WO2020103939A1 - Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associée - Google Patents

Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associée

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Publication number
WO2020103939A1
WO2020103939A1 PCT/CN2019/120284 CN2019120284W WO2020103939A1 WO 2020103939 A1 WO2020103939 A1 WO 2020103939A1 CN 2019120284 W CN2019120284 W CN 2019120284W WO 2020103939 A1 WO2020103939 A1 WO 2020103939A1
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group
substituted
unsubstituted
alkylene
heteroalkylene
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PCT/CN2019/120284
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Chinese (zh)
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程建军
闫文仲
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上海科技大学
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Publication of WO2020103939A1 publication Critical patent/WO2020103939A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings

Definitions

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

Abstract

La présente invention concerne un composé à cycle triazolo, son procédé de préparation, des intermédiaires de celui-ci et une utilisation associée. En outre, le composé à cycle triazolo selon la présente invention peut avoir simultanément une activité antagoniste du récepteur de l'adénosine A2A et une activité inhibitrice de l'histone désacétylase (HDAC), et peut donc être utilisé pour traiter des maladies telles que des maladies tumorales et des maladies du système nerveux central.
PCT/CN2019/120284 2018-11-22 2019-11-22 Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associée WO2020103939A1 (fr)

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