WO2020103930A1 - 噻唑并环类化合物、其制备方法、中间体和应用 - Google Patents

噻唑并环类化合物、其制备方法、中间体和应用

Info

Publication number
WO2020103930A1
WO2020103930A1 PCT/CN2019/120259 CN2019120259W WO2020103930A1 WO 2020103930 A1 WO2020103930 A1 WO 2020103930A1 CN 2019120259 W CN2019120259 W CN 2019120259W WO 2020103930 A1 WO2020103930 A1 WO 2020103930A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
membered
satisfies
chain atoms
case
Prior art date
Application number
PCT/CN2019/120259
Other languages
English (en)
French (fr)
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 WO2020103930A1 publication Critical patent/WO2020103930A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to a thiazolo ring compound, 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-time transmembrane receptors, 7TMR) and are divided into 4 subtypes: A1, A2A, A2B, and A3.
  • A2A receptors are located in the central nervous system and peripheral All are widely distributed.
  • A2A receptors are distributed in the central nervous system at a high density, 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) al., 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 heterodimerization After the A2A receptor is activated by adenosine, it will inhibit the dopamine D2 receptor signaling (Shook and Jackson, ACS Chemical Neuroscience, 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 have entered clinical research as drugs for the treatment of Parkinson's disease (Aren, Waarde, et al., Medicinal Research, Reviews, 2018, 38, 5-56), of which istrafylline (istradefylline) , KW-6002) was approved for marketing in Japan in 2013 as a treatment for Parkinson's disease.
  • the tumor's hypoxic microenvironment limits the use of energy and induces the accumulation of extracellular ATP, which can be hydrolyzed and converted into adenosine by nucleotidase CD39 and CD73, thereby significantly increasing the level of adenosine at the periphery of the tumor .
  • Adenosine binds to adenosine A1, A2A, A2B, and A3 receptors to activate the receptors and play different regulatory functions.
  • the A2A receptor plays a major role in the process of tumor immunosuppression, and the binding of adenosine to the A2A receptor on the surface of immune cells can inhibit the immune function of these cells.
  • inhibiting the A2A receptor can significantly enhance the function of immune cells and promote the infiltration of immune cells into tumor tissues, which is beneficial to the killing effect of immune cells on tumors.
  • 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
  • HATs can catalyze the acetylation of lysine residues at the N-terminus of histones to make chromatin in a relatively loose and open state, so that transcription factors can easily access DNA to promote gene expression; HDACs function is to catalyze the removal of the histone The acetyl group on the lysine residue puts the chromatin in a tight conformation to block DNA transcription and gene expression (Kazantsev and Thompson, Nature Reviews Drug Discovery, 2008, 7,854-868). There are currently 18 subtypes of human HDACs that can be classified 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 HDACs.
  • 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 cell cycle inhibitor p21 and block the cell cycle; it can also regulate the removal of p53 protein.
  • Acetylation blocks its binding to DNA and blocks the transcription of apoptotic genes; in addition, HDAC is also related to the formation of blood vessels in tumor tissues and the regulation of immune cell functions (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
  • HDAC inhibitors such as abexinostat / PCI024781, givinostat / ITF2375, entinostat / MS-275, etc. are in different stages of clinical research.
  • HDAC2 can regulate brain function and the development and deterioration of the nervous system; 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 (Guan et al. ., Nature, 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 disease can be reversed by inhibiting HDAC function (Siebzehnrübl et al., PNAS 2018, 115 (37), E8765-E8774).
  • 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 dual-target small molecule compounds with HDAC and A2A receptors No reports.
  • the problem to be solved by the present invention is to provide a thiazolocyclic compound, its preparation method, intermediate and application.
  • the thiazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylase HDAC Inhibitor. Further, the thiazolocyclic compounds of the present invention may have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity.
  • the thiazolocyclic compounds of the invention can be used to treat and / or prevent diseases associated with adenosine A2A receptor and / or histone deacetylase HDAC, such as tumors and central nervous system diseases.
  • the present invention provides a compound represented by formula I, its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites Or prodrug:
  • R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NR 6 R 7 , substituted or unsubstituted C 3 -C 10 cycloalkyl (eg cyclohexyl), substituted Or unsubstituted 3-10 membered heterocycloalkyl (e.g.
  • U is CH or N, R 10 , R 11 and U are connected to form a 5, 6, 7 or 8 membered heterocycloalkyl;
  • Each U is independently CH or N, each U 1 is independently O, S, or CH 2 , and p is 1 or 2;
  • the substituents in 10 -cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl are each independently C 1 -C 6 alkyl Or C 1 -C 6 alkoxy, the number of substituents is one or more, and when the number of substituents is plural, the substituents are the same or different;
  • R 2 is hydrogen, halogen or C 1 -C 6 alkyl
  • R 3 is hydrogen, C 1 -C 6 alkyl (for example, methyl, ethyl, n-propyl, or isopropyl, such as methyl or ethyl), C 3 -C 10 cycloalkyl, or-(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl);
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 6 and R 7 are each independently hydrogen or C 1 -C 6 alkyl
  • X is N or CR 5 ;
  • R 5 is hydrogen, halogen or C 1 -C 6 alkyl
  • L is substituted or unsubstituted -M 1- (M 2 ) m- (M 3 ) n- ; the substituted -M 1- (M 2 ) m- (M 3 ) n -refers to a Multiple R 20 substitutions; when the number of R 20 is multiple, R 20 is the same or different;
  • m is 1, and n is 0,
  • M 1 is -NH-, -O-, -S-, C 1 -C 10 alkylene (for example, C 1 -C 6 alkylene, like C 1 , C 2 , C 3 or C 4 alkylene), C 2 -C 10 alkenylene (eg C 2 -C 6 alkenylene, such as C 2 , C 3 or C 4 alkenylene), C 2 -C 10 alkynylene (for example, C 2 -C 6 alkynylene, such as C 2 , C 3, or C 4 alkynylene), heteroalkylene having 2-10 chain atoms (for example, having 2-5 Heteroalkylene groups with 2 chain atoms, such as heteroalkylene groups with 2, 3 or 4 chain atoms, for example Another example ), Heteroalkenylene having 2-10 chain atoms (for example, heteroalkenylene having 2-5 chain atoms, such as heteroalkenylene having 2, 3, or 4 chain
  • M 2 is a 3-10 membered cycloalkylene group (for example, cyclohexylene group, as in 1,4-cyclohexylene), a 3-10 membered heterocycloalkylene group (for example, 6 membered heterocycloalkylene group, as in 1 , 4- (6 membered heterocycloalkylene)), C 6 -C 12 arylene (eg 1,4-phenylene) or 5-12 membered heteroarylene (eg 6 membered heteroarylene, Another example is 1,4- (6-membered heteroarylene); the 1,4- (6-membered heteroarylene) is for example );
  • M 1 is a 3-10 membered cycloalkylene group (eg 1,4-cyclohexylene), a 3-10 membered heterocycloalkylene group (eg 1,4- ( 6-membered heterocycloalkylene), again ), C 6 -C 12 arylene (eg 1,4-phenylene) or 5-12 membered heteroarylene (eg 5 or 6 membered heteroarylene; the 5 membered heteroarylene group such as 1,3- (5-membered heteroarylene), the 1,3- (5-membered heteroarylene) for example
  • the 6-membered heteroarylene group is, for example, 1,4- (6-membered heteroarylene group);
  • M 2 is C 1 -C 10 alkylene (for example, C 1 -C 6 alkylene, such as C 1 , C 2 , C 3 or C 4 alkylene), C 2 -C 10 alkenylene (for example C 2 -C 6 alkenylene, such as C 2 , C 3 or C 4 alkenylene, and then vinylidene, the vinylidene is preferably in a trans configuration), C 2 -C 10 alkynylene Radicals (eg C 2 -C 6 alkynylenes, such as C 2 , C 3 or C 4 alkynylenes), heteroalkylene groups having 2-10 chain atoms (eg subgroups having 2-5 chain atoms Heteroalkyl, like heteroalkylene with 2, 3 or 4 chain atoms, like ) Or a heteroalkenylene group having 2-10 chain atoms (for example, a heteroalkenylene group having 2-5 chain atoms, such as a heteroalkenylene group having 2, 3, or
  • m is 1, and n is 1,
  • M 1 is -NH-, -O-, -S-, C 1 -C 4 alkylene (for example, methylene or ethylene), C 2 -C 4 -alkenylene (such as vinylidene, the vinylidene is preferably in a trans configuration), C 2 -C 4 alkynylene (such as ethynylene), an alkylene having 2, 3 or 4 chain atoms Heteroalkyl (e.g. heteroalkylene with 2 chain atoms, like ) Or heteroalkenylene having 2, 3 or 4 chain atoms;
  • M 2 is a 3-10 membered cycloalkylene group (such as cyclohexylene group, such as 1,4-cyclohexylene group), and a 3-10 membered heterocycloalkylene group (such as 1,4- (6 membered heterocycloalkylene group Radical)), C 6 -C 12 arylene (eg 1,4-phenylene) or 5-12 membered heteroarylene (eg 6 membered heteroarylene, such as 1,4- (6 membered arylene Heteroaryl));
  • M 3 is C 1 -C 4 alkylene (such as methylene or ethylene), C 2 -C 4 alkenylene (such as vinylidene, the vinylidene is preferably in a trans configuration), C 2 -C 4 alkynylene (eg ethynylene), heteroalkylene having 2, 3 or 4 chain atoms or heteroalkenylene having 2, 3 or 4 chain atoms (eg having 2 chains) (Atom heteroalkenylene, double bond can be trans configuration);
  • M 1 is a 3-10 membered cycloalkylene group (for example, cyclohexylene group, such as 1,4-cyclohexylene group), 3-10 membered heterocycloalkylene group ( For example, 6-membered heterocycloalkylene, and then 1,4- (6-membered heterocycloalkylene)), C 6 -C 12 arylene (eg 1,4-phenylene) or 5-12 membered alkylene Heteroaryl (for example, 6-membered heteroarylene, and then 1,4- (6-membered heteroarylene));
  • cycloalkylene group for example, cyclohexylene group, such as 1,4-cyclohexylene group
  • 3-10 membered heterocycloalkylene group for example, 6-membered heterocycloalkylene, and then 1,4- (6-membered heterocycloalkylene)
  • C 6 -C 12 arylene eg 1,4-phenylene
  • M 2 is -NH-, -O-, -S-, C 1 -C 4 alkylene (eg, methylene) or heteroalkylene having 2, 3 or 4 chain atoms;
  • M 3 is a 3-10 membered cycloalkylene group (for example, 5, 6 or 7 membered cycloalkylene group, such as cyclohexylene group and then 1,4-cyclohexylene group), 3-10 membered heterocycloalkylene group (E.g. 6-membered heterocycloalkylene, and then 1,4- (6-membered heterocycloalkylene)), C 6 -C 12 arylene (eg 1,4-phenylene) or 5-12 member Heteroarylene (for example, 6-membered heteroarylene, and then 1,4- (6-membered heteroarylene); the 1,4- (6-membered heteroarylene) for example );
  • 3-10 membered cycloalkylene group for example, 5, 6 or 7 membered cycloalkylene group, such as cyclohexylene group and then 1,4-cyclohexylene group
  • 3-10 membered heterocycloalkylene group E.g. 6-membered heterocycl
  • m is 1, and n is 1,
  • M 1 is -NH-, -O-, -S-, C 1 -C 4 alkylene (eg methylene), C 2 -C 4 alkenylene (Eg vinylene), C 2 -C 4 alkynylene (eg ethynylene), heteroalkylene having 2, 3 or 4 chain atoms (eg heteroalkylene having 2 chain atoms, and Such as ) Or heteroalkenylene having 2, 3 or 4 chain atoms;
  • M 2 is a 3-10 membered cycloalkylene group (for example, cyclohexylene group, as in 1,4-cyclohexylene), a 3-10 membered heterocycloalkylene group (for example, 6 membered heterocycloalkylene group, as in 1 , 4- (6-membered heterocycloalkylene) or The 1,4- (6-membered heterocycloalkylene) example ), C 6 -C 12 arylene (such as 1,4-phenylene) or 5-12 membered heteroarylene (eg 6 membered heteroarylene, such as 1,4- (6 membered heteroarylene base));
  • cycloalkylene group for example, cyclohexylene group, as in 1,4-cyclohexylene
  • a 3-10 membered heterocycloalkylene group for example, 6 membered heterocycloalkylene group, as in 1 , 4- (6-membered heterocycloalkylene) or The 1,4- (6-membere
  • M 3 is a 3-10 membered cycloalkylene group (for example, cyclohexylene group, as in 1,4-cyclohexylene), a 3-10 membered heterocycloalkylene group (for example, 6 membered heterocycloalkylene group, as in 1 , 4- (6 membered heterocycloalkylene)), C 6 -C 12 arylene (eg 1,4-phenylene) or 5-12 membered heteroarylene (eg 6 membered heteroarylene, Another example is 1,4- (6-membered heteroarylene); the 1,4- (6-membered heteroarylene) is for example );
  • 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 the hetero atoms 1, 2, 3, or 4 independently;
  • Each R 20 is independently oxo, thio, halogen, cyano, hydroxy, amino, nitro, C 1 -C 6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl Radical), C 2 -C 6 alkenyl (e.g.
  • C 1 -C 6 haloalkyl C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 heteroalkynyl, C 3 -C 10 Cycloalkyl (eg cyclopropyl), 3-10 membered heterocycloalkyl, C 6 -C 12 aryl, 5-12 membered heteroaryl,-(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl) (e.g.
  • Each R 41 or R 42 is independently hydrogen or C 1 -C 6 alkyl
  • Each R 8 (ie, substituent on the benzene ring) is independently halogen (eg, fluorine), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-6 Heterocyclic heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl (eg thienyl, such as thien-2-yl); y is 0, 1, 2, 3 or 4;
  • R 9 is hydrogen or C 1 -C 6 alkyl (such as n-propyl);
  • hetero atoms in the heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of the heteroatoms is independently 1 , 2, 3 or 4.
  • C 1 -C 6 alkyl, C 1 -C 6 haloalkyl of C 1 -C 6 alkyl and C 1 -C 6 alkoxy C 1 -C 6 alkyl groups may each independently C 1 -C 4 alkyl.
  • the above C 2 -C 6 alkenyl groups may each independently be C 2 -C 4 alkenyl groups.
  • the aforementioned C 3 -C 10 cycloalkyl and - (C 1 -C 3 alkylene) - (C 3 -C 10 cycloalkyl) the C 3 -C 10 cycloalkyl groups may each independently be C 3 -C 8 cycloalkyl.
  • the above 3-10 membered heterocyclic alkyl group and the 3-10 membered heterocyclic alkyl group in-(C 1 -C 3 alkylene)-(3-10 membered heterocycloalkyl group) may each independently be 3, 4, 5, 6, 7 or 8-membered heterocycloalkyl.
  • C 6 -C 12 aryl group and a - (C 1 -C 3 alkylene) - (C 6 -C 12 aryl group) in C 6 -C 12 aryl groups may each independently phenyl.
  • the above 5-12 membered heteroaryl and-(C 1 -C 3 alkylene)-(5-12 membered heteroaryl) in the 5-12 membered heteroaryl may each independently be 5, 6 or 7 Yuan heteroaryl.
  • the above 3-10 membered cycloalkylene groups may each independently be 3, 4, 5, 6, 7 or 8 membered cycloalkylene groups.
  • the above 3-10 membered heterocycloalkylene groups may each independently be 3, 4, 5, 6, 7 or 8 membered heterocycloalkylene groups.
  • the above C 6 -C 12 arylene groups may each independently be a phenylene group.
  • the above 5-12 membered heteroarylene groups may each independently be 5, 6 or 7 membered heteroarylene groups.
  • M 1 is C 1 -C 10 alkylene, heteroalkylene having 2-10 chain atoms, 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C 6 -C 12 arylene Radical or 5-12 membered heteroarylene.
  • M 1 is C 4 , C 5 , C 6 or C 7 alkylene, heteroalkylene having 4, 5, 6 or 7 chain atoms, 1,4-cyclohexylene, 1,4-phenylene, 1,4- (6-membered heteroarylene) or 1,4- (6-membered heterocycloalkylene).
  • M 1 is C 4 , C 5 , C 6 or C 7 alkylene, heteroalkylene having 4, 5, 6 or 7 chain atoms, 1,4-cyclohexylene or 1,4- (6-membered Heterocycloalkyl).
  • M 1 is a C 4 , C 5 , C 6 or C 7 alkylene group, or a heteroalkylene group having 4, 5, 6 or 7 chain atoms.
  • L for W 2 is -CH (R 21 )-or -N (R 22 )-
  • R 21 is hydrogen or R 20
  • R 22 is hydrogen or R 20
  • each R 20 is independently as defined in the present invention.
  • M 1 is -NH-, -O-, -S-, C 1 -C 10 alkylene, heteroalkylene having 2-10 chain atoms, 3-10 membered cycloalkylene, 3-10 membered alkylene Heterocycloalkyl, C 6 -C 12 arylene or 5-12 membered heteroarylene
  • M 2 is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C 6 -C 12 Arylene or 5-12 membered heteroarylene.
  • M 1 is -NH-, -O-, -S-, C 1 -C 10 alkylene, heteroalkylene having 2-10 chain atoms, 3-10 membered cycloalkylene or 3-10 membered alkylene Heterocycloalkyl
  • M 2 is C 6 -C 12 arylene or 5-12 membered heteroarylene.
  • M 1 is -NH-, -O-, -S-, C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, or an alkylene having 2, 3 or 4 chain atoms Heteroalkyl, 1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene), 1,4- (6-membered heterocycloalkylene), or 2,6- (heterospira [3,3] heptyl), M 2 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 1 is -NH-, -O-, -S-, C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, or an alkylene having 2, 3 or 4 chain atoms Heteroalkyl
  • M 2 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • M 1 is 3-10 membered cycloalkylene group, 3-10 membered heterocycloalkylene group, C 6 -C 12 arylene group or 5-12 membered heteroarylene group
  • M 2 is C 1 -C 10 alkylene group , C 2 -C 10 alkenylene, heteroalkylene having 2-10 chain atoms or heteroalkenylene having 2-10 chain atoms.
  • M 1 is a 3-10 membered cycloalkylene group or a 3-10 membered heterocycloalkylene group
  • M 2 is a C 3 alkylene group or a heteroalkylene group having 3 chain atoms
  • M 1 is C 6 -C 12 arylene or 5-12 membered heteroarylene
  • M 2 is a vinylidene in trans configuration.
  • M 1 is 1,4-cyclohexylene or 1,4- (6-membered heteroalkylene)
  • M 2 is C 3 alkylene or heteroalkylene having 3 chain atoms; alternatively, M 1 is 1, 3- (5-membered heteroarylene), M 2 is a vinylidene of trans configuration.
  • M 1 is -NH-, -O-, -S-, C 1 -C 4 alkylene, C 2 -C 4 alkenylene, heteroalkylene having 2, 3 or 4 chain atoms or having 2, Heteroalkenylene of 3 or 4 chain atoms;
  • M 2 is 3-10 membered cycloalkylene group, 3-10 membered heterocycloalkylene group, C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical;
  • M 3 is C 1 -C 4 alkylene, C 2 -C 4 alkenylene, heteroalkylene having 2, 3 or 4 chain atoms or heteroalkylene having 2, 3 or 4 chain atoms Alkenyl.
  • M 1 is -NH-, -O-, -S-, C 1 -C 4 alkylene, C 2 -C 4 alkenylene, heteroalkylene having 2, 3 or 4 chain atoms or having 2, Heteroalkenylene of 3 or 4 chain atoms;
  • M 2 is 3-10 membered cycloalkylene group, 3-10 membered heterocycloalkylene group, C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical;
  • M 3 is a vinylidene in trans configuration.
  • M 1 is -NH-, -O-, -S-, methylene, ethylene or heteroalkylene having 2 chain atoms
  • M 2 is 1,4-phenylene or 1,4- (6 Element heteroarylene)
  • M 3 is a vinylidene group in trans configuration (ie ).
  • M 1 is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C 6 -C 12 arylene or 5-12 membered heteroarylene
  • M 2 is -NH-, -O-, -S- or methylene
  • M 3 is a 3-10 membered cycloalkylene group, a 3-10 membered heterocycloalkylene group, a C 6 -C 12 arylene group or a 5-12 membered heteroarylene group.
  • M 1 is a 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene
  • M 2 is -NH-, -O-, -S- or methylene
  • M 3 is C 6 -C 12 arylene Radical or 5-12 membered heteroarylene.
  • M 1 is 1,4-cyclohexylene or 1,4- (6-membered heterocycloalkylene);
  • M 2 is -NH-, -O-, -S- or methylene;
  • M 3 is 1,4- Phenylene or 1,4- (6-membered heteroarylene).
  • M 1 is -NH-, -O-, -S- or methylene
  • M 2 is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C 6 -C 12 arylene or 5 -12 membered heteroarylene
  • M 3 is 3-10 membered cycloalkylene, 3-10 membered heterocycloalkylene, C 6 -C 12 arylene or 5-12 membered heteroarylene.
  • M 1 is -NH-, -O-, -S- or methylene
  • M 2 is 3-10 membered cycloalkylene or 3-10 membered heterocycloalkylene
  • M 3 is C 6 -C 12 arylene Radical or 5-12 membered heteroarylene.
  • M 1 is -NH-, -O-, -S- or methylene
  • M 2 is 1,4-cyclohexylene
  • M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
  • X is CH or N, preferably CH.
  • R 2 is hydrogen
  • R 3 is C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or-(C 1- C 3 alkylene)-(C 3 -C 10 cycloalkyl).
  • R 3 is C 1 -C 6 alkyl, such as methyl or ethyl, preferably methyl.
  • R 4 is hydrogen
  • ZBG is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • ZBG is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 8 is halogen, C 6 -C 12 aryl, or 5-12 membered heteroaryl.
  • y is 0 or 1.
  • R 8 is fluorine or thiophen-2-yl.
  • ZBG is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • ZBG is Preferably
  • R 20 is oxo, thio, halogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, or-(C 1 -C 3 alkylene)-(C 3 -C 10 ring alkyl).
  • R 20 is oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1- C 6 heteroalkyl, C 3 -C 10 cycloalkyl or-(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl).
  • R 20 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 ring Alkyl or-(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl).
  • the number of R 20 may be 1, 2, 3, 4, 5, 6, or 7, for example, 1, 2, or 3.
  • R 20 is methyl, ethyl, n-propyl, isopropyl, n-butyl, Cyclopropyl or
  • R 1 is a substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted Substituted or unsubstituted C 6 -C 12 aryl or substituted or unsubstituted 5-12 membered heteroaryl
  • U is CH or N
  • R 10 , R 11 and U are connected together to form 5, 6, 7 or 8-membered heterocycloalkyl
  • the number of substituents is one or more, and each substituent is independently C 1 -C 6 alkyl.
  • R 1 is substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted C 6 -C 12 aryl or substituted or unsubstituted 5-12 membered heteroaryl, each U is independently CH or N, and each U 1 is independently O, S, or CH 2 , p is 1 or 2; the number of substituents is one or more, and each substituent is independently C 1 -C 6 alkyl.
  • R 1 is substituted or unsubstituted Or substituted or unsubstituted U is N, each U 1 is independently O, S, or CH 2 , and p is 1 or 2; the number of substituents is one or more, and each substituent is independently C 1 -C 6 alkyl.
  • R 1 is Preferably
  • -M 1- (M 2 ) m- (M 3 ) n satisfies case (i) or (ii) .
  • -M 1- (M 2 ) m- (M 3 ) n satisfies case (i).
  • -M 1- (M 2 ) m- (M 3 ) n satisfies case (ii).
  • R 1 is a substituted or unsubstituted 3-10 membered heterocycloalkyl group, a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 3
