[M+H] +计算值:384.1784,实测值:384.1779. Replace the methyl 4- (2-bromoethyl) benzoate in Step 1 of Example 40 with methyl 7-bromoheptanoate. The remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40 to obtain a white solid Intermediate (Int-24). 1 H NMR (800 MHz, DMSO) δ 8.15 (s, 1H), 8.06 (s, 2H), 7.96–7.93 (m, 1H), 7.25–7.22 (m, 1H), 6.74 (dd, J = 3.4, 1.7Hz, 1H), 4.25 (t, J = 7.1Hz, 2H), 3.56 (s, 3H), 2.26 (t, J = 7.4Hz, 2H), 1.85-1.79 (m, 2H), 1.52-1.46 ( m, 2H), 1.31-1.24 (m, 4H). HRMS (ESI) C 18 H 22 N 7 O 3 + [M + H] + calculated value: 384.1784, measured value: 384.1779.
另外，该反应还可同时分离得到中间体Int-24的另一同分异构体Int-25。具体将在实施例52中进行描述。In addition, the reaction can also isolate Int-25, another isomer of intermediate Int-24. The details will be described in Example 52.
步骤2：7-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)-N-羟基庚酰胺(化合物I-51)的制备Step 2: 7- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7- ) -N-hydroxyheptanamide (Compound I-51)
Figure PCTCN2019120284-appb-000358
Figure PCTCN2019120284-appb-000358
将实施例1步骤2中的中间体Int-1替换成中间体Int-24，其余所需原料，试剂及制备方法同实施例1步骤2，得白色固体化合物(I-51)。 1H NMR(800MHz,DMSO-d 6)δ10.32(s,1H),8.65(s,1H),8.16(s,1H),8.05(s,2H),7.95(dd,J＝1.6,0.6Hz,1H),7.23(dd,J＝3.3,0.6Hz,1H),6.74(dd,J＝3.3,1.7Hz,1H),4.25(t,J＝7.1Hz,2H),1.92(t,J＝7.4Hz,2H),1.87–1.77(m,2H),1.51–1.41(m,2H),1.35–1.18(m,4H).HRMS(ESI)C 17H 21N 8O 3 +[M+H] +计算值:385.1737,实测值:385.1730. The intermediate Int-1 in Step 2 of Example 1 was replaced with the intermediate Int-24, and the remaining required raw materials, reagents and preparation methods were the same as those in Step 2 of Example 1, to obtain a white solid compound (I-51). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.65 (s, 1H), 8.16 (s, 1H), 8.05 (s, 2H), 7.95 (dd, J = 1.6, 0.6 Hz, 1H), 7.23 (dd, J = 3.3, 0.6 Hz, 1H), 6.74 (dd, J = 3.3, 1.7 Hz, 1H), 4.25 (t, J = 7.1 Hz, 2H), 1.92 (t, J = 7.4Hz, 2H), 1.87–1.77 (m, 2H), 1.51–1.41 (m, 2H), 1.35–1.18 (m, 4H). HRMS (ESI) C 17 H 21 N 8 O 3 + [M + H) + calculated value: 385.1737, measured value: 385.1730.
实施例52：7-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)-N-羟基庚酰胺(化合物I’-52)的制备Example 52: 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) -N-hydroxyheptanamide (Compound I'-52)
步骤1：7-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)庚酸甲酯(中间体Int-25)的制备Step 1: 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8- Preparation of Methyl) heptanoate (Intermediate Int-25)
Figure PCTCN2019120284-appb-000359
Figure PCTCN2019120284-appb-000359
按照实施例51步骤1的方法可同时分离得到中间体Int-24的另一同分异构体(Int-25)。 1H NMR(800MHz,DMSO)δ8.61(s,1H),7.94(dd,J＝1.6,0.7Hz,1H),7.60(s,2H),7.20(dd,J＝3.4,0.7Hz,1H),6.73(dd,J＝3.3,1.7Hz,1H),4.26(t,J＝7.0Hz,2H),3.57(s,3H),2.28(t,J＝7.4Hz,2H),1.91–1.80(m,2H),1.54–1.47(m,2H),1.33–1.28(m,2H),1.26–1.22(m,2H).HRMS(ESI)C 18H 22N 7O 3 +[M+H] +计算值:384.1784,实测值:384.1777. According to the method of Step 1 in Example 51, another isomer of the intermediate Int-24 (Int-25) can be simultaneously separated. 1 H NMR (800 MHz, DMSO) δ 8.61 (s, 1H), 7.94 (dd, J = 1.6, 0.7 Hz, 1H), 7.60 (s, 2H), 7.20 (dd, J = 3.4, 0.7 Hz, 1H ), 6.73 (dd, J = 3.3, 1.7 Hz, 1H), 4.26 (t, J = 7.0 Hz, 2H), 3.57 (s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 1.91–1.80 (m, 2H), 1.54–1.47 (m, 2H), 1.33–1.28 (m, 2H), 1.26–1.22 (m, 2H). HRMS (ESI) C 18 H 22 N 7 O 3 + (M + H ] + Calculated value: 384.1784, measured value: 384.1777.
步骤2：7-(5-氨基-2-((呋喃-2-基)-8H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-8-基)-N-羟基庚酰胺(化合物I’-52)的制备Step 2: 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8- ) -N-hydroxyheptanamide (Compound I'-52)
Figure PCTCN2019120284-appb-000360
Figure PCTCN2019120284-appb-000360
将实施例1步骤2中的中间体Int-1替换成中间体Int-25，其余所需原料，试剂及制备方法同实施例1步骤2，得白色固体化合物(I’-52)。 1H NMR(800MHz,DMSO-d 6)δ10.32(s,1H),8.61(s,1H),7.94(d,J＝0.9Hz,1H),7.60(s,2H),7.20(d,J＝3.3Hz,1H),6.73(dd,J＝3.3,1.7Hz,1H),4.26(t,J＝7.0Hz,2H),1.93(t,J＝7.4Hz,2H),1.88–1.84(m,2H),1.53–1.41(m,2H),1.34–1.15(m,4H).HRMS(ESI)C 17H 21N 8O 3 +[M+H] +计算值:385.1737,实测值:385.1731. The intermediate Int-1 in Step 2 of Example 1 was replaced with the intermediate Int-25, and the remaining required raw materials, reagents and preparation methods were the same as those in Step 2 of Example 1, to obtain a white solid compound (I'-52). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.61 (s, 1H), 7.94 (d, J = 0.9 Hz, 1H), 7.60 (s, 2H), 7.20 (d, J = 3.3 Hz, 1H), 6.73 (dd, J = 3.3, 1.7 Hz, 1H), 4.26 (t, J = 7.0 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.88-1.84 ( m, 2H), 1.53–1.41 (m, 2H), 1.34–1.15 (m, 4H). HRMS (ESI) C 17 H 21 N 8 O 3 + [M + H] + calculated value: 385.1737, measured value: 385.1731.
实施例53：6-(4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯氧基)-N-羟基己酰胺(化合物I-53)的制备Example 53: 6- (4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) ethyl) phenoxy) -N-hydroxyhexanamide (compound I-53)
步骤1：6-(4-(2-羟基乙基)苯氧基)己酸甲酯(中间体Int-26)的制备Step 1: Preparation of 6- (4- (2-hydroxyethyl) phenoxy) hexanoic acid methyl ester (Intermediate Int-26)
Figure PCTCN2019120284-appb-000361
Figure PCTCN2019120284-appb-000361
将4-(2-羟基乙基)苯酚(0.69g，5mmol)，6-溴己酸甲酯(1.04g，5mmol)和碳酸钾(1.38g，10mmol)溶于DMF(10mL)中，室温搅拌过夜。将反应液用乙酸乙酯/水萃取3次。合并酯相，减压蒸干溶剂并用硅胶柱层析分离纯化得油状中间体Int-26(0.66g，收率50％)。 1H NMR(800MHz,CDCl 3)δ7.15–7.12(m,2H),6.86–6.83(m,2H),3.94(t,J＝6.4Hz,2H),3.81(t,J＝6.7Hz,2H),3.68(s,3H),2.81(t,J＝6.7Hz,2H),2.36(t,J＝7.5Hz,2H),1.84–1.77(m,2H),1.74–1.68(m,2H),1.54–1.48(m,2H). Dissolve 4- (2-hydroxyethyl) phenol (0.69g, 5mmol), methyl 6-bromohexanoate (1.04g, 5mmol) and potassium carbonate (1.38g, 10mmol) in DMF (10mL) and stir at room temperature overnight. The reaction solution was extracted 3 times with ethyl acetate / water. Combine the ester phases, evaporate the solvent under reduced pressure and separate and purify by silica gel column chromatography to obtain the oily intermediate Int-26 (0.66g, yield 50%). 1 H NMR (800 MHz, CDCl 3 ) δ 7.15–7.12 (m, 2H), 6.86–6.83 (m, 2H), 3.94 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 6.7 Hz, 2H), 3.68 (s, 3H), 2.81 (t, J = 6.7Hz, 2H), 2.36 (t, J = 7.5Hz, 2H), 1.84-1.77 (m, 2H), 1.74-1.68 (m, 2H) ), 1.54–1.48 (m, 2H).
步骤2：6-(4-(2-溴乙基)苯氧基)己酸甲酯(中间体Int-27)的制备Step 2: Preparation of 6- (4- (2-bromoethyl) phenoxy) hexanoic acid methyl ester (Intermediate Int-27)
Figure PCTCN2019120284-appb-000362
Figure PCTCN2019120284-appb-000362
将中间体Int-26(0.266g，1mmol)溶于甲苯(5mL)中，加入三溴化磷(0.09g，0.33mmol)，回流搅拌2h。将反应液用饱和碳酸氢钠水溶液洗涤，酯相浓缩蒸干并用硅胶柱层析分离纯化得油状中间体Int-27(0.28g，收率85％)。 1H NMR(800MHz,CDCl 3)δ7.12(t,J＝5.6Hz,2H),6.87–6.84(m,2H),3.95(t,J＝6.4Hz,2H),3.69(s,3H),3.56–3.52(m,2H),3.11(t,J＝7.7Hz,2H),2.39–2.34(m,2H),1.83–1.79(m,2H),1.74–1.69(m,2H),1.54–1.49(m,2H). The intermediate Int-26 (0.266 g, 1 mmol) was dissolved in toluene (5 mL), phosphorus tribromide (0.09 g, 0.33 mmol) was added, and the mixture was stirred under reflux for 2 h. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, the ester phase was concentrated and evaporated to dryness, and separated and purified by silica gel column chromatography to obtain an oily intermediate Int-27 (0.28 g, yield 85%). 1 H NMR (800 MHz, CDCl 3 ) δ 7.12 (t, J = 5.6 Hz, 2H), 6.87–6.84 (m, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.69 (s, 3H) , 3.56–3.52 (m, 2H), 3.11 (t, J = 7.7Hz, 2H), 2.39–2.34 (m, 2H), 1.83–1.79 (m, 2H), 1.74–1.69 (m, 2H), 1.54 –1.49 (m, 2H).
步骤3：6-(4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯氧基)己酸甲酯(中间体Int-28)的制备Step 3: 6- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of methyl pyrimidin-7-yl) ethyl) phenoxy) hexanoate (intermediate Int-28)
Figure PCTCN2019120284-appb-000363
Figure PCTCN2019120284-appb-000363
将实施例40步骤1中的4-(2-溴乙基)苯甲酸甲酯替换成中间体Int-27，其余所需原料，试剂及制备方法同实施例40步骤1，得白色固体中间体(Int-27)。 1H NMR(800MHz,DMSO-d 6)δ8.17(s,1H),8.06(s,2H),7.95–7.94(m,1H),7.24–7.22(m,1H),7.06(d,J＝8.6Hz,2H),6.79(d,J＝8.6Hz,2H),6.74(dd,J＝3.3,1.7Hz,1H),4.45(t,J＝7.4Hz,2H),3.88(t,J＝6.5Hz,2H),3.58(s,3H),3.11(t,J＝7.4Hz,2H),2.31(t,J＝7.4Hz,2H),1.70–1.63(m,2H),1.59–1.53(m,2H),1.41–1.37(m,2H).HRMS(ESI)C 25H 28N 7O 4 +[M+H] +计算值:490.2203,实测值:490.2200. Replace methyl 4- (2-bromoethyl) benzoate in step 1 of Example 40 with intermediate Int-27. The remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40 to obtain a white solid intermediate (Int-27). 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 8.06 (s, 2H), 7.95–7.94 (m, 1H), 7.24–7.22 (m, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.74 (dd, J = 3.3, 1.7 Hz, 1H), 4.45 (t, J = 7.4 Hz, 2H), 3.88 (t, J = 6.5 Hz, 2H), 3.58 (s, 3H), 3.11 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.70–1.63 (m, 2H), 1.59–1.53 (m, 2H), 1.41-1.37 (m, 2H). HRMS (ESI) C 25 H 28 N 7 O 4 + [M + H] + calculated value: 490.2203, measured value: 490.2200.
步骤4：6-(4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯氧基)-N-羟基己酰胺(化合物I-53)的制备Step 4: 6- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of pyrimidin-7-yl) ethyl) phenoxy) -N-hydroxyhexanamide (compound I-53)
Figure PCTCN2019120284-appb-000364
Figure PCTCN2019120284-appb-000364
将实施例1步骤2中的中间体Int-1替换成中间体Int-28，其余所需原料，试剂及制备方法同实施例1步骤2，得白色固体化合物(I-53)。 1H NMR(800MHz,DMSO-d 6)δ10.33(s,1H),8.66(s,1H),8.17(s,1H),8.06(s,2H),7.95(dd,J＝1.5,0.6Hz,1H),7.23(dd,J＝3.3,0.6Hz,1H),7.06(d,J＝8.6Hz,2H),6.79(d,J＝8.6Hz,2H),6.74(dd,J＝3.3,1.7Hz,1H),4.45(t,J＝7.4Hz,2H),3.87(t,J＝6.5Hz,2H),3.11(t,J＝7.4Hz,2H),1.96(t,J＝7.4Hz,2H),1.72–1.62(m,2H),1.57–1.49(m,2H),1.41–1.31(m,2H).HRMS(ESI)C 24H 27N 8O 4 +[M+H] +计算值:491.2155,实测值:491.2145. The intermediate Int-1 in Step 2 of Example 1 was replaced with intermediate Int-28, and the remaining required raw materials, reagents and preparation methods were the same as those in Step 2 of Example 1, to obtain a white solid compound (I-53). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 8.66 (s, 1H), 8.17 (s, 1H), 8.06 (s, 2H), 7.95 (dd, J = 1.5, 0.6 Hz, 1H), 7.23 (dd, J = 3.3, 0.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.74 (dd, J = 3.3 , 1.7Hz, 1H), 4.45 (t, J = 7.4Hz, 2H), 3.87 (t, J = 6.5Hz, 2H), 3.11 (t, J = 7.4Hz, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.72–1.62 (m, 2H), 1.57–1.49 (m, 2H), 1.41–1.31 (m, 2H). HRMS (ESI) C 24 H 27 N 8 O 4 + [M + H] + Calculated value: 491.2155, measured value: 491.2145.
实施例54：N 1-(4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯基)-N 8-羟基辛烷二酰胺(化合物I-54)的制备 Example 54: N 1- (4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1, 5-c] pyrimidin-7-yl) ethyl) phenyl) -N 8 -hydroxyoctanediamide (compound I-54)
步骤1：8-((4-(2-羟基乙基)苯基)氨基)-8-氧代辛酸甲酯(中间体Int-29)的制备Step 1: Preparation of 8-((4- (2-hydroxyethyl) phenyl) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-29)
Figure PCTCN2019120284-appb-000365
Figure PCTCN2019120284-appb-000365
将辛二酸单甲酯(1.88g，10mmol)溶于甲苯(10mL)中，加入氯化亚砜(0.5mL)及1滴DMF，回流搅拌2h。减压蒸干溶剂，残留物用二氯甲烷溶解，并滴加至2-(4-氨基苯基)乙醇(2.74g，20mmol)的二氯甲烷(10mL)溶液中，室温搅拌2h。减压蒸干溶剂，剩余固体用硅胶柱层析分离纯化，得油状中间体Int-29(2.21g，收率72％)。 1H NMR(800MHz,CDCl 3)δ7.50–7.43(m,3H),7.18(d,J＝8.3Hz,2H),3.84(t,J＝6.5Hz,2H),3.68(s,3H),2.84(t,J＝6.5Hz,2H),2.38–2.29(m,4H),1.77–1.70(m,2H),1.68–1.60(m,2H),1.44–1.32(m,4H).HRMS(ESI)C 17H 26NO 4 +[M+H] +计算值:308.1862,实测值:308.1855. Dissolve monomethyl suberate (1.88 g, 10 mmol) in toluene (10 mL), add sulfoxide chloride (0.5 mL) and 1 drop of DMF, and stir at reflux for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved with dichloromethane, and added dropwise to a solution of 2- (4-aminophenyl) ethanol (2.74 g, 20 mmol) in dichloromethane (10 mL), and stirred at room temperature for 2 h. The solvent was evaporated to dryness under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain an oily intermediate Int-29 (2.21 g, yield 72%). 1 H NMR (800 MHz, CDCl 3 ) δ 7.50 – 7.43 (m, 3H), 7.18 (d, J = 8.3 Hz, 2H), 3.84 (t, J = 6.5 Hz, 2H), 3.68 (s, 3H) , 2.84 (t, J = 6.5 Hz, 2H), 2.38–2.29 (m, 4H), 1.77–1.70 (m, 2H), 1.68–1.60 (m, 2H), 1.44–1.32 (m, 4H). HRMS (ESI) C 17 H 26 NO 4 + [M + H] + calculated value: 308.1862, actual value: 308.1855.
步骤2：N 1-(4-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)苯基)-N 8-羟基辛烷二酰胺(化合物I-54)的制备 Step 2: N 1- (4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) ethyl) phenyl) -N 8 -hydroxyoctanediamide (Compound I-54)
Figure PCTCN2019120284-appb-000366
Figure PCTCN2019120284-appb-000366
将实施例53步骤2中的中间体Int-26替换成Int-29，其余所需原料，试剂及制备方法同实施例53步骤2～4，得白色固体化合物(I-54)。 1H NMR(800MHz,DMSO-d 6)δ10.32(s,1H),9.77(s,1H),8.65(d,J＝1.5Hz,1H),8.16(s,1H),8.07(s,2H),7.96–7.92(m,1H),7.46(d,J＝8.4Hz,2H),7.25–7.20(m,1H),7.09(d,J＝8.4Hz,2H),6.74(dd,J＝3.3,1.7Hz,1H),4.46(t,J＝7.4Hz,2H),3.13(t,J＝7.4Hz,2H),2.25(t,J＝7.4Hz,2H),1.93(t,J＝7.4Hz,2H),1.59–1.52(m,2H),1.52–1.43(m,2H),1.33–1.19(m,4H).HRMS(ESI)C 26H 30N 9O 4 +[M+H] +计算值:532.2421,实测值:532.2415. The intermediate Int-26 in Step 2 of Example 53 was replaced with Int-29, and the remaining required raw materials, reagents and preparation methods were the same as Steps 2 to 4 of Example 53 to obtain a white solid compound (I-54). 1 H NMR (800 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 9.77 (s, 1H), 8.65 (d, J = 1.5 Hz, 1H), 8.16 (s, 1H), 8.07 (s, 2H), 7.96–7.92 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.25–7.20 (m, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.74 (dd, J = 3.3, 1.7 Hz, 1H), 4.46 (t, J = 7.4 Hz, 2H), 3.13 (t, J = 7.4 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.59–1.52 (m, 2H), 1.52–1.43 (m, 2H), 1.33–1.19 (m, 4H). HRMS (ESI) C 26 H 30 N 9 O 4 + [M + H) + calculated value: 532.2421, measured value: 532.2415.
实施例55：4-(1-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)哌啶-4-基)-N-羟基苯甲酰胺(化合物I-55)的制备Example 55: 4- (1- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) ethyl) piperidin-4-yl) -N-hydroxybenzamide (compound I-55)
步骤1：4-(1-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)哌啶-4-基)苯甲酸甲酯(中间体Int-30)的制备Step 1: 4- (1- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of methyl pyrimidin-7-yl) ethyl) piperidin-4-yl) benzoate (intermediate Int-30)
Figure PCTCN2019120284-appb-000367
Figure PCTCN2019120284-appb-000367
将7-(2-溴乙基)-2-(呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-5-胺(制备方法参见WO 2001092264)(0.348g，1.0mmol)，4-(哌啶-4-基)苯甲酸甲酯盐酸盐(0.51g，2.0mmol)及DIPEA(0.387g，3.0mmol)溶于DMF(10mL)中，80℃搅拌过夜。减压蒸干溶剂，剩余固体用硅胶柱层析分离纯化，得油状中间体Int-30(0.398g，收率82％)。HRMS(ESI)C 25H 27N 8O 3 +[M+H] +计算值:487.2206,实测值:487.2202. 7- (2-Bromoethyl) -2- (furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-5- Amine (see WO 2001092264 for preparation method) (0.348g, 1.0mmol), methyl 4- (piperidin-4-yl) benzoate hydrochloride (0.51g, 2.0mmol) and DIPEA (0.387g, 3.0mmol) Stir in DMF (10 mL) at 80 ° C overnight. The solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain an oily intermediate Int-30 (0.398 g, yield 82%). HRMS (ESI) C 25 H 27 N 8 O 3 + [M + H] + calculated value: 487.2206, measured value: 487.2202.
