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WO2019072143A1 - Dérivé de 4-aminopyridine, composition pharmaceutique contenant celui-ci, procédé de préparation associé et utilisation correspondante - Google Patents

Dérivé de 4-aminopyridine, composition pharmaceutique contenant celui-ci, procédé de préparation associé et utilisation correspondante Download PDF

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WO2019072143A1
WO2019072143A1 PCT/CN2018/109300 CN2018109300W WO2019072143A1 WO 2019072143 A1 WO2019072143 A1 WO 2019072143A1 CN 2018109300 W CN2018109300 W CN 2018109300W WO 2019072143 A1 WO2019072143 A1 WO 2019072143A1
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陈寿军
高大新
郭洪利
陈涛
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Shanghai de Novo Pharmatech Co Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
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    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a 4-aminopyridine derivative having an antagonistic action against an A2a receptor, a pharmaceutical composition comprising the derivative and a pharmaceutically acceptable salt thereof, and the derivative and a pharmaceutically acceptable salt thereof.
  • a medicament for the treatment of a disease associated with a disorder of A2a receptor levels.
  • G protein-coupled receptors have long been the most important class of drug targets. More than 30% of prescription drugs have been targeted by GPCR (Congreve, M.; Dias, JM; Marshall, FHStructure-Based DrugDesign for GProtein-Coupled Receptors. 2014, 53, 1-63). Even at a time when biotherapeutics are rapidly evolving, this ratio is maintained. GPCR is widely expressed in vivo. It not only participates in the coordination of intercellular signal communication, but also plays an extremely important role in the regulation of signaling, such as hormones, neurotransmitters and metabolites involved in maintaining homeostasis. Drugs targeting GPCRs are used in the treatment of a variety of diseases, including neurological diseases ( Komatsu, H.
  • Adenylate belongs to the class of steroid nucleotides and can be produced by all metabolically active cells in the body. It exerts its biological action by binding to the adenylate receptor on the surface of the cell membrane.
  • the adenylate receptor belongs to the GPCR superfamily and contains four subtypes A1, A2a, A2b and A3 (Stiles, GL Journal of Biological Chemistry, 1992, 267, 6451). Among them, A1 and A3 subtype receptors mediate inhibition.
  • the G protein signal, A2A and A2B regulates the agonistic G protein signal.
  • A2a is mainly distributed in brain tissue, including nerve and glial cells (where the expression level is highest in striatum and nucleus accumbens, followed by olfactory bulb, hypothalamus and hippocampus) (Rosin, DL; Robeva, A.; Woodard, RL; Guyenet, PG; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).
  • the A2a subtype has important roles in both immune response regulation and neurological regulation.
  • Current tumor immunotherapy focuses on T cell-based cellular immunotherapy and checkpoint inhibitors, both of which show significant tumor rejection in clinical studies (Yang JC, Rosenberg SA: Adoptive T-cell therapy for cancer. AdvImmunol 2016, 130: 279-294).
  • checkpoint inhibitors which induce antigen-specific immune responses by targeting inhibitory signaling receptors such as CTLA-4 and PD-1.
  • inhibitory signaling receptors such as CTLA-4 and PD-1.
  • CTLA-4 and PD-1 inhibitory signaling receptors
  • anti-cancer effects Studies have shown that tumor cells achieve immune evasion through negative regulation of normal immune response signaling pathways.
  • One of the representative negative regulation signals is the activation signal of adenosine A2a receptor caused by adenosine in the tumor microenvironment.
  • the A2a receptor expressed on activated immune cells is a key factor regulating physiological immunosuppressive signals.
  • the immunosuppressive effect induced by adenosine at the site of inflammation indirectly reflects its role in the tumor microenvironment.
  • Hypoxia and adenosine enrichment are two prominent features of tumor microenvironment (TME).
  • TME tumor microenvironment
  • Tumor-associated T cells and natural killer NK cells must overcome the "anoxia-A2a receptor activation" in the tumor microenvironment. This disorder is able to test tumor infiltration and kill tumor cells.
  • A2A receptor signaling drives the expression of FOXP3 transcription factor-mediated gene, which drives CD4+ T cells to differentiate into Treg cell-like phenotypes that express CD39 and CD73, and thus forms an immunosuppressive amplification loop capable of continuously producing adenosine.
  • FOXP3 transcription factor-mediated gene drives CD4+ T cells to differentiate into Treg cell-like phenotypes that express CD39 and CD73, and thus forms an immunosuppressive amplification loop capable of continuously producing adenosine.