  • the substituents in the -C 10 cycloalkyl, substituted 3-10 membered heterocycloalkyl, substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl are each independently C 1 -C 6 Alkyl or C 1 -C 6 alkoxy, the number of substituents is one or more, when the number of substituents is multiple, the substituents are the same or different;
  • R 2 is hydrogen
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or-(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl);
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 6 and R 7 are each independently hydrogen or C 1 -C 6 alkyl
  • X is N or CR 5 ;
  • R 5 is hydrogen, halogen or C 1 -C 6 alkyl
  • L is substituted or unsubstituted -M 1- (M 2 ) m- (M 3 ) n- ; the substituted -M 1- (M 2 ) m- (M 3 ) n -refers to a Multiple R 20 substitutions; when the number of R 20 is multiple, R 20 is the same or different;
  • M 1 is C 4 , C 5 , C 6 or C 7 alkylene, heteroalkylene having 4, 5, 6 or 7 chain atoms, 1, 4 -Cyclohexylene, 1,4-phenylene, 1,4- (6-membered heteroarylene) or 1,4- (6-membered heterocycloalkylene);
  • M 1 is -NH-, -O-, -S-, C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene , Or a heteroalkylene group having 2, 3 or 4 chain atoms, 1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene), 1,4- (6-membered heterocycloalkylene), or 2,6- (heterospiro) [3,3] heptyl), M 2 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
  • M 1 is 1,4-cyclohexylene or 1,4- (6-membered heteroalkylene)
  • M 2 is C 3 alkylene or has 3 chain atoms A heteroalkylene group, or, M 1 is 1,3- (5-membered heteroarylene), and M 2 is a vinylidene group in a trans configuration;
  • m is 1, and n is 1, M 1 is -NH-, -O-, -S-, methylene, ethylene or a heteroalkylene group having 2 chain atoms; M 2 is 1 , 4-phenylene or 1,4- (6-membered heteroarylene); M 3 is vinylidene in trans configuration;
  • (v) m is 1, and n is 1, M 1 is 1,4-cyclohexylene or 1,4- (6-membered heterocycloalkylene); M 2 is -NH-, -O-, -S -Or methylene; M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
  • n 1
  • M 1 is -NH-, -O-, -S- or methylene
  • M 2 is 1,4-cyclohexylene
  • M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
  • 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 the hetero atoms 1, 2, 3, or 4 independently;
  • Each R 20 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, or-(C 1 -C 3 alkylene)-(C 3 -C 10 Cycloalkyl);
  • Each R 41 or R 42 is independently hydrogen or C 1 -C 6 alkyl
  • Each R 8 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl Or 5-12 membered heteroaryl;
  • y is 0, 1, 2, 3 or 4;
  • R 9 is hydrogen or C 1 -C 6 alkyl
  • hetero atoms in the heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of the heteroatoms is independently 1 , 2, 3 or 4.
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • L is substituted or unsubstituted -M 1- (M 2 ) m- (M 3 ) n- ; the substituted -M 1- (M 2 ) m- (M 3 ) n -refers to a Multiple R 20 substitutions; when the number of R 20 is multiple, R 20 is the same or different;
  • M 1 is -NH-, -O-, -S-, C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene , Heteroalkylene with 2, 3 or 4 chain atoms, 1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene) or 1,4- (6-membered heterocycloalkylene), M 2 is 1,4-alkylene Phenyl or 1,4- (6-membered heteroarylene);
  • the compound represented by Formula I has the following structure:
  • L is substituted or unsubstituted -M 1- (M 2 ) m- (M 3 ) n- ; the substituted -M 1- (M 2 ) m- (M 3 ) n -refers to a Multiple R 20 substitutions; when the number of R 20 is multiple, R 20 is the same or different;
  • M 1 is 1,4-cyclohexylene, 1,4-phenylene, 1,4- (6-membered heteroarylene) or 1,4- (6 Member heterocycloalkylene);
  • M 1 is -NH-, -O-, -S-, C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene , Heteroalkylene with 2, 3 or 4 chain atoms, 1,3- (4-membered heterocycloalkylene), 1,3- (5-membered heterocycloalkylene) or 1,4- (6-membered heterocycloalkylene), M 2 is 1,4-alkylene Phenyl or 1,4- (6-membered heteroarylene);
  • the compound represented by Formula I has the following structure:
  • L is substituted or unsubstituted -M 1- (M 2 ) m- (M 3 ) n- ; the substituted -M 1- (M 2 ) m- (M 3 ) n -refers to a Multiple R 20 substitutions; when the number of R 20 is multiple, R 20 is the same or different;
  • M 1 is -NH-, -O-, -S-, C 1 alkylene, C 2 alkylene, C 3 alkylene, or having 2 or 3 Heteroalkylene groups of chain atoms, Or 1,4- (6-membered heterocycloalkylene), M 2 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
  • the compound represented by Formula 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;
  • a base such as potassium hydroxide
  • ZBG is R 1 , R 2 , R 3 , R 4 , X, 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 dichloromethane and / or 1,4-dioxane), the compound represented by formula IV is reacted in the presence of an acid (such as hydrogen chloride) to obtain The compound represented by formula I is sufficient; wherein, ZBG is R 1 , R 2 , R 3 , R 4 , X, And L are as defined above;
  • Scheme three 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 4 , R 8 , X, The definitions of y and L are as described above;
  • Scheme 4 includes the following steps: In an organic solvent (such as DMF), the compound shown in formula III is combined with 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 4 , R 9 , X, And L are as defined above;
  • a condensing agent such as HATU
  • DIPEA a base
  • Scheme 5 includes the following steps: In an organic solvent, the compound represented by Formula V is subjected to a reduction reaction to obtain the compound represented by Formula I; wherein, ZBG is R 1 , R 2 , R 3 , R 4 , R 9 , X, And L are as defined above, and R 9 is not hydrogen.
  • the preparation method of the compound shown in Formula III may include the following steps: In a solvent (such as a mixed solvent of tetrahydrofuran and water), the compound shown in Formula II is added to a base (such as lithium hydroxide and sodium hydroxide) Or potassium hydroxide) in the presence of hydrolysis reaction to obtain the compound represented by formula III; wherein R 1 , R 2 , R 3 , R 4 , X, And L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl);
  • a solvent such as a mixed solvent of tetrahydrofuran and water
  • a base such as lithium hydroxide and sodium hydroxide
  • X, And L are as defined above
  • R a is C 1 -C 6 alkyl (e.g. methyl or ethyl)
  • the preparation method of the compound represented by Formula IV can be at least one of the following schemes:
  • Scheme one includes the following steps: In an organic solvent (such as DMF), the compound shown in formula III and The condensation reaction is 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 IV; wherein, R 1 , R 2 , R 3 , R 4 , X, And L are as defined above;
  • a condensing agent such as HATU
  • DIPEA such as DIPEA
  • Scheme 2 includes the following steps: in an organic solvent (such as DMF), compound A and compound K are subjected to a condensation reaction in the presence of a condensing agent (such as HATU) and a base (such as DIPEA) to obtain a compound represented by formula IV That is, where R 1 , R 2 , R 3 , R 4 , X and L are as defined above, for
  • the preparation method of the compound shown in Formula II can be at least one of the following schemes:
  • Scheme one includes the following steps: in an organic solvent (such as dichloromethane or chloroform), compound B and compound C are reacted in the presence of a base (such as DIPEA) to obtain the compound shown in formula II Or, in an organic solvent (such as dichloromethane or chloroform), compound A and compound D are reacted in the presence of a base (such as DIPEA) to obtain the compound shown in formula II; wherein, R 1 , R 2 , R 3 , R 4 , X and L are as defined above, and L and The connected atoms are N, O or S, for R a is C 1 -C 6 alkyl (such as methyl or ethyl), and R b is hydrogen or nitro.
  • Compound D can be obtained by combining Compound B with Obtained through the reaction.
  • Compound C can be obtained by combining Compound A with Obtained through the reaction.
  • Scheme 2 includes the following steps: in an organic solvent (such as DMF), compound A and compound F are subjected to a condensation reaction in the presence of a condensing agent (such as HATU) and a base (such as DIPEA) to obtain a compound represented by formula II Or, in an organic solvent (such as dichloromethane), the compound A and the compound G are subjected to a condensation reaction in the presence of a base (such as triethylamine or DIPEA) to obtain the compound shown in Formula II ; Where R 1 , R 2 , R 3 , R 4 , X and L are as defined above, and L and The connected atom is C, for R a is C 1 -C 6 alkyl (such as methyl or ethyl).
  • M 2 is an arylene or heteroarylene group, and wherein M 1 by heteroatom (N, O or S, for example, N) is connected with the M 2, L 'is -M 1 -H, L "is Hal-M 2- ; or, when L is -M 1 -M 2 -M 3- , M 3 is arylene or heteroarylene, and M 2
  • L ′ is -M 1 -M 2 -H, and L ”is Hal-M 3- ;
  • Scheme 3 can be used, which includes compound K and The substitution reaction or coupling reaction can be carried out to prepare the compound represented by formula II; wherein, R 1 , R 2 , R 3 , R 4 , X and L are as defined above, for R a is C 1 -C 6 alkyl (e.g.
  • Hal is halogen (e.g. chlorine, bromine or iodine).
  • L 'and When the connected atom is N, O or S, the preparation method of compound K is as described above in the first scheme for preparing the compound shown by formula II; when L 'is When the connected atom is C, the preparation method of compound K is as described above in the second scheme for preparing the compound shown by formula II.
  • the present invention also provides a compound, which has any of the following structures:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula I as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, Tautomers, solvates, metabolites or prodrugs, and at least one pharmaceutical excipient.
  • the present invention also provides a compound represented by formula I as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a tautomer, The use of solvates, metabolites or prodrugs, or the pharmaceutical composition in the preparation of adenosine A2A receptor antagonists and / or histone deacetylase HDAC inhibitors.
  • the present invention also provides a compound represented by formula I as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a tautomer, Use of solvates, metabolites or prodrugs, or the pharmaceutical composition in the preparation of a medicament for treating and / or preventing diseases related to adenosine A2A receptor and / or histone deacetylase HDAC .
  • the compound of formula I its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or prodrugs
  • the body dose can 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 compound of formula I as described above can also be used in any disease process characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, renal small Glomerulonephritis, restenosis after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxic shock, and fungal infection.
  • abnormal cell proliferation such as benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, renal small Glomerulonephritis, restenosis after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxic shock, and fungal infection.
  • the present invention also provides a compound represented by formula I as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, a tautomer, The use of solvates, metabolites or prodrugs, or said pharmaceutical composition in the preparation of products 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 optionally be 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).
  • haloalkyl means that one or more hydrogen atoms in the alkyl group (as defined in the present invention) are replaced by halogen (as defined in the present invention), and the number of halogens may be one Or more; when there are more than one halogen, the halogen is the same or different.
  • haloalkyl include, but are not limited to, trifluoromethyl and difluoromethyl.
  • 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) means 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 .
  • heteroalkynyl refers to a linear or branched monovalent hydrocarbon group having the specified number of carbon atoms, at least one hetero atom selected from N, O, and S, and at least one triple bond.
  • the heteroalkynyl group may be connected to other parts of the molecule through a heteroatom or a carbon atom therein.
  • the heteroalkynyl group may be connected to other parts of the molecule through a single bond or a triple bond therein. Examples of heteroalkynyl groups include, but are not limited to
  • 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
  • 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.
  • heterocyclic heterocycloalkylene examples 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
  • the 6-membered heterocycloalkylene in 1,4- (6-membered heterocycloalkylene) is a monocyclic structure, and 1 and 4 do not refer to the original number of the ring atoms in the 6-membered heterocycloalkylene , But refers to the relative position of the two connection sites of 6-membered heterocycloalkylene is para, and examples of 1,4- (6-membered heterocycloalkylene) include but are not limited to Etc .; 1,3- (4-membered heterocycloalkylene) and 1,3- (5-membered heterocycloalkylene) are the same as 1,4- (6-membered heterocycloalkylene), 1,3 -Examples of (5-membered heterocycloalkylene) include but
  • 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, without limitation, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, 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 case of 1,3- (5-membered heteroarylene) is the same as above, and examples of 1,3- (5-membered heteroarylene) include but are not limited to
  • linking group When the number of a linking group is 0, such as-(CRR) 0- , it means that the linking group is a single bond. When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in ALZ, the structure is actually AZ.
  • 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
  • L is -M 1 -M 2 -M 3-
  • the structure formed is Instead of When enumerating L is , The structure formed is Instead of
  • halogen refers to F, Cl, Br, I.
  • -CH 2 -is oxo to form -C ( O)-
  • -S- is oxo to form -S (O)-or -S (O) 2-
  • the nitrogen atom in is formed by oxygenation
  • 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, which remains as represented by Formula I Biological activity of the compound.
  • 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 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.
  • the isotopic derivative is preferably a deuterium.
  • the number of deuterium atoms in the deuterium can be 1, 2, 3, 4, or 5.
  • 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 tests.
  • 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 thiazolocyclic compound, its preparation method, intermediate and application.
  • the thiazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylase HDAC inhibitor. Further, the thiazolocyclic compounds of the present invention may have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity.
  • the thiazolocyclic compounds of the present invention can be used to treat and / or prevent diseases associated with adenosine A2A receptor and / or histone deacetylase HDAC, such as tumors and central nervous system diseases.
  • Step 1 Preparation of 6- (3- (4-methoxy-7-N-morpholinobenzo [d] thiazol-2-yl) ureido) hexanoic acid methyl ester (Intermediate Int-1)
  • Step 2 Preparation of 6- (3- (4-methoxy-7-N-morpholinobenzo [d] thiazol-2-yl) ureido) hexanoic acid (intermediate Int-2)
  • Step 3 6- (3- (4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) ureido) -N-((tetrahydro-2H-pyran-2 -Yl) oxy) hexanamide (Intermediate Int-3)
  • Step 4 Preparation of N-hydroxy-6- (3- (4-methoxy-7-N-morpholinobenzo [d] thiazol-2-yl) ureido) hexanamide (Compound I-1)
  • Examples 1-6 by changing the corresponding raw materials, the compounds listed in Examples 7-8 can be prepared by the same method, see Table 1.
  • Step 1 Preparation of ethyl 2- (4-tert-butoxycarbonylpiperazin-1-yl) pyrimidine-5-carboxylate (Intermediate Int-4)
  • Step 2 Preparation of ethyl 2- (piperazin-1-yl) pyrimidine-5-carboxylate (Intermediate Int-5)
  • Step 1 6-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) amino) -6-oxohexanoic acid methyl ester (intermediate Int-6) preparation
  • Step 2 Preparation of N 1 -hydroxy-N 6- (4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) adipamide (Compound I-32)
  • Step 1 8-((7-Methoxy-4-morpholinylpyrido [5,4-c] thiazol-2-yl) amino) -6-oxooctanoic acid methyl ester (Intermediate Int-7) Preparation
  • reaction solution was extracted three times with ethyl acetate / water, 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 the intermediate Int-7 (0.080 g, yield 54%).
  • Step 2 Preparation of N 1 -hydroxy-N 8- (7-methoxy-4-morpholinylpyrido [5,4-c] thiazol-2-yl) suberamide (Compound I-36) preparation
  • Example 42 According to the method provided in Example 32, by changing the corresponding raw materials, the compounds listed in Example 42 can be prepared by the same method, see Table 4.
  • Step 1 Preparation of 4-hydroxy-N-((tetrahydro-2H-pyran-2-yl) oxy) benzamide (intermediate Int-8)
  • Step 2 2-Methyl-2- (4-(((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) phenoxy) propionic acid methyl ester (Intermediate Int-9) The preparation of the preparation
  • Step 3 Preparation of 2-methyl-2- (4-(((tetrahydro-2H-pyran-2-yl) oxy) carbamoyl) phenoxy) propionic acid (intermediate Int-10) Preparation
  • Step 4 4-((1-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) amino) -2-methyl-1-oxopropan-2 -Yl) oxy) -N-((tetrahydro-2H-pyran-2-yl) oxy) benzamide (intermediate Int-11)
  • Step 5 N-hydroxy-4-((1-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) amino) -2-methyl-1-oxy Preparation of Propyl-2-yl) oxy) benzamide (Compound I-43)
  • Example 43 According to the listed methods provided in Example 43, the compounds listed in Examples 45-47 can be prepared in the same way by changing the corresponding raw materials. See Table 5 for details.
  • Step 1 3-((4-Methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) azetidine-1-carboxylic acid tert-butyl ester (intermediate Int- 12) Preparation
  • Step 2 Preparation of N- (4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) azetidine-3-carboxamide (intermediate Int-13)
  • Step 3 2- (3-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) azetin-1-yl) pyrimidine-5- Preparation of ethyl formate (intermediate Int-14)
  • Step 4 N-hydroxy-2- (3-((4-methoxy-7-N-morpholinobenzo [d] thiazol-2-yl) carbamoyl) azetin-1-yl) Preparation of pyrimidine-5-carboxamide (Compound I-48)
  • Example 48 Replace the "1-N-Boc-3-azetidine carboxylic acid" in Step 1 of Example 48 with "1-N-Boc-4-piperidinecarboxylic acid", the remaining required raw materials, reagents and preparation methods are the same as the implementation In Example 48, pink solid compound I-49 was obtained.
  • Example 48 by changing the corresponding raw materials, the compounds listed in Examples 50-55 can be prepared by the same method, see Table 6 for details.
  • Step 1 4- (3-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) amino) -3-oxopropyl) benzoic acid (intermediate Int -15) Preparation
  • Step 2 N- (2-aminophenyl) -4- (3-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) amino) -3-oxo Preparation of propyl) benzamide (compound I-56)
  • Example 56 by changing the corresponding raw materials, the compounds listed in Examples 57-60 can be prepared by the same method, see Table 7 for details.
  • Step 1 (E) -3- (1-((4-Methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) -1H-pyrrol-3-yl ) Preparation of ethyl acrylate (Intermediate Int-16).
  • Step 2 (E) -3- (1-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) -1H-pyrrol-3-yl ) Preparation of acrylic acid (intermediate Int-17).
  • Step 3 (E) -3- (3- (hydroxyamino) -3oxoprop-1-en-1-yl) -N- (4-methoxy-7-N-morpholinylbenzo [ d) Preparation of thiazol-2-yl) -1H-pyrrole-1-carboxamide (Compound 1-62)
  • Step 1 4-hydroxy-N- (4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) cyclohexane-1-carboxamide (intermediate Int -18) Preparation.
  • Step 2 4-hydroxy-N- (4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) cyclohexane-1-carboxamide (intermediate Int -19) Preparation.
  • Step 3 4-hydroxy-N- (4-methoxy-7-N-morpholinobenzo [d] thiazol-2-yl) carbamoyl) cyclohexane-1-carboxamide (Compound I- 63) Preparation.
  • Example 64 According to the method listed in Example 63, the compound listed in Example 64 can be prepared in the same way by changing the corresponding raw materials, as shown in Table 8.
  • Example 9 by changing the corresponding raw materials, the compounds listed in Examples 65-74 can be prepared by the same method, see Table 9 for details.
  • Step 1 2- (4-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) piperidin-1-yl) pyrimidine-5-carboxy Preparation of acid (intermediate Int-20)
  • Step 2 N- (2-aminophenyl) -2- (4-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) piperidine Preparation of -1-yl) pyrimidine-5-carboxamide (Compound I-76)
  • Step 1 Preparation of methyl 4-((4-methoxy-7-N-morpholinobenzo [d] thiazol-2-yl) carbamoyl) benzoate (Intermediate Int-21)
  • Step 2 Preparation of 4-((4-methoxy-7-N-morpholinylbenzo [d] thiazol-2-yl) carbamoyl) benzoic acid (intermediate Int-22)
  • Step 3 N 1 - (2- aminophenyl) -N 4 - (4- methoxy-phenyl -7-N- morpholino and [d] thiazol-2-yl) terephthalamide (compound I -81) Preparation
  • Example 82 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;
  • Table 10 shows that compounds 56, 76-81 have better selectivity for HDAC1. It can also be analyzed from this that ZBG is It can make the compound have better HDAC1 selectivity.
  • Example 83 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 84 Determination of the inhibitory activity of the compounds of the invention on A2A receptor function.
  • the inhibitory activity of the compound on human A2A receptor function was measured using the cAMP test (Perkin Elmer) based on HTRF.
  • the specific operation method is as follows:
  • Cell culture HEK293 / A2A cell line, medium: 150mL DMEM, 17mL 10% FBS, 1.4mL G418, 37 ° C 5% CO 2 ;
  • Example 85 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.
  • d Discard the culture medium of HCT-116 and B16F10 cells, and digest with trypsin. After digestion, neutralize with culture medium containing serum, blow the cells 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.

Abstract

本发明公开了一种噻唑并环类化合物、其制备方法、中间体和应用。本发明的噻唑并环类化合物的结构如式I所示，其可以作为腺苷A2A受体拮抗剂和/或组蛋白去乙酰化酶HDAC抑制剂。进一步地，本发明的噻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。本发明的噻唑并环类化合物可以用于治疗和/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，例如肿瘤和中枢神经系统疾病。

Description

噻唑并环类化合物、其制备方法、中间体和应用
本申请要求申请日为2018/11/22的中国专利申请201811398327.3的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种噻唑并环类化合物、制备方法、中间体和应用。
背景技术
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受体在中枢神经系统及外周均有广泛分布。A2A受体在中枢神经系统呈高密度分布，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有着密切的联系(Gomes et al.,Biochimica et Biophysica Acta,2011,1808,1380-1399)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物，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。多个A2A受体的小分子拮抗剂作为治疗帕金森氏症的药物进入了临床研究(Aren van Waarde et al.,Medicinal Research Reviews,2018,38,5-56)，其中伊曲茶碱(istradefylline，KW-6002)作为治疗帕金森氏症的药物于2013年在日本获批上市。化合物tozadenant(SYN-115),vipadenant(BIIB-014)等也曾进入临床研究。虽然大部分的A2A受体拮抗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。
Figure PCTCN2019120259-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)。近年来，A2A受体作为一个肿瘤免疫治疗的靶点受到了越来越多的关注。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PD-1、PD-L1抗体Keytruda,Opdivo和Tecentriq，CTLA4抗体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。在作用机制上，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受体可显著的增强免疫细胞的功能并促进免疫细胞向肿瘤组织的浸润，有利于免疫细胞对于肿瘤的杀伤作用。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。
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。HATs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，以便使转录因子易于接近DNA而促进基因的表达；而HDACs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的转录和基因的表达(Kazantsev and Thompson,Nature Reviews Drug Discovery,2008,7,854-868)。目前已发现的人源HDACs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HDACs。而Class III又被称为sirtuins，包括SIRT 1-7，依赖NAD +发挥催化活性。
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，另有一些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。
Figure PCTCN2019120259-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，多种模型已证明HDAC2可以调节脑功能和神经系统发展与恶化；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 2018，115(37),E8765-E8774)。
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 PCTCN2019120259-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)，但同时具备HDAC与A2A受体的双靶点小分子化合物却未见报导。
发明内容
本发明所要解决的问题是提供一种噻唑并环类化合物、其制备方法、中间体和应用，本发明的噻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，本发明的噻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。本发明的噻唑并环类化合物可以用于治疗和/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，例如肿瘤和中枢神经系统疾病。
本发明提供了一种如式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：
Figure PCTCN2019120259-appb-000004
其中，
R 1为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-NR 6R 7、取代或未取代的C 3-C 10环烷基(例如环己基)、取代或未取代的3-10元杂环烷基(例如
Figure PCTCN2019120259-appb-000005
U为CH或N，R 10、R 11和U相连共同形成5、6、7或8元杂环烷基；又如
Figure PCTCN2019120259-appb-000006
每个U独立地为CH或N，每个U 1独立地为O、S或CH 2，p为1或2；再如
Figure PCTCN2019120259-appb-000007
Figure PCTCN2019120259-appb-000008
)、取代或未取代的C 6-C 12芳基(例如苯基)或取代或未取代的5-12元杂芳基(例如6元杂芳基)；所述的取代的C 3-C 10环烷基、取代的3-10元杂环烷基、取代的C 6-C 12芳基或取代的5-12元杂芳基中的取代基各自独立地为C 1-C 6烷基或C 1-C 6烷氧基，取代基的个数为一个或多个，当取代基的个数为多个时，所述的取代基相同或不同；
R 2为氢、卤素或C 1-C 6烷基；
R 3为氢、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基，又如甲基或乙基)、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)；
R 4为氢或C 1-C 6烷基；
R 6和R 7各自独立地为氢或C 1-C 6烷基；
X为N或CR 5；
R 5为氢、卤素或C 1-C 6烷基；
如式I所示的化合物中的
Figure PCTCN2019120259-appb-000009
为
Figure PCTCN2019120259-appb-000010
L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
-M 1-(M 2) m-(M 3) n-满足如下情形(i)、(ii)、(iii)、(iv)、(v)或(vi)：
(i)m为0，且n为0，M 1为-NH-、-O-、-S-、C 1-C 10亚烷基(例如C 1-C 7亚烷基，又如C 4、C 5、C 6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 4、C 5、C 6或C 7亚烯基)、C 2-C 10亚炔基(例如C 2-C 7亚炔基，又如C 4、C 5、C 6或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4、5、6或7个链原子的亚杂烷基，再如
Figure PCTCN2019120259-appb-000011
Figure PCTCN2019120259-appb-000012
)、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4、5、6或7个链原子的亚杂烯基)、具有3-10个链原子的亚杂炔基(例如具有3-7个链原子的亚杂炔基，又如具有4、5、6或7个链原子的亚杂炔基)、3-10元亚环烷基(例如3-7元亚环烷基，又如1,4-亚环己基)、3-10元亚杂环烷基(例如6元亚杂环烷基，又如1,4-(6元亚杂环烷基)，再如
Figure PCTCN2019120259-appb-000013
)、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，又如1,4-(6元亚杂芳基))；
(ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1-C 10亚烷基(例如C 1-C 6亚烷基，又如C 1、C 2、C 3或C 4亚烷基)、C 2-C 10亚烯基(例如C 2-C 6亚烯基，又如C 2、C 3或C 4亚烯基)、C 2-C 10亚炔基(例如C 2-C 6亚炔基，又如C 2、C 3或C 4亚炔基)、具有2-10个链原子的亚杂烷基(例如具有2-5个链原子的亚杂烷基，又如具有2、3或4个链原子的亚杂烷基，再例如
Figure PCTCN2019120259-appb-000014
Figure PCTCN2019120259-appb-000015
再例如
Figure PCTCN2019120259-appb-000016
Figure PCTCN2019120259-appb-000017
)、具有2-10个链原子的亚杂烯基(例如具有2-5个链原子的亚杂烯基，又如具有2、3或4个链原子的亚杂烯基)、3-10元亚环烷基(例如亚环丁基、亚环戊基、亚环己基或亚螺[3,3]庚基，又如
Figure PCTCN2019120259-appb-000018
Figure PCTCN2019120259-appb-000019
)、3-10元亚杂环烷基(例如1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)、1,4-(6元亚杂环烷基)或2,6-(亚杂螺[3,3]庚基)；其中，所述的1,3-(4元亚杂环烷基)例如
Figure PCTCN2019120259-appb-000020
所述的1,3-(5元亚杂环烷基)例如
Figure PCTCN2019120259-appb-000021
所述的1,4-(6元亚杂环烷基)例如
Figure PCTCN2019120259-appb-000022
所述的2,6-(亚杂螺[3,3]庚基)例如
Figure PCTCN2019120259-appb-000023
)、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，又如1,4-(6元亚杂芳基))；
M 2为3-10元亚环烷基(例如亚环己基，又如1,4-亚环己基)、3-10元亚杂环烷基(例如6元亚杂环烷基，又如1,4-(6元亚杂环烷基))、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，又如1,4-(6元亚杂芳基)；所述的1,4-(6元亚杂芳基)例如
Figure PCTCN2019120259-appb-000024
)；
(iii)m为1，且n为0，M 1为3-10元亚环烷基(例如1,4-亚环己基)、3-10元亚杂 环烷基(例如1,4-(6元亚杂环烷基)，再如
Figure PCTCN2019120259-appb-000025
)、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如5或6元亚杂芳基；所述的5元亚杂芳基例如1,3-(5元亚杂芳基)，所述的1,3-(5元亚杂芳基)例如
Figure PCTCN2019120259-appb-000026
所述的6元亚杂芳基例如1,4-(6元亚杂芳基))；
M 2为C 1-C 10亚烷基(例如C 1-C 6亚烷基，又如C 1、C 2、C 3或C 4亚烷基)、C 2-C 10亚烯基(例如C 2-C 6亚烯基，又如C 2、C 3或C 4亚烯基，再如亚乙烯基，所述的亚乙烯基优选为反式构型)、C 2-C 10亚炔基(例如C 2-C 6亚炔基，又如C 2、C 3或C 4亚炔基)、具有2-10个链原子的亚杂烷基(例如具有2-5个链原子的亚杂烷基，又如具有2、3或4个链原子的亚杂烷基，再如
Figure PCTCN2019120259-appb-000027
)或具有2-10个链原子的亚杂烯基(例如具有2-5个链原子的亚杂烯基，又如具有2、3或4个链原子的亚杂烯基)；
(iv)m为1，且n为1，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基(例如亚甲基或亚乙基)、C 2-C 4亚烯基(例如亚乙烯基，所述的亚乙烯基优选为反式构型)、C 2-C 4亚炔基(例如亚乙炔基)、具有2、3或4个链原子的亚杂烷基(例如具有2个链原子的亚杂烷基，又如
Figure PCTCN2019120259-appb-000028
)或具有2、3或4个链原子的亚杂烯基；
M 2为3-10元亚环烷基(例如亚环己基，又如1,4-亚环己基)、3-10元亚杂环烷基(例如1,4-(6元亚杂环烷基))、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，又如1,4-(6元亚杂芳基))；
M 3为C 1-C 4亚烷基(例如亚甲基或亚乙基)、C 2-C 4亚烯基(例如亚乙烯基，所述的亚乙烯基优选为反式构型)、C 2-C 4亚炔基(例如亚乙炔基)、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基(例如具有2个链原子的亚杂烯基，双键可以为反式构型)；
(v)m为1，且n为1，M 1为3-10元亚环烷基(例如亚环己基，又如1,4-亚环己基)、3-10元亚杂环烷基(例如6元亚杂环烷基，再如1,4-(6元亚杂环烷基))、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，再如1,4-(6元亚杂芳基))；
M 2为-NH-、-O-、-S-、C 1-C 4亚烷基(例如亚甲基)或具有2、3或4个链原子的亚杂烷基；
M 3为3-10元亚环烷基(例如5、6或7元亚环烷基，又如亚环己基，再如1,4-亚环己基)、3-10元亚杂环烷基(例如6元亚杂环烷基，再如1,4-(6元亚杂环烷基))、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，再如1,4-(6元亚杂芳基)；所述的1,4-(6元亚杂芳基)例如
Figure PCTCN2019120259-appb-000029
)；
(vi)m为1，且n为1，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基(例如亚甲基)、C 2-C 4亚烯基(例如亚乙烯基)、C 2-C 4亚炔基(例如亚乙炔基)、具有2、3或4个链原子的亚杂烷基(例如具有2个链原子的亚杂烷基，又如
Figure PCTCN2019120259-appb-000030
)或具有2、3或4个链原子的亚杂烯基；
M 2为3-10元亚环烷基(例如亚环己基，又如1,4-亚环己基)、3-10元亚杂环烷基(例如6元亚杂环烷基，又如1,4-(6元亚杂环烷基)或
Figure PCTCN2019120259-appb-000031
所述的1,4-(6元亚杂环烷基)例如
Figure PCTCN2019120259-appb-000032
)、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，又如1,4-(6元亚杂芳基))；
M 3为3-10元亚环烷基(例如亚环己基，又如1,4-亚环己基)、3-10元亚杂环烷基(例如6元亚杂环烷基，又如1,4-(6元亚杂环烷基))、C 6-C 12亚芳基(例如1,4-亚苯基)或5-12元亚杂芳基(例如6元亚杂芳基，又如1,4-(6元亚杂芳基)；所述的1,4-(6元亚杂芳基)例如
Figure PCTCN2019120259-appb-000033
)；
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，所述的杂原子的个数各自独立地为1、2、3或4个；
每个R 20独立地为氧代、硫代、卤素、氰基、羟基、氨基、硝基、C 1-C 6烷基(例如甲基、乙基、正丙基、异丙基或正丁基)、C 2-C 6烯基(例如
Figure PCTCN2019120259-appb-000034
)、C 1-C 6卤代烷基、C 1-C 6杂烷基、C 2-C 6杂烯基、C 2-C 6炔基、C 3-C 6杂炔基、C 3-C 10环烷基(例如环丙基)、3-10元杂环烷基、C 6-C 12芳基、5-12元杂芳基、-(C 1-C 3亚烷基)-(C 3-C 10环烷基)(例如
Figure PCTCN2019120259-appb-000035
)、-(C 1-C 3亚烷基)-(3-10元杂环烷基)、-(C 1-C 3亚烷基)-(C 6-C 12芳基)、-(C 1-C 3亚烷基)-(5-12 元杂芳基)、-NR 41R 42、-OR 41、-SR 41、-C(＝O)O-R 41、-C(＝O)-NR 41R 42、-N(R 42)-C(＝O)-R 41、-O-C(＝O)-R 41、-S(O) 2-R 41、-O-S(O) 2-R 41、-S(O) 2-OR 41、-S(O) 2-NR 41R 42或-N(R 41)-S(O) 2-R 42；
每个R 41或R 42各自独立地为氢或C 1-C 6烷基；
ZBG为
Figure PCTCN2019120259-appb-000036
每个R 8(即苯环上的取代基)独立地为卤素(例如氟)、C 1-C 6烷基、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(例如噻吩基，又如噻吩-2-基)；y为0、1、2、3或4；
R 9为氢或C 1-C 6烷基(如正丙基)；
所述的杂烷基、杂烯基、杂炔基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，所述的杂原子的个数各自独立地为1、2、3或4个。
上述的C 1-C 6烷基、C 1-C 6卤代烷基中的C 1-C 6烷基和C 1-C 6烷氧基中的C 1-C 6烷基可以各自独立地为C 1-C 4烷基。
上述的C 2-C 6烯基可以各自独立地为C 2-C 4烯基。
上述的C 3-C 10环烷基和-(C 1-C 3亚烷基)-(C 3-C 10环烷基)中的C 3-C 10环烷基可以各自独立地为C 3-C 8环烷基。
上述的3-10元杂环烷基和-(C 1-C 3亚烷基)-(3-10元杂环烷基)中的3-10元杂环烷基可以各自独立地为3、4、5、6、7或8元杂环烷基。
上述的C 6-C 12芳基和-(C 1-C 3亚烷基)-(C 6-C 12芳基)中的C 6-C 12芳基可以各自独立地为苯基。
上述的5-12元杂芳基和-(C 1-C 3亚烷基)-(5-12元杂芳基)中的5-12元杂芳基可以各自独立地为5、6或7元杂芳基。
上述的3-10元亚环烷基可以各自独立地为3、4、5、6、7或8元亚环烷基。
上述的3-10元亚杂环烷基可以各自独立地为3、4、5、6、7或8元亚杂环烷基。
上述的C 6-C 12亚芳基可以各自独立地为亚苯基。
上述的5-12元亚杂芳基可以各自独立地为5、6或7元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为C 1-C 10亚烷基、具有2-10个链原子的亚杂烷基、3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1- (M 2) m-(M 3) n-满足情形(i)时，M 1为C 4、C 5、C 6或C 7亚烷基、具有4、5、6或7个链原子的亚杂烷基、1,4-亚环己基、1,4-亚苯基、1,4-(6元亚杂芳基)或1,4-(6元亚杂环烷基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为C 4、C 5、C 6或C 7亚烷基、具有4、5、6或7个链原子的亚杂烷基、1,4-亚环己基或1,4-(6元亚杂环烷基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为C 4、C 5、C 6或C 7亚烷基、或具有4、5、6或7个链原子的亚杂烷基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为
Figure PCTCN2019120259-appb-000037
Figure PCTCN2019120259-appb-000038
W 1为-CH 2-或-NH-。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为
Figure PCTCN2019120259-appb-000039
Figure PCTCN2019120259-appb-000040
W 1为-CH 2-或-NH-。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为
Figure PCTCN2019120259-appb-000041
Figure PCTCN2019120259-appb-000042
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为
Figure PCTCN2019120259-appb-000043
Figure PCTCN2019120259-appb-000044
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，L为
Figure PCTCN2019120259-appb-000045
Figure PCTCN2019120259-appb-000046
W 2为-CH(R 21)-或-N(R 22)-，R 21为氢或R 20，R 22为氢或R 20，每个R 20各自独立地如本发明中所定义。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，L为
Figure PCTCN2019120259-appb-000047
Figure PCTCN2019120259-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所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(i)时，L为
Figure PCTCN2019120259-appb-000049
Figure PCTCN2019120259-appb-000050
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1-C 10亚烷基、具有2-10个链原子的亚杂烷基、3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基，M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1-C 10亚烷基、具有2-10个链原 子的亚杂烷基、3-10元亚环烷基或3-10元亚杂环烷基，M 2为C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、或具有2、3或4个链原子的亚杂烷基、
Figure PCTCN2019120259-appb-000051
Figure PCTCN2019120259-appb-000052
1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)、1,4-(6元亚杂环烷基)或2,6-(亚杂螺[3,3]庚基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、或具有2、3或4个链原子的亚杂烷基，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，-M 1-M 2-为
Figure PCTCN2019120259-appb-000053
Figure PCTCN2019120259-appb-000054
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1- (M 2) m-(M 3) n-满足情形(ii)时，-M 1-M 2-为
Figure PCTCN2019120259-appb-000055
Figure PCTCN2019120259-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所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，L为
Figure PCTCN2019120259-appb-000057
Figure PCTCN2019120259-appb-000058
Figure PCTCN2019120259-appb-000059
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，L为
Figure PCTCN2019120259-appb-000060
Figure PCTCN2019120259-appb-000061
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，M 1为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚 芳基或5-12元亚杂芳基，M 2为C 1-C 10亚烷基、C 2-C 10亚烯基、具有2-10个链原子的亚杂烷基或具有2-10个链原子的亚杂烯基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，M 1为3-10元亚环烷基或3-10元亚杂环烷基，M 2为C 3亚烷基或具有3个链原子的亚杂烷基；或者，M 1为C 6-C 12亚芳基或5-12元亚杂芳基，M 2为反式构型的亚乙烯基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，M 1为1,4-亚环己基或1,4-(6元亚杂烷基)，M 2为C 3亚烷基或具有3个链原子的亚杂烷基；或者，M 1为1,3-(5元亚杂芳基)，M 2为反式构型的亚乙烯基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，-M 1-M 2-为
Figure PCTCN2019120259-appb-000062
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，L为
Figure PCTCN2019120259-appb-000063
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基、C 2-C 4亚烯基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 3为C 1-C 4亚烷基、C 2-C 4亚烯基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基、C 2-C 4亚烯基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 3为反式构型的亚乙烯基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，M 1为-NH-、-O-、-S-、亚甲基、亚乙基或具有2个链原子的亚杂烷基；M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；M 3为反式构型的亚乙烯基(即
Figure PCTCN2019120259-appb-000064
)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m- (M 3) n-满足情形(iv)时，-M 1-M 2-M 3-为
Figure PCTCN2019120259-appb-000065
Figure PCTCN2019120259-appb-000066
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，L为
Figure PCTCN2019120259-appb-000067
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，M 1为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 2为-NH-、-O-、-S-或亚甲基；M 3为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，M 1为3-10元亚环烷基或3-10元亚杂环烷基；M 2为-NH-、-O-、-S-或亚甲基；M 3为C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，M 1为1,4-亚环己基或1,4-(6元亚杂环烷基)；M 2为-NH-、-O-、-S-或亚甲基；M 3为1,4-亚苯基或1,4-(6元亚杂芳基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，-M 1-M 2-M 3-为
Figure PCTCN2019120259-appb-000068
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，L为
Figure PCTCN2019120259-appb-000069
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，M 1为-NH-、-O-、-S-或亚甲基；M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 3为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m- (M 3) n-满足情形(vi)时，M 1为-NH-、-O-、-S-或亚甲基；M 2为3-10元亚环烷基或3-10元亚杂环烷基；M 3为C 6-C 12亚芳基或5-12元亚杂芳基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，M 1为-NH-、-O-、-S-或亚甲基，M 2为1,4-亚环己基、1,4-(6元亚杂环烷基)、
Figure PCTCN2019120259-appb-000070
M 3为1,4-亚苯基或1,4-(6元亚杂芳基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，-M 1-M 2-M 3-为
Figure PCTCN2019120259-appb-000071
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，L为
Figure PCTCN2019120259-appb-000072
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，X为CH或N，优选为CH。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 2为氢。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 3为C 1-C 6烷基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 3为C 1-C 6烷基，例如甲基或乙基，优选为甲基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 4为氢。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，
Figure PCTCN2019120259-appb-000073
为
Figure PCTCN2019120259-appb-000074
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，ZBG为
Figure PCTCN2019120259-appb-000075
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，ZBG为
Figure PCTCN2019120259-appb-000076
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 8为卤素、C 6-C 12芳基或5-12元杂芳基。在本发明的一些方案中，y为0或1。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 8为氟或噻吩-2-基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，ZBG为
Figure PCTCN2019120259-appb-000077
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，ZBG为
Figure PCTCN2019120259-appb-000078
优选为
Figure PCTCN2019120259-appb-000079
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 20为氧代、硫代、卤素、羟基、C 1-C 6烷基、C 2-C 6烯基、C 1-C 6杂烷基、C 3-C 10环烷基、3-10元杂环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 20为氧代、C 1-C 6烷基、C 2-C 6烯基、C 1-C 6杂烷基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 20为C 1-C 6烷基、C 2-C 6烯基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当-M 1-(M 2) m-(M 3) n-被一个或多个R 20取代时，R 20的个数可以为1、2、3、4、5、6或7个，例如1、2或3。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 20为甲 基、乙基、正丙基、异丙基、正丁基、
Figure PCTCN2019120259-appb-000080
环丙基或
Figure PCTCN2019120259-appb-000081
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 1为取代或未取代的C 3-C 10环烷基、取代的或未取代的
Figure PCTCN2019120259-appb-000082
取代的或未取代的C 6-C 12芳基或取代的或未取代的5-12元杂芳基，U为CH或N，R 10、R 11和U相连共同形成5、6、7或8元杂环烷基；取代基的个数为一个或多个，每个取代基独立地为C 1-C 6烷基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 1为取代或未取代的
Figure PCTCN2019120259-appb-000083
取代或未取代的
Figure PCTCN2019120259-appb-000084
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，每个U独立地为CH或N，每个U 1独立地为O、S或CH 2，p为1或2；取代基的个数为一个或多个，每个取代基独立地为C 1-C 6烷基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 1为取代或未取代的
Figure PCTCN2019120259-appb-000085
或取代或未取代的
Figure PCTCN2019120259-appb-000086
U为N，每个U 1独立地为O、S或CH 2，p为1或2；取代基的个数为一个或多个，每个取代基独立地为C 1-C 6烷基。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，R 1为
Figure PCTCN2019120259-appb-000087
优选为
Figure PCTCN2019120259-appb-000088
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，
Figure PCTCN2019120259-appb-000089
为
Figure PCTCN2019120259-appb-000090
Figure PCTCN2019120259-appb-000091
优选为
Figure PCTCN2019120259-appb-000092
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，-M 1-(M 2) m-(M 3) n-满足情形(i)或(ii)。在一些方案中，-M 1-(M 2) m-(M 3) n-满足情形(i)。在一些方案中，-M 1-(M 2) m-(M 3) n-满足情形(ii)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，当ZBG为
Figure PCTCN2019120259-appb-000093
时，-M 1-(M 2) m-(M 3) n-满足情形(i)或(ii)。
在本发明的一些方案中，如前述任一方案所述的如式I所示的化合物中，
其中，
R 1为取代或未取代的3-10元杂环烷基、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 3-C 10环烷基、取代的3-10元杂环烷基、取代的C 6-C 12芳基或取代的5-12元杂芳基中的取代基各自独立地为C 1-C 6烷基或C 1-C 6烷氧基，取代基的个数为一个或多个，当取代基的个数为多个时，所述的取代基相同或不同；
R 2为氢；
R 3为氢、C 1-C 6烷基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)；
R 4为氢或C 1-C 6烷基；
R 6和R 7各自独立地为氢或C 1-C 6烷基；
X为N或CR 5；
R 5为氢、卤素或C 1-C 6烷基；
如式I所示的化合物中的
Figure PCTCN2019120259-appb-000094
为
Figure PCTCN2019120259-appb-000095
L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
-M 1-(M 2) m-(M 3) n-满足如下情形(i)、(ii)、(iii)、(iv)、(v)或(vi)：
(i)m为0，且n为0，M 1为C 4、C 5、C 6或C 7亚烷基、具有4、5、6或7个链原 子的亚杂烷基、1,4-亚环己基、1,4-亚苯基、1,4-(6元亚杂芳基)或1,4-(6元亚杂环烷基)；
(ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、或具有2、3或4个链原子的亚杂烷基、
Figure PCTCN2019120259-appb-000096
Figure PCTCN2019120259-appb-000097
1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)、1,4-(6元亚杂环烷基)或2,6-(亚杂螺[3,3]庚基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
(iii)m为1，且n为0，M 1为1,4-亚环己基或1,4-(6元亚杂烷基)，M 2为C 3亚烷基或具有3个链原子的亚杂烷基，或者，M 1为1,3-(5元亚杂芳基)，M 2为反式构型的亚乙烯基；
(iv)m为1，且n为1，M 1为-NH-、-O-、-S-、亚甲基、亚乙基或具有2个链原子的亚杂烷基；M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；M 3为反式构型的亚乙烯基；
(v)m为1，且n为1，M 1为1,4-亚环己基或1,4-(6元亚杂环烷基)；M 2为-NH-、-O-、-S-或亚甲基；M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；
(vi)m为1，且n为1，M 1为-NH-、-O-、-S-或亚甲基，M 2为1,4-亚环己基、1,4-(6元亚杂环烷基)、
Figure PCTCN2019120259-appb-000098
M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；
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，所述的杂原子的个数各自独立地为1、2、3或4个；
每个R 20独立地为C 1-C 6烷基、C 2-C 6烯基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)；
每个R 41或R 42各自独立地为氢或C 1-C 6烷基；
ZBG为
Figure PCTCN2019120259-appb-000099
每个R 8独立地为卤素、C 1-C 6烷基、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；
y为0、1、2、3或4；
R 9为氢或C 1-C 6烷基；
所述的杂烷基、杂烯基、杂炔基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，所述的杂原子的个数各自独立地为1、2、3或4个。
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：
Figure PCTCN2019120259-appb-000100
各变量的定义如前述任一方案中所述。
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：
Figure PCTCN2019120259-appb-000101
L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
-M 1-(M 2) m-(M 3) n-满足如下情形(i)或(ii)：
(i)m为0，且n为0，M 1为C 4、C 5、C 6或C 7亚烷基、或具有4、5、6或7个链原子的亚杂烷基；
(ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、具有2、3或4个链原子的亚杂烷基、
Figure PCTCN2019120259-appb-000102
1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)或1,4-(6元亚杂环烷基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
其他变量的定义如前述任一方案中所述。
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：
Figure PCTCN2019120259-appb-000103
L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
-M 1-(M 2) m-(M 3) n-满足如下情形(i)或(ii)：
(i)m为0，且n为0，M 1为1,4-亚环己基、1,4-亚苯基、1,4-(6元亚杂芳基)或1,4-(6元亚杂环烷基)；
(ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、具有2、3或4个链原子的亚杂烷基、
Figure PCTCN2019120259-appb-000104
1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)或1,4-(6元亚杂环烷基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
其他变量的定义如前述任一方案中所述。
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：
Figure PCTCN2019120259-appb-000105
L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
-M 1-(M 2) m-(M 3) n-满足如下情形(i)或(ii)：
(i)m为0，且n为0，M 1为1,4-亚苯基或1,4-(6元亚杂芳基)；
(ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、或具有2或3个链原子的亚杂烷基、
Figure PCTCN2019120259-appb-000106
或1,4-(6元亚杂环烷基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
其他变量的定义如前述任一方案中所述。
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：
Figure PCTCN2019120259-appb-000107
Figure PCTCN2019120259-appb-000108
Figure PCTCN2019120259-appb-000109
Figure PCTCN2019120259-appb-000110
Figure PCTCN2019120259-appb-000111
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：
方案一
Figure PCTCN2019120259-appb-000112
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 PCTCN2019120259-appb-000113
R 1、R 2、R 3、R 4、X、
Figure PCTCN2019120259-appb-000114
和L的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)；
方案二
Figure PCTCN2019120259-appb-000115
方案二包括如下步骤：在有机溶剂(如二氯甲烷和/或1,4-二氧六环)中，将如式IV所示的化合物在酸(如氯化氢)存在的条件下进行反应得到如式I所示的化合物即可；其中，ZBG为
Figure PCTCN2019120259-appb-000116
R 1、R 2、R 3、R 4、X、
Figure PCTCN2019120259-appb-000117
和L的定义如上所述；
方案三
Figure PCTCN2019120259-appb-000118
方案三包括如下步骤：在有机溶剂(如DMF)中，将如式III所示的化合物与
Figure PCTCN2019120259-appb-000119
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 PCTCN2019120259-appb-000120
R 1、R 2、R 3、R 4、R 8、X、
Figure PCTCN2019120259-appb-000121
y和L的定义如上所述；
方案四
Figure PCTCN2019120259-appb-000122
方案四包括如下步骤：在有机溶剂(如DMF)中，将如式III所示的化合物与
Figure PCTCN2019120259-appb-000123
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 PCTCN2019120259-appb-000124
R 1、R 2、R 3、R 4、R 9、X、
Figure PCTCN2019120259-appb-000125
和L的定义如上所述；
方案五
Figure PCTCN2019120259-appb-000126
方案五包括如下步骤：在有机溶剂中，将如式V所示的化合物进行还原反应，得到如式I所示的化合物即可；其中，ZBG为
Figure PCTCN2019120259-appb-000127
R 1、R 2、R 3、R 4、R 9、X、
Figure PCTCN2019120259-appb-000128
和L的定义如上所述，并且R 9不为氢。
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、氢氧化钠或氢氧化钾)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、R 4、X、
Figure PCTCN2019120259-appb-000129
和L的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)；
Figure PCTCN2019120259-appb-000130
所述的如式IV所示的化合物的制备方法可以为如下至少一种方案：
方案一
Figure PCTCN2019120259-appb-000131
方案一包括如下步骤：在有机溶剂(如DMF)中，将如式III所示的化合物与
Figure PCTCN2019120259-appb-000132
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IV所示的化合物即可；其中，R 1、R 2、R 3、R 4、X、
Figure PCTCN2019120259-appb-000133
和L的定义如上所述；
方案二
Figure PCTCN2019120259-appb-000134
方案二包括如下步骤：在有机溶剂(如DMF)中，将化合物A与化合物K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IV所示的化合物即可；其中，R 1、R 2、R 3、R 4、X和L的定义如上所述，
Figure PCTCN2019120259-appb-000135
为
Figure PCTCN2019120259-appb-000136
所述的如式II所示的化合物的制备方法可以为如下至少一种方案：
方案一
Figure PCTCN2019120259-appb-000137
方案一包括如下步骤：在有机溶剂(如二氯甲烷或三氯甲烷)中，将化合物B与化合物C在碱(如DIPEA)存在的条件下进行反应，得到如式II所示的化合物即可；或者，在有机溶剂(如二氯甲烷或三氯甲烷)中，将化合物A和化合物D在碱(如DIPEA)存在的条件下进行反应，得到如式II所示的化合物即可；其中，R 1、R 2、R 3、R 4、X和L的定义如上所述，并且L与
Figure PCTCN2019120259-appb-000138
连接的原子为N、O或S，
Figure PCTCN2019120259-appb-000139
为
Figure PCTCN2019120259-appb-000140
R a为C 1-C 6烷基(如甲基或乙基)，R b为氢或硝基。化合物D可以通过将化合物B与
Figure PCTCN2019120259-appb-000141
进行反应制备得到。化合物C可以通过将化合物A与
Figure PCTCN2019120259-appb-000142
进行反应制备得到。
方案二
Figure PCTCN2019120259-appb-000143
方案二包括如下步骤：在有机溶剂(如DMF)中，将化合物A与化合物F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II所示的化合物即可；或者，在有机溶剂(如二氯甲烷)中，将化合物A与化合物G在碱(例如三乙胺或DIPEA)存在的条件下进行缩合反应，得到如式II所示的化合物即可；其中，R 1、R 2、R 3、R 4、X和L的定义如上所述，并且L与
Figure PCTCN2019120259-appb-000144
连接的原子为C，
Figure PCTCN2019120259-appb-000145
为
Figure PCTCN2019120259-appb-000146
R a为C 1-C 6烷基(如甲基或乙基)。
方案三
Figure PCTCN2019120259-appb-000147
当L为-M 1-M 2-，M 2为亚芳基或亚杂芳基，并且M 1通过其中的杂原子(N、O或S，例如N)与M 2连接时，L’为-M 1-H，L”为Hal-M 2-；或者，当L为-M 1-M 2-M 3-，M 3为亚芳基或亚杂芳基，并且M 2通过其中的杂原子(N、O或S，例如N)与M 3连接时，L’为-M 1-M 2-H，L”为Hal-M 3-；可以采用方案三，其包括将化合物K与
Figure PCTCN2019120259-appb-000148
进行取代反应或偶联反应，制得如式II所示的化合物即可；其中，R 1、R 2、R 3、R 4、X和L的定义如上所述，
Figure PCTCN2019120259-appb-000149
为
Figure PCTCN2019120259-appb-000150
R a为C 1-C 6烷基(如甲基或乙基)，Hal为卤素(例如氯、溴或碘)。当L’与
Figure PCTCN2019120259-appb-000151
连接的原子为N、O或S时，化合物K的制备方法如上述制备 如式II所示的化合物的方案一；当L’与
Figure PCTCN2019120259-appb-000152
连接的原子为C时，化合物K的制备方法如上述制备如式II所示的化合物的方案二。
本发明还提供了一种化合物，其为如下任一结构：
Figure PCTCN2019120259-appb-000153
其中，R 1、R 2、R 3、R 4、X、L和
Figure PCTCN2019120259-appb-000154
的定义如上所述，R a为C 1-C 6烷基(如甲基或乙基)。
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。
本发明还提供了一种如上所述的如式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。
本发明还提供了一种如上所述的如式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。
所述的如式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。
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。
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。
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。
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)。
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。
如上所述的如式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。
本发明还提供了一种如上所述的如式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。
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。
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。
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：
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。
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。
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。
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)。
在本发明中，术语“卤代烷基”是指烷基(如本发明中所定义)中的一个或多个氢原子被卤素(如本发明中所定义)所取代，卤素的个数可以为一个或多个；当卤素的个数为多个时，卤素相同或不同。卤代烷基的例子包括但不限于三氟甲基和二氟甲基。
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)。
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。
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。
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-。
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-。
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 PCTCN2019120259-appb-000155
C 3亚炔基指
Figure PCTCN2019120259-appb-000156
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。
在本发明中，术语“杂烯基”是指具有指定数目碳原子、至少一个选自N、O和S的杂原子和至少一个双键的直链或支链的一价烃基。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。杂烯基可以通过其内部的单键或双键的原子连接到分子中的其他部分。杂烯基的例子包括但不限于-N＝CH 2、-N＝CH-CH 3、-CH 2-CH 2＝N-CH 3和-O-CH(CH 3)-CH 2＝N-CH 3。
在本发明中，术语“杂炔基”是指具有指定数目碳原子、至少一个选自N、O和S的杂原子和至少一个三键的直链或支链的一价烃基。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。杂炔基可以通过其中的单键或三键连接到分子中的其他部分。杂炔基的例子包括但不限于
Figure PCTCN2019120259-appb-000157
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-。
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。
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 PCTCN2019120259-appb-000158
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。
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 PCTCN2019120259-appb-000159
Figure PCTCN2019120259-appb-000160
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 PCTCN2019120259-appb-000161
(即1,3-亚环丁基)、
Figure PCTCN2019120259-appb-000162
(即1,3-亚环戊基)、
Figure PCTCN2019120259-appb-000163
(即1,4-亚环己基)或
Figure PCTCN2019120259-appb-000164
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 PCTCN2019120259-appb-000165
Figure PCTCN2019120259-appb-000166
桥环的亚杂环烷基包括但不限于
Figure PCTCN2019120259-appb-000167
Figure PCTCN2019120259-appb-000168
螺环的亚杂环烷基包括但不限于
Figure PCTCN2019120259-appb-000169
Figure PCTCN2019120259-appb-000170
在本发明中，1,4-(6元亚杂环烷基)中的6元亚杂环烷基为单环结构，1和4并不指6元亚杂环烷基中环原子本来的编号，而是指6元亚杂环烷基的两个连接位点的相对位置为对位，1,4-(6元亚杂环烷基)的例子包括但不限于
Figure PCTCN2019120259-appb-000171
Figure PCTCN2019120259-appb-000172
等；1,3-(4元亚杂环烷基)和1,3-(5元亚杂环烷基)的情形与1,4-(6元亚杂环烷基)相同，1,3-(5元亚杂环烷基)的例子包括但不限于
Figure PCTCN2019120259-appb-000173
但是，2,6-(亚杂螺[3,3]庚基)中的2和6指的是螺环的环原子的本来的编号，2,6-(亚杂螺[3,3]庚基)的例子包括但不限于
Figure PCTCN2019120259-appb-000174
Figure PCTCN2019120259-appb-000175
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、联苯基、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。
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 PCTCN2019120259-appb-000176
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 PCTCN2019120259-appb-000177
吡咯-2-基即
Figure PCTCN2019120259-appb-000178
)、 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。
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 PCTCN2019120259-appb-000179
Figure PCTCN2019120259-appb-000180
1,3-(5元亚杂芳基)的情形同上，1,3-(5元亚杂芳基)的例子包括但不限于
Figure PCTCN2019120259-appb-000181
Figure PCTCN2019120259-appb-000182
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。具体至本发明中，在-M 1-(M 2) m-(M 3) n-中，当m为0，n为0时，-M 1-(M 2) m-(M 3) n-实际上是-M 1-；当m为1，n为0，-M 1-(M 2) m-(M 3) n-实际上是-M 1-M 2-。
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 PCTCN2019120259-appb-000183
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 PCTCN2019120259-appb-000184
而不构成
Figure PCTCN2019120259-appb-000185
具体到本发明中，
Figure PCTCN2019120259-appb-000186
中，当L为-M 1-M 2-M 3-时，形成的结构为
Figure PCTCN2019120259-appb-000187
而不为
Figure PCTCN2019120259-appb-000188
当列举L为
Figure PCTCN2019120259-appb-000189
时，形成的结构为
Figure PCTCN2019120259-appb-000190
而不 为
Figure PCTCN2019120259-appb-000191
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。
在本发明中，除非另有说明，术语“卤素”是指F、Cl、Br、I。
在本发明中，术语“氧代”是指＝O或
Figure PCTCN2019120259-appb-000192
例如-CH 2-被氧代后形成-C(＝O)-，-S-被氧代后形成-S(O)-或-S(O) 2-，
Figure PCTCN2019120259-appb-000193
中的氮原子被氧代后形成
Figure PCTCN2019120259-appb-000194
在本发明中，术语“硫代”是指＝S。例如-CH 2-被硫代后形成-C(＝S)-。
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所示的化合物形成的盐，其保留如式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。
术语“溶剂化物”表示如式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。
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。
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。
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。
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。
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。氘代物中氘原子的个数可以为1、2、3、4或5个。
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。
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。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：提供一种噻唑并环类化合物、其制备方法、中间体和应用，本发明的噻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，本发明的噻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。本发明的噻唑并环类化合物可以用于治疗和/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，例如肿瘤和中枢神经系统疾病。
具体实施方式
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。实施例中的所有参数以及其余的说明，除另有说明外，都是以质量(克)为单位。
实施例1：N-羟基-6-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)己酰胺(化合物I-1)的制备
步骤1：6-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)己酸甲酯(中间体Int-1)的制备
Figure PCTCN2019120259-appb-000195
以4-甲氧基-7-吗啉基苯并[d]噻唑-2-氨(制备方法参见US 20040138465)为原料，参照专利US20050261289中所描述的方法将其转化为N-(4-甲氧基-7-吗啉基苯并[d]噻唑-2-基)氨基甲酸苯酯。将N-(4-甲氧基-7-吗啉基苯并[d]噻唑-2-基)氨基甲酸苯酯(0.385g，1.0mmol)溶于氯仿(5mL)中，加入DIPEA(0.388g，1.0mmol)及6-氨基己酸甲酯(0.145g，1.0mmol)，快速升温至回流后搅拌3小时。冷却至室温，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(0.27g，收率62％)。 1H NMR(800MHz,chloroform-d)δ6.88(d,J＝8.3Hz,1H),6.81(d,J＝8.1Hz,1H),3.96(s,3H),3.91–3.86(m, 4H),3.64(s,3H),3.26(q,J＝6.4Hz,2H),3.16–3.09(m,4H),2.19(t,J＝7.0Hz,2H),1.58–1.52(m,2H),1.50–1.45(m,2H),1.24–1.18(m,2H).HRMS(ESI)C 24H 29N 4O 5S +[M+H] +计算值:437.1859,实测值:437.1871.
步骤2：6-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)己酸(中间体Int-2)的制备
Figure PCTCN2019120259-appb-000196
将步骤1得到的中间体Int-1(0.218g，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-2粗品，直接用于下一步反应。HRMS(ESI)C 23H 27N 4O 5S +[M+H] +计算值:423.1702,实测值:423.1711.
步骤3：6-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)-N-((四氢-2H-吡喃-2-基)氧基)己酰胺(中间体Int-3)的制备
Figure PCTCN2019120259-appb-000197
将步骤2得到的全部中间体Int-2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O-(四氢-2H-吡喃-2-基)羟基胺(0.117g，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，得中间体Int-3(0.104g，收率40％)。 1H NMR(500MHz,methanol-d 4)δ6.94–6.86(m,2H),4.88–4.85(m,1H),4.01–3.95(m,1H),3.94(s,3H),3.89–3.82(m,4H),3.60–3.52(m,1H),3.30–3.24(m,2H),3.10–3.03(m,4H),2.15(t,J＝7.2Hz,2H),1.84–1.73(m,2H),1.73–1.56(m,6H),1.55–1.47(m,2H),1.47–1.37(m,2H).HRMS(ESI)C 24H 36N 5O 6S +[M+H] +计算值:522.2386,实测值:522.2389.
步骤4：N-羟基-6-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)己酰胺(化合物I-1)的制备
Figure PCTCN2019120259-appb-000198
将步骤3得到的化合物Int-3(0.10g，0.19mmol)溶于二氯甲烷(5mL)中，加入4M的氯化氢/1,4-二氧六环溶液(0.6mL)，室温搅拌过夜。减压蒸除溶剂，固体残留物用乙酸乙酯洗涤得化合物(I-1)盐酸盐(63mg，收率75％)。 1H NMR(800MHz,DMSO-d 6)δ10.66(s,1H),10.33(s,1H),6.87(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),6.72(s,1H),3.84(s,3H),3.78–3.75(m,4H),3.13(q,J＝6.7Hz,2H),3.00–2.97(m,4H),1.95(t,J＝7.4Hz,2H),1.54–1.49(m,2H),1.48–1.42(m,2H),1.27–1.24(m,2H).HRMS(ESI)C 19H 28N 5O 5S +[M+H] +计算值:438.1806,实测值:438.1814.
实施例2：N-羟基-5-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)戊酰胺(化合物I-2)的制备
Figure PCTCN2019120259-appb-000199
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“5-氨基戊酸甲酯”，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-2)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ10.38(s,1H),6.94(d,J＝7.6Hz,1H),6.87(d,J＝8.5Hz,1H),6.82(d,J＝8.5Hz,1H),3.84(s,3H),3.77(t,J＝4.5Hz,4H),3.13(q,J＝6.5Hz,2H),3.00(t,J＝4.5Hz,4H),1.97(t,J＝7.3Hz,2H),1.47(dt,J＝66.1,7.3Hz,4H).HRMS(ESI)C 18H 26N 5O 5S +[M+H] +计算值:424.1649,实测值:424.1660.
实施例3：N-羟基-7-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)庚酰胺(化合物I-3)的制备
Figure PCTCN2019120259-appb-000200
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“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-3)盐酸盐。 1H NMR(500MHz,DMSO-d 6)δ10.68(s,1H),10.35(s,1H),8.68(s,1H),6.84(dd,J＝34.7,8.5Hz,2H),6.74(s,1H),3.84(s,3H),3.79–3.72(m,4H),3.13(dd,J＝12.8,6.6Hz,2H),3.03–2.93(m,4H),1.94(t,J＝7.4Hz,2H),1.52–1.42(m,4H),1.31–1.22(m,4H).HRMS(ESI)C 20H 30N 5O 5S +[M+H] +计算值：452.1968；实测值:452.1963。
实施例4：N-羟基-5-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-甲基脲基)戊酰胺(化合物I-4)的制备
Figure PCTCN2019120259-appb-000201
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“5-甲氨基戊酸甲酯”，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-4)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.10(s,1H),10.35(s,1H),6.88(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),3.85(s,3H),3.78–3.75(m,4H),3.40–3.31(m,2H),3.06–2.89(m,7H),2.00–1.56(m,2H),1.54–1.43(m,4H).HRMS(ESI)C 19H 28N 5O 5S +([M+H] +)计算值:438.1806,实测值:438.1810.
实施例5：N-羟基-6-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-甲基脲基)己酰胺(化合物I-5)的制备
Figure PCTCN2019120259-appb-000202
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“6-甲氨基己酸甲酯”，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-5)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ10.33(s,1H),6.88(d,J＝8.5Hz,1H),6.81(d,J＝8.5Hz,1H),3.84(s,3H),3.79–3.74(m,4H),3.38–3.29(m,2H),3.03–2.92(m,7H),1.95(t,J＝7.4Hz,2H),1.51–1.46(m,4H),1.24–1.21(m,2H).HRMS(ESI)C 20H 30N 5O 5S +([M+H] +)计算值:452.1962,实测值:452.1970.
实施例6：N-羟基-7-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-甲基脲基)庚酰胺(化合物I-6)的制备
Figure PCTCN2019120259-appb-000203
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“7-甲氨基庚酸甲酯”，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-6)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ10.32(s,1H),6.88(d,J＝8.5Hz,1H),6.80(d,J＝8.5Hz,1H),3.84(s,3H),3.79–3.75(m,4H),3.39–3.29(m,2H),3.04–2.91(m,7H),1.94(t,J＝7.4Hz,2H),1.54–1.44(m,4H),1.29–1.22(m,4H).HRMS(ESI)C 21H 32N 5O 5S +([M+H] +)计算值:466.2119,实测值:466.2126.
根据实施例1-6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7-8所列的化合物，详见表1.
表1
Figure PCTCN2019120259-appb-000204
实施例9：N-羟基-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)甲基)苯甲酰胺(化合物I-9)的制备
Figure PCTCN2019120259-appb-000205
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-氨甲基苯甲酸甲酯”，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-9)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.17(s,1H),7.73(d,J＝8.2Hz,2H),7.51(s,1H),7.38(d,J＝8.1Hz,2H),6.88(d,J＝8.5Hz,1H),6.83(d,J＝8.5Hz,1H),4.39(d,J＝5.7Hz,2H),3.85(s,3H),3.79–3.72(m,4H),3.04–2.96(m,4H)；HRMS(ESI)C 21H 24N 5O 5S +([M+H] +)计算值:458.1498,实测值:458.1491.
实施例10：N-羟基-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-甲基脲基)甲基)苯甲酰胺(化合物I-10)的制备
Figure PCTCN2019120259-appb-000206
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-甲氨基甲基苯甲酸甲酯”(制备方法参见WO 2004064721)，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)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.32(s,1H),11.18(s,1H),9.00(s,1H),7.73(d,J＝8.2Hz,2H),7.32(d,J＝8.0Hz,2H),6.89(d,J＝8.5Hz,1H),6.82(d,J＝8.5Hz,1H),4.66(s,2H),3.85(s,3H),3.81–3.73(m,4H),3.07–2.92(m,7H).HRMS(ESI)C 22H 26N 5O 5S +([M+H] +)计算值:472.1655,实测值:472.1660.
实施例11：N-羟基-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-乙基脲基)甲基)苯甲酰胺(化合物I-11)的制备
Figure PCTCN2019120259-appb-000207
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-乙氨基甲基苯甲酸甲酯”(制备方法参见WO 2015025164)，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-11)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.31(s,1H),11.17(s,1H),8.99(s,1H),7.73(d,J＝8.0Hz,2H),7.33(d,J＝7.5Hz,2H),6.88(d,J＝7.9Hz,1H),6.82(d,J＝7.8Hz,1H),4.68(s,2H),3.84(s,3H),3.79–3.72(m,4H),3.50–3.38(m,2H),3.03–2.96(m,4H),1.08(t,J＝6.8Hz,3H).HRMS(ESI)C 23H 27N 5O 5S +([M+H] +)计算值:486.1806,实测值:486.1828.
实施例12：N-羟基-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-正丙基脲基)甲基) 苯甲酰胺(化合物I-12)的制备
Figure PCTCN2019120259-appb-000208
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-((正丙基)氨基)甲基苯甲酸甲酯”(制备方法参见ChemMedChem,2017,12,646-651)，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-12)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.32(s,1H),11.17(s,1H),8.99(s,1H),7.72(d,J＝8.1Hz,2H),7.32(d,J＝7.4Hz,2H),6.89(d,J＝8.4Hz,1H),6.81(d,J＝8.3Hz,1H),4.68(s,2H),3.84(s,3H),3.80–3.73(m,4H),3.40–3.32(m,2H),3.05–2.94(m,4H),1.59–1.45(m,2H),0.84(t,J＝7.3Hz,3H).HRMS(ESI)C 24H 30N 5O 5S +([M+H] +)计算值:500.1968,实测值:500.1966.
实施例13：N-羟基-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-正丁基脲基)甲基)苯甲酰胺(化合物I-13)的制备
Figure PCTCN2019120259-appb-000209
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-((正丁基)氨基)甲基苯甲酸甲酯”(制备方法参见WO 2015017546)，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-13)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.32(s,1H),11.17(s,1H),9.00(s,1H),7.73(d,J＝7.8Hz,2H),7.32(d,J＝7.3Hz,2H),6.89(d,J＝7.7Hz,1H),6.82(d,J＝7.9Hz,1H),4.69(s,2H),3.84(s,3H),3.80–3.71(m,4H),3.47–3.35(m,2H),3.07–2.91(m,4H),1.50(qui,J＝7.7Hz,2H),1.30–1.23(m,2H),0.88(t,J＝7.4Hz,3H).HRMS(ESI)C 25H 32N 5O 5S +([M+H] +)计算值:514.2119,实测值:514.2129.
实施例14：N-羟基-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-(环丙基甲基)脲基)甲基)苯甲酰胺(化合物I-14)的制备
Figure PCTCN2019120259-appb-000210
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-((环丙基甲基)氨基)甲基苯甲酸甲酯”(制备方法参见WO 2015017546)，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-14)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.30(s,1H),11.16(s,1H),8.80(s,1H),7.72(d,J＝8.1Hz,2H),7.32(d,J＝7.9Hz,2H),6.89(d,J＝8.4Hz,1H),6.81(d,J＝8.4Hz,1H),4.79(s,2H),3.84(s,3H),3.79–3.73(m,4H),3.40–3.28(m,2H),3.06–2.92(m,4H),1.05–0.99(m,1H),0.46–0.36(m,2H),0.29–0.17(m,2H).HRMS(ESI)C 25H 30N 5O 5S +([M+H] +)计算值:512.1968,实测值:512.1962.
根据实施例9-14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15-21所列的化合物，详见表2.
表2
Figure PCTCN2019120259-appb-000211
Figure PCTCN2019120259-appb-000212
实施例22：N-羟基-4-(2-(3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1-甲基脲基)乙基)苯甲酰胺(化合物I-22)的制备
Figure PCTCN2019120259-appb-000213
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“4-(2-(甲氨基)乙基)苯甲酸甲酯”(制备方法参见WO 2008156820)，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)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ11.16(s,1H),7.69(d,J＝8.2Hz,2H),7.39–7.32(m,2H),6.91–6.79(m,2H),3.85(s,3H),3.79–3.75(m,4H),3.68–3.56(m,,2H),3.05–2.93(m,7H),2.90–2.85(m,2H).HRMS(ESI)C 23H 28N 5O 5S +([M+H] +)计算值:486.1806,实测值:486.1815.
实施例23：N 4-羟基-N 1-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)哌啶-1，4-二甲酰胺(化合物I-23)的制备
Figure PCTCN2019120259-appb-000214
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“哌啶-4-甲酸甲酯”，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-23)盐酸盐。 1H NMR(500MHz,DMSO-d 6)δ10.51(s,1H),6.86(dd,J＝34.4,8.5Hz,2H),4.24(d,J＝12.4Hz,2H),3.85(s,3H),3.80–3.70(m,4H),3.07–2.94(m,4H),2.87(t,J＝11.9Hz,2H),2.29–2.21(m,1H),1.69–1.56(m,2H),1.56–1.44(m,2H).HRMS(ESI)C 19H 26N 5O 5S +([M+H] +)计算值：436.1655；实测值：436.1660.
实施例24：4-(4-(羟基胺甲酰基)苯基-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)哌嗪-1-甲酰胺(化合物I-24)的制备
Figure PCTCN2019120259-appb-000215
将实施例1步骤1中的“6-氨基己酸甲酯”替换成“(4-哌嗪-1-基)苯甲酸乙酯”，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-24)盐酸盐。 1H NMR(800MHz,DMSO-d 6)δ10.97(s,1H),7.66(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,1H),6.90(d,J＝8.5Hz,1H),6.84(d,J＝8.4Hz,1H),3.86(s,3H),3.81–3.75(m,4H),3.75–3.66(m,4H),3.35–3.28(m,4H),3.05–2.97(m,4H).HRMS(ESI)C 24H 29N 6O 5S +([M+H] +)计算值：513.1920；实测值：513.1915.
实施例25：N-羟基-2-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)哌嗪-1-基)嘧啶-5-甲酰胺(化合物I-25)的制备
步骤1：2-(4-叔丁氧羰基哌嗪-1-基)嘧啶-5-甲酸乙酯(中间体Int-4)的制备
Figure PCTCN2019120259-appb-000216
将1-叔丁氧羰基哌嗪(1.86g,10mmol)，2-氯嘧啶-5-甲酸乙酯(1.86g,10mmol)及三乙胺(1.01g,10mmol)溶于DMF(10mL)中，室温搅拌过夜。减压蒸除溶剂，固体残留物用硅胶柱层析分离得中间体Int-4(2.98g，收率89％)。MS([M+H] +):337.19.
步骤2：2-(哌嗪-1-基)嘧啶-5-甲酸乙酯(中间体Int-5)的制备
Figure PCTCN2019120259-appb-000217
将步骤1得到的化合物Int-4(1.68g，5mmol)溶于二氯甲烷(5mL)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，固体残留物用乙酸乙酯洗涤得中间体Int-5(1.18g，收率100％)。MS([M+H] +):237.14.
步骤3：N-羟基-2-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)哌嗪-1-基)嘧啶-5-甲酰胺(化合物I-25)的制备
Figure PCTCN2019120259-appb-000218
将实施例1步骤1中的6-氨基己酸甲酯替换成Int-5，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-25)盐酸盐。 1H NMR(500MHz,DMSO-d 6)δ11.44(s,1H),11.12(s,1H),9.04(s,1H),8.71(s,2H),6.90(d,J＝8.5Hz,1H),6.82(d,J＝8.4Hz,1H),3.86(s,7H),3.79–3.73(m,4H),3.66(s,4H),3.00(s,4H).HRMS(ESI)C 22H 27N 8O 5S +([M+H] +)计算值：515.1825；实测值：515.1824.
根据实施例24-25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26-31所列的化合物，详见表3.
表3
Figure PCTCN2019120259-appb-000219
Figure PCTCN2019120259-appb-000220
实施例32：N 1-羟基-N 6-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)己二酰胺(化合物I-32)的制备
步骤1：6-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-6-氧代己酸甲酯(中间体Int-6)的制备
Figure PCTCN2019120259-appb-000221
将己二酸单甲酯(0.080g,0.50mmol)溶于无水DMF(5mL)中，加入HATU(0.38g，1.0mmol),室温搅拌20分钟，再加入4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-胺(0.132g，0.50mmol)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，得中间体Int-6(0.092g，收率45％)。 1H NMR(800MHz,DMSO-d 6)δ12.44(s,1H),6.95–6.87(m,2H),3.87(s,3H),3.80–3.75(m,4H),3.58(s,3H),3.03–2.98(m,4H),2.47(t,J＝7.2Hz,2H),2.34(t,J＝7.4Hz,2H),1.65–1.53(m,4H).HRMS(ESI)C 19H 26N 3O 5S +([M+H] +)计算值:408.1588,实测值:408.1594.
步骤2：N 1-羟基-N 6-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)己二酰胺(化合物I-32)的 制备
Figure PCTCN2019120259-appb-000222
将氢氧化钾(1.29g,23mmol)的无水甲醇溶液(3.22mL)于0℃下滴加至盐酸羟胺(1.07g,15.4mmol)的无水甲醇溶液(5.52mL)中，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6-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-6-氧代己酸甲酯(中间体Int-6)(0.080g，0.20mmol)溶于上述羟胺的甲醇溶液中，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，抽滤得白色固体(I-32)(0.056g，收率70％)。H NMR(800MHz,DMSO-d 6)δ12.43(s,1H),10.35(s,1H),6.95–6.88(m,2H),3.87(s,3H),3.79–3.76(m,4H),3.02–2.99(m,4H),2.46(t,J＝7.3Hz,2H),1.97(t,J＝7.3Hz,2H),1.61–1.49(m,4H).HRMS(ESI)C 18H 25N 4O 5S +([M+H] +)计算值:409.1540,实测值:409.1545.
实施例33：N 1-羟基-N 7-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)庚二酰胺(化合物I-33)的制备
Figure PCTCN2019120259-appb-000223
将实施例32步骤1中的己二酸单甲酯替换成庚二酸单甲酯，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-33)。 1H NMR(800MHz,DMSO-d 6)δ12.43(s,1H),10.32(s,1H),8.65(s,1H),6.93(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),3.87(s,3H),3.80–3.74(m,4H),3.04–2.97(m,4H),2.45(t,J＝7.3Hz,2H),1.94(t,J＝7.4Hz,2H),1.64–1.57(m,2H),1.53–1.47(m,2H),1.29–1.25(m,2H).HRMS(ESI)C 19H 27N 4O 5S +([M+H] +)计算值:423.1697,实测值:423.1708.
实施例34：N 1-羟基-N 8-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)辛二酰胺(化合物I-34)的制备
Figure PCTCN2019120259-appb-000224
将实施例32步骤1中的己二酸单甲酯替换成辛二酸单甲酯，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-34)。 1H NMR(800MHz,DMSO-d 6)δ12.42(s,1H),10.32(s,1H),8.64(s,1H),6.93(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),3.87(s,3H),3.79–3.75(m,4H),3.03–2.99(m,4H),2.45(t,J＝7.4Hz,2H),1.93(t,J＝7.4Hz,2H),1.62–1.57(m,2H),1.50–1.46(m,2H),1.31–1.22(m,4H).HRMS(ESI)C 20H 29N 4O 5S +([M+H] +)计算值:437.1853,实测值:437.1564.
实施例35：N 1-羟基-N 9-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)壬二酰胺(化合物I-35)的制备
Figure PCTCN2019120259-appb-000225
将实施例32步骤1中的己二酸单甲酯替换成壬二酸单甲酯，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-35)。 1H NMR(800MHz,DMSO-d 6)δ12.42(s,1H),10.31(s,1H),8.63(s,1H),6.93(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),3.87(s,3H),3.79–3.75(m,4H),3.04–2.98(m,4H),2.45(t,J＝7.4Hz,2H),1.93(t,J＝7.4Hz,2H),1.62–1.57(m,2H),1.50–1.43(m,2H),1.31–1.25(m,4H),1.25–1.20(m,2H).HRMS(ESI)C 21H 31N 4O 5S +([M+H] +)计算值:451.2010,实测值:451.2024.
实施例36：N 1-羟基-N 8-(7-甲氧基-4-吗啉基吡啶并[5,4-c]噻唑-2-基)辛二酰胺(化合物I-36)的制备的制备
步骤1：8-((7-甲氧基-4-吗啉基吡啶并[5,4-c]噻唑-2-基)氨基)-6-氧代辛酸甲酯(中间体Int-7)的制备
Figure PCTCN2019120259-appb-000226
将辛二酸单甲酯(0.095g,0.51mmol)溶于甲苯(5mL)中，加入氯化亚砜(5mL)回流搅拌2小时，减压蒸干溶剂，将残留物溶于二氯甲烷中，滴加至7-甲氧基-4-吗啉基吡啶并[5,4-c]噻唑-2-胺(0.09g,0.34mmol，制备方法参见US 20050065151)和三乙胺(0.068g,0.68mmol)的二氯甲烷溶液(5mL)中，室温搅拌2小时。用乙酸乙酯/水对反应液萃取三次，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-7(0.080g，收率54％)。
1H NMR(600MHz,CDCl 3)δ9.49(s,1H),7.86(s,1H),4.01(s,3H),3.93–3.86(m,4H),3.67(s,3H),3.53–3.41(m,4H),2.52(t,J＝7.5Hz,2H),2.31(t,J＝7.4Hz,2H),1.80–1.72(m,2H),1.66–1.61(m,2H),1.43–1.31(m,4H).HRMS(ESI)C 20H 29N 4O 5S +([M+H] +)计算值：437.1859，实测值:437.1856.
步骤2：N 1-羟基-N 8-(7-甲氧基-4-吗啉基吡啶并[5,4-c]噻唑-2-基)辛二酰胺(化合物I-36)的制备的制备
Figure PCTCN2019120259-appb-000227
将步骤1中的“6-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-6-氧代己酸甲酯”替换成“8-((7-甲氧基-4-吗啉基吡啶并[5,4-c]噻唑-2-基)氨基)-6-氧代辛酸甲酯”，其余所需原料，试剂及制备方法同实施例32步骤2，得白色固体化合物(I-36)。 1H NMR(800MHz,DMSO)δ12.74(s,1H),10.32(s,1H),8.64(d,J＝1.5Hz,1H),7.89(s,1H),3.92(s,3H),3.79–3.75(m,4H),3.34–3.32(m,4H),2.50–2.48(m,2H),1.93(t,J＝7.4Hz,2H),1.63–1.58(m,2H),1.50–1.46(m,2H),1.30–1.23(m,4H).HRMS(ESI)C 19H 28N 5O 5S +([M+H] +)计算值：438.1811，实测值:438.1815.
实施例37：N-羟基-4-(2-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯甲酰胺(化合物I-37)的制备
Figure PCTCN2019120259-appb-000228
将实施例32步骤1中的“己二酸单甲酯”替换成“4-(甲氧羰基)苯乙酸”，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-37)。 1H NMR(800MHz,DMSO- d 6)δ12.76(s,1H),11.19(s,1H),7.72(d,J＝8.2Hz,2H),7.41(d,J＝8.2Hz,2H),6.96–6.88(m,2H),3.89–3.85(m,5H),3.77–3.72(m,4H),3.01–2.97(m,4H).HRMS(ESI)C 21H 23N 4O 5S +([M+H] +)计算值:443.1384,实测值:443.1390.
实施例38：N-羟基-4-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-3-氧代丙基)苯甲酰胺(化合物I-38)的制备
Figure PCTCN2019120259-appb-000229
将实施例32步骤1中的“己二酸单甲酯”替换成“3-(4-甲氧羰基苯基)丙酸”，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-38)。 1H NMR(800MHz,DMSO-d 6)δ12.49(s,1H),11.13(s,1H),8.96(s,1H),7.69–7.65(m,2H),7.32(d,J＝8.2Hz,2H),6.95–6.87(m,2H),3.86(s,3H),3.80–3.76(m,4H),3.03–2.96(m,6H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)C 22H 24N 4O 5S +([M+H] +)计算值:457.1540,实测值:457.1547.
实施例39：N-羟基-4-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-4-氧代丁基)苯甲酰胺(化合物I-39)的制备
Figure PCTCN2019120259-appb-000230
将实施例32步骤1中的“己二酸单甲酯”替换成“4-(4-甲氧羰基苯基)丁酸”(制备方法参见WO 2015134973)，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-39)。 1H NMR(800MHz,DMSO-d 6)δ12.44(s,1H),11.14(s,1H),7.68(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),6.95–6.87(m,2H),3.87(s,3H),3.80–3.75(m,4H),3.03–2.97(m,4H),2.70–2.64(m,2H),2.52–2.51(m,2H),1.93(p,J＝7.4Hz,2H).HRMS(ESI)C 23H 27N 4O 5S +([M+H] +)计算值:471.1697,实测值:471.1701.
实施例40：N-羟基-4-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-3-氧代丙氧基)苯甲酰胺(化合物I-40)的制备
Figure PCTCN2019120259-appb-000231
将实施例32步骤1中的“己二酸单甲酯”替换成“3-(4-(甲氧羰基)苯氧基)丙酸”，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-40)。 1H NMR(800MHz,DMSO-d 6)δ12.62(s,1H),11.07(s,1H),7.72(d,J＝8.7Hz,2H),6.99(d,J＝8.8Hz,2H),6.94(d,J＝8.5Hz,1H),6.90(d,J＝8.5Hz,1H),4.36(t,J＝5.9Hz,2H),3.88(s,3H),3.78–3.75(m,4H),3.02–2.96(m,6H).HRMS(ESI)C 22H 25N 4O 6S +([M+H] +)计算值:473.1489,实测值:473.1492.
实施例41：(E)-N-羟基-3-(4-(2-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯基)丙烯酰胺(化合物I-41)的制备
Figure PCTCN2019120259-appb-000232
将实施例32步骤1中的“己二酸单甲酯”替换成“(E)-2-(4-(3-甲氧基-3-氧代丙-1-烯-1基)苯基)乙酸”(制备方法参见US20020173421)，其余所需原料，试剂及制备方法同实施例32，得白色固体化合物(I-41)。 1H NMR(800MHz,DMSO-d 6)δ12.75(s,1H),10.74(s,1H),7.53(d,J＝8.1Hz,2H),7.44(d,J＝15.6Hz,1H),7.38(d,J＝8.0Hz,2H),6.94–6.89(m,2H),6.44(d,J＝15.8Hz,1H),3.88(s,3H),3.83(s,2H),3.76–3.74(m,4H),3.00–2.98(m,4H).HRMS(ESI)C 23H 25N 4O 5S +([M+H] +)计算值:469.1540,实测值:469.1545。
根据实施例32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42所列的化合物，详见表4.
表4
Figure PCTCN2019120259-appb-000233
实施例43：N-羟基-4-((1-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-甲基-1-氧代丙-2-基)氧基)苯甲酰胺(化合物I-43)的制备
步骤1：4-羟基-N-((四氢-2H-吡喃-2-基)氧基)苯甲酰胺(中间体Int-8)的制备的制备
Figure PCTCN2019120259-appb-000234
将实施例1步骤3中的Int-2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1步骤3，得中间体Int-8。MS([M+H] +):238.11。
步骤2：2-甲基-2-(4-(((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯氧基)丙酸甲酯(中间体Int-9)的制备的制备
Figure PCTCN2019120259-appb-000235
将步骤1中得到的中间体Int-8(2.37g,10mmol)，2-溴代异丁酸甲酯(2.35g,13mmol)及碳酸钾(4.14g,30mmol)溶于DMF(20mL)中，50℃搅拌过夜。减压蒸除溶剂，固体残留物用硅胶柱层析分离得中间体Int-9(1.35g,收率40％)。MS([M+H] +):338.16。
步骤3：2-甲基-2-(4-(((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯氧基)丙酸(中间体Int-10)的制备的制备
Figure PCTCN2019120259-appb-000236
将实施例1步骤2中的“己二酸单甲酯”替换成中间体Int-9，其余所需原料，试剂及制备方法同实施例1步骤2，得中间体Int-10。MS([M+H] +):324.14。
步骤4：4-((1-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-甲基-1-氧代丙-2-基)氧基)-N-((四氢-2H-吡喃-2-基)氧基)苯甲酰胺(中间体Int-11)的制备
Figure PCTCN2019120259-appb-000237
将实施例32步骤1中的“己二酸单甲酯”替换成中间体Int-10，其余所需原料，试剂及制备方法同实施例32步骤1，得中间体Int-11。 1H NMR(600MHz,DMSO-d 6)δ7.69–7.62(m,2H),6.96–6.84(m,4H),4.95–4.90(m,1H),4.02–3.95(m,1H),3.84(s,3H),3.81–3.75(m,4H),3.59–3.55(m,1H),3.06–2.98(m,4H),1.95–1.39(m,12H).HRMS(ESI)C 28H 35N 4O 7S +([M+H] +)计算值：571.2221,实测值：571.2230。
步骤5：N-羟基-4-((1-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-甲基-1-氧代丙-2-基)氧基)苯甲酰胺(化合物I-43)的制备
Figure PCTCN2019120259-appb-000238
将实施例1步骤4中的中间体Int-3替换成中间体Int-11，其余所需原料，试剂及制备方法同实施例1步骤4，得白色固体化合物(I-43)。 1H NMR(800MHz,DMSO-d 6)δ7.67–7.64(m,2H),6.96–6.90(m,2H),6.88(d,J＝8.8Hz,2H),3.84(s,3H),3.81–3.77(m,4H),3.05–2.99(m,4H),1.64(s,6H).HRMS(ESI)C 23H 279N 4O 6S +([M+H] +)计算值:487.1646,实测值:487.1658.
实施例44：(E)-N-羟基-3-(4-((1-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-甲基-1-氧代丙-2-基)氧基)苯基)丙烯酰胺(化合物I-44)的制备
Figure PCTCN2019120259-appb-000239
将实施例43步骤1中的4-羟基苯甲酸替换成4-羟基肉桂酸，其余所需原料，试剂及制备方法同实施例43，得白色固体化合物(I-44)。 1H NMR(800MHz,DMSO-d 6)δ12.71(s,1H),7.47(d,J＝8.7Hz,2H),7.35(d,J＝15.7Hz,1H),6.96–6.90(m,2H),6.88(d,J＝8.8Hz,2H),6.29(d,J＝15.8Hz,1H),3.84(s,3H),3.80–3.78(m,4H),3.06–2.99(m,4H),1.63(s,6H).HRMS(ESI)C 25H 29N 4O 6S +([M+H] +)计算值:513.1802,实测值:513.1810。
根据实施例43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45-47所列的化合物，详见表5。
表5
Figure PCTCN2019120259-appb-000240
实施例48：N-羟基-2-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)吖丁啶-1-基)嘧啶-5-甲酰胺(化合物I-48)的制备
步骤1：3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)吖丁啶-1-甲酸叔丁酯(中间体Int-12)的制备
Figure PCTCN2019120259-appb-000241
将己1-N-Boc-3-吖丁啶羧酸(0.201g，1.0mmol)溶于无水DMF(5mL)中，加入HATU(0.76g，2.0mmol),室温搅拌20分钟，再加入4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-胺(0.265g，1.0mmol)及DIPEA(0.774g，6.0mmol)，室温搅拌过夜。反应液加水稀释，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-12(0.193g，收率43％)。 1H NMR(600MHz,CDCl 3)δ6.94–6.90(m,1H),6.89–6.86(m,1H),4.21–4.16(m,2H),4.07–4.00(m,2H),3.95–3.89(m,7H),3.54–3.47(m,1H),3.17–3.12(m,4H),1.43(s,9H).HRMS(ESI)C 21H 29N 4O 5S +([M+H] +)计算值:449.1859,实测值:449.1856。
步骤2：N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)吖丁啶-3-甲酰胺(中间体Int-13)的制备
Figure PCTCN2019120259-appb-000242
将步骤1得到的化合物Int-12(0.19g，0.42mmol)溶于二氯甲烷(5mL)中，加入4M的氯化氢/1，4-二氧六环溶液(1mL)，室温搅拌过夜。减压蒸除溶剂，固体残留物用乙酸乙酯洗涤得中间体Int-13(0.148g，收率100％)。HRMS(ESI)计算值C 16H 21N 4O 3S +([M+H] +):349.1334,实测值：349.1327。
步骤3：2-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)吖丁啶-1-基)嘧啶-5-甲酸乙酯(中间体Int-14)的制备
Figure PCTCN2019120259-appb-000243
将步骤2得到的化合物Int-13(0.14g，0.4mmol)溶于DMF中,加入2-氯嘧啶-5-羧酸乙酯(0.09g，0.48mmol)及DIPEA(0.104g，0.8mmol)，室温搅拌3小时。反应液加水稀释，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-14(0.148g，收率74％)。 1H NMR(800MHz,CDCl 3)δ8.87(s,2H),7.00(d,J＝8.4Hz,1H),6.93–6.89(m,1H),4.56–4.50(m,2H),4.46(t,J＝9.1Hz,2H),4.36(q,J＝7.1Hz,2H),3.97(s,3H),3.95–3.91(m,4H),3.81–3.77(m,1H),3.19–3.11(m,4H),1.40–1.38(m,3H).HRMS(ESI)C 23H 27N 6O 5S +([M+H] +)计算值:499.1764,实测值:499.1758。
步骤4：N-羟基-2-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)吖丁啶-1-基)嘧啶-5-甲酰胺(化合物I-48)的制备
Figure PCTCN2019120259-appb-000244
将实施例32步骤2中的“6-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-6-氧代己 酸甲酯”替换成“2-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)吖丁啶-1-基)嘧啶-5-甲酸乙酯”(中间体Int-14)，其余所需原料，试剂及制备方法同实施例32步骤2，得粉红色固体化合物I-48。 1H NMR(800MHz,DMSO-d 6)δ12.69(s,1H),11.12(s,1H),9.02(s,1H),8.68(s,2H),6.95(d,J＝8.5Hz,1H),6.91(d,J＝8.4Hz,1H),4.33(t,J＝8.9Hz,2H),4.26–4.20(m,2H),3.88(s,3H),3.86–3.81(m,1H),3.80–3.74(m,4H),3.05–2.97(m,4H).HRMS(ESI)C 21H 24N 7O 5S +([M+H] +)计算值:486.1560,实测值:486.1550。
实施例49：N-羟基-2-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)哌啶-1-基)嘧啶-5-甲酰胺(化合物I-49)的制备
Figure PCTCN2019120259-appb-000245
将实施例48步骤1中的“1-N-Boc-3-吖丁啶羧酸”替换成“1-N-Boc-4-哌啶甲酸”，其余所需原料，试剂及制备方法同实施例48，得粉红色固体化合物I-49。 1H NMR(800MHz,DMSO-d 6)δ12.56(s,1H),11.07(s,1H),8.68(s,2H),6.94(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),4.76–4.69(m,2H),3.87(s,3H),3.77–3.76(m,4H),3.10–3.04(m,2H),3.02–2.97(m,4H),2.90–2.84(m,1H),1.98–1.89(m,2H),1.63–1.55(m,2H).HRMS(ESI)C 23H 28N 7O 5S +([M+H] +)计算值:514.1873,实测值:514.1865。
根据实施例48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50-55所列的化合物，详见表6。
表6
Figure PCTCN2019120259-appb-000246
Figure PCTCN2019120259-appb-000247
实施例56：N-(2-氨基苯基)-4-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-3-氧代丙基)苯甲酰胺(化合物I-56)的制备
步骤1：4-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-3-氧代丙基)苯甲酸(中间体Int-15)的制备
Figure PCTCN2019120259-appb-000248
将实施例38中得到的酯类中间体(0.228g，0.5mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶液中，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，得羧酸中间体Int-15粗品，直接用于下一步反应。HRMS(ESI)C 22H 24N 3O 5S +([M+H] +)计算值:442.1437,实测值:442.1440。
步骤2：N-(2-氨基苯基)-4-(3-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-3-氧代丙基)苯甲酰胺(化合物I-56)的制备
Figure PCTCN2019120259-appb-000249
将步骤1得到的全部中间体Int-15与氯化锂的混合物溶于无水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，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-56(0.106g，收率40％)。 1H NMR(800MHz,DMSO-d 6)δ12.50(s,1H),9.58(s,1H),7.91(d,J＝8.0Hz,2H),7.41–7.37(m,2H),7.15(d,J＝7.6Hz,1H),6.98–6.88(m,3H),6.79–6.75(m,1H),6.61–6.56(m,1H),4.87(s,2H),3.87(s,3H),3.81–3.74(m,4H),3.06–2.98(m,6H),2.85(t,J＝7.6Hz,2H)。HRMS(ESI)C 28H 30N 5O 4S +([M+H] +)计算值:532.2013,实测值:532.2020。
根据实施例56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57-60所列的化合物，详见表7。
表7
Figure PCTCN2019120259-appb-000250
Figure PCTCN2019120259-appb-000251
实施例61：N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-3-(4-(2-丙基肼-1-羰基)苯基)丙酰胺(化合物I-61)的制备
Figure PCTCN2019120259-appb-000252
将实施例56步骤2中的邻苯二胺替换成丙基肼，其余所需原料，试剂及制备方法同实施例56步骤2，得化合物I-61。 1H NMR(600MHz,DMSO-d 6)δ12.52(s,1H),7.80(d,J＝8.3Hz,2H),7.42(d,J＝8.3Hz,2H),6.95–6.88(m,2H),3.86(s,3H),3.79–3.77(m,4H),3.07–2.96(m,8H),2.84(t,J＝7.5Hz,2H),1.59(dt,J＝14.9,7.4Hz,2H),0.92(t,J＝7.4Hz,3H).HRMS(ESI)C 25H 32N 5O 4S +([M+H] +)计算值:498.2170,实测值:498.2180。
实施例62：(E)-3-(3-(羟胺基)-3-氧代丙-1-烯-1-基)-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1H-吡咯-1-甲酰胺(化合物I-62)的制备
步骤1：(E)-3-(1-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨甲酰基)-1H-吡咯-3-基)丙烯酸乙酯(中间体Int-16)的制备。
Figure PCTCN2019120259-appb-000253
将60％NaH(0.41g,1.73mmol)悬浮于四氢呋喃(2mL)中，在N 2保护下置于0℃下搅拌。向该溶液中缓慢加入(E)-3-(1H-吡咯-3-基)丙烯酸乙酯(0.094g，0.57mmol)的四氢呋喃(7mL)溶液，0℃下搅拌1小时。然后向该反应液中加入4-硝基氯甲酸苯酯(0.14g，0.69mmol)的四氢呋喃(2mL)溶液，而后室温搅拌15小时。向反应液中加入乙酸乙酯(100mL)，用水洗涤，酯相干燥，减压蒸干。将残留物溶于氯仿(20mL)中，加入N-(4-甲氧基-7-吗啉基苯并[d]噻唑-2-基)氨基甲酸苯酯(0.151g，0.57mmol)和DIPEA(0.074g， 0.57mmol)，100℃搅拌至溶剂蒸干并过夜，固体残留物用硅胶柱层析分离得中间体Int-16(0.114g，收率43％)。 1H NMR(800MHz,CDCl 3)δ7.74(s,1H),7.58(d,J＝15.8Hz,1H),7.56–7.53(m,1H),6.83(d,J＝8.5Hz,1H),6.79(d,J＝8.5Hz,1H),6.47–6.42(m,1H),6.15(d,J＝15.8Hz,1H),4.24(q,J＝7.1Hz,2H),3.92–3.86(m,4H),3.80(s,3H),3.11–3.03(m,4H),1.32(t,J＝7.1Hz,3H)。
步骤2：(E)-3-(1-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨甲酰基)-1H-吡咯-3-基)丙烯酸(中间体Int-17)的制备。
Figure PCTCN2019120259-appb-000254
将步骤1得到的中间体Int-16(0.114g，0.25mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶液中，加入氢氧化钠(0.10g，2.5mmol)，50℃下搅拌2天。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-17粗品，直接用于下一步反应。HRMS(ESI)C 20H 21N 4O 5S +([M+H] +)计算值:429.1233,实测值:429.1238。
步骤3：(E)-3-(3-(羟胺基)-3氧代丙-1-烯-1-基)-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)-1H-吡咯-1-甲酰胺(化合物I-62)的制备
Figure PCTCN2019120259-appb-000255
将实施例1步骤3中的Int-2替换成Int-17，其余所需原料，试剂及制备方法同实施例1中的步骤3至步骤4，得白色固体化合物I-62。 1H NMR(600MHz,DMSO-d 6)δ7.82(s,1H),7.61(s,1H),7.38(d,J＝15.6Hz,1H),7.04(d,J＝8.4Hz,1H),6.96(d,J＝8.6Hz,1H),6.53(s,1H),6.17(d,J＝15.6Hz,1H),3.91(s,3H),3.84–3.74(m,4H),3.06–2.96(m,4H).HRMS(ESI)C 20H 22N 5O 5S +([M+H] +)计算值:444.1342,实测值:444.1339.
实施例63：(4-(3-(羟胺基)-3-氧代丙基)-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)环己烷-1-甲酰胺(化合物I-63)的制备
步骤1：4-羟基-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨甲酰基)环己烷-1-甲酰胺(中间体Int-18)的制备。
Figure PCTCN2019120259-appb-000256
将实施例32步骤1中的“己二酸单甲酯”替换成“4-羟基哌啶甲酸”，其余所需原料，试剂及制备方法同实施例32步骤1，得中间体Int-18。 1H NMR(600MHz,DMSO-d 6)δ12.44–12.35(m,1H),6.95–6.85(m,2H),4.65–4.60(m,1H),3.86(s,3H),3.80–3.73(m,4H),3.04–2.94(m,4H),2.76–2.71(m,1H),2.45–2.37(m,1H),1.97–1.78(m,4H),1.70–1.51(m,2H),1.50–1.41(m,2H)。HRMS(ESI)C 19H 26N 3O 4S +([M+H] +)计算值:392.1639,实测值:392.1641。
步骤2：4-羟基-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨甲酰基)环己烷-1-甲酰胺(中间体Int-19)的制备。
Figure PCTCN2019120259-appb-000257
将步骤1中得到的中间体Int-18(3.92g,10mmol)，3-溴丙酸乙酯(2.35g,13mmol)及碳酸钾(4.14g,30mmol)溶于DMF(20mL)中，50℃搅拌过夜。减压蒸除溶剂，固体残留物用硅胶柱层析分离得中间体Int-19(0.34g，收率10％)。MS([M+H] +):492.22。
步骤3：4-羟基-N-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨甲酰基)环己烷-1-甲酰胺(化合物I-63)的制备。
Figure PCTCN2019120259-appb-000258
将实施例32步骤2中的“6-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-6-氧代己酸甲酯”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32步骤2，得粉红色固体化合物I-63。 1H NMR(600MHz,DMSO-d 6)δ6.96–6.87(m,2H),3.87(s,3H),3.84–3.81(m,2H),3.79–3.76(m,4H),3.35–3.27(m,1H),3.06–2.95(m,4H),2.78–2.59(m,3H),1.84–1.25(m,8H).HRMS(ESI)C 22H 31N 4O 6S +([M+H] +)计算值:479.1959,实测 值:479.1966。
根据实施例63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64所列的化合物，详见表8。
表8
Figure PCTCN2019120259-appb-000259
根据实施例9及实施例34，通过变换相对应的原料，用相同的方法可制备实施例65-74所列的化合物，详见表9。
表9
Figure PCTCN2019120259-appb-000260
Figure PCTCN2019120259-appb-000261
实施例75：N-羟基-2-(2-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)2-氧代乙基)(甲基)氨基)嘧啶-5-甲酰胺(化合物I-75)的制备
Figure PCTCN2019120259-appb-000262
将实施例48步骤1中的“1-N-Boc-3-吖丁啶羧酸”替换成“N-Boc-N-甲基甘氨酸”，其余所需原料，试剂及制备方法同实施例48，得粉红色固体化合物I-75。 1H NMR(800MHz,DMSO-d 6)δ12.69(s,1H),11.09(s,1H),9.02(s,1H),8.67(d,J＝108.7Hz,2H),6.94(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),4.63(s,2H),3.88(s,3H),3.77–3.70(m,4H),3.26(s,3H),3.01–2.97(m,4H).HRMS(ESI)C 20H 24N 7O 5S +([M+H] +)计算值:474.1560,实测值:474.1554.
实施例76：N-(2-氨基苯基)-2-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)哌啶-1-基)嘧啶-5-甲酰胺(化合物I-76)的制备
步骤1：2-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)哌啶-1-基)嘧啶-5-羧酸(中间体Int-20)的制备
Figure PCTCN2019120259-appb-000263
将实施例49中得到的酯类中间体(0.263g，0.5mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶液中，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，得羧酸中间体Int-20粗品，直接用于下一步反应。HRMS(ESI)C 23H 27N 6O 5S +([M+H] +)计算值:499.1764,实测值:499.1760.
步骤2：N-(2-氨基苯基)-2-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)哌啶-1-基)嘧啶-5-甲酰胺(化合物I-76)的制备
Figure PCTCN2019120259-appb-000264
将步骤1得到的全部中间体Int-20与氯化锂的混合物溶于无水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，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-76(0.097g，收率33％)。 1H NMR(800MHz,DMSO-d 6)δ12.58(s,1H),9.49(s,1H),8.91(s,2H),7.14(d,J＝7.6Hz,1H),6.98–6.95(m,1H),6.94(d,J＝8.5Hz,1H),6.89(d,J＝8.5Hz,1H),6.76(dd,J ＝8.0,1.3Hz,1H),6.58(td,J＝7.6,1.3Hz,1H),4.94(s,2H),4.78(d,J＝13.3Hz,2H),3.88(s,3H),3.79–3.74(m,4H),3.18–3.07(m,2H),3.04–2.97(m,4H),2.94–2.81(m,1H),2.03–1.92(m,2H),1.67–1.54(m,2H).HRMS(ESI)C 29H 33N 8O 4S +([M+H] +)计算值:589.2345,实测值:589.2340.
实施例77：N-(2-氨基苯基)-2-(2-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)2-氧代乙基)(甲基)氨基)嘧啶-5-甲酰胺(化合物I-77)的制备
Figure PCTCN2019120259-appb-000265
将实施例75中得到的酯类中间体按实施例76中描述的制备方法进行转化制备，得化合物I-77。 1H NMR(800MHz,DMSO-d 6)δ12.72(s,1H),9.49(s,1H),8.90(d,J＝91.0Hz,2H),7.13(d,J＝7.6Hz,1H),6.98–6.92(m,2H),6.89(d,J＝8.5Hz,1H),6.75(dd,J＝8.0,1.3Hz,1H),6.58–6.54(m,1H),4.94(s,2H),4.66(s,2H),3.88(s,3H),3.78–3.70(m,4H),3.30(s,3H),3.03–2.95(m,4H).HRMS(ESI)C 26H 29N 8O 4S +([M+H] +)计算值:549.2032,实测值:549.2035.
实施例78：N-(2-氨基苯基)-4-((3-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)脲基)甲基)苯甲酰胺(化合物I-78)的制备
Figure PCTCN2019120259-appb-000266
将实施例9中得到的酯类中间体按实施例56中描述的制备方法进行转化制备，得化合物I-78。 1H NMR(800MHz,DMSO-d 6)δ10.97(s,1H),9.63(s,1H),7.96(d,J＝7.9Hz,2H),7.44(d,J＝8.1Hz,2H),7.32(s,1H),7.16(d,J＝7.6Hz,1H),7.00–6.93(m,1H),6.88(d,J＝8.5Hz,1H),6.81(d,J＝8.5Hz,1H),6.79–6.76(m,1H),6.59(t,J＝7.4Hz,1H),4.88(s,2H),4.43(d,J＝5.7Hz,2H),3.85(s,3H),3.79–3.72(m,4H),3.04–2.94(m,4H).HRMS(ESI)C 27H 29N 6O 4S +([M+H] +)计算值:533.1971,实测值:533.1968.
实施例79：N-(2-氨基苯基)-4-(2-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯甲酰胺(化合物I-79)的制备
Figure PCTCN2019120259-appb-000267
将实施例37中得到的酯类中间体按实施例56中描述的制备方法进行转化制备，得化合物I-79。 1H NMR(800MHz,DMSO-d 6)δ12.79(s,1H),9.63(s,1H),7.96(d,J＝8.1Hz,2H),7.48(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.98–6.95(m,1H),6.94(d,J＝8.5Hz,1H),6.90(d,J＝8.5Hz,1H),6.79–6.75(m,1H),6.59(t,J＝7.3Hz,1H),4.89(s,2H),3.91(s,2H),3.88(s,3H),3.77–3.73(m,4H),3.02–2.97(m,4H).HRMS(ESI)C 27H 28N 5O 4S +([M+H] +)计算值:518.1862,实测值:518.1873.
实施例80：N-(2-氨基苯基)-4-(4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基)-4-氧代丁基)苯甲酰胺(化合物I-80)的制备
Figure PCTCN2019120259-appb-000268
将实施例39中得到的酯类中间体按实施例56中描述的制备方法进行转化制备，得化合物I-80。 1H NMR(800MHz,DMSO-d 6)δ12.46(s,1H),9.60(s,1H),7.92(d,J＝8.0Hz,2H),7.36(d,J＝8.1Hz,2H),7.16(d,J＝7.7Hz,1H),6.98–6.95(m,1H),6.93(d,J＝8.5Hz,1H),6.90(d,J＝8.4Hz,1H),6.79–6.76(m,1H),6.59(t,J＝7.0Hz,1H),4.88(s,2H),3.87(s,3H),3.79–3.77(m,4H),3.03–3.00(m,4H),2.73–2.69(m,2H),2.53–2.51(m,2H),1.99–1.94(m,2H).HRMS(ESI)C 29H 32N 5O 4S +([M+H] +)计算值:546.2175,实测值:546.2162.
实施例81：N 1-(2-氨基苯基)-N 4-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)对苯二甲酰胺(化合物I-81)的制备
步骤1：4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)苯甲酸甲酯(中间体Int-21)的制备
Figure PCTCN2019120259-appb-000269
将4-(甲氧基羰基)苯甲酸(0.090g,0.50mmol)溶于无水DMF(5mL)中，加入HATU(0.38g，1.0mmol),室温搅拌20分钟，再加入4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-胺(0.132g，0.50mmol)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，得中间体Int-21(0.10g，收率30％)。 1H NMR(800MHz,DMSO-d 6)δ13.24(s,1H),8.27(d,J＝8.4Hz,2H),8.13–8.10(m,2H),6.99(d,J＝8.5Hz,1H),6.96(d,J＝8.4Hz,1H),3.92–3.90(m,6H),3.83–3.79(m,4H),3.08–3.03(m,4H).HRMS(ESI)C 21H 22N 3O 5S +([M+H] +)计算值:428.1280,实测值:428.1271.
步骤2：4-((4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)氨基甲酰基)苯甲酸(中间体Int-22)的制备
Figure PCTCN2019120259-appb-000270
将本实施例步骤1中得到的中间体Int-21(0.10g，0.23mmol)溶于四氢呋喃(10mL)和水(2.5mL)的混合溶液中，加入氢氧化锂(0.028g，1.17mmol)，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，得羧酸中间体Int-
Figure PCTCN2019120259-appb-000271
20粗品，直接用于下一步反应。HRMS(ESI)C 20H 20N 3O 5S +([M+H] +)计算值:414.1124,实测值:414.1125.
步骤3：N 1-(2-氨基苯基)-N 4-(4-甲氧基-7-N-吗啉基苯并[d]噻唑-2-基)对苯二甲酰胺(化合物I-81)的制备
将步骤2得到的全部中间体Int-22与氯化锂的混合物溶于无水DMF(5mL)中，加入 HATU(0.178g，0.46mmol),室温搅拌20分钟，再加入邻苯二胺(0.051g，0.46mmol)及DIPEA(0.09g，0.69mmol)，室温搅拌过夜。反应液加水稀释，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-81(0.047g，收率40％)。 1H NMR(800MHz,DMSO-d 6)δ13.19(s,1H),9.82(s,1H),8.27(d,J＝8.2Hz,2H),8.14(d,J＝8.2Hz,2H),7.19(d,J＝7.3Hz,1H),7.01–6.97(m,2H),6.95(d,J＝8.4Hz,1H),6.79(dd,J＝8.0,1.1Hz,1H),6.61(t,J＝7.1Hz,1H),4.96(s,2H),3.91(s,3H),3.86–3.77(m,4H),3.07–3.03(m,4H).HRMS(ESI)C 26H 26N 5O 4S +([M+H] +)计算值:504.1706,实测值:504.1692.
实施例82：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：
(1)配制实验用缓冲液(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；
(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％)；
(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；
(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；
(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；
(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；
(8)用Synergy MX读取数值(最大激发光：355nm，最大发射光460nm)；
(9)用GraphPad Prism5处理数据，计算IC 50值，结果如表10所示。
表10.化合物对于HDAC1和HDAC6的抑制活性。
Figure PCTCN2019120259-appb-000272
Figure PCTCN2019120259-appb-000273
Figure PCTCN2019120259-appb-000274
表10显示出化合物56、76-81对HDAC1具有较好的选择性。由此也可以分析得出，ZBG为
Figure PCTCN2019120259-appb-000275
能够使化合物具有较佳的HDAC1选择性。
实施例83：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竞争结合实验来进行测定。具体操作方法如下：
(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；
(2)用Echo将不同浓度的待测化合物转移到384孔板上，每孔50nL；
(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；
(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；
(5)向每孔中加入30μL A2a细胞膜/SPA珠的混悬液，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；
(6)用Microbeta 2(Perkin Elmer)读取CPM值；
(7)用GraphPad Prism 5处理数据，计算IC 50值，结果如表11所示。
表11 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
Figure PCTCN2019120259-appb-000276
Figure PCTCN2019120259-appb-000277
实施例84：本发明化合物对A2A受体功能的抑制活性测定。化合物对人源A2A受体功能的抑制活性采用基于HTRF的cAMP实验(Perkin Elmer)来进行测定。具体操作方法如下：
(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；
(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；
(3)加入8mL溶液(DMEM+10％FBS+G418)终止消化，吹打混匀，1000rmp离心4分钟；
(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；
(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以10μM为起始浓度，3倍梯度稀释，10个浓度点；激动剂NECA配制成150μM浓度；
(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；
(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；
(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；
(9)用EnVision(Perkin Elmer)读取cAMP水平(最大激发光：320nm，最大发射光615/665nm)；
(10)用GraphPad Prism处理数据，计算IC 50值，结果如表12所示。
表12 化合物拮抗A2A受体的cAMP实验结果。
Figure PCTCN2019120259-appb-000278
实施例85：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。
(1)细胞铺板
a.配制完全培养基,充分混匀。
b.选择生长状态良好的细胞株。
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。
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。
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。
f.使用Vi-Cell XR细胞计数仪计数，将细胞悬液调至合适浓度。
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。
(2)细胞实验:
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。
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。
c.在倒置显微镜下观察细胞形态。
d.将细胞培养板放置室温中平衡30分钟，每孔加入25μL CTG，而后在振板机上混匀10分钟，诱导细胞溶解。
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Flexstation 3读板(相关设置为：发光,整合时间500ms)。
f.记录分析所得的实验结果，结果如表13所示。
表13 化合物抑制肿瘤细胞增殖的实验结果。
Figure PCTCN2019120259-appb-000279
Figure PCTCN2019120259-appb-000280
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。

Claims (17)

  1. 一种如式I所示的化合物：
    Figure PCTCN2019120259-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；
    其中，R 1为氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、-NR 6R 7、取代或未取代的C 3-C 10环烷基、取代或未取代的3-10元杂环烷基、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 3-C 10环烷基、取代的3-10元杂环烷基、取代的C 6-C 12芳基或取代的5-12元杂芳基中的取代基各自独立地为C 1-C 6烷基或C 1-C 6烷氧基，取代基的个数为一个或多个，当取代基的个数为多个时，所述的取代基相同或不同；
    R 2为氢、卤素或C 1-C 6烷基；
    R 3为氢、C 1-C 6烷基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)；
    R 4为氢或C 1-C 6烷基；
    R 6和R 7各自独立地为氢或C 1-C 6烷基；
    X为N或CR 5；
    R 5为氢、卤素或C 1-C 6烷基；
    如式I所示的化合物中的
    Figure PCTCN2019120259-appb-100002
    为
    Figure PCTCN2019120259-appb-100003
    L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
    -M 1-(M 2) m-(M 3) n-满足如下情形(i)、(ii)、(iii)、(iv)、(v)或(vi)：
    (i)m为0，且n为0，M 1为-NH-、-O-、-S-、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、具有3-10个链原子的亚杂炔基、3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    (ii)m为1，且n为0，M 1为-NH-、-O-、-S-、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、3-10元亚环烷基、3-10元亚杂环烷基或C 6-C 12亚芳基；
    M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    (iii)m为1，且n为0，M 1为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    M 2为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或具有2-10个链原子的亚杂烯基；
    (iv)m为1，且n为1，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基、C 2-C 4亚烯基、C 2-C 4亚炔基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；
    M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    M 3为C 1-C 4亚烷基、C 2-C 4亚烯基、C 2-C 4亚炔基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；
    (v)m为1，且n为1，M 1为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    M 2为-NH-、-O-、-S-、C 1-C 4亚烷基或具有2、3或4个链原子的亚杂烷基；
    M 3为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    (vi)m为1，且n为1，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基、C 2-C 4亚烯基、C 2-C 4亚炔基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；
    M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    M 3为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    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，所述的杂原子的个数各自独立地为1、2、3或4个；
    每个R 20独立地为氧代、硫代、卤素、氰基、羟基、氨基、硝基、C 1-C 6烷基、C 2-C 6烯基、C 1-C 6卤代烷基、C 1-C 6杂烷基、C 2-C 6杂烯基、C 2-C 6炔基、C 3-C 6杂炔基、C 3-C 10环烷基、3-10元杂环烷基、C 6-C 12芳基、5-12元杂芳基、-(C 1-C 3亚烷基)-(C 3-C 10环烷基)、-(C 1-C 3亚烷基)-(3-10元杂环烷基)、-(C 1-C 3亚烷基)-(C 6-C 12芳基)、-(C 1-C 3亚烷基)-(5-12元杂芳基)、-NR 41R 42、-OR 41、-SR 41、-C(＝O)O-R 41、-C(＝O)-NR 41R 42、-N(R 42)-C(＝O)-R 41、-O-C(＝O)-R 41、-S(O) 2-R 41、-O-S(O) 2-R 41、-S(O) 2-OR 41、-S(O) 2-NR 41R 42或-N(R 41)-S(O) 2-R 42；
    每个R 41或R 42各自独立地为氢或C 1-C 6烷基；
    ZBG为
    Figure PCTCN2019120259-appb-100004
    每个R 8独立地为卤素、C 1-C 6烷基、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；y为0、1、2、3或4；
    R 9为氢或C 1-C 6烷基；
    所述的杂烷基、杂烯基、杂炔基、杂环烷基和杂芳基中的杂原子各自独立地为氮、氧或硫，所述的杂原子的个数各自独立地为1、2、3或4个。
  2. 如权利要求1所述的如式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C 1-C 6烷基、C 1-C 6卤代烷基中的C 1-C 6烷基和C 1-C 6烷氧基中的C 1-C 6烷基各自独立地为C 1-C 4烷基；
    和/或，所述的C 2-C 6烯基各自独立地为C 2-C 4烯基；
    和/或，所述的C 3-C 10环烷基和-(C 1-C 3亚烷基)-(C 3-C 10环烷基)中的C 3-C 10环烷基各自独立地为C 3-C 8环烷基；
    和/或，所述的3-10元杂环烷基和-(C 1-C 3亚烷基)-(3-10元杂环烷基)中的3-10元杂环烷基各自独立地为3、4、5、6、7或8元杂环烷基；
    和/或，所述的C 6-C 12芳基和-(C 1-C 3亚烷基)-(C 6-C 12芳基)中的C 6-C 12芳基各自独立地为苯基；
    和/或，所述的5-12元杂芳基和-(C 1-C 3亚烷基)-(5-12元杂芳基)中的5-12元杂芳基各自独立地为5、6或7元杂芳基；
    和/或，所述的3-10元亚环烷基各自独立地为3、4、5、6、7或8元亚环烷基；
    和/或，所述的3-10元亚杂环烷基各自独立地为3、4、5、6、7或8元亚杂环烷基；
    和/或，所述的C 6-C 12亚芳基各自独立地为亚苯基；
    和/或，所述的5-12元亚杂芳基各自独立地为5、6或7元亚杂芳基。
  3. 如权利要求1或2所述的如式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为取代或未取代的C 3-C 10环烷基时，所述的C 3-C 10环烷基为环己基；
    和/或，当R 1为取代或未取代的3-10元杂环烷基时，所述的3-10元杂环烷基为
    Figure PCTCN2019120259-appb-100005
    U为CH或N，R 10、R 11和U相连共同形成5、6、7或8元杂环烷基；
    和/或，当R 1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；
    和/或，当R 1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6元杂芳基；
    和/或，当R 3为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、正丙基或异丙基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 2-C 7亚炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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3-7个链原子的亚杂炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为3-10元亚环烷基时，所述的3-10元亚环烷基为3-7元亚环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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 6亚烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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 6亚烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 2-C 6亚炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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2-5个链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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2-5个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为3-10元亚环烷基时，所述的为3-10元亚环烷基为亚环丁基、亚环戊基、亚环己基或亚螺[3,3]庚基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)、1,4-(6元亚杂环烷基)或2,6-(亚杂螺[3,3]庚基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2为3-10元亚环烷基时，所述的3-10元亚环烷基为亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1为5-12元亚杂芳基时，所述的5-12元亚杂芳基为5或6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 1-C 10亚烷基时，所述的C 1-C 10亚烷基为C 1-C 6亚烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 2-C 10亚烯基时，所述的C 2-C 10亚烯基为C 2-C 6亚烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 2-C 6亚炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2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2-5个链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2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2-5个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 1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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 1为C 2-C 4亚烯基时，所述的C 2-C 4亚烯基为亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 1为C 2-C 4亚炔基时，所述的C 2-C 4亚炔基为亚乙炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 1为具有2、3或4个链原子的亚杂烷基时，所述的“具有2、3或4个链原子的亚杂烷基”为具有个2链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 2为3-10元亚环烷基时，所述的3-10元亚环烷基为亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 2为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 2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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 2为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 3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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 3为C 2-C 4亚烯基时，所述的C 2-C 4亚烯基为亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 3为C 2-C 4亚炔基时，所述的C 2-C 4亚炔基为亚乙炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 3为具有2、3或4个链原子的亚杂烯基 时，所述的“具有2、3或4个链原子的亚杂烯基”为具有2个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1为3-10元亚环烷基时，所述的3-10元亚环烷基为亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 2为C 1-C 4亚烷基时，所述的C 1-C 4亚烷基为亚甲基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为3-10元亚环烷基时，所述的3-10元亚环烷基为5、6或7元亚环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 1为C 1-C 4亚烷基时，所述的C 1-C 4亚烷基为亚甲基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 1为C 2-C 4亚烯基时，所述的C 2-C 4亚烯基为亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 1为C 2-C 4亚炔基时，所述的C 2-C 4亚炔基为亚乙炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 1为具有2、3或4个链原子的亚杂烷基时，所述的“具有2、3或4个链原子的亚杂烷基”为具有2个链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2为3-10元亚环烷基时，所述的3-10元亚环烷基为亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 3为3-10元亚环烷基时，所述的3-10元亚环烷基为亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 3为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，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；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为6元亚杂芳基；
    和/或，当R 20为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、正丙基、异丙基或正丁基；
    和/或，当R 20为C 2-C 6烯基时，所述的C 2-C 6烯基为
    Figure PCTCN2019120259-appb-100006
    和/或，当R 20为C 3-C 10环烷基时，所述的C 3-C 10环烷基为环丙基；
    和/或，当R 20为-(C 1-C 3亚烷基)-(3-10元杂环烷基)时，所述的-(C 1-C 3亚烷基)-(3-10元杂环烷基)为
    Figure PCTCN2019120259-appb-100007
    和/或，当R 8独立地为卤素时，所述的卤素为氟；
    和/或，当R 8独立地为5-12元杂芳基时，所述的5-12元杂芳基为噻吩基；
    和/或，当R 9为C 1-C 6烷基时，所述的C 1-C 6烷基为正丙基。
  4. 如权利要求1-3中任一项所述的如式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为取代或未取代的3-10元杂环烷基时，所述的3-10元杂环烷基为
    Figure PCTCN2019120259-appb-100008
    每个U独立地为CH或N，每个U 1独立地为O、S或CH 2，p为1或2；
    和/或，当R 3为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基或乙基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为C 1-C 10亚烷基时，所述的C 1-C 10亚烷基为C 4、C 5、C 6或C 7亚烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为C 2-C 10亚烯基时，所述的C 2-C 10亚烯基为C 4、C 5、C 6或C 7亚烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 4、C 5、C 6或C 7亚炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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4、5、6或7个链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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4、5、6或7个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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4、5、6或7个链原子的亚杂炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为6元亚杂环烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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 2、C 3或C 4亚烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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 3或C 4亚烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 2、C 3或C 4亚炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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、3或4个链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，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、3或4个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为3-10元亚环烷基时，所述的3-10元 亚环烷基为
    Figure PCTCN2019120259-appb-100009
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为
    Figure PCTCN2019120259-appb-100010
    Figure PCTCN2019120259-appb-100011
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 1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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为
    Figure PCTCN2019120259-appb-100012
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1为5-12元亚杂芳基时，所述的5-12元亚杂芳基为1,3-(5元亚杂芳基)或1,4-(6元亚杂芳基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 1-C 10亚烷基时，所述的C 1-C 10亚烷基为C 1、C 2、C 3或C 4亚烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 2-C 10亚烯基时，所述的C 2-C 10亚烯基为C 2、C 3或C 4亚烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 2-C 10亚炔基时，所述的C 2-C 10亚炔基为C 2、C 3或C 4亚炔基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2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、3或4个链原子的亚杂烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2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、3或4个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 1为C 2-C 4亚烯基时，所述的C 2-C 4亚烯 基为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 1为具有2、3或4个链原子的亚杂烷基时，所述的“具有2、3或4个链原子的亚杂烷基”为
    Figure PCTCN2019120259-appb-100013
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 2为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 2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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 3为C 2-C 4亚烯基时，所述的C 2-C 4亚烯基为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)，M 3为具有2、3或4个链原子的亚杂烯基时，所述的“具有2、3或4个链原子的亚杂烯基”为具有2个链原子的亚杂烯基，其中双键为反式构型；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 1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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为3-10元亚环烷基时，所述的3-10元亚环烷基为亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 1为“具有2、3或4个链原子的亚杂烷基”时，所述的具有2、3或4个链原子的亚杂烷基为
    Figure PCTCN2019120259-appb-100014
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2为3-10元亚杂环烷基时，所述的3-10 元亚杂环烷基为1,4-(6元亚杂环烷基)或
    Figure PCTCN2019120259-appb-100015
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2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)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 3为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 3为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，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)；
    和/或，当R 8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。
  5. 如权利要求1-4中任一项所述的如式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为取代或未取代的3-10元杂环烷基时，所述的3-10元杂环烷基为
    Figure PCTCN2019120259-appb-100016
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，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
    Figure PCTCN2019120259-appb-100017
    Figure PCTCN2019120259-appb-100018
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(i)，M 1为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为
    Figure PCTCN2019120259-appb-100019
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2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
    Figure PCTCN2019120259-appb-100020
    Figure PCTCN2019120259-appb-100021
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)，M 2为5-12元亚杂芳基时，所述的5-12元 亚杂芳基为
    Figure PCTCN2019120259-appb-100022
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 1为5-12元亚杂芳基时，所述的5-12元亚杂芳基为
    Figure PCTCN2019120259-appb-100023
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2为C 2-C 10亚烯基时，所述的C 2-C 10亚烯基为亚乙烯基，优选为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)，M 2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
    Figure PCTCN2019120259-appb-100024
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为3-10元亚环烷基时，所述的3-10元亚环烷基为1,4-亚环己基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为
    Figure PCTCN2019120259-appb-100025
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 2为3-10元亚杂环烷基时，所述的3-10元亚杂环烷基为
    Figure PCTCN2019120259-appb-100026
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)，M 3为5-12元亚杂芳基时，所述的5-12元亚杂芳基为
    Figure PCTCN2019120259-appb-100027
  6. 如权利要求1-5中任一项所述的如式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-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为C 1-C 10亚烷基、具有2-10个链原子的亚杂烷基、3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1-C 10亚烷基、具有2-10个链原子的亚杂烷基、3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或 5-12元亚杂芳基，M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，M 1为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基，M 2为C 1-C 10亚烷基、C 2-C 10亚烯基、具有2-10个链原子的亚杂烷基或具有2-10个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基、C 2-C 4亚烯基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 3为C 1-C 4亚烷基、C 2-C 4亚烯基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，M 1为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 2为-NH-、-O-、-S-或亚甲基；M 3为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，M 1为-NH-、-O-、-S-或亚甲基；M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 3为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，R 1为取代的或未取代的C 3-C 10环烷基、取代的或未取代的
    Figure PCTCN2019120259-appb-100028
    取代的或未取代的C 6-C 12芳基或取代的或未取代的5-12元杂芳基，U为CH或N，R 10、R 11和U相连共同形成5、6、7或8元杂环烷基；取代基的个数为一个或多个，每个取代基独立地为C 1-C 6烷基；
    和/或，R 20为氧代、硫代、卤素、羟基、C 1-C 6烷基、C 2-C 6烯基、C 1-C 6杂烷基、C 3-C 10环烷基、3-10元杂环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
  7. 如权利要求1-6中任一项所述的如式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-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为C 4、C 5、C 6或C 7亚烷基、具有4、5、6或7个链原子的亚杂烷基、1,4-亚环己基、1,4-亚苯基、1,4-(6元亚杂芳基)或1,4-(6元亚杂环烷基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1-C 10亚烷基、具有2-10个链原子的亚杂烷基、3-10元亚环烷基或3-10元亚杂环烷基，M 2为C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，M 1为3-10元亚环烷基或3-10元亚杂环烷基，M 2为C 3亚烷基或具有3个链原子的亚杂烷基；或者，M 1为C 6-C 12亚芳基或5-12元亚杂芳基，M 2为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，M 1为-NH-、-O-、-S-、C 1-C 4亚烷基、C 2-C 4亚烯基、具有2、3或4个链原子的亚杂烷基或具有2、3或4个链原子的亚杂烯基；M 2为3-10元亚环烷基、3-10元亚杂环烷基、C 6-C 12亚芳基或5-12元亚杂芳基；M 3为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，M 1为3-10元亚环烷基或3-10元亚杂环烷基；M 2为-NH-、-O-、-S-或亚甲基；M 3为C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，M 1为-NH-、-O-、-S-或亚甲基；M 2为3-10元亚环烷基或3-10元亚杂环烷基；M 3为C 6-C 12亚芳基或5-12元亚杂芳基；
    和/或，R 1为取代或未取代的
    Figure PCTCN2019120259-appb-100029
    取代或未取代的
    Figure PCTCN2019120259-appb-100030
    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，每个U独立地为CH或N，每个U 1独立地为O、S或CH 2，p为1或2；取代基的个数为一个或多个，每个取代基独立地为C 1-C 6烷基；
    和/或，每个R 8独立地为卤素、C 6-C 12芳基或5-12元杂芳基；
    和/或，R 3为C 1-C 6烷基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)；
    和/或，R 20为氧代、C 1-C 6烷基、C 2-C 6烯基、C 1-C 6杂烷基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
  8. 如权利要求1-7中任一项所述的如式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-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为
    Figure PCTCN2019120259-appb-100031
    Figure PCTCN2019120259-appb-100032
    W 1为-CH 2-或-NH-；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、或具有2、3或4个链原子的亚杂烷基、
    Figure PCTCN2019120259-appb-100033
    Figure PCTCN2019120259-appb-100034
    1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)、1,4- (6元亚杂环烷基)或2,6-(亚杂螺[3,3]庚基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，M 1为1,4-亚环己基或1,4-(6元亚杂烷基)，M 2为C 3亚烷基或具有3个链原子的亚杂烷基，或者，M 1为1,3-(5元亚杂芳基)，M 2为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，M 1为-NH-、-O-、-S-、亚甲基、亚乙基或具有2个链原子的亚杂烷基；M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；M 3为反式构型的亚乙烯基；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，M 1为1,4-亚环己基或1,4-(6元亚杂环烷基)；M 2为-NH-、-O-、-S-或亚甲基；M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，M 1为-NH-、-O-、-S-或亚甲基，M 2为1,4-亚环己基、1,4-(6元亚杂环烷基)、
    Figure PCTCN2019120259-appb-100035
    M 3为1,4-亚苯基或1,4-(6元亚杂芳基)；
    和/或，R 1为取代或未取代的
    Figure PCTCN2019120259-appb-100036
    或取代或未取代的
    Figure PCTCN2019120259-appb-100037
    U为N，每个U 1独立地为O、S或CH 2，p为1或2；取代基的个数为一个或多个，每个取代基独立地为C 1-C 6烷基；
    和/或，每个R 8独立地为氟或噻吩-2-基；
    和/或，R 3为C 1-C 6烷基；
    和/或，当-M 1-(M 2) m-(M 3) n-指被一个或多个R 20取代时，R 20的个数为1、2、3、4、5、6或7个；
    和/或，R 20为C 1-C 6烷基、C 2-C 6烯基、C 3-C 10环烷基或-(C 1-C 3亚烷基)-(C 3-C 10环烷基)。
  9. 如权利要求1-8中任一项所述的如式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-M 1-(M 2) m-(M 3) n-满足情形(i)时，M 1为
    Figure PCTCN2019120259-appb-100038
    Figure PCTCN2019120259-appb-100039
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，-M 1-M 2-为
    Figure PCTCN2019120259-appb-100040
    Figure PCTCN2019120259-appb-100041
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，-M 1-M 2-为
    Figure PCTCN2019120259-appb-100042
    Figure PCTCN2019120259-appb-100043
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，-M 1-M 2-M 3-为
    Figure PCTCN2019120259-appb-100044
    Figure PCTCN2019120259-appb-100045
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，-M 1-M 2-M 3-为
    Figure PCTCN2019120259-appb-100046
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，-M 1-M 2-M 3-为
    Figure PCTCN2019120259-appb-100047
    Figure PCTCN2019120259-appb-100048
    和/或，R 1为
    Figure PCTCN2019120259-appb-100049
    和/或，ZBG为
    Figure PCTCN2019120259-appb-100050
    和/或，X为CH或N；
    和/或，R 3为甲基或乙基；
    和/或，当-M 1-(M 2) m-(M 3) n-被一个或多个R 20取代时，R 20的个数为1、2或3个；
    和/或，R 20为甲基、乙基、正丙基、异丙基、正丁基、
    Figure PCTCN2019120259-appb-100051
    环丙基或
    Figure PCTCN2019120259-appb-100052
  10. 如权利要求1-9中任一项所述的如式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-M 1-(M 2) m-(M 3) n-满足情形(i)时，L为
    Figure PCTCN2019120259-appb-100053
    Figure PCTCN2019120259-appb-100054
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(ii)时，L为
    Figure PCTCN2019120259-appb-100055
    Figure PCTCN2019120259-appb-100056
    Figure PCTCN2019120259-appb-100057
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iii)时，L为
    Figure PCTCN2019120259-appb-100058
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(iv)时，L为
    Figure PCTCN2019120259-appb-100059
    Figure PCTCN2019120259-appb-100060
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(v)时，L为
    Figure PCTCN2019120259-appb-100061
    和/或，当-M 1-(M 2) m-(M 3) n-满足情形(vi)时，L为
    Figure PCTCN2019120259-appb-100062
    Figure PCTCN2019120259-appb-100063
    和/或，
    Figure PCTCN2019120259-appb-100064
    为
    Figure PCTCN2019120259-appb-100065
    和/或，R 1为
    Figure PCTCN2019120259-appb-100066
    和/或，ZBG为
    Figure PCTCN2019120259-appb-100067
    和/或，X为CH；
    和/或，R 2为氢；
    和/或，R 3为甲基；
    和/或，R 4为氢；
    和/或，所述的同位素衍生物为氘代物。
  11. 如权利要求1中所述的如式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所示的化合物选自如下方案(1)或(2)：
    方案(1)
    Figure PCTCN2019120259-appb-100068
    其中L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
    -M 1-(M 2) m-(M 3) n-满足如下情形(i)或(ii)：
    (i)m为0，且n为0，M 1为C 4、C 5、C 6或C 7亚烷基、或具有4、5、6或7个链原子的亚杂烷基；
    (ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、C 4亚烷基、具有2、3或4个链原子的亚杂烷基、
    Figure PCTCN2019120259-appb-100069
    1,3-(4元亚杂环烷基)、1,3-(5元亚杂环烷基)或1,4-(6元亚杂环烷基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
    R 1、R 2、R 3、R 4、R 20和X的定义如权利要求1-10中任一项所述；
    方案(2)
    Figure PCTCN2019120259-appb-100070
    L为取代或未取代的-M 1-(M 2) m-(M 3) n-；所述的取代的-M 1-(M 2) m-(M 3) n-是指被一个或多个R 20取代；当R 20的个数为多个时，R 20相同或不同；
    -M 1-(M 2) m-(M 3) n-满足如下情形(i)或(ii)：
    (i)m为0，且n为0，M 1为1,4-亚苯基或1,4-(6元亚杂芳基)；
    (ii)m为1，且n为0，M 1为-NH-、-O-、-S-、C 1亚烷基、C 2亚烷基、C 3亚烷基、或具有2或3个链原子的亚杂烷基、
    Figure PCTCN2019120259-appb-100071
    或1,4-(6元亚杂环烷基)，M 2为1,4-亚苯基或1,4-(6元亚杂芳基)；
    R 1、R 2、R 3、R 4、R 20和X的定义如权利要求1-10中任一项所述。
  12. 如权利要求1所述的如式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所示的化合物选自以下任一结构：
    Figure PCTCN2019120259-appb-100072
    Figure PCTCN2019120259-appb-100073
    Figure PCTCN2019120259-appb-100074
    Figure PCTCN2019120259-appb-100075
    Figure PCTCN2019120259-appb-100076
  13. 一种如权利要求1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：
    方案一
    Figure PCTCN2019120259-appb-100077
    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 PCTCN2019120259-appb-100078
    R 1、R 2、R 3、R 4、X、
    Figure PCTCN2019120259-appb-100079
    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；
    方案二
    Figure PCTCN2019120259-appb-100080
    方案二包括如下步骤：在有机溶剂中，将如式IV所示的化合物在酸存在的条件下进行反应得到如式I所示的化合物即可；其中，ZBG为
    Figure PCTCN2019120259-appb-100081
    R 1、R 2、R 3、R 4、X、
    Figure PCTCN2019120259-appb-100082
    和L的定义如权利要求1-12中任一项所述；
    方案三
    Figure PCTCN2019120259-appb-100083
    方案三包括如下步骤：在有机溶剂中，将如式III所示的化合物与
    Figure PCTCN2019120259-appb-100084
    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 PCTCN2019120259-appb-100085
    R 1、R 2、R 3、R 4、R 8、X、
    Figure PCTCN2019120259-appb-100086
    y和L的定义如权利要求1-12中任一项所述；
    方案四
    Figure PCTCN2019120259-appb-100087
    方案四包括如下步骤：在有机溶剂中，将如式III所示的化合物与
    Figure PCTCN2019120259-appb-100088
    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 PCTCN2019120259-appb-100089
    R 1、R 2、R 3、R 4、R 9、X、
    Figure PCTCN2019120259-appb-100090
    和L的定义如权利要求1-12中任一项所述；
    方案五
    Figure PCTCN2019120259-appb-100091
    方案五包括如下步骤：在有机溶剂中，将如式V所示的化合物进行还原反应，得到如式I所示的化合物即可；其中，ZBG为
    Figure PCTCN2019120259-appb-100092
    R 1、R 2、R 3、R 4、R 9、X、
    Figure PCTCN2019120259-appb-100093
    和L的定义如权利要求1-12中任一项所述，并且R 9不为氢。
  14. 一种化合物，其为如下任一结构：
    Figure PCTCN2019120259-appb-100094
    其中，R 1、R 2、R 3、R 4、X、L和
    Figure PCTCN2019120259-appb-100095
    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。
  15. 一种药物组合物，其包含治疗有效量的如权利要求1-12中任一项所述的如式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。
  16. 一种如权利要求1-12中任一项所述的如式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15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。
  17. 如权利要求16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。
PCT/CN2019/120259 2018-11-22 2019-11-22 噻唑并环类化合物、其制备方法、中间体和应用 WO2020103930A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811398327 2018-11-22
CN201811398327.3 2018-11-22

Publications (1)

Publication Number Publication Date
WO2020103930A1 true WO2020103930A1 (zh) 2020-05-28

Family

ID=70774297

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/120259 WO2020103930A1 (zh) 2018-11-22 2019-11-22 噻唑并环类化合物、其制备方法、中间体和应用

Country Status (2)

Country Link
CN (1) CN111205244B (zh)
WO (1) WO2020103930A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1596112A (zh) * 2001-11-29 2005-03-16 弗·哈夫曼-拉罗切有限公司 苯并噻唑衍生物
CN1617722A (zh) * 2001-11-19 2005-05-18 弗·哈夫曼-拉罗切有限公司 烟碱或异烟碱苯并噻唑衍生物
CN1871244A (zh) * 2003-09-19 2006-11-29 弗·哈夫曼-拉罗切有限公司 作为腺苷受体配体的噻唑并吡啶衍生物
CN1905881A (zh) * 2003-11-26 2007-01-31 阿托恩药品公司 二胺和亚氨二醋酸异羟肟酸衍生物
CN1997649A (zh) * 2004-03-26 2007-07-11 梅特希尔基因公司 组蛋白脱乙酰基酶的抑制剂

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57149280A (en) * 1981-03-10 1982-09-14 Kyowa Hakko Kogyo Co Ltd Amino acid derivative and its preparation
JPS61289079A (ja) * 1985-06-14 1986-12-19 Chisso Corp マロン酸誘導体
CZ2004535A3 (cs) * 2001-11-09 2005-01-12 Novo Nordisk Health Care Ag Farmaceutický prostředek obsahující polypeptidy faktoru Vlla polypeptidy PAI-1
US6727247B2 (en) * 2001-12-10 2004-04-27 Hoffman-La Roche Inc. Substituted benzothiazole amide derivatives
CN103204827B (zh) * 2012-01-17 2014-12-03 上海科州药物研发有限公司 作为蛋白激酶抑制剂的苯并噻二唑化合物及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1617722A (zh) * 2001-11-19 2005-05-18 弗·哈夫曼-拉罗切有限公司 烟碱或异烟碱苯并噻唑衍生物
CN1596112A (zh) * 2001-11-29 2005-03-16 弗·哈夫曼-拉罗切有限公司 苯并噻唑衍生物
CN1871244A (zh) * 2003-09-19 2006-11-29 弗·哈夫曼-拉罗切有限公司 作为腺苷受体配体的噻唑并吡啶衍生物
CN1905881A (zh) * 2003-11-26 2007-01-31 阿托恩药品公司 二胺和亚氨二醋酸异羟肟酸衍生物
CN1997649A (zh) * 2004-03-26 2007-07-11 梅特希尔基因公司 组蛋白脱乙酰基酶的抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BASU: "Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation", JOURNAL OF MEDICINAL CHEMISTRY, 5 January 2017 (2017-01-05), XP055711198, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN111205244B (zh) 2023-08-18
CN111205244A (zh) 2020-05-29

Similar Documents

Publication Publication Date Title
JP6926189B2 (ja) エストロゲン受容体調節薬
CA2777565C (en) Hematopoietic growth factor mimetic diphenylamine small molecule compounds and their uses
CN113387938B (zh) 一种取代嘧啶类化合物、其制备方法、中间体及应用
WO2020064002A1 (zh) 异吲哚啉类化合物、其制备方法、药物组合物及用途
US20120238588A1 (en) 1H-Pyrrolo[2,3-B]Pyridines
ES2423851T3 (es) Compuesto de aciltiourea o sal del mismo y uso del mismo
CA3133753A1 (en) Novel small molecule inhibitors of tead transcription factors
CA3119526A1 (en) Small molecule degraders of helios and methods of use
TW201718592A (zh) 新穎吡唑并［3,4-d］嘧啶化合物或其鹽
BRPI0610833A2 (pt) derivados de acetileno
JP2012502986A (ja) Ｐ２ｘ３受容体活性のモジュレーター
US9783513B2 (en) STAT3 inhibitors and their anticancer use
WO2020103939A1 (zh) 三唑并环类化合物、其制备方法、中间体和应用
TW201625620A (zh) 作為蛋白去乙醯酶抑制劑及雙蛋白去乙醯酶蛋白激酶抑制劑之雜環氧肟酸及其使用方法
FR3066761A1 (fr) Nouveaux composes inhibiteurs des canaux ioniques
WO2023016540A1 (zh) 脲类多靶点酪氨酸激酶抑制剂及其医药应用
JP2023036991A (ja) Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物、その塩、及びそれらの合成方法
JP2006503875A (ja) 抗痛覚過敏剤として有用なキナゾリノン誘導体
WO2020182159A1 (zh) Jak激酶抑制剂及其制备方法和在医药领域的应用
KR20100135248A (ko) 인돌리논 화합물
WO2020103930A1 (zh) 噻唑并环类化合物、其制备方法、中间体和应用
AU2020255702B2 (en) Quinolyl-containing compound and pharmaceutical composition, and use thereof
JP5663743B2 (ja) モチリン受容体作動活性を有するオキシインドール誘導体
US9688684B2 (en) Substituted tetrazolo[1,5-a]pyrazines as ROR-gamma inhibitors
JP2012519153A5 (zh)

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: 19886866

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: 19886866

Country of ref document: EP

Kind code of ref document: A1