步骤2：4-(1-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)哌啶-4-基)-N-羟基苯甲酰胺(化合物I-55)的制备Step 2: 4- (1- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of pyrimidin-7-yl) ethyl) piperidin-4-yl) -N-hydroxybenzamide (compound I-55)
Figure PCTCN2019120284-appb-000368
Figure PCTCN2019120284-appb-000368
将实施例1步骤2中的中间体Int-1替换成中间体Int-30，其余所需原料，试剂及制备方法同实施例1步骤2，得粉红色固体化合物(I-55)。 1H NMR(800MHz,DMSO-d 6)δ11.11(s,1H),8.96(s,1H),8.18(s,1H),8.10(s,2H),7.98–7.92(m,1H),7.66(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),7.24(d,J＝3.2Hz,1H),6.74(dd,J＝3.3,1.7Hz,1H),4.41(t,J＝6.9Hz,2H),3.04(d,J＝11.2Hz,2H),2.83(t,J＝7.0Hz,2H),2.54–2.52(m,1H),2.13(t,J＝10.8Hz,2H),1.76–1.70(m,2H),1.64–1.54(m,2H).HRMS(ESI)C 24H 26N 9O 3 +[M+H] +计算值:488.2159,实测值:488.2153. The intermediate Int-1 in Step 2 of Example 1 was replaced with the intermediate Int-30. The remaining required raw materials, reagents and preparation methods were the same as those in Step 2 of Example 1, to obtain a pink solid compound (I-55). 1 H NMR (800 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 8.96 (s, 1H), 8.18 (s, 1H), 8.10 (s, 2H), 7.98–7.92 (m, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 3.2 Hz, 1H), 6.74 (dd, J = 3.3, 1.7 Hz, 1H), 4.41 (t, J = 6.9 Hz, 2H), 3.04 (d, J = 11.2 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H), 2.54-2.52 (m, 1H), 2.13 (t, J = 10.8 Hz, 2H), 1.76–1.70 (m, 2H), 1.64–1.54 (m, 2H). HRMS (ESI) C 24 H 26 N 9 O 3 + [M + H] + calculated value: 488.2159, actual measurement Value: 488.2153.
实施例56：2-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙基)-N-羟基-1,2,3,4-四氢异喹啉-7-甲酰胺(化合物I-56)的制备Example 56: 2- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N-hydroxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Compound I-56)
Figure PCTCN2019120284-appb-000369
Figure PCTCN2019120284-appb-000369
将实施例步骤1中的4-(哌啶-4-基)苯甲酸甲酯盐酸盐替换为1,2,3,4-四氢异喹啉-7-甲酸甲酯盐酸盐，其余所需原料，试剂及制备方法同实施例55，得粉红色固体化合物(I-56)。 1H NMR(800MHz,DMSO-d 6)δ8.17(s,1H),8.07(s,2H),7.94(s,1H),7.47(d,J＝7.7Hz,1H),7.44(s,1H),7.23(d,J＝3.2Hz,1H),7.10(d,J＝7.9Hz,1H),6.76–6.69(m,1H),4.49(t,J＝6.6Hz,2H),3.74–3.61(m,2H),2.98(t,J＝6.6Hz,2H),2.82–2.70(m,4H).HRMS(ESI)C 22H 22N 9O 3 +[M+H] +计算值:460.1846,实测值:460.1844. The methyl 4- (piperidin-4-yl) benzoate hydrochloride in step 1 of the example was replaced with methyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate hydrochloride, the rest The required raw materials, reagents and preparation methods are the same as in Example 55 to obtain a pink solid compound (I-56). 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 8.07 (s, 2H), 7.94 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.44 (s, 1H), 7.23 (d, J = 3.2Hz, 1H), 7.10 (d, J = 7.9Hz, 1H), 6.76-6.69 (m, 1H), 4.49 (t, J = 6.6Hz, 2H), 3.74- 3.61 (m, 2H), 2.98 (t, J = 6.6 Hz, 2H), 2.82-2.70 (m, 4H). HRMS (ESI) C 22 H 22 N 9 O 3 + [M + H] + calculated value: 460.1846, measured value: 460.1844.
实施例57：2-(2-(5-氨基-2-((呋喃-2-基)-7H吡唑[4,3-e][1,2,4三唑[1,5-c]嘧啶-7-基)乙 基)-N-羟基异吲哚啉-5-甲酰胺(化合物I-57)的制备Example 57: 2- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N-hydroxyisoindoline-5-carboxamide (Compound I-57)
Figure PCTCN2019120284-appb-000370
Figure PCTCN2019120284-appb-000370
将实施例步骤1中的4-(哌啶-4-基)苯甲酸甲酯盐酸盐替换为异吲哚啉-5-甲酸甲酯盐酸盐，其余所需原料，试剂及制备方法同实施例55，得粉红色固体化合物(I-57)。 1H NMR(800MHz,DMSO-d 6)δ8.18(s,1H),8.09(s,2H),7.96–7.91(m,1H),7.61–7.49(m,2H),7.23(d,J＝3.3Hz,1H),7.10–7.01(m,1H),6.73(dd,J＝3.3,1.6Hz,1H),4.46(t,J＝6.6Hz,2H),3.92(s,2H),3.90(s,2H),3.18(t,J＝6.5Hz,2H).HRMS(ESI)C 21H 20N 9O 3 +[M+H] +计算值:446.1689,实测值:446.1683. Replace 4- (piperidin-4-yl) benzoic acid methyl ester hydrochloride in step 1 of the example with isoindolin-5-carboxylic acid methyl ester hydrochloride, the remaining required raw materials, reagents and preparation methods are the same In Example 55, a pink solid compound (I-57) was obtained. 1 H NMR (800 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 8.09 (s, 2H), 7.96–7.91 (m, 1H), 7.61–7.49 (m, 2H), 7.23 (d, J = 3.3 Hz, 1H), 7.10–7.01 (m, 1H), 6.73 (dd, J = 3.3, 1.6 Hz, 1H), 4.46 (t, J = 6.6 Hz, 2H), 3.92 (s, 2H), 3.90 (s, 2H), 3.18 (t, J = 6.5 Hz, 2H). HRMS (ESI) C 21 H 20 N 9 O 3 + [M + H] + calculated value: 446.1689, measured value: 446.1683.
实施例58：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-58)的制备Example 58: 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-58)
步骤1：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)苯甲酸甲酯(中间体Int-31)的制备Step 1: 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of Methyl Amino) propyl) benzoate (Intermediate Int-31)
Figure PCTCN2019120284-appb-000371
Figure PCTCN2019120284-appb-000371
将7-氯-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-5-胺(制备方法参见WO 2003048164)(0.235g，0.1mmol)，4-(3-(甲基氨基)丙基)苯甲酸甲酯(制备方法参见WO 2004064721)(0.207g，0.1mmol)及氟化铯(0.152g，0.1mmol)溶于DMSO(10mL)中，120℃搅拌18h。减压蒸干溶剂，剩余固体用硅胶柱层析分离纯化，得固体中间体Int-31(0.21g，收率52％)。 1H NMR(800MHz,CDCl 3)δ7.94(d,J＝8.0Hz,2H),7.59–7.54(m,1H),7.23(d,J＝7.9Hz,2H),7.15(d,J＝3.2Hz,1H),6.56–6.51(m,1H),5.84(s,1H),5.77(s,2H),3.89(s,3H),3.54(t,J＝7.2Hz,2H),2.97(s,3H),2.66(t,J＝7.7Hz,2H),1.96–1.87(m,2H).HRMS(ESI)C 21H 23N 6O 3 +[M+H] +计算值:407.1832,实测值:407.1828. 7-chloro-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-5-amine (for the preparation method, see WO 2003048164) (0.235g, 0.1mmol) , Methyl 4- (3- (methylamino) propyl) benzoate (see WO 2004064721 for preparation method) (0.207g, 0.1mmol) and cesium fluoride (0.152g, 0.1mmol) dissolved in DMSO (10mL) , Stir at 120 ℃ for 18h. The solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain a solid intermediate Int-31 (0.21 g, yield 52%). 1 H NMR (800 MHz, CDCl 3 ) δ 7.94 (d, J = 8.0 Hz, 2H), 7.59–7.54 (m, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 3.2Hz, 1H), 6.56-6.51 (m, 1H), 5.84 (s, 1H), 5.77 (s, 2H), 3.89 (s, 3H), 3.54 (t, J = 7.2Hz, 2H), 2.97 ( s, 3H), 2.66 (t, J = 7.7 Hz, 2H), 1.96–1.87 (m, 2H). HRMS (ESI) C 21 H 23 N 6 O 3 + [M + H] + calculated value: 407.1832, Found value: 407.1828.
步骤2：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)苯甲酸甲酯(中间体Int-32)的制备Step 2: 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of Methyl Amino) propyl) benzoate (Intermediate Int-32)
Figure PCTCN2019120284-appb-000372
Figure PCTCN2019120284-appb-000372
将步骤1得到的酯类中间体Int-31(0.203g，0.50mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶剂中，加入氢氧化锂(0.060g，2.5mmol)，室温下搅拌过夜。用氯化氢的1，4-二氧六环溶液(4M)中和反应液至pH7.4，减压蒸干溶剂，得相应羧酸中间体Int-32粗品，直接用于下一步反应。HRMS(ESI)C 20H 21N 6O 3 +[M+H] +计算值:393.1675,实测值:393.1688. Dissolve the ester intermediate Int-31 (0.203g, 0.50mmol) obtained in Step 1 in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), add lithium hydroxide (0.060g, 2.5mmol) at room temperature Stir overnight. The reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-32, which was directly used in the next reaction. HRMS (ESI) C 20 H 21 N 6 O 3 + [M + H] + calculated value: 393.1675, measured value: 393.1688.
步骤3：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-58)的制备Step 3: 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-58)
Figure PCTCN2019120284-appb-000373
Figure PCTCN2019120284-appb-000373
将步骤2得到的全部中间体Int-32粗品溶于无水DMF(5mL)中，加入HATU(0.38g，1.0mmol),室温搅拌20分钟，再加入邻苯二胺(0.108g，1.0mmol)及DIPEA(0.387g，3.0mmol)，室温搅拌过夜。反应液加水稀释，以乙酸乙酯萃取三次，合并有机相，减压蒸除溶剂，剩余固体用硅胶柱层析分离纯化，得化合物I-58(0.152g，收率63％)。 1H NMR(800MHz,DMSO-d 6)δ9.61(s,1H),7.92(d,J＝7.9Hz,2H),7.88–7.84(m,1H),7.53(s,2H),7.38(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),7.05(dd,J＝3.3,0.6Hz,1H),7.00–6.94(m,1H),6.78(dd,J＝8.0,1.2Hz,1H),6.67(dd,J＝3.3,1.7Hz,1H),6.63–6.57(m,1H),5.79(s,1H),4.88(s,2H),3.62–3.54(m,2H),3.01(s,3H),2.72–2.64(m,2H),1.94–1.86(m,2H).HRMS(ESI)C 26H 27N 8O 2 +[M+H] +计算值:483.2257,实测值:483.2253. Dissolve all crude intermediate Int-32 obtained in Step 2 in anhydrous DMF (5mL), add HATU (0.38g, 1.0mmol), stir at room temperature for 20 minutes, then add o-phenylenediamine (0.108g, 1.0mmol) And DIPEA (0.387g, 3.0mmol), stirred at room temperature overnight. The reaction solution was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, the solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain compound I-58 (0.152 g, yield 63%). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.61 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.88–7.84 (m, 1H), 7.53 (s, 2H), 7.38 ( d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 3.3, 0.6 Hz, 1H), 7.00–6.94 (m, 1H), 6.78 (dd, J = 8.0, 1.2 Hz, 1H), 6.67 (dd, J = 3.3, 1.7 Hz, 1H), 6.63–6.57 (m, 1H), 5.79 (s, 1H), 4.88 (s, 2H), 3.62–3.54 ( m, 2H), 3.01 (s, 3H), 2.72–2.64 (m, 2H), 1.94–1.86 (m, 2H). HRMS (ESI) C 26 H 27 N 8 O 2 + [M + H] + calculation Value: 483.2257, measured value: 483.2253.
实施例59：4-(2-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)乙氧基)-N-(2-氨基苯基)苯甲酰胺(化合物I-59)的制备Example 59: 4- (2-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) ethoxy) -N- (2-aminophenyl) benzamide (Compound I-59)
Figure PCTCN2019120284-appb-000374
Figure PCTCN2019120284-appb-000374
将实施例58步骤1中的4-(3-(甲基氨基)丙基)苯甲酸甲酯替换为4-(2-(甲氨基)乙氧基)苯甲酸甲酯(中间体Int-4)，其余所需原料，试剂及制备方法同实施例58，得黄色固体化合物(I-59)。 1H NMR(800MHz,DMSO-d 6)δ9.54(s,1H),7.97(d,J＝8.7Hz,2H),7.89–7.83(m,1H),7.60(s,2H),7.15(d,J＝7.6Hz,1H),7.08–7.03(m,3H),7.00–6.93(m,1H),6.78(dd,J＝8.0,1.2Hz,1H),6.67(dd,J＝3.3,1.7Hz,1H),6.62–6.56(m,1H),5.87(s,1H), 4.86(s,2H),4.26(t,J＝6.0Hz,2H),3.98(t,J＝5.9Hz,2H),3.10(s,3H).HRMS(ESI)C 25H 25N 8O 3 +[M+H] +计算值:485.2050,实测值:485.2047. Replace methyl 4- (3- (methylamino) propyl) benzoate in Step 1 of Example 58 with methyl 4- (2- (methylamino) ethoxy) benzoate (Intermediate Int-4 ), The remaining required raw materials, reagents and preparation methods are the same as in Example 58, to obtain a yellow solid compound (I-59). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.89–7.83 (m, 1H), 7.60 (s, 2H), 7.15 ( d, J = 7.6 Hz, 1H), 7.08–7.03 (m, 3H), 7.00–6.93 (m, 1H), 6.78 (dd, J = 8.0, 1.2 Hz, 1H), 6.67 (dd, J = 3.3, 1.7Hz, 1H), 6.62-6.56 (m, 1H), 5.87 (s, 1H), 4.86 (s, 2H), 4.26 (t, J = 6.0Hz, 2H), 3.98 (t, J = 5.9Hz, 2H), 3.10 (s, 3H). HRMS (ESI) C 25 H 25 N 8 O 3 + [M + H] + calculated value: 485.2050, measured value: 485.2047.
实施例60：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)氨基)丙基)-N-(2-氨基苯基)苯甲酰胺(化合物I-60)的制备Example 60: 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) amino) propane ) -N- (2-aminophenyl) benzamide (Compound I-60)
Figure PCTCN2019120284-appb-000375
Figure PCTCN2019120284-appb-000375
将实施例58步骤1中的4-(3-(甲基氨基)丙基)苯甲酸甲酯替换为4-(3-氨丙基)苯甲酸甲酯(制备方法参见WO2012117421)，其余所需原料，试剂及制备方法同实施例58，得黄色固体化合物(I-60)。 1H NMR(800MHz,DMSO-d 6)δ9.60(s,1H),7.92(d,J＝7.9Hz,2H),7.87–7.84(m,1H),7.47(s,2H),7.38(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),7.07–7.02(m,1H),7.00–6.94(m,1H),6.80–6.74(m,2H),6.67(dd,J＝3.3,1.8Hz,1H),6.63–6.57(m,1H),5.67(s,1H),4.85(s,2H),3.23–3.12(m,2H),2.80–2.71(m,2H),1.95–1.84(m,2H).HRMS(ESI)C 25H 25N 8O 2 +[M+H] +计算值:469.2100,实测值:469.2102. Replace methyl 4- (3- (methylamino) propyl) benzoate in step 1 of Example 58 with methyl 4- (3-aminopropyl) benzoate (for the preparation method, see WO2012117421) The raw materials, reagents and preparation methods are the same as in Example 58, to obtain a yellow solid compound (I-60). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.87–7.84 (m, 1H), 7.47 (s, 2H), 7.38 ( d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.07–7.02 (m, 1H), 7.00–6.94 (m, 1H), 6.80–6.74 (m, 2H), 6.67 (dd, J = 3.3, 1.8Hz, 1H), 6.63–6.57 (m, 1H), 5.67 (s, 1H), 4.85 (s, 2H), 3.23–3.12 (m, 2H), 2.80–2.71 (m , 2H), 1.95–1.84 (m, 2H). HRMS (ESI) C 25 H 25 N 8 O 2 + [M + H] + calculated value: 469.2100, measured value: 469.2102.
实施例61：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-61)的制备Example 61: 4- (3-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-61)
步骤1：(2-(4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)苯甲酰胺基)-5-氟苯基)氨基甲酸叔丁酯(中间体Int-33)的制备Step 1: (2- (4- (3-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) Preparation of (methyl) amino) propyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-33)
Figure PCTCN2019120284-appb-000376
Figure PCTCN2019120284-appb-000376
将实施例58步骤3中的邻苯二胺替换成(2-氨基-5-氟苯基)氨基甲酸叔丁酯，其余所需原料，试剂及制备方法同实施例58步骤3，得泡沫状中间体(Int-33)。 1H NMR(800MHz,CDCl 3)δ9.07(s,1H),7.86(d,J＝7.6Hz,2H),7.55–7.46(m,2H),7.31(d,J＝8.5Hz,2H),7.28–7.25(m,2H),7.14(s,1H),6.85–6.80(m,1H),6.53(dd,J＝3.2,1.6Hz,1H),5.73–5.62(m,3H),3.53(t,J＝7.1Hz,2H),3.01(s,3H),2.71(t,J＝7.4Hz,2H),1.99–1.91(m,2H),1.48(s,9H).HRMS(ESI)C 31H 34FN 8O 4 +[M+H] +计算值:601.2687,实测值:601.2613. Replace o-phenylenediamine in Step 3 of Example 58 with tert-butyl (2-amino-5-fluorophenyl) carbamate, the remaining required raw materials, reagents and preparation methods are the same as Step 3 of Example 58 to obtain a foam Intermediate (Int-33). 1 H NMR (800 MHz, CDCl 3 ) δ 9.07 (s, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.55–7.46 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H) , 7.28–7.25 (m, 2H), 7.14 (s, 1H), 6.85–6.80 (m, 1H), 6.53 (dd, J = 3.2, 1.6Hz, 1H), 5.73–5.62 (m, 3H), 3.53 (t, J = 7.1 Hz, 2H), 3.01 (s, 3H), 2.71 (t, J = 7.4 Hz, 2H), 1.99-1.91 (m, 2H), 1.48 (s, 9H). HRMS (ESI) C 31 H 34 FN 8 O 4 + [M + H] + Calculated value: 601.2687, measured value: 601.2613.
步骤2：4-(3-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)丙基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-61)的制备Step 2: 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-61)
Figure PCTCN2019120284-appb-000377
Figure PCTCN2019120284-appb-000377
将步骤1中得到的中间体Int-33按照实施例42步骤2所描述的方法脱去Boc保护基得固体化合物(I-61)。 1H NMR(800MHz,DMSO-d 6)δ9.54(s,1H),7.92(d,J＝8.0Hz,2H),7.86–7.84(m,1H),7.53(s,2H),7.37(d,J＝8.1Hz,2H),7.14–7.07(m,1H),7.05(d,J＝3.4Hz,1H),6.70–6.63(m,1H),6.55(dd,J＝11.2,2.9Hz,1H),6.39–6.29(m,1H),5.79(s,1H),5.21(s,2H),3.59–3.55(m,2H),3.01(s,3H),2.72–2.63(m,2H),1.94–1.83(m,2H).HRMS(ESI)C 26H 26FN 8O 2 +[M+H] +计算值:501.2163,实测值:501.2159. The intermediate Int-33 obtained in Step 1 was deprotected according to the method described in Step 2 of Example 42 to obtain a solid compound (I-61). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.86-7.84 (m, 1H), 7.53 (s, 2H), 7.37 ( d, J = 8.1 Hz, 2H), 7.14-7.07 (m, 1H), 7.05 (d, J = 3.4 Hz, 1H), 6.70-6.63 (m, 1H), 6.55 (dd, J = 11.2, 2.9 Hz , 1H), 6.39–6.29 (m, 1H), 5.79 (s, 1H), 5.21 (s, 2H), 3.59–3.55 (m, 2H), 3.01 (s, 3H), 2.72–2.63 (m, 2H ), 1.94–1.83 (m, 2H). HRMS (ESI) C 26 H 26 FN 8 O 2 + [M + H] + calculated value: 501.2163, measured value: 501.2159.
实施例62：4-(2-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)乙氧基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-62)的制备Example 62: 4- (2-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) ethoxy) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-62)
步骤1：(2-(4-(2-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)乙氧基)苯甲酰胺基)-5-氟苯基)氨基甲酸叔丁酯(中间体Int-34)的制备Step 1: (2- (4- (2-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) Preparation of (methyl) amino) ethoxy) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-34)
Figure PCTCN2019120284-appb-000378
Figure PCTCN2019120284-appb-000378
将实施例59中的邻苯二胺替换成(2-氨基-5-氟苯基)氨基甲酸叔丁酯，其余所需原料，试剂及制备方法同实施例59，得泡沫状中间体(Int-34)。 1H NMR(800MHz,CDCl 3)δ8.89(s,1H),7.90(d,J＝8.4Hz,2H),7.58(d,J＝1.0Hz,1H),7.53–7.46(m,1H),7.25–7.21(m,2H),7.20(d,J＝3.1Hz,1H),6.93(d,J＝8.7Hz,2H),6.86–6.79(m,1H),6.56(dd,J＝3.4,1.7Hz,1H),5.91(s,1H),5.77(s,2H),4.22(t,J＝5.6Hz,2H),3.98(t,J＝5.5Hz,2H),3.14(s,3H),1.49(s,9H).HRMS(ESI)C 30H 32FN 8O 5 +[M+H] +计算值:603.2480,实测值:603.2407. Replace o-phenylenediamine in Example 59 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 59 to obtain a foamy intermediate (Int -34). 1 H NMR (800 MHz, CDCl 3 ) δ 8.89 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 1.0 Hz, 1H), 7.53–7.46 (m, 1H) , 7.25-7.21 (m, 2H), 7.20 (d, J = 3.1 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.86-6.79 (m, 1H), 6.56 (dd, J = 3.4 , 1.7Hz, 1H), 5.91 (s, 1H), 5.77 (s, 2H), 4.22 (t, J = 5.6Hz, 2H), 3.98 (t, J = 5.5Hz, 2H), 3.14 (s, 3H ), 1.49 (s, 9H). HRMS (ESI) C 30 H 32 FN 8 O 5 + [M + H] + calculated value: 603.2480, measured value: 603.2407.
步骤2：4-(2-((5-氨基-2-(呋喃-2-基)-[1,2,4]三唑[1,5-c]嘧啶-7-基)(甲基)氨基)乙氧基)-N-(2-氨基-4-氟苯基)苯甲酰胺(化合物I-62)的制备Step 2: 4- (2-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) ethoxy) -N- (2-amino-4-fluorophenyl) benzamide (compound I-62)
Figure PCTCN2019120284-appb-000379
Figure PCTCN2019120284-appb-000379
将步骤1中得到的中间体Int-34按照实施例42步骤2所描述的方法脱去Boc保护基得固体化合物(I-62)。 1H NMR(800MHz,DMSO-d 6)δ9.47(s,1H),7.96(d,J＝8.6Hz,2H),7.87(dd,J＝1.6,0.7Hz,1H),7.60(s,2H),7.11–7.07(m,1H),7.07–7.03(m,3H),6.67 (dd,J＝3.3,1.7Hz,1H),6.54(dd,J＝11.2,2.9Hz,1H),6.35(td,J＝8.5,2.9Hz,1H),5.87(s,1H),5.18(s,2H),4.26(t,J＝6.0Hz,2H),3.97(t,J＝5.9Hz,2H),3.10(s,3H).HRMS(ESI)C 25H 24FN 8O 3 +[M+H] +计算值:503.1955,实测值:503.1945. The intermediate Int-34 obtained in Step 1 was deprotected by the method described in Step 2 of Example 42 to obtain a solid compound (I-62). 1 H NMR (800 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.87 (dd, J = 1.6, 0.7 Hz, 1 H), 7.60 (s, 2H), 7.11–7.07 (m, 1H), 7.07–7.03 (m, 3H), 6.67 (dd, J = 3.3, 1.7Hz, 1H), 6.54 (dd, J = 11.2, 2.9Hz, 1H), 6.35 (td, J = 8.5, 2.9Hz, 1H), 5.87 (s, 1H), 5.18 (s, 2H), 4.26 (t, J = 6.0Hz, 2H), 3.97 (t, J = 5.9Hz, 2H) , 3.10 (s, 3H). HRMS (ESI) C 25 H 24 FN 8 O 3 + [M + H] + calculated value: 503.1955, measured value: 503.1945.
实施例63：化合物对组蛋白去乙酰化酶HDAC抑制活性的测定。具体操作方法如下：Example 63: Determination of the inhibitory activity of the compound on histone deacetylase HDAC. The specific operation method is as follows:
(1)配制实验用缓冲液(50mM Tris PH,0.01％Tween-20,50mM NaCl)；(1) Prepare experiment buffer (50mM Tris PH, 0.01% Tween-20, 50mM NaCl);
(2)将待测化合物配成相应10mM浓度的DMSO溶液，然后用DMSO稀释至1mM,再3倍梯度稀释，10个浓度点；(2) The compound to be tested is formulated into a corresponding DMSO solution at a concentration of 10 mM, and then diluted with DMSO to 1 mM, followed by a 3-fold gradient dilution at 10 concentration points;
(3)用Echo将不同浓度的待测化合物转移到384孔板(Perkin Elmer,Cat.No.6007279)上，每孔250nL(最终DMSO含量为1％)；(3) Use Echo to transfer the test compounds of different concentrations to a 384-well plate (Perkin Elmer, Cat. No. 6007279), 250nL per well (final DMSO content is 1%);
(4)用步骤(1)中的缓冲液配制组蛋白去乙酰化酶的溶液，HDAC1(BPS bioscience,Cat.No.50051)终浓度为4nM，HDAC6(BPS bioscience,Cat.No.50056)终浓度为5nM；(4) Prepare the solution of histone deacetylase with the buffer in step (1), the final concentration of HDAC1 (BPS bioscience, Cat. No. 50051) is 4 nM, and the final concentration of HDAC6 (BPS bioscience, Cat. No. 50056) The concentration is 5nM;
(5)用步骤(1)中的缓冲液配制底物(LGK(Ac)-AMC，Trypsin)的混合溶液，对于HDAC1活性的测定：LGK(Ac)-AMC(吉尔生化)浓度为8μM，Trypsin浓度为0.05μM，对于HDAC6活性的测定：LGK(Ac)-AMC终浓度为11μM，Trypsin终浓度为0.01μM；(5) Prepare a mixed solution of substrate (LGK (Ac) -AMC, Trypsin) with the buffer in step (1), and measure the activity of HDAC1: LGK (Ac) -AMC (Gill Biochemical) concentration is 8 μM, Trypsin The concentration is 0.05 μM. For the determination of HDAC6 activity: the final concentration of LGK (Ac) -AMC is 11 μM, and the final concentration of Trypsin is 0.01 μM;
(6)向测试384孔板中每孔加入15μL步骤(4)中所配的酶溶液，对于low control组加入15μL步骤(1)中的缓冲液，1000rmp离心1分钟，而后室温孵育15分钟；(6) Add 15 μL of the enzyme solution prepared in step (4) to each well of the test 384-well plate, add 15 μL of the buffer in step (1) to the low control group, centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 15 minutes;
(7)向测试384孔板中每孔加入10μL步骤(5)中所配的酶溶液，1000rmp离心1分钟，而后室温孵育60分钟；(7) Add 10 μL of the enzyme solution prepared in step (5) to each well of the test 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 60 minutes;
(8)用Synergy MX读取数值(最大激发光：355nm，最大发射光460nm)；(8) Use Synergy MX to read the value (maximum excitation light: 355nm, maximum emission light 460nm);
(9)用GraphPad Prism5处理数据，计算IC 50值，结果如表6所示。 (9) Use GraphPad Prism5 to process the data and calculate the IC 50 value. The results are shown in Table 6.
表6实施例化合物对于HDAC1和HDAC6的抑制活性(“-”未测试)。Table 6 Inhibitory activity of the compounds of the examples on HDAC1 and HDAC6 ("-" not tested).
Figure PCTCN2019120284-appb-000380
Figure PCTCN2019120284-appb-000380
Figure PCTCN2019120284-appb-000381
Figure PCTCN2019120284-appb-000381
Figure PCTCN2019120284-appb-000382
Figure PCTCN2019120284-appb-000382
表6结果显示化合物13-14、37-40具有较好的HDAC1选择性。由此分析得出ZBG为
Figure PCTCN2019120284-appb-000383
能够使化合物具有较好的HDAC1选择性。 The results in Table 6 show that compounds 13-14 and 37-40 have good HDAC1 selectivity. From this analysis, ZBG is
Figure PCTCN2019120284-appb-000383
It can make the compound have better HDAC1 selectivity.
实施例64：本发明化合物对A2A受体结合活性的测定。化合物对人源A2A受体结合活性的测试采用基于放射性同位素配体的竞争结合实验来进行测定。具体操作方法如下：Example 64: Determination of the A2A receptor binding activity of the compounds of the invention. The compounds were tested for human A2A receptor binding activity using competitive binding experiments based on radioisotope ligands. The specific operation method is as follows:
(1)将待测化合物配成相应10mM浓度的DMSO溶液。然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，10个浓度点；(1) The test compound is formulated into a DMSO solution with a corresponding concentration of 10 mM. Then dilute with buffer to 10 μM, then dilute with buffer 3 times, 10 concentration points;
(2)用Echo将不同浓度的待测化合物转移到384孔板上，每孔50nL；(2) Use Echo to transfer test compounds of different concentrations to 384-well plates, 50nL per well;
(3)配制人源A2a受体细胞膜(RBHA2AM400UA；Perkin Elmer)和小麦胚芽凝集素涂层的硅酸钇SPA珠子(RPNQ0023；Perkin Elmer)的混悬液：(0.0334mg/mL A2a细胞膜,3.33mg/mL SPA珠,0.02mg/mL ADA,实验缓冲液包含1×DPBS,10mM MgCl 2,1％DMSO)，室温孵育20分钟； (3) Prepare a suspension of human A2a receptor cell membrane (RBHA2AM400UA; Perkin Elmer) and wheat germ agglutinin coated yttrium silicate SPA beads (RPNQ0023; Perkin Elmer): (0.0334mg / mL A2a cell membrane, 3.33mg / mL SPA beads, 0.02mg / mL ADA, the experiment buffer contains 1 × DPBS, 10mM MgCl 2 , 1% DMSO), and incubate at room temperature for 20 minutes;
(4)向每孔中加入20μL  3H SCH58261(ART2128；ARC)的溶液(15nM SCH 58261，实验缓冲液包含1×DPBS,10mM MgCl 2,1％DMSO)，1000rmp离心1分钟； (4) Add 20 μL of 3 H SCH58261 (ART2128; ARC) solution (15 nM SCH 58261, experiment buffer containing 1 × DPBS, 10 mM MgCl 2 , 1% DMSO) to each well, and centrifuge at 1000 rpm for 1 minute;
(5)向每孔中加入30μL A2a细胞膜-SPA珠子的混悬液，1000rmp离心1分钟后将板密封并置于室温下持续震荡孵育60分钟；(5) Add 30 μL of A2a cell membrane-SPA bead suspension to each well, centrifuge at 1000 rpm for 1 minute, seal the plate and incubate at room temperature for 60 minutes with continuous shaking;
(6)用Microbeta 2(PerkinElmer)读取CPM值；(6) Use Microbeta 2 (PerkinElmer) to read the CPM value;
(7)用GraphPad Prism 5处理数据，计算IC 50值，结果如表7所示。 (7) Use GraphPad Prism 5 to process the data and calculate the IC 50 value. The results are shown in Table 7.
表7实施例化合物对于A2A受体的的放射性同位配体竞争结合强度结果Table 7 The results of the competition binding strength of the radioactive isomer ligands for the A2A receptor of the compounds of the examples
Figure PCTCN2019120284-appb-000384
Figure PCTCN2019120284-appb-000384
Figure PCTCN2019120284-appb-000385
Figure PCTCN2019120284-appb-000385
实施例65：本发明化合物对A2A受体功能活性的测定。化合物对人源A2A受体功能实验的活性采用基于HTRF的cAMP实验(Perkin Elmer)来进行测定。具体操作方法如下：Example 65: Determination of the functional activity of the compounds of the invention on the A2A receptor. The activity of the compound on the human A2A receptor function test was measured using the cAMP test (Perkin Elmer) based on HTRF. The specific operation method is as follows:
(1)细胞培养[HEK293/A2A细胞株，培养基：150mL DMEM,17mL 10％FBS,1.4mL G418],37℃ 5％CO 2； (1) Cell culture [HEK293 / A2A cell line, medium: 150mL DMEM, 17mL 10% FBS, 1.4mL G418], 37 ° C 5% CO 2 ;
(2)将细胞从T75培养瓶中移出，用8mL缓冲液(Biosera，Lot.No.11169)洗涤细胞，去除缓冲液，再加入2mL胰酶(Gibca，REF 25200-072,Lot.No.1732496)消化细胞；(2) Remove the cells from the T75 flask, wash the cells with 8mL buffer (Biosera, Lot. No. 11169), remove the buffer, and then add 2mL pancreatin (Gibca, REF 25200-072, Lot. No. 1732496) ) Digestive cells;
(3)加入8mL溶液(DMEM+10％FBS+G418)终止消化，吹打混匀，1000rmp离心4分钟；(3) Add 8mL solution (DMEM + 10% FBS + G418) to stop the digestion, mix by pipetting, centrifuge at 1000rmp for 4 minutes;
(4)用刺激缓冲液(5mM HEPES,0.05mM IBMX,0.1％BSA)将细胞重新悬浮并进行细胞计数调整细胞密度为5×10 5细胞/mL； (4) Resuspend cells with stimulation buffer (5mM HEPES, 0.05mM IBMX, 0.1% BSA) and perform cell counting to adjust the cell density to 5 × 10 5 cells / mL;
(5)将待测化合物配成相应10mM浓度的DMSO溶液，然后用DMSO稀释至10μM,再3倍梯度稀释，10个浓度点，阳性对照CGS15943 10μM起始，3倍梯度稀释，10个浓度点；激动剂NECA配制成150μM浓度；(5) Prepare the compound to be tested into the corresponding 10mM concentration of DMSO solution, and then dilute with DMSO to 10μM, then 3-fold gradient dilution, 10 concentration points, positive control CGS15943 starting at 10μM, 3-fold gradient dilution, 10 concentration points ; The agonist NECA is formulated to a concentration of 150 μM;
(6)用Echo将不同浓度的待测化合物转移到384孔板(Optiplate-384)上，每孔100nL，激动剂转移至所有待测孔内，每孔10nL；(6) Use Echo to transfer test compounds of different concentrations to a 384-well plate (Optiplate-384), 100 nL per well, and transfer the agonist to all test wells, 10 nL per well;
(7)向测试384孔板中，每孔加入10μL细胞液，每孔细胞数为5000，1000rmp离心1分钟，室温孵育60分钟；(7) To the test 384-well plate, add 10 μL of cell solution to each well, the number of cells per well is 5000, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 60 minutes;
(8)向每孔中加入5μL 4×Eu-cAMP tracer(TRF,0264)溶液和5μL 4×ULight TM-anti-cAMP溶液，600rmp离心3分钟而后室温孵育60分钟； (8) Add 5 μL 4 × Eu-cAMP tracer (TRF, 0264) solution and 5 μL 4 × ULight TM -anti-cAMP solution to each well, centrifuge at 600 rmp for 3 minutes and incubate at room temperature for 60 minutes;
(9)用EnVision(Perkin Elmer)读取cAMP水平(最大激发光：320nm，最大发射光615/665nm)；(9) Use EnVision (Perkin Elmer) to read the cAMP level (maximum excitation light: 320 nm, maximum emission light 615/665 nm);
(10)用GraphPad Prism处理数据，计算IC 50值，结果如表8所示。 (10) Use GraphPad Prism to process the data and calculate the IC 50 value. The results are shown in Table 8.
表8化合物拮抗A2A受体的cAMP实验结果。Table 8 Results of cAMP experiment of compounds antagonizing A2A receptor.
Figure PCTCN2019120284-appb-000386
Figure PCTCN2019120284-appb-000386
实施例66：本发明化合物抑制肿瘤细胞增殖活性的测试。化合物对肿瘤细胞增殖抑制的活性测定选用HCT-116、HL-60、B16F10三种细胞进行测定。Example 66: Test of compounds of the present invention for inhibiting tumor cell proliferation activity. The compound's activity in inhibiting the proliferation of tumor cells was determined using HCT-116, HL-60, and B16F10 cells.
(1)细胞铺板(1) Cell plating
a.配制完全培养基,充分混匀。a. Prepare complete medium and mix well.
b.选择生长状态良好的细胞株。b. Select cell lines with good growth status.
c.将细胞培养瓶从培养箱中取出,核对瓶上标记的细胞名称,培养基类型及细胞代数。c. Remove the cell culture flask from the incubator and check the cell name, medium type and cell generation number marked on the flask.
d.HCT-116、B16F10细胞弃去培养基，用胰酶消化，消化完后，用含血清的培养基中和，吹打细胞，使细胞脱落。用移液管将细胞悬液移入离心管中,800-1000rmp离心3-5分钟。HL-60细胞用移液管吸取细胞悬液移入离心管中，800-1000rmp离心3-5分钟。d. The HCT-116 and B16F10 cells were discarded from the culture medium and digested with trypsin. After digestion, they were neutralized with serum-containing medium, and the cells were pipetted to make the cells fall off. Pipette the cell suspension into a centrifuge tube and centrifuge at 800-1000rmp for 3-5 minutes. HL-60 cells were pipetted into the centrifuge tube, and centrifuged at 800-1000rmp for 3-5 minutes.
e.吸弃离心管中的细胞上清液，向离心管中加适当体积的培养基,轻柔吹打使细胞重悬均匀。e. Aspirate the cell supernatant from the centrifuge tube, add an appropriate volume of medium to the centrifuge tube, and gently pipette to resuspend the cells evenly.
f.使用Vi-Cell XR细胞计数仪计数，将细胞悬液调至合适浓度。f. Count with Vi-Cell XR cell counter and adjust the cell suspension to the appropriate concentration.
g.将细胞悬液加入底透壁白的384孔板中，36μL/孔。标记细胞名称，种板密度，日期等详细信息，将培养板放置于CO 2培养箱中过夜。 g. Add the cell suspension to a 384-well plate with a white bottom wall, 36 μL / well. Mark the cell name, seed plate density, date and other details, and place the culture plate in a CO 2 incubator overnight.
(2)细胞实验:(2) Cell experiment:
a.用DMSO将待测化合物配制成200×，以DMSO将化合物3倍稀释，得到10个浓度梯度的化合物。a. Prepare the compound to be tested with DMSO to 200 ×, and dilute the compound three times with DMSO to obtain 10 concentration gradient compounds.
b.细胞种板24小时后，取1μL化合物加到19μL培养基中配成10×的中间板，然后每孔中加入4μL 10×相应化合物，然后在37℃培养箱中孵育72小时。b. After 24 hours of cell seeding, add 1 μL of compound to 19 μL of medium to make a 10 × intermediate plate, then add 4 μL of 10 × corresponding compound to each well, and then incubate in a 37 ° C incubator for 72 hours.
c.在倒置显微镜下观察细胞形态。c. Observe the cell morphology under an inverted microscope.
d.将细胞培养板3707放置室温中平衡30分钟，每孔加入25μL将CTG，而后在振板机上混匀10分钟，诱导细胞溶解。d. Place the cell culture plate 3707 at room temperature and equilibrate for 30 minutes, add 25 μL of CTG to each well, and then mix on the shaker for 10 minutes to induce cell lysis.
e.将384孔板在室温中放置10分钟，使其发光信号稳定，而后粘贴白色的底膜于培养板底部，使用Flexstation3测板。e. Place the 384-well plate at room temperature for 10 minutes to stabilize the luminescence signal, and then paste a white base film on the bottom of the culture plate, using the Flexstation3 test plate.
f.记录分析所得的实验结果，如表9所示。f. Record the experimental results of the analysis, as shown in Table 9.
表9化合物抑制肿瘤细胞增殖的实验结果Table 9 Experimental results of compounds inhibiting tumor cell proliferation
Figure PCTCN2019120284-appb-000387
Figure PCTCN2019120284-appb-000387
Figure PCTCN2019120284-appb-000388
Figure PCTCN2019120284-appb-000388
注：NA表示没有活性；“-”表示没有测试Note: NA means no activity; "-" means no test
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these embodiments without departing from the principle and essence of the present invention modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (18)

  1. 一种如式I或I’所示的化合物：A compound represented by formula I or I ’:
    Figure PCTCN2019120284-appb-100001
    Figure PCTCN2019120284-appb-100001
    或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体；Or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer, solvate, metabolite, or prodrug thereof;
    其中，R 1和R 2各自独立地为氢、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 10环烷基、C 6-C 12芳基、5-12元杂芳基或-C(＝O)-R 7；或者，R 1、R 2和与其相连的氮原子一起共同形成3-10元杂环烷基； Wherein R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 6 -C 12 aryl, 5-12 Member heteroaryl or -C (= O) -R 7 ; or, R 1 and R 2 together with the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl;
    R 7为C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(6-12元芳基)或-(C 1-C 3亚烷基)-(5-12元杂芳基)； R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
    R 3为取代或未取代的C 6-C 12芳基或取代或未取代的5-12元杂芳基；所述的取代的C 6-C 12芳基或取代的5-12元杂芳基是指其被一个或多个R 19取代，每个R 19独立地为卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 3-C 6环烷基； R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
    X为N或CR 4； X is N or CR 4 ;
    R 4为氢、氟或C 1-C 3烷基； R 4 is hydrogen, fluorine or C 1 -C 3 alkyl;
    Y为
    Figure PCTCN2019120284-appb-100002
    或取代或未取代的
    Figure PCTCN2019120284-appb-100003
    所述的
    Figure PCTCN2019120284-appb-100004
    为3-10元亚杂环烷基；所述的取代的
    Figure PCTCN2019120284-appb-100005
    是指其被一个或多个R 20取代；     Y is
    Figure PCTCN2019120284-appb-100002
    Or substituted or unsubstituted
    Figure PCTCN2019120284-appb-100003
    Said
    Figure PCTCN2019120284-appb-100004
    Is a 3-10 membered heterocycloalkylene; the substituted
    Figure PCTCN2019120284-appb-100005
    Means it is replaced by one or more R 20 ;
    R 5为氢、C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(C 3-C 6环烷基)、C 2-C 6烯基或C 2-C 6炔基； R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), C 2 -C 6 Alkenyl or C 2 -C 6 alkynyl;
    或者，R 5与R 4以及它们连接的原子一起共同形成
    Figure PCTCN2019120284-appb-100006
    Or, R 5 and R 4 together with the atoms to which they are attached together form
    Figure PCTCN2019120284-appb-100006
    每个L独立地为如下情形(i)、(ii)、(iii)、(iv)或(v)：Each L is independently the following case (i), (ii), (iii), (iv) or (v):
    (i)L为取代或未取代的-M 1-，M 1为-NH-、-O-、-S-、单键、C 1-C 10亚烷基、C 2-C 10亚烯基、C 2-C 10亚炔基、具有2-10个链原子的亚杂烷基、具有2-10个链原子的亚杂烯基或具有3-10个链原子的亚杂炔基；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene , C 2 -C 10 alkynylene, heteroalkylene having 2-10 chain atoms, heteroalkenylene having 2-10 chain atoms or heteroalkynylene having 3-10 chain atoms; The substituted -M 1 -refers to its substitution by one or more R 21 ;
    (ii)L为取代或未取代的-M 2-M 3-，M 2为-NH-、-O-、-S-、单键、C 1-C 6亚烷基、具有2-6个链原子的亚杂烷基、“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”；M 3为C 6-C 12亚芳基或5-12元亚杂芳基；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene, having 2-6 heteroalkylene chain atoms, "C 1 -C 6 alkylene in which one carbon atom is independently selected from -C (= O) O -, - OC (= O) -, - C (= O) NH- and -NHC (= O)-groups replace the group formed "; M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene; the substituted -M 2 -M 3 -means that it is replaced by one or more R 22 ;
    (iii)L为取代或未取代的-M 4-M 5-M 6-，M 4为-NH-、-O-、-S-、单键、C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基；M 5为C 6-C 12亚芳基或5-12元亚杂芳基；M 6为C 1-C 9亚烷基、具有2-9个链原子的亚杂烷基、“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-的基团后代替形成的基团”、“具有2-9个链原子的亚杂烷基中的1或2个链原子被独立选自-C(＝O)-、-C(＝O)O-和-C(＝O)NH-的基团代替后形成的基团”、C 2-C 9亚炔基或具有2-9个链原子的亚杂烯基；所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene group or having 2 -6 chain atoms of heteroalkylene; M 5 is C 6 -C 12 arylene or 5-12 membered heteroarylene; M 6 is C 1 -C 9 alkylene with 2-9 chains heteroalkylene atoms, "C 1 -C 9 alkylene group of 2 or 3 carbon atoms are independently selected from -C (= O) O -, - OC (= O) -, - C ( = O) NH- or -NHC (= O)-group after replacing the formed group "," 1 or 2 chain atoms in the heteroalkylene group having 2-9 chain atoms are independently selected from C (= O)-, -C (= O) O- and -C (= O) NH- groups replace the group formed later ", C 2 -C 9 alkynylene group or have 2-9 chains Atomic heteroalkenylene; said substituted -M 4 -M 5 -M 6 -means that it is substituted with one or more R 23 ;
    (iv)L为取代或未取代的-M 7-M 8-M 9-，M 7为-NH-、-O-、-S-、C 1-C 4亚烷基或具有2-4个链原子的亚杂烷基，M 8为C 3-C 12亚环烷基或3-12元亚杂环烷基，M 9为C 6-C 12亚芳基或5-12元亚杂芳基；所述的取代的-M 7-M 8-M 9-是指其被一个或多个R 24取代； (iv) L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene or has 2-4 Heteroalkylene group of chain atom, M 8 is C 3 -C 12 cycloalkylene group or 3-12 membered heterocycloalkylene group, M 9 is C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical; the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
    (v)取代或未取代的-M 10-M 11-，其中M 10为亚甲基、亚乙基或亚丙基，M 11为
    Figure PCTCN2019120284-appb-100007
    Z 1、Z 2和Z 3各自独立地为CH或N；所述的取代的-M 10-M 11-是指其被一个或多个R 25取代；     (v) substituted or unsubstituted -M 10 -M 11- , wherein M 10 is methylene, ethylene or propylene, and M 11 is
    Figure PCTCN2019120284-appb-100007
    Z 1 , Z 2 and Z 3 are each independently CH or N; the substituted -M 10 -M 11 -means that it is substituted with one or more R 25 ;
    每个R 20、R 21、R 22、R 23、R 24和R 25各自独立地为卤素、羟基、C 1-C 6烷基或C 1-C 6烷氧基； Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
    所述的亚杂烷基、亚杂烯基、亚杂炔基、亚杂环烷基和亚杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个；The hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
    ZBG为
    Figure PCTCN2019120284-appb-100008
    ZBG is
    Figure PCTCN2019120284-appb-100008
    R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 12芳基或5-12元杂芳基； R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
    所述的杂烷基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个。The hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
  2. 如权利要求1所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于，所述的化合物结构如下：The compound represented by formula I or I 'according to claim 1, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a tautomer, a solvent Compounds, metabolites or prodrugs, characterized in that the structure of the compound is as follows:
    Figure PCTCN2019120284-appb-100009
    Figure PCTCN2019120284-appb-100009
    其中，among them,
    R 1和R 2各自独立地为氢、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 10环烷基、C 6-C 12芳基、5-12元杂芳基或-C(＝O)-R 7；或者，R 1、R 2和与其相连的氮原子一起共同形成3-10元杂环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, C 6 -C 12 aryl, 5-12 membered hetero Aryl or -C (= O) -R 7 ; alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached together form a 3-10 membered heterocycloalkyl;
    R 7为C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(6-12元芳基)或-(C 1-C 3亚烷基)-(5-12元杂芳基)； R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
    R 3为取代或未取代的C 6-C 12芳基或取代或未取代的5-12元杂芳基；所述的取代的C 6-C 12芳基或取代的5-12元杂芳基是指其被一个或多个R 19取代，每个R 19独立地为卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 3-C 6环烷基； R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
    X为N或CR 4； X is N or CR 4 ;
    R 4为氢、氟或C 1-C 3烷基； R 4 is hydrogen, fluorine or C 1 -C 3 alkyl;
    Y为
    Figure PCTCN2019120284-appb-100010
    或取代或未取代的
    Figure PCTCN2019120284-appb-100011
    所述的
    Figure PCTCN2019120284-appb-100012
    为3-10元亚杂环烷基； 所述的取代的
    Figure PCTCN2019120284-appb-100013
    是指其被一个或多个R 20取代；     Y is
    Figure PCTCN2019120284-appb-100010
    Or substituted or unsubstituted
    Figure PCTCN2019120284-appb-100011
    Said
    Figure PCTCN2019120284-appb-100012
    Is a 3-10 membered heterocycloalkylene; the substituted
    Figure PCTCN2019120284-appb-100013
    Means it is replaced by one or more R 20 ;
    R 5为氢、C 1-C 6烷基、C 3-C 6环烷基、-(C 1-C 3亚烷基)-(C 3-C 6环烷基)、C 2-C 6烯基或C 2-C 6炔基； R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), C 2 -C 6 Alkenyl or C 2 -C 6 alkynyl;
    L为如下情形(i)、(ii)、(iii)或(iv)：L is the following case (i), (ii), (iii) or (iv):
    (i)L为取代或未取代的-M 1-，M 1为-NH-、-O-、-S-、单键、C 1-C 10亚烷基、C 2-C 10亚烯基、C 2-C 10亚炔基、具有2-10个链原子的亚杂烷基、具有2-10个链原子的亚杂烯基或具有3-10个链原子的亚杂炔基；所述的取代的-M 1-是指其被一个或多个R 21取代； (i) L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene , C 2 -C 10 alkynylene, heteroalkylene having 2-10 chain atoms, heteroalkenylene having 2-10 chain atoms or heteroalkynylene having 3-10 chain atoms; The substituted -M 1 -refers to its substitution by one or more R 21 ;
    (ii)L为取代或未取代的-M 2-M 3-，M 2为-NH-、-O-、-S-、单键、C 1-C 6亚烷基、具有2-6个链原子的亚杂烷基、“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”；M 3为C 6-C 12亚芳基或5-12元亚杂芳基；所述的取代的-M 2-M 3-是指其被一个或多个R 22取代； (ii) L is substituted or unsubstituted -M 2 -M 3- , M 2 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene, having 2-6 heteroalkylene chain atoms, "C 1 -C 6 alkylene in which one carbon atom is independently selected from -C (= O) O -, - OC (= O) -, - C (= O) NH- and -NHC (= O)-groups replace the group formed "; M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene; the substituted -M 2 -M 3 -means that it is replaced by one or more R 22 ;
    (iii)L为取代或未取代的-M 4-M 5-M 6-，M 4为-NH-、-O-、-S-、单键、C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基；M 5为C 6-C 12亚芳基或5-12元亚杂芳基；M 6为C 1-C 9亚烷基、具有2-9个链原子的亚杂烷基、“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-的基团后代替形成的基团”、“具有2-9个链原子的亚杂烷基中的1或2个链原子被独立选自-C(＝O)-、-C(＝O)O-和-C(＝O)NH-的基团代替后形成的基团”、C 2-C 9亚炔基或具有2-9个链原子的亚杂烯基；所述的取代的-M 4-M 5-M 6-是指其被一个或多个R 23取代； (iii) L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene group or having 2 -6 chain atoms of heteroalkylene; M 5 is C 6 -C 12 arylene or 5-12 membered heteroarylene; M 6 is C 1 -C 9 alkylene with 2-9 chains heteroalkylene atoms, "C 1 -C 9 alkylene group of 2 or 3 carbon atoms are independently selected from -C (= O) O -, - OC (= O) -, - C ( = O) NH- or -NHC (= O)-group after replacing the formed group "," 1 or 2 chain atoms in the heteroalkylene group having 2-9 chain atoms are independently selected from C (= O)-, -C (= O) O- and -C (= O) NH- groups replace the group formed later ", C 2 -C 9 alkynylene group or have 2-9 chains Atomic heteroalkenylene; said substituted -M 4 -M 5 -M 6 -means that it is substituted with one or more R 23 ;
    (iv)L为取代或未取代的-M 7-M 8-M 9-，M 7为-NH-、-O-、-S-、C 1-C 4亚烷基或具有2-4个链原子的亚杂烷基，M 8为C 3-C 12亚环烷基或3-12元亚杂环烷基，M 9为C 6-C 12亚芳基或5-12元亚杂芳基；所述的取代的-M 7-M 8-M 9-是指其被一个或多个R 24取代； (iv) L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene or has 2-4 Heteroalkylene group of chain atom, M 8 is C 3 -C 12 cycloalkylene group or 3-12 membered heterocycloalkylene group, M 9 is C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical; the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
    每个R 20、R 21、R 22、R 23和R 24各自独立地为卤素、羟基、C 1-C 6烷基或C 1-C 6烷氧基； Each R 20 , R 21 , R 22 , R 23 and R 24 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
    所述的亚杂烷基、亚杂烯基、亚杂炔基、亚杂环烷基和亚杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个；The hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
    ZBG为
    Figure PCTCN2019120284-appb-100014
    ZBG is
    Figure PCTCN2019120284-appb-100014
    R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代 烷基、C 3-C 6环烷基、3-6元杂环烷基、C 6-C 12芳基或5-12元杂芳基； R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
    所述的杂烷基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，杂原子的个数各自独立地为1、2、3或4个。The hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
  3. 如权利要求1或2所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当R 1和R 2各自独立地为C 3-C 10环烷基时，所述的C 3-C 10环烷基为C 3-C 6环烷基； The compound represented by formula I or I 'according to claim 1 or 2, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a tautomer , Solvates, metabolites or prodrugs, characterized in that when R 1 and R 2 are each independently C 3 -C 10 cycloalkyl, the C 3 -C 10 cycloalkyl is C 3- C 6 cycloalkyl;
    和/或，当R 3为取代或未取代的C 6-C 12芳基时，所述的C 6-C 12芳基为苯基； And / or, when R 3 is a substituted or unsubstituted C 6 -C 12 aryl group, the C 6 -C 12 aryl group is phenyl;
    和/或，当R 3为取代或未取代的5-12元杂芳基时，所述的5-12元杂芳基为5、6或7元杂芳基； And / or, when R 3 is a substituted or unsubstituted 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is a 5, 6 or 7 membered heteroaryl group;
    和/或，当R 19独立地为卤素时，所述的卤素为氟； And / or, when R 19 is independently halogen, the halogen is fluorine;
    和/或，当R 19独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为C 1-C 4烷基； And / or, when R 19 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl;
    和/或，当R 5为C 1-C 6烷基时，所述的C 1-C 6烷基为C 1-C 4烷基； And / or, when R 5 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 4 alkyl;
    和/或，当所述的
    Figure PCTCN2019120284-appb-100015
    为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为3-8元亚杂环烷基；     And / or when said
    Figure PCTCN2019120284-appb-100015
    When it is a 3-10 membered heterocycloalkylene group, the 3-10 membered heterocycloalkylene group is a 3-8 membered heterocycloalkylene group;
    和/或，当L为取代或未取代的-M 1-，M 1为C 1-C 10亚烷基时，所述的C 1-C 10亚烷基为C 1-C 7亚烷基； And / or, when L is substituted or unsubstituted -M 1 -and M 1 is C 1 -C 10 alkylene, the C 1 -C 10 alkylene is C 1 -C 7 alkylene ;
    和/或，当L为取代或未取代的-M 1-，M 1为C 2-C 10亚烯基时，所述的C 2-C 10亚烯基为C 2-C 7亚烯基； And / or, when L is substituted or unsubstituted -M 1- , and M 1 is C 2 -C 10 alkenylene, the C 2 -C 10 alkenylene is C 2 -C 7 alkenylene ;
    和/或，当L为取代或未取代的-M 1-，M 1为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 5-C 7亚炔基； And / or, when L is substituted or unsubstituted -M 1- , and M 1 is C 2 -C 10 alkynylene, the C 2 -C 10 alkynylene is C 5 -C 7 alkynylene ;
    和/或，当L为取代或未取代的-M 1-，M 1为具有2-10个链原子的亚杂烷基时，所述的具有2-10个链原子的亚杂烷基为具有2-7个链原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 1- , and M 1 is a heteroalkylene group having 2-10 chain atoms, the heteroalkylene group having 2-10 chain atoms is Heteroalkylene having 2-7 chain atoms;
    和/或，当L为取代或未取代的-M 1-，M 1为具有2-10个链原子的亚杂烯基时，所述的具有2-10个链原子的亚杂烯基为具有2-7个链原子的亚杂烯基； And / or, when L is substituted or unsubstituted -M 1- , and M 1 is a heteroalkenylene group having 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is Heteroalkenylene having 2-7 chain atoms;
    和/或，当L为取代或未取代的-M 1-，M 1为具有3-10个链原子的亚杂炔基时，所述的具有3-10个链原子的亚杂炔基为具有5、6或7个链原子的亚杂炔基； And / or, when L is substituted or unsubstituted -M 1- , and M 1 is a heteroalkynylene group having 3-10 chain atoms, the heteroalkynylene group having 3-10 chain atoms is Heteroalkynylene with 5, 6 or 7 chain atoms;
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为C 1-C 6亚烷基时，所述的C 1-C 6亚烷基为C 1-C 4亚烷基； And / or, when L is substituted or unsubstituted -M 2 -M 3- , and M 2 is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is C 1 -C 4 Alkylene
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为具有2-6个链原子的亚杂烷基时，所 述的具有2-6个链原子的亚杂烷基为具有2或3个链原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 2 -M 3- , and M 2 is a heteroalkylene group having 2-6 chain atoms, the heteroatom having 2-6 chain atoms The alkyl group is a heteroalkylene group having 2 or 3 chain atoms;
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”时，所述的“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”中的C 1-C 6亚烷基为C 2-C 3亚烷基； And / or, when L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a "C 1 -C 6 alkylene group, one carbon atom is independently selected from -C (= O) O- , -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups replace the group formed later ", the" C 1 -C 6 alkylene group 1 carbon atom is replaced by a group independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)- C 1 -C 6 alkylene in the group ”is C 2 -C 3 alkylene;
    和/或，当L为取代或未取代的-M 2-M 3-，M 3为C 6-C 12亚芳基时，所述的C 6-C 12亚芳基为亚苯基； And / or, when L is substituted or unsubstituted -M 2 -M 3- , and M 3 is C 6 -C 12 arylene, the C 6 -C 12 arylene is phenylene;
    和/或，当L为取代或未取代的-M 2-M 3-，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为5、6或7元亚杂芳基； And / or, when L is substituted or unsubstituted -M 2 -M 3- , and M 3 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 5, 6 or 7 Meta-heteroaryl;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 4为C 1-C 6亚烷基时，所述的C 1-C 6亚烷基为亚甲基、亚乙基或亚丙基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 4 is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is methylene Radical, ethylene or propylene;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 4为具有2-6个链原子的亚杂烷基时，所述的具有2-6个链原子的亚杂烷基为具有2、3或4个原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 4 is a heteroalkylene group having 2-6 chain atoms, the said having 2-6 chain atoms Is a heteroalkylene group having 2, 3 or 4 atoms;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 5为C 6-C 12亚芳基时，所述的C 6-C 12亚芳基为亚苯基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 5 is C 6 -C 12 arylene, the C 6 -C 12 arylene is benzene base;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 5为5-12元亚杂芳基时，所述的5-12元亚杂芳基为5、6或7元亚杂芳基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 5 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 5, 6 or 7 membered heteroarylene;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为C 1-C 9亚烷基时，所述的C 1-C 9亚烷基为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或C 6亚烷基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 6 is C 1 -C 9 alkylene, the C 1 -C 9 alkylene is C 2 Alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or C 6 alkylene;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为具有2-9个链原子的亚杂烷基时，所述的具有2-9个链原子的亚杂烷基为具有2、3、4、5或6个原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 6 is a heteroalkylene group having 2-9 chain atoms, the said having 2-9 chain atoms Is a heteroalkylene group having 2, 3, 4, 5 or 6 atoms;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团后代替形成的基团”时，所述的“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团后代替形成的基团”为-W 1-W 2-，其中W 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，W 2为C 4亚烷基、C 5亚烷基、C 6亚烷基或C 7亚烷基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 6 is "C 1 -C 9 alkylene group 1, 2 or 3 carbon atoms are independently selected from- When C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups are substituted for the formed group ", the" C 1 1, 2 or 3 carbon atoms in the -C 9 alkylene group are independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)-group after the replacement of the formed group "is -W 1 -W 2- , where W 1 is -C (= O) O-, -OC (= O)-, -C (= O) NH -Or -NHC (= O)-, W 2 is C 4 alkylene, C 5 alkylene, C 6 alkylene or C 7 alkylene;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为“具有2-9个链原子的亚杂烷基中的1或2个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”为-V 1-V 2-，其中V 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，V 2为具有4、5、6或7个链原子的亚杂烷基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 6 is "1 or 2 carbon atoms in a heteroalkylene group having 2-9 chain atoms are independently selected from -C (= O) O -, - OC (= O) -, - C (= O) NH- and -NHC (= O) - radical group, "instead be formed after -V 1 -V 2- , where V 1 is -C (= O) O-, -OC (= O)-, -C (= O) NH- or -NHC (= O)-, V 2 is having 4, 5, 6 Or a heteroalkylene group of 7 chain atoms;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为C 2-C 9亚烯基时，所述的C 2-C 9亚烯基为亚乙烯基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 6 is C 2 -C 9 alkenylene, the C 2 -C 9 alkenylene is ethylene base;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 7为C 1-C 4亚烷基时，所述的C 1-C 4亚烷基为亚甲基或亚乙基； And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 7 is C 1 -C 4 alkylene, the C 1 -C 4 alkylene is methylene Radical or ethylene;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 7为具有2-4个链原子的亚杂烷基时，所述的具有2-4个链原子的亚杂烷基为具有2个链原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 7 -M 8 -M 9- , and M 7 is a heteroalkylene group having 2-4 chain atoms, the said having 2-4 chain atoms The heteroalkylene group is a heteroalkylene group having 2 chain atoms;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 8为C 3-C 12亚环烷基时，所述的C 3-C 12亚环烷基为C 3-C 8亚环烷基； And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 8 is C 3 -C 12 cycloalkylene, the C 3 -C 12 cycloalkylene is C 3 -C 8 cycloalkylene;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 8为3-12元亚杂环烷基时，所述的3-12元亚杂环烷基为3-8元亚杂环烷基； And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 8 is a 3-12 membered heterocycloalkylene group, the 3-12 membered heterocycloalkylene group is 3-8 membered heterocycloalkylene;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 9为C 6-C 12亚芳基时，所述的C 6-C 12亚芳基为亚苯基； And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9 -and M 9 is C 6 -C 12 arylene, the C 6 -C 12 arylene is benzene base;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 9为5-12元亚杂芳基时，所述的5-12元亚杂芳基为5、6或7元亚杂芳基； And / or, when L is a substituted or unsubstituted -M 7 -M 8 -M 9- , and M 9 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 5, 6 or 7 membered heteroarylene;
    和/或，当R 20、R 21、R 22、R 23、R 24和R 25各自独立地为卤素时，所述的卤素为氟或氯； And / or, when R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are each independently halogen, the halogen is fluorine or chlorine;
    和/或，当R 20、R 21、R 22、R 23、R 24和R 25各自独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为C 1-C 3烷基； And / or, when R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are each independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is C 1 -C 3 alkyl;
    和/或，当R 20、R 21、R 22、R 23、R 24和R 25各自独立地为C 1-C 6烷氧基时，所述的C 1-C 6烷氧基为C 1-C 3烷氧基； And / or, when R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are each independently C 1 -C 6 alkoxy, the C 1 -C 6 alkoxy is C 1 -C 3 alkoxy;
    和/或，当R 10、R 11、R 12和R 13各自独立地为卤素时，所述的卤素为氟； And / or, when R 10 , R 11 , R 12 and R 13 are each independently halogen, the halogen is fluorine;
    和/或，当R 10、R 11、R 12和R 13各自独立地为5-12元杂芳基时，所述的5-12元杂芳基为5、6或7元杂芳基。 And / or, when R 10 , R 11 , R 12 and R 13 are each independently a 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is a 5, 6 or 7 membered heteroaryl group.
  4. 如权利要求1-3中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当R 3为取代或未取代的5-12元杂芳基时，所述的5-12元杂芳基为呋喃基； The compound according to any one of claims 1 to 3, a compound represented by formula I or I ', a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a mutual Variable isomers, solvates, metabolites or prodrugs, characterized in that when R 3 is a substituted or unsubstituted 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is furanyl ;
    和/或，当R 19独立地为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基； And / or, when R 19 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl;
    和/或，当所述的
    Figure PCTCN2019120284-appb-100016
    为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为
    Figure PCTCN2019120284-appb-100017
    And / or when said
    Figure PCTCN2019120284-appb-100016
    When it is a 3-10 membered heterocycloalkylene, the 3-10 membered heterocycloalkylene is
    Figure PCTCN2019120284-appb-100017
    Figure PCTCN2019120284-appb-100018
    Figure PCTCN2019120284-appb-100018
    和/或，当R 5为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基或乙基； And / or, when R 5 is C 1 -C 6 alkyl, the C 1 -C 6 alkyl is methyl or ethyl;
    和/或，当L为取代或未取代的-M 1-，M 1为C 1-C 10亚烷基时，所述的C 1-C 10亚烷基为C 5亚烷基、C 6亚烷基或C 7亚烷基； And / or, when L is substituted or unsubstituted -M 1- , and M 1 is C 1 -C 10 alkylene, the C 1 -C 10 alkylene is C 5 alkylene, C 6 Alkylene or C 7 alkylene;
    和/或，当L为取代或未取代的-M 1-，M 1为C 2-C 10亚烯基时，所述的C 2-C 10亚烯基为C 5、C 6或C 7亚烯基； And / or, when L is substituted or unsubstituted -M 1 -and M 1 is C 2 -C 10 alkenylene, the C 2 -C 10 alkenylene is C 5 , C 6 or C 7 Alkenylene
    和/或，当L为取代或未取代的-M 1-，M 1为具有2-10个链原子的亚杂烷基时，所述的具有2-10个链原子的亚杂烷基为具有5、6或7个链原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 1- , and M 1 is a heteroalkylene group having 2-10 chain atoms, the heteroalkylene group having 2-10 chain atoms is Heteroalkylene with 5, 6 or 7 chain atoms;
    和/或，当L为取代或未取代的-M 1-，M 1为具有2-10个链原子的亚杂烯基时，所述的具有2-10个链原子的亚杂烯基为具有5、6或7个原子的亚杂烯基； And / or, when L is substituted or unsubstituted -M 1- , and M 1 is a heteroalkenylene group having 2 to 10 chain atoms, the heteroalkenylene group having 2 to 10 chain atoms is Heteroalkenylene having 5, 6 or 7 atoms;
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为C 1-C 6亚烷基时，所述的C 1-C 6亚烷基为亚甲基、亚乙基或亚丙基； And / or, when L is substituted or unsubstituted -M 2 -M 3- , and M 2 is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is methylene, methylene Ethyl or propylene;
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为具有2-6个链原子的亚杂烷基时，所述的具有2-6个链原子的亚杂烷基为
    Figure PCTCN2019120284-appb-100019
    And / or, when L is a substituted or unsubstituted -M 2 -M 3- , and M 2 is a heteroalkylene group having 2-6 chain atoms, the heteroatom having 2-6 chain atoms Alkyl is
    Figure PCTCN2019120284-appb-100019
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”时，所述的“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”为
    Figure PCTCN2019120284-appb-100020
    And / or, when L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a "C 1 -C 6 alkylene group, one carbon atom is independently selected from -C (= O) O- , -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups replace the group formed later ", the" C 1 -C 6 alkylene group 1 carbon atom is replaced by a group independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)- Group "is
    Figure PCTCN2019120284-appb-100020
    和/或，当L为取代或未取代的-M 2-M 3-，M 3为C 6-C 12亚芳基时，所述的C 6-C 12亚芳基为1,4-亚苯基； And / or, when L is a substituted or unsubstituted -M 2 -M 3- , and M 3 is a C 6 -C 12 arylene group, the C 6 -C 12 arylene group is 1,4-arylene Phenyl
    和/或，当L为取代或未取代的-M 2-M 3-，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为1,4-(6元亚杂芳基)； And / or, when L is substituted or unsubstituted -M 2 -M 3- , and M 3 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 1,4- ( 6-membered heteroarylene);
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 4为C 1-C 6亚烷基时，所述的C 1-C 6亚烷基为亚甲基或亚乙基； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 4 is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is methylene Radical or ethylene;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 4为具有2-6个链原子的亚杂烷基时，所述的具有2-6个链原子的亚杂烷基为具有2个原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 4 is a heteroalkylene group having 2-6 chain atoms, the said having 2-6 chain atoms Is a heteroalkylene group having 2 atoms;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 5为C 6-C 12亚芳基时，所述的C 6-C 12亚芳基为1,4-亚苯基； And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 5 is a C 6 -C 12 arylene group, the C 6 -C 12 arylene group is 1, 4-phenylene;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 5为5-12元亚杂芳基时，所述的5-12元亚杂芳基为1,4-(6元亚杂芳基)； And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 5 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 1, 4- (6-membered heteroarylene);
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为具有2-9个链原子的亚杂烷基时，所述的具有2-9个链原子的亚杂烷基为-U 1-U 2-，其中U 1为-NH-、-O-或-S-，U 2为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或具有2、3、4或5个链原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 6 is a heteroalkylene group having 2-9 chain atoms, the said having 2-9 chain atoms Heteroalkylene is -U 1 -U 2- , where U 1 is -NH-, -O- or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene , C 5 alkylene or heteroalkylene having 2, 3, 4 or 5 chain atoms;
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团后代替形成的基团”时，所述的“C 1-C 9亚烷基中的1、2或3个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团后代替形成的基团”为
    Figure PCTCN2019120284-appb-100021
    Figure PCTCN2019120284-appb-100022
    And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 6 is "C 1 -C 9 alkylene group 1, 2 or 3 carbon atoms are independently selected from- When C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups are substituted for the formed group ", the" C 1 1, 2 or 3 carbon atoms in the -C 9 alkylene group are independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)-group after replacing the formed group "is
    Figure PCTCN2019120284-appb-100021
    Figure PCTCN2019120284-appb-100022
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为C 2-C 9亚烯基时，所述的C 2-C 9亚烯基为
    Figure PCTCN2019120284-appb-100023
    And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 6 is a C 2 -C 9 alkenylene group, the C 2 -C 9 alkenylene group is
    Figure PCTCN2019120284-appb-100023
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 7为C 1-C 4亚烷基时，所述的C 1-C 4亚烷基为亚乙基； And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9 -and M 7 is C 1 -C 4 alkylene, the C 1 -C 4 alkylene is ethylene base;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 7为具有2-4个链原子的亚杂烷基时，所述的具有2-4个链原子的亚杂烷基为具有2个链原子的亚杂烷基； And / or, when L is a substituted or unsubstituted -M 7 -M 8 -M 9- , and M 7 is a heteroalkylene group having 2-4 chain atoms, the said having 2-4 chain atoms The heteroalkylene group is a heteroalkylene group having 2 chain atoms;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 8为C 3-C 12亚环烷基时，所述的C 3-C 12亚环烷基为
    Figure PCTCN2019120284-appb-100024
    And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 8 is C 3 -C 12 cycloalkylene, the C 3 -C 12 cycloalkylene is
    Figure PCTCN2019120284-appb-100024
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 8为3-12元亚杂环烷基时，所述的3-12元亚杂环烷基为
    Figure PCTCN2019120284-appb-100025
    Figure PCTCN2019120284-appb-100026
    And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 8 is a 3-12 membered heterocycloalkylene group, the 3-12 membered heterocycloalkylene group is
    Figure PCTCN2019120284-appb-100025
    Figure PCTCN2019120284-appb-100026
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 9为C 6-C 12亚芳基时，所述的C 6-C 12亚芳基为1,4-亚苯基； And / or, when L is a substituted or unsubstituted -M 7 -M 8 -M 9- , and M 9 is a C 6 -C 12 arylene group, the C 6 -C 12 arylene group is 1, 4-phenylene;
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 9为5-12元亚杂芳基时，所述的5-12 元亚杂芳基为1,4-(6元亚杂芳基)； And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 9 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is 1, 4- (6-membered heteroarylene);
    和/或，当L为取代或未取代的-M 10-M 11-时，M 10为亚乙基； And / or, when L is substituted or unsubstituted -M 10 -M 11- , M 10 is ethylene;
    和/或，当L为取代或未取代的-M 10-M 11-时，M 11为
    Figure PCTCN2019120284-appb-100027
    And / or, when L is substituted or unsubstituted -M 10 -M 11- , M 11 is
    Figure PCTCN2019120284-appb-100027
    和/或，当R 20、R 21、R 22、R 23、R 24和R 25各自独立地为卤素时，所述的卤素为氟； And / or, when R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are each independently halogen, the halogen is fluorine;
    和/或，当R 10、R 11、R 12和R 13各自独立地为5-12元杂芳基时，所述的5-12元杂芳基为噻吩基。 And / or, when R 10 , R 11 , R 12 and R 13 are each independently a 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is thienyl.
  5. 如权利要求1-4中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当R 3为取代或未取代的5-12元杂芳基时，所述的5-12元杂芳基为
    Figure PCTCN2019120284-appb-100028
    The compound according to any one of claims 1-4, a compound represented by formula I or I ', a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a mutual Variable isomers, solvates, metabolites or prodrugs, characterized in that when R 3 is a substituted or unsubstituted 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is
    Figure PCTCN2019120284-appb-100028
    和/或，当L为取代或未取代的-M 2-M 3-，M 2为“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”时，所述的“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”为
    Figure PCTCN2019120284-appb-100029
    And / or, when L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a "C 1 -C 6 alkylene group, one carbon atom is independently selected from -C (= O) O- , -OC (= O)-, -C (= O) NH- and -NHC (= O)-groups replace the group formed later ", the" C 1 -C 6 alkylene group 1 carbon atom is replaced by a group independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)- Group "is
    Figure PCTCN2019120284-appb-100029
    和/或，当L为取代或未取代的-M 2-M 3-，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为
    Figure PCTCN2019120284-appb-100030
    And / or, when L is substituted or unsubstituted -M 2 -M 3- , and M 3 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is
    Figure PCTCN2019120284-appb-100030
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 5为5-12元亚杂芳基时，所述的5-12元亚杂芳基为
    Figure PCTCN2019120284-appb-100031
    And / or, when L is substituted or unsubstituted -M 4 -M 5 -M 6- , and M 5 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is
    Figure PCTCN2019120284-appb-100031
    和/或，当L为取代或未取代的-M 4-M 5-M 6-，M 6为具有2-9个链原子的亚杂烷基时，所述的具有2-9个链原子的亚杂烷基为
    Figure PCTCN2019120284-appb-100032
    Figure PCTCN2019120284-appb-100033
    And / or, when L is a substituted or unsubstituted -M 4 -M 5 -M 6- , and M 6 is a heteroalkylene group having 2-9 chain atoms, the said having 2-9 chain atoms The heteroalkylene group is
    Figure PCTCN2019120284-appb-100032
    Figure PCTCN2019120284-appb-100033
    和/或，当L为取代或未取代的-M 7-M 8-M 9-，M 9为5-12元亚杂芳基时，所述的5-12 元亚杂芳基为
    Figure PCTCN2019120284-appb-100034
    And / or, when L is substituted or unsubstituted -M 7 -M 8 -M 9- , and M 9 is a 5-12 membered heteroarylene group, the 5-12 membered heteroarylene group is
    Figure PCTCN2019120284-appb-100034
    和/或，当R 10、R 11、R 12和R 13各自独立地为5-12元杂芳基时，所述的5-12元杂芳基为噻吩-2-基； And / or, when R 10 , R 11 , R 12 and R 13 are each independently a 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is thiophen-2-yl;
    和/或，当Y为取代或未取代的
    Figure PCTCN2019120284-appb-100035
    时，L为取代或未取代的-M 2-M 3-；     And / or when Y is substituted or unsubstituted
    Figure PCTCN2019120284-appb-100035
    , L is substituted or unsubstituted -M 2 -M 3- ;
    和/或，当ZBG为
    Figure PCTCN2019120284-appb-100036
    时，Y为
    Figure PCTCN2019120284-appb-100037
    L为取代或未取代的-M 2-M 3-、或取代或未取代的-M 4-M 5-M 6-；M 6为
    Figure PCTCN2019120284-appb-100038
    And / or when ZBG is
    Figure PCTCN2019120284-appb-100036
    , Y is
    Figure PCTCN2019120284-appb-100037
    L is substituted or unsubstituted -M 2 -M 3- , or substituted or unsubstituted -M 4 -M 5 -M 6- ; M 6 is
    Figure PCTCN2019120284-appb-100038
    和/或，每个R 20、R 21、R 22、R 23、R 24和R 25各自独立地为C 1-C 6烷基。 And / or, each of R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently C 1 -C 6 alkyl.
  6. 如权利要求1-5中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当Y为
    Figure PCTCN2019120284-appb-100039
    L为取代或未取代的-M 1-时，M 1为C 1-C 10亚烷基或具有2-10个链原子的亚杂烷基；     The compound represented by formula I or I 'according to any one of claims 1 to 5, its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, and Variable isomers, solvates, metabolites or prodrugs, characterized by: when Y is
    Figure PCTCN2019120284-appb-100039
    When L is substituted or unsubstituted -M 1- , M 1 is C 1 -C 10 alkylene or heteroalkylene having 2-10 chain atoms;
    和/或，当Y为
    Figure PCTCN2019120284-appb-100040
    L为取代或未取代的-M 2-M 3-时，M 2为C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基，M 3为C 6-C 12亚芳基或5-12元亚杂芳基；     And / or when Y is
    Figure PCTCN2019120284-appb-100040
    When L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a C 1 -C 6 alkylene group or a heteroalkylene group having 2 to 6 chain atoms, and M 3 is a C 6 -C 12 subgroup Aryl or 5-12 membered heteroarylene;
    和/或，当Y为取代或未取代的
    Figure PCTCN2019120284-appb-100041
    L为取代或未取代的-M 2-M 3-时，M 2为C 1-C 6亚烷基、具有2-6个链原子的亚杂烷基或“C 1-C 6亚烷基中的1个碳原子被独立选自-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-和-NHC(＝O)-的基团代替后形成的基团”；M 3为C 6-C 12亚芳基或5-12元亚杂芳基；     And / or when Y is substituted or unsubstituted
    Figure PCTCN2019120284-appb-100041
    When L is a substituted or unsubstituted -M 2 -M 3- , M 2 is a C 1 -C 6 alkylene group, a heteroalkylene group having 2 to 6 chain atoms, or “C 1 -C 6 alkylene group Formed by replacing one carbon atom in a group independently selected from -C (= O) O-, -OC (= O)-, -C (= O) NH- and -NHC (= O)- "Group"; M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene;
    和/或，当Y为
    Figure PCTCN2019120284-appb-100042
    L为取代或未取代的-M 4-M 5-M 6-时，M 4为C 1-C 6亚烷基或具有2-6个链原子的亚杂烷基，M 5为C 6-C 12亚芳基或5-12元亚杂芳基，M 6为
    Figure PCTCN2019120284-appb-100043
    C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基、具有2、3、4、5或6个链原 子的亚杂烷基、“-W 1-W 2-，其中W 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，W 2为C 4亚烷基、C 5亚烷基、C 6亚烷基或C 7亚烷基”或“-V 1-V 2-，其中V 1为-C(＝O)O-、-OC(＝O)-、-C(＝O)NH-或-NHC(＝O)-，V 2为具有4、5、6或7个链原子的亚杂烷基”；     And / or when Y is
    Figure PCTCN2019120284-appb-100042
    When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms, and M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene, M 6 is
    Figure PCTCN2019120284-appb-100043
    C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, heteroalkylene having 2, 3, 4, 5 or 6 chain atoms, “ -W 1 -W 2- , where W 1 is -C (= O) O-, -OC (= O)-, -C (= O) NH- or -NHC (= O)-, W 2 is C 4 alkylene, C 5 alkylene, C 6 alkylene or C 7 alkylene "or" -V 1 -V 2- , where V 1 is -C (= O) O-, -OC (= O)-, -C (= O) NH- or -NHC (= O)-, V 2 is a heteroalkylene group having 4, 5, 6 or 7 chain atoms ";
    和/或，当Y为
    Figure PCTCN2019120284-appb-100044
    L为取代或未取代的-M 7-M 8-M 9-时，M 7为C 1-C 4亚烷基或具有2-4个链原子的亚杂烷基，M 8为
    Figure PCTCN2019120284-appb-100045
    Figure PCTCN2019120284-appb-100046
    Figure PCTCN2019120284-appb-100047
    M 9为1,4-亚苯基或1,4-(6元亚杂芳基)。     And / or when Y is
    Figure PCTCN2019120284-appb-100044
    When L is a substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is a C 1 -C 4 alkylene group or a heteroalkylene group having 2-4 chain atoms, and M 8 is
    Figure PCTCN2019120284-appb-100045
    Figure PCTCN2019120284-appb-100046
    Figure PCTCN2019120284-appb-100047
    M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  7. 如权利要求1-6任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当Y为
    Figure PCTCN2019120284-appb-100048
    L为取代或未取代的-M 1-时，M 1为C 5亚烷基、C 6亚烷基、C 7亚烷基或具有5、6或7个链原子的亚杂烷基；     The compound represented by formula I or I 'according to any one of claims 1 to 6, its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, and tautomers Isomers, solvates, metabolites or prodrugs, characterized by: when Y is
    Figure PCTCN2019120284-appb-100048
    When L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 chain atoms;
    和/或，当Y为
    Figure PCTCN2019120284-appb-100049
    L为取代或未取代的-M 2-M 3-时，M 2为亚甲基、亚乙基、亚丙基或具有2或3个链原子的亚杂烷基，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；     And / or when Y is
    Figure PCTCN2019120284-appb-100049
    When L is substituted or unsubstituted -M 2 -M 3- , M 2 is methylene, ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms, and M 3 is 1,4 -Phenylene or 1,4- (6-membered heteroarylene);
    和/或，当Y为取代或未取代的
    Figure PCTCN2019120284-appb-100050
    L为取代或未取代的-M 2-M 3-时，M 2为亚乙基、亚丙基或具有2或3个链原子的亚杂烷基、
    Figure PCTCN2019120284-appb-100051
    Figure PCTCN2019120284-appb-100052
    M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；     And / or when Y is substituted or unsubstituted
    Figure PCTCN2019120284-appb-100050
    When L is substituted or unsubstituted -M 2 -M 3- , M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms,
    Figure PCTCN2019120284-appb-100051
    Figure PCTCN2019120284-appb-100052
    M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
    和/或，当Y为
    Figure PCTCN2019120284-appb-100053
    L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基、亚乙基或具有2个链原子的亚杂烷基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)，M 6为
    Figure PCTCN2019120284-appb-100054
    C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基、C 6亚烷基、“-U 1-U 2-，其中U 1为-NH-、-O- 或-S-，U 2为C 2亚烷基、C 3亚烷基、C 4亚烷基、C 5亚烷基或具有2、3、4或5个链原子的亚杂烷基”、
    Figure PCTCN2019120284-appb-100055
    Figure PCTCN2019120284-appb-100056
    And / or when Y is
    Figure PCTCN2019120284-appb-100053
    When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms, and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene), M 6 is
    Figure PCTCN2019120284-appb-100054
    C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, “-U 1 -U 2- , where U 1 is -NH-, -O- Or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or heteroalkylene having 2, 3, 4 or 5 chain atoms ",
    Figure PCTCN2019120284-appb-100055
    Figure PCTCN2019120284-appb-100056
    和/或，当Y为
    Figure PCTCN2019120284-appb-100057
    L为取代或未取代的-M 7-M 8-M 9-时，M 7为亚乙基或具有两个链原子的亚杂烷基，M 8为
    Figure PCTCN2019120284-appb-100058
    Figure PCTCN2019120284-appb-100059
    Figure PCTCN2019120284-appb-100060
    M 9为1,4-亚苯基或1,4-(6元亚杂芳基)；     And / or when Y is
    Figure PCTCN2019120284-appb-100057
    When L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene or heteroalkylene having two chain atoms, M 8 is
    Figure PCTCN2019120284-appb-100058
    Figure PCTCN2019120284-appb-100059
    Figure PCTCN2019120284-appb-100060
    M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
    和/或，R 3为取代或未取代的C 6-C 12芳基或取代或未取代的5-12元杂芳基；所述的取代的C 6-C 12芳基或取代的5-12元杂芳基中的取代基独立地为C 1-C 6烷基； And / or, R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or substituted 5- The substituent in the 12-membered heteroaryl group is independently C 1 -C 6 alkyl;
    和/或，ZBG为
    Figure PCTCN2019120284-appb-100061
    R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 6-C 12芳基或5-12元杂芳基。     And / or, ZBG is
    Figure PCTCN2019120284-appb-100061
    R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 6 -C 12 aryl or 5-12 membered heteroaryl.
  8. 如权利要求1-7中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当Y为
    Figure PCTCN2019120284-appb-100062
    L为取代或未取代的-M 2-M 3-时，M 2为亚甲基、亚乙基、亚丙基或
    Figure PCTCN2019120284-appb-100063
    M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；     The compound represented by formula I or I 'according to any one of claims 1-7, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a mutual Variable isomers, solvates, metabolites or prodrugs, characterized by: when Y is
    Figure PCTCN2019120284-appb-100062
    When L is substituted or unsubstituted -M 2 -M 3- , M 2 is methylene, ethylene, propylene or
    Figure PCTCN2019120284-appb-100063
    M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
    和/或，当Y为取代或未取代的
    Figure PCTCN2019120284-appb-100064
    L为取代或未取代的-M 2-M 3-时，
    Figure PCTCN2019120284-appb-100065
    为
    Figure PCTCN2019120284-appb-100066
    Figure PCTCN2019120284-appb-100067
    M 2为
    Figure PCTCN2019120284-appb-100068
    M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；或者，
    Figure PCTCN2019120284-appb-100069
    为
    Figure PCTCN2019120284-appb-100070
    Figure PCTCN2019120284-appb-100071
    Figure PCTCN2019120284-appb-100072
    M 2为亚乙基，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；或者，
    Figure PCTCN2019120284-appb-100073
    为
    Figure PCTCN2019120284-appb-100074
    M 2为亚丙基或具有3个链原子的亚杂烷基，M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；     And / or when Y is substituted or unsubstituted
    Figure PCTCN2019120284-appb-100064
    When L is substituted or unsubstituted -M 2 -M 3- ,
    Figure PCTCN2019120284-appb-100065
    for
    Figure PCTCN2019120284-appb-100066
    Figure PCTCN2019120284-appb-100067
    M 2 is
    Figure PCTCN2019120284-appb-100068
    M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); or,
    Figure PCTCN2019120284-appb-100069
    for
    Figure PCTCN2019120284-appb-100070
    Figure PCTCN2019120284-appb-100071
    Figure PCTCN2019120284-appb-100072
    M 2 is ethylene and M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); or,
    Figure PCTCN2019120284-appb-100073
    for
    Figure PCTCN2019120284-appb-100074
    M 2 is propylene or a heteroalkylene group having 3 chain atoms, and M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
    和/或，当Y为
    Figure PCTCN2019120284-appb-100075
    L为取代或未取代的-M 4-M 5-M 6-时，M 4为亚甲基或亚乙基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)，M 6为
    Figure PCTCN2019120284-appb-100076
    Figure PCTCN2019120284-appb-100077
    或者，M 4为亚乙基，M 5为1,4-亚苯基或1,4-(6元亚杂芳基)，M 6为
    Figure PCTCN2019120284-appb-100078
    Figure PCTCN2019120284-appb-100079
    And / or when Y is
    Figure PCTCN2019120284-appb-100075
    When L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene, and M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl), M 6 is
    Figure PCTCN2019120284-appb-100076
    Figure PCTCN2019120284-appb-100077
    Alternatively, M 4 is ethylene, M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene), M 6 is
    Figure PCTCN2019120284-appb-100078
    Figure PCTCN2019120284-appb-100079
    和/或，当Y为
    Figure PCTCN2019120284-appb-100080
    L为取代或未取代的-M 7-M 8-M 9-时，M 7为亚乙基，M 8为
    Figure PCTCN2019120284-appb-100081
    M 9为1,4-亚苯基或1,4-(6元亚杂芳基)；     And / or when Y is
    Figure PCTCN2019120284-appb-100080
    When L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is
    Figure PCTCN2019120284-appb-100081
    M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
    和/或，当L为取代或未取代的-M 10-M 11-时，M 10为亚乙基，M 11为
    Figure PCTCN2019120284-appb-100082
    Figure PCTCN2019120284-appb-100083
    And / or, when L is substituted or unsubstituted -M 10 -M 11- , M 10 is ethylene and M 11 is
    Figure PCTCN2019120284-appb-100082
    Figure PCTCN2019120284-appb-100083
    和/或，当Y为
    Figure PCTCN2019120284-appb-100084
    时，R 5为氢或C 1-C 6烷基；     And / or when Y is
    Figure PCTCN2019120284-appb-100084
    , R 5 is hydrogen or C 1 -C 6 alkyl;
    和/或，R 3为取代或未取代的苯基或取代或未取代的
    Figure PCTCN2019120284-appb-100085
    取代基独立地为C 1-C 6烷基；     And / or R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted
    Figure PCTCN2019120284-appb-100085
    The substituents are independently C 1 -C 6 alkyl;
    和/或，ZBG为
    Figure PCTCN2019120284-appb-100086
    R 10、R 11、R 12和R 13各自独立地为氢、卤素、C 6-C 12芳基或5-12元杂芳基；     And / or, ZBG is
    Figure PCTCN2019120284-appb-100086
    R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 6 -C 12 aryl or 5-12 membered heteroaryl;
    和/或，R 4为氢。 And / or, R 4 is hydrogen.
  9. 如权利要求1-8中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当Y为
    Figure PCTCN2019120284-appb-100087
    L为取代或未取代的-M 1-时，M 1为C 5亚烷基、C 6亚烷基或C 7亚烷基；     The compound according to any one of claims 1 to 8 represented by formula I or I ', pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, Variable isomers, solvates, metabolites or prodrugs, characterized by: when Y is
    Figure PCTCN2019120284-appb-100087
    When L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene or C 7 alkylene;
    和/或，当Y为
    Figure PCTCN2019120284-appb-100088
    L为取代或未取代的-M 2-M 3-时，-M 2-M 3-为
    Figure PCTCN2019120284-appb-100089
    Figure PCTCN2019120284-appb-100090
    And / or when Y is
    Figure PCTCN2019120284-appb-100088
    When L is substituted or unsubstituted -M 2 -M 3- , -M 2 -M 3 -is
    Figure PCTCN2019120284-appb-100089
    Figure PCTCN2019120284-appb-100090
    和/或，当Y为取代或未取代的
    Figure PCTCN2019120284-appb-100091
    L为取代或未取代的-M 2-M 3-时，
    Figure PCTCN2019120284-appb-100092
    为
    Figure PCTCN2019120284-appb-100093
    M 2-M 3-为
    Figure PCTCN2019120284-appb-100094
    或者，
    Figure PCTCN2019120284-appb-100095
    为
    Figure PCTCN2019120284-appb-100096
    -M 2-M 3-为
    Figure PCTCN2019120284-appb-100097
    或者，
    Figure PCTCN2019120284-appb-100098
    为
    Figure PCTCN2019120284-appb-100099
    -M 2-M 3-为
    Figure PCTCN2019120284-appb-100100
    And / or when Y is substituted or unsubstituted
    Figure PCTCN2019120284-appb-100091
    When L is substituted or unsubstituted -M 2 -M 3- ,
    Figure PCTCN2019120284-appb-100092
    for
    Figure PCTCN2019120284-appb-100093
    M 2 -M 3 -is
    Figure PCTCN2019120284-appb-100094
    or,
    Figure PCTCN2019120284-appb-100095
    for
    Figure PCTCN2019120284-appb-100096
    -M 2 -M 3 -is
    Figure PCTCN2019120284-appb-100097
    or,
    Figure PCTCN2019120284-appb-100098
    for
    Figure PCTCN2019120284-appb-100099
    -M 2 -M 3 -is
    Figure PCTCN2019120284-appb-100100
    和/或，当Y为
    Figure PCTCN2019120284-appb-100101
    L为取代或未取代的-M 4-M 5-M 6-时，-M 4-M 5-M 6-为
    Figure PCTCN2019120284-appb-100102
    And / or when Y is
    Figure PCTCN2019120284-appb-100101
    When L is substituted or unsubstituted -M 4 -M 5 -M 6- , -M 4 -M 5 -M 6 -is
    Figure PCTCN2019120284-appb-100102
    和/或，当Y为
    Figure PCTCN2019120284-appb-100103
    L为取代或未取代的-M 7-M 8-M 9-时，-M 7-M 8-M 9-为
    Figure PCTCN2019120284-appb-100104
    And / or when Y is
    Figure PCTCN2019120284-appb-100103
    When L is substituted or unsubstituted -M 7 -M 8 -M 9- , -M 7 -M 8 -M 9 -is
    Figure PCTCN2019120284-appb-100104
    和/或，当L为取代或未取代的-M 10-M 11-时，-M 10-M 11-为
    Figure PCTCN2019120284-appb-100105
    Figure PCTCN2019120284-appb-100106
    And / or, when L is substituted or unsubstituted -M 10 -M 11- , -M 10 -M 11 -is
    Figure PCTCN2019120284-appb-100105
    Figure PCTCN2019120284-appb-100106
    和/或，当Y为
    Figure PCTCN2019120284-appb-100107
    时，R 5为氢、甲基或乙基；     And / or when Y is
    Figure PCTCN2019120284-appb-100107
    , R 5 is hydrogen, methyl or ethyl;
    和/或，X为N或CH；And / or, X is N or CH;
    和/或，R 3为苯基、
    Figure PCTCN2019120284-appb-100108
    And / or R 3 is phenyl,
    Figure PCTCN2019120284-appb-100108
    和/或，ZBG为
    Figure PCTCN2019120284-appb-100109
    And / or, ZBG is
    Figure PCTCN2019120284-appb-100109
  10. 如权利要求1-9中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：当Y为
    Figure PCTCN2019120284-appb-100110
    L为取代或未取代的-M 1-时，L为C 5亚烷基、C 6亚烷基或C 7亚烷基；     The compound represented by formula I or I 'according to any one of claims 1-9, its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, Variable isomers, solvates, metabolites or prodrugs, characterized by: when Y is
    Figure PCTCN2019120284-appb-100110
    When L is substituted or unsubstituted -M 1- , L is C 5 alkylene, C 6 alkylene or C 7 alkylene;
    和/或，当Y为
    Figure PCTCN2019120284-appb-100111
    L为取代或未取代的-M 2-M 3-时，L为
    Figure PCTCN2019120284-appb-100112
    Figure PCTCN2019120284-appb-100113
    And / or when Y is
    Figure PCTCN2019120284-appb-100111
    When L is substituted or unsubstituted -M 2 -M 3- , L is
    Figure PCTCN2019120284-appb-100112
    Figure PCTCN2019120284-appb-100113
    和/或，当Y为取代或未取代的
    Figure PCTCN2019120284-appb-100114
    L为取代或未取代的-M 2-M 3-时，Y为
    Figure PCTCN2019120284-appb-100115
    L为
    Figure PCTCN2019120284-appb-100116
    或者，Y为
    Figure PCTCN2019120284-appb-100117
    Figure PCTCN2019120284-appb-100118
    L为
    Figure PCTCN2019120284-appb-100119
    或者，Y为
    Figure PCTCN2019120284-appb-100120
    L为
    Figure PCTCN2019120284-appb-100121
    And / or when Y is substituted or unsubstituted
    Figure PCTCN2019120284-appb-100114
    When L is substituted or unsubstituted -M 2 -M 3- , Y is
    Figure PCTCN2019120284-appb-100115
    L is
    Figure PCTCN2019120284-appb-100116
    Or, Y is
    Figure PCTCN2019120284-appb-100117
    Figure PCTCN2019120284-appb-100118
    L is
    Figure PCTCN2019120284-appb-100119
    Or, Y is
    Figure PCTCN2019120284-appb-100120
    L is
    Figure PCTCN2019120284-appb-100121
    和/或，当Y为
    Figure PCTCN2019120284-appb-100122
    L为取代或未取代的-M 4-M 5-M 6-时，L为
    Figure PCTCN2019120284-appb-100123
    Figure PCTCN2019120284-appb-100124
    And / or when Y is
    Figure PCTCN2019120284-appb-100122
    When L is substituted or unsubstituted -M 4 -M 5 -M 6- , L is
    Figure PCTCN2019120284-appb-100123
    Figure PCTCN2019120284-appb-100124
    Figure PCTCN2019120284-appb-100125
    Figure PCTCN2019120284-appb-100125
    和/或，当Y为
    Figure PCTCN2019120284-appb-100126
    L为取代或未取代的-M 7-M 8-M 9-时，L为
    Figure PCTCN2019120284-appb-100127
    Figure PCTCN2019120284-appb-100128
    And / or when Y is
    Figure PCTCN2019120284-appb-100126
    When L is substituted or unsubstituted -M 7 -M 8 -M 9- , L is
    Figure PCTCN2019120284-appb-100127
    Figure PCTCN2019120284-appb-100128
    和/或，当L为取代或未取代的-M 10-M 11-时，L为
    Figure PCTCN2019120284-appb-100129
    Figure PCTCN2019120284-appb-100130
    And / or, when L is substituted or unsubstituted -M 10 -M 11- , L is
    Figure PCTCN2019120284-appb-100129
    Figure PCTCN2019120284-appb-100130
    和/或，当Y为
    Figure PCTCN2019120284-appb-100131
    时，R 5为H；     And / or when Y is
    Figure PCTCN2019120284-appb-100131
    , R 5 is H;
    和/或，R 1和R 2为氢； And / or, R 1 and R 2 are hydrogen;
    和/或，X为N；And / or, X is N;
    和/或，R 3为
    Figure PCTCN2019120284-appb-100132
    And / or R 3 is
    Figure PCTCN2019120284-appb-100132
    和/或，ZBG为
    Figure PCTCN2019120284-appb-100133
    And / or, ZBG is
    Figure PCTCN2019120284-appb-100133
  11. 如权利要求1-10中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药 物前体，其特征在于：所述的如式I或I’所示的化合物选自以下任一结构：The compound represented by formula I or I 'according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a mutual Variants, solvates, metabolites or prodrugs, characterized in that the compound represented by formula I or I 'is selected from any of the following structures:
    Figure PCTCN2019120284-appb-100134
    Figure PCTCN2019120284-appb-100134
    Figure PCTCN2019120284-appb-100135
    Figure PCTCN2019120284-appb-100135
    其中，R 1、R 2、R 3、R 4、R 5、
    Figure PCTCN2019120284-appb-100136
    L、R 10、R 11、R 12和R 13的定义如权利要求1-10中任一项所述。     Among them, R 1 , R 2 , R 3 , R 4 , R 5 ,
    Figure PCTCN2019120284-appb-100136
    L, R 10 , R 11 , R 12 and R 13 are as defined in any one of claims 1-10.
  12. 如权利要求1所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，其特征在于：所述的如式I或I’所示的化合物选自以下任一结构，The compound represented by formula I or I 'according to claim 1, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a tautomer, a solvent Compounds, metabolites or prodrugs, characterized in that the compound represented by formula I or I 'is selected from any of the following structures,
    Figure PCTCN2019120284-appb-100137
    Figure PCTCN2019120284-appb-100137
    Figure PCTCN2019120284-appb-100138
    Figure PCTCN2019120284-appb-100138
    Figure PCTCN2019120284-appb-100139
    Figure PCTCN2019120284-appb-100139
    Figure PCTCN2019120284-appb-100140
    Figure PCTCN2019120284-appb-100140
    Figure PCTCN2019120284-appb-100141
    Figure PCTCN2019120284-appb-100141
    Figure PCTCN2019120284-appb-100142
    Figure PCTCN2019120284-appb-100142
  13. 一种如式I所示的化合物的制备方法，其为如下至少一种方案：A method for preparing a compound represented by Formula I, which is at least one of the following schemes:
    方案一Option One
    Figure PCTCN2019120284-appb-100143
    Figure PCTCN2019120284-appb-100143
    方案一包括如下步骤：在有机溶剂中，将如式II所示的化合物和NH 2-OH在碱存在的条件下进行取代反应，得到如式I所示的化合物即可；其中，ZBG为
    Figure PCTCN2019120284-appb-100144
    R 1、R 2、R 3、X、Y和L的定义如权利要求1-12中任一项所述，R a为C 1-C 6烷基；     Scheme one includes the following steps: in an organic solvent, the compound represented by Formula II and NH 2 —OH are substituted in the presence of a base to obtain the compound represented by Formula I;
    Figure PCTCN2019120284-appb-100144
    R 1 , R 2 , R 3 , X, Y and L are as defined in any one of claims 1-12, and R a is C 1 -C 6 alkyl;
    方案二Option II
    Figure PCTCN2019120284-appb-100145
    Figure PCTCN2019120284-appb-100145
    方案二包括如下步骤：在有机溶剂中，将如式III所示的化合物和
    Figure PCTCN2019120284-appb-100146
    在 缩合剂和碱存在的条件下进行缩合反应，得到如式I所示的化合物即可；其中，ZBG为
    Figure PCTCN2019120284-appb-100147
    R 1、R 2、R 3、R 10、R 11、R 12、R 13、X、Y和L的定义如权利要求1-12中任一项所述。     Scheme two includes the following steps: In an organic solvent, the compound shown in formula III and
    Figure PCTCN2019120284-appb-100146
    The condensation reaction can be carried out in the presence of a condensing agent and a base to obtain the compound represented by Formula I; where, ZBG is
    Figure PCTCN2019120284-appb-100147
    The definitions of R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , X, Y and L are as defined in any one of claims 1-12.
  14. 一种化合物，其为如下任一结构：A compound with any of the following structures:
    Figure PCTCN2019120284-appb-100148
    Figure PCTCN2019120284-appb-100148
    其中，R 1、R 2、R 3、X、Y和L的定义如权利要求13所述，R a为C 1-C 6烷基。 Wherein, R 1 , R 2 , R 3 , X, Y and L are as defined in claim 13, and R a is C 1 -C 6 alkyl.
  15. 如权利要求14所述的化合物，其特征在于，所述的如式II所述的化合物为如下任一结构：The compound of claim 14, wherein the compound of formula II has any of the following structures:
    Figure PCTCN2019120284-appb-100149
    Figure PCTCN2019120284-appb-100149
    Figure PCTCN2019120284-appb-100150
    Figure PCTCN2019120284-appb-100150
    Figure PCTCN2019120284-appb-100151
    Figure PCTCN2019120284-appb-100151
    Figure PCTCN2019120284-appb-100152
    Figure PCTCN2019120284-appb-100152
    所述的如式III所述的化合物为如下任一结构：The compound according to formula III has any of the following structures:
    Figure PCTCN2019120284-appb-100153
    Figure PCTCN2019120284-appb-100153
    Figure PCTCN2019120284-appb-100154
    Figure PCTCN2019120284-appb-100154
    Figure PCTCN2019120284-appb-100155
    Figure PCTCN2019120284-appb-100155
  16. 一种药物组合物，其包含如权利要求1-12中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，以及至少一种药用辅料。A pharmaceutical composition comprising a compound represented by any one of claims 1-12 according to formula I or I ', a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, Diastereomers, tautomers, solvates, metabolites or prodrugs, and at least one pharmaceutical excipient.
  17. 一种如权利要求1-12中任一项所述的如式I或I’所示的化合物、其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体、溶剂化物、代谢产物或药物前体，或如权利要求16所述的药物组合物在制备用于治疗和/或预防与腺苷A2A受体和/或组蛋白去乙酰化酶HDAC相关的疾病的药物中的应用。A compound represented by formula I or I 'according to any one of claims 1-12, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer , Tautomers, solvates, metabolites or prodrugs, or the pharmaceutical composition according to claim 16 is prepared for the treatment and / or prevention of deacetylation with adenosine A2A receptor and / or histone The application of the enzyme HDAC-related diseases in medicine.
  18. 如权利要求17所述的应用，其特征在于：所述的“与腺苷A2A受体和/或组蛋白去乙酰化酶HDAC相关的疾病”为癌症或中枢神经系统疾病。The use according to claim 17, characterized in that the "disease related to adenosine A2A receptor and / or histone deacetylase HDAC" is cancer or central nervous system disease.
PCT/CN2019/120284 2018-11-22 2019-11-22 Triazolo cycle compound, preparation method therefor, intermediate thereof and application thereof WO2020103939A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811397796 2018-11-22
CN201811397796.3 2018-11-22

Publications (1)

Publication Number Publication Date
WO2020103939A1 true WO2020103939A1 (en) 2020-05-28

Family

ID=70773751

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/120284 WO2020103939A1 (en) 2018-11-22 2019-11-22 Triazolo cycle compound, preparation method therefor, intermediate thereof and application thereof

Country Status (2)

Country Link
CN (1) CN111205291B (en)
WO (1) WO2020103939A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023191400A1 (en) * 2022-04-01 2023-10-05 에이치케이이노엔 주식회사 Ethyl piperidine triazolo triazine derivatives, synthesis method therefor, and pharmaceutical composition containing same for prevention or treatment of cancer
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117263936B (en) * 2023-11-21 2024-02-23 中国中医科学院医学实验中心 Imidazo [1,2-a ] pyridine derivative, preparation method thereof and application thereof in drug for inhibiting central nervous system penetrating HDAC6

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5356894A (en) * 1990-05-29 1994-10-18 Rodney Peter W Morpholinyl substituted [1,2,4]-triazolo[1,5-a]triazine as antagonist
WO2000015231A1 (en) * 1998-09-16 2000-03-23 Medco Research Inc. Adenosine a3 receptor modulators
US7285550B2 (en) * 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459702A1 (en) * 1990-05-29 1991-12-04 Zeneca Limited Azole Derivatives
US7122548B2 (en) * 2003-07-02 2006-10-17 Sugen, Inc. Triazolotriazine compounds and uses thereof
CA2888324A1 (en) * 2012-11-07 2014-05-15 Alexander Flohr Triazolo compounds
CA3103068A1 (en) * 2018-06-26 2020-01-02 Zhejiang Vimgreen Pharmaceuticals, Ltd Triazolotriazine derivatives as a2a receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5356894A (en) * 1990-05-29 1994-10-18 Rodney Peter W Morpholinyl substituted [1,2,4]-triazolo[1,5-a]triazine as antagonist
WO2000015231A1 (en) * 1998-09-16 2000-03-23 Medco Research Inc. Adenosine a3 receptor modulators
US7285550B2 (en) * 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MANUELA JOERG ET AL.: "Synthesis and Pharmacological Evaluation of Dual Acting Ligands Targeting the Adenosine A2A and Dopamine D2 Receptors for the Potential Treatment of Parkinson's Disease", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 2, 9 December 2014 (2014-12-09), pages 718 - 738, XP055709666 *
STEPHANIE FEDERICO ET AL.: "Synthesis and Biological Evaluation of a New Series of 1, 2, 4- Triazolo[1, 5-a]-1, 3, 5-triazines as Human A2A Adenosine Receptor Antagonists with Improved Water Solubility", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 3, 7 January 2011 (2011-01-07), pages 877 - 889, XP055709658 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023191400A1 (en) * 2022-04-01 2023-10-05 에이치케이이노엔 주식회사 Ethyl piperidine triazolo triazine derivatives, synthesis method therefor, and pharmaceutical composition containing same for prevention or treatment of cancer
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers

Also Published As

Publication number Publication date
CN111205291A (en) 2020-05-29
CN111205291B (en) 2022-08-23

Similar Documents

Publication Publication Date Title
CA2997051C (en) Novel pyrazolo[3,4-d]pyrimidine compound or salt thereof
CA3119526A1 (en) Small molecule degraders of helios and methods of use
CN113387938B (en) Substituted pyrimidine compound, preparation method, intermediate and application thereof
CA3133753A1 (en) Novel small molecule inhibitors of tead transcription factors
WO2020064002A1 (en) Isoindoline compound, preparation method, pharmaceutical composition and use thereof
NL1026438C2 (en) New connections.
JP2016528197A (en) IDO inhibitor
JP2016523974A (en) IDO inhibitor
WO2020103939A1 (en) Triazolo cycle compound, preparation method therefor, intermediate thereof and application thereof
TWI531573B (en) Novel compounds of reverse-turn mimetics and use therefor
CN102482283A (en) Raf inhibitor compounds and methods of use thereof
BR112015017963A2 (en) deuterated phenyl amino pyrimidine compound, method for preparing the pharmaceutical composition, pharmaceutical composition and use of the compound
WO2020254289A1 (en) N-(phenyl)-indole-3-sulfonamide derivatives and related compounds as gpr17 modulators for treating cns disorders such as multiple sclerosis
JP2023036991A (en) Amine-substituted heterocyclic compounds as ehmt2 inhibitors, salts thereof, and methods of synthesis thereof
JP2015527351A (en) STAT3 inhibitor and its anticancer use
CA3064484A1 (en) Ion channel inhibitor compounds for cancer treatment
WO2021052501A1 (en) Heterocyclic amide compound, pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof
WO2020182159A1 (en) Jak kinase inhibitor, preparation method for same, and applications thereof in field of medicine
KR20120099457A (en) Inhibitors of diacylglycerol acyltransferase
CN116348468A (en) CFTR modulator compounds, compositions and uses thereof
KR20100135248A (en) Indolinone compound
AU2020255702B2 (en) Quinolyl-containing compound and pharmaceutical composition, and use thereof
Sun et al. Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists
CN111205244B (en) Thiazolo-ring compound, preparation method, intermediate and application thereof
WO2023016540A1 (en) Urea multi-target tyrosine kinase inhibitor and medical use thereof

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: 19887014

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19887014

Country of ref document: EP

Kind code of ref document: A1