  • the process of causing the related inflammatory reaction is rapidly inhibited, further aggravating the immunosuppressive state of the tumor microenvironment. Given the relatively high levels of adenosine in the tumor microenvironment, it is expected that the blocking of A2a receptor activation in a mouse tumor model may significantly enhance the anti-tumor immune response.
  • A2a receptors In addition to participating in the regulation of immune responses, A2a receptors also play an important role in central nervous system diseases.
  • the striatum is the area of the brain that is primarily responsible for motor control. This function is primarily achieved through its control of the dopaminergic nerves originating from the substantia nigra. At the same time, this site is the main area of dopaminergic neurodegeneration in Parkinson's patients.
  • A2a knockout mice also have reduced sensitivity to neurotoxin MPTP-induced motor injury and neurobiochemical changes (Chen, JF; Xu, K.; I Petzer, JP; Steal, R.; Xu) , YH; Beilstein, M.; Sonsalla, PK; Castagnoli, K.; Castagnoli, N., Jr.; Schwarsschild, MA Journal of Neuroscience, 2001, 1 21, RC1 43).
  • the use of the adenylate receptor antagonist theophylline can bring certain benefits to Parkinson's patients.
  • adenosine A2 receptor antagonists may be a new class Drugs used to treat Parkinson's.
  • A2a receptor antagonists may also be used to treat drug addiction.
  • Most drugs that are easy to abuse (such as opium, cocaine, alcohol, etc.) can directly or indirectly affect dopamine nerve signals, especially in the nucleus accumbens, while nerve cells in this region express high levels of adenosine. Acid A2a receptor.
  • A2a receptor antagonism can be expected.
  • Agents may also be suitable for the treatment of ADHD (Clinical Genetics (2000), 58(1), 31-40 and references therein.).
  • A2a receptor antagonists can also be used as potential therapeutic agents for depression.
  • A2a receptor antagonists are shown to induce enhanced animal activity in forced swimming and tail suspension experiments. This positive effect is mediated by dopaminergic nerves and is primarily due to escape behavior rather than stimulation of motor nerves (Neurology (2003), 61 (suppl 6) S82-S87.).
  • A2a receptor antagonists have also been shown to prevent emotional or anxiety responses, so A2a receptor antagonists can also be used as potential drugs for the treatment of anxiety disorders.
  • adenosine A2 receptor antagonists may be used as a new class of drugs for the treatment of a variety of central nervous system diseases, such as: neurodegenerative motor diseases (Parkinson's treatment, Huntington's disease), Alzheimer's disease, Attention deficit hyperactivity disorder, stroke (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635; Fredholm, Annu. Rev. Pharmacol. Toxicol. 2005, 45: 385-412; Behav. Brain Res. 2007, 185: 32-42).
  • A2A antagonists may also have the role of neuroprotective agents, as well as for the treatment of sleep disorders. (Stone TW., Drug Dev. Res. 2001, 52: 323-330; Dunwiddie TV., Ann. Rev. Neurosci. 2001, 24: 31-55).
  • A2a receptor antagonists can be used as a potential therapeutic drug for tumor immunotherapy and various central nervous system diseases.
  • the present invention discloses a series of 4-aminopyridine derivatives as A2a receptor antagonists.
  • the technical problem to be solved by the present invention is to provide a novel 4-aminopyridine derivative, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the 4-aminopyridine derivative of the present invention has a good A2a receptor antagonism and can effectively treat or alleviate related diseases caused by abnormal adenosine A2a receptor levels.
  • the present invention provides a 4-aminopyridine derivative (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • L is a linking bond, -N(R 3 )-C 0-6 alkylene-, -OC 0-6 alkylene-, -S(O) 0-2 -C 0-6 alkylene- , -N(R 3 )-Cy 2 -C 0-6 alkylene-, or -Cy 2 -C 0-6 alkylene-;
  • R 1 is hydrogen, helium or fluorine
  • R 2 is hydrogen or -Cy 3 ;
  • Cy 1 is a phenyl group or a 5-6 membered heteroaryl group; the Cy 1 is unsubstituted or optionally 1 to 3 is selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, decyl, alkyl, cyano, nitro, Substituents for alkoxy, alkylthio, haloalkyl, haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are substituted at any position;
  • Cy 2 is an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; the Cy 2 is unsubstituted or optionally 1 to 3 selected from the group consisting of hydrogen, hydrazine, halogen, hydroxy, decyl, alkyl, Cyano, nitro, alkylthio, haloalkyl, haloalkoxy, aminoalkyl, hydroxyalkyl, -OR 4 , -OC(O)R 4 , -OC(O)OR 4 , -OC(O) NR 4 R 4a , -C(O)OR 4 , -C(O)R 4 , -C(O)NR 4 R 4a , -S(O) 0-2 R 4 , -NR 4 R 4a , -NR 4 S(O) 2 R 4a and -S(O) 2 NR 4 R 4a are substituted at any position; or, the Cy
  • Cy 3 is an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group; the Cy 3 is unsubstituted or optionally 1-4 selected from hydrogen, hydrazine, halogen, hydroxy, decyl, cyano, Nitro, alkylthio, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OR 5 , -C(O)R 5 , -C(O)NR 5 R 5a , -S(O) 0-2 R 5 , -NR 5 S( O) 2 R 5a , -S(O) 2 NR 5 R 5a and -NR 5 S(O) 2 NR 5 R 5a is substituted at any position;
  • R 3 is hydrogen or C 1-6 alkyl
  • R 4 and R 4a are each independently hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted a substituted alkyl group; when the cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl group is substituted, optionally 1 to 3 are selected from the group consisting of hydrazine, halogen, hydroxy, decyl, alkyl , cyano, nitro, alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkoxyalkyl, C 3-8 cycloalkyl and The substituent of the 3-8 membered heterocycloalkyl group is substituted at any position; or, R 4 and R 4
  • R 5 and R 5a are each independently hydrogen or a substituted or unsubstituted alkyl group; when the alkyl group is substituted, it may be optionally 1 to 3 selected from the group consisting of hydrazine, halogen, hydroxy, decyl, alkyl, The substituents of the cyano group, the nitro group, the alkylthio group, the haloalkyl group, the haloalkoxy group, the alkoxy group, the C 3-8 cycloalkyl group and the 3-8 membered heterocycloalkyl group are substituted at any position.
  • the R 1 is preferably H.
  • the 5-6 membered heteroaryl group is preferably a substituted or unsubstituted group such as pyridyl, pyridine-2(1H)-one, pyrimidinyl, pyridazinyl, pyridazine -3(2H)-keto, pyrazinyl, 1,3,5-triazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, furyl, thienyl, pyrrolyl 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4 - thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, or tetrazolyl; more preferably substituted or Is a substituted pyrazoly
  • Cy 1 the Cy 1 is preferably unsubstituted.
  • Cy 1 when Cy 1 is substituted, it is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is as defined above.
  • Cy 1 When Cy 1 is substituted, it is preferably 1 to 2 or 1 selected from the group consisting of H, D, F, Cl, -OH, -CN, C 1-3 alkyl, C 1-3 alkoxy, halogen C a substituent of 1-3 alkyl, halo C 1-3 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl substituted at any position;
  • Cy 1 When Cy 1 is substituted, preferably 1 to 2 or 1 is selected from the group consisting of H, D, -OH, F, Cl, C 1-3 alkyl, C 1-3 alkoxy, halogen C 1-3 The substituent of the alkyl group and the halogenated C 1-3 alkoxy group is substituted at any position;
  • Cy 1 When Cy 1 is substituted, it is more preferably substituted at any position by 1 to 2 or 1 substituent selected from H, F, Cl and methyl.
  • the L is preferably a linkage, -S(O) 0-2 -C 0-3 alkylene-, -NH-C 0-3 alkylene-, -NH-Cy 2 -, or -Cy 2 - .
  • L is -Cy 2 -.
  • the Cy 2 is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted C 3-8 cycloalkyl group, or a substituted or unsubstituted group. 3-8 membered heterocycloalkyl;
  • the Cy 2 is more preferably a 5-6 membered heteroaryl ring, and the 5-6 membered heteroaryl group is preferably a substituted or unsubstituted group such as pyridyl or pyridine-2 (1H).
  • the 5-6 membered heteroaryl group is more preferably a substituted or unsubstituted pyridyl group
  • the 5-6 membered heteroaryl group is more preferably a substituted or unsubstituted pyrazinyl group
  • the 5-6 membered heteroaryl group is more preferably a substituted or unsubstituted pyrimidinyl group
  • the Cy 2 is more preferably a 3-8 membered heterocycloalkyl group
  • the 3-8 membered heterocycloalkyl group is more preferably a substituted or unsubstituted group such as pyrrolidinyl or piperidin Pyridyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, azacyclobutyl, 2,5-diazabicyclo[2.2.1]heptyl;
  • Cy 2 is preferably unsubstituted
  • the Cy 2 is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is preferably hydrogen, halogen, hydroxy, alkyl, cyano, or alkyl halide.
  • the substituent is preferably hydrogen, halogen, hydroxy, alkyl, cyano, or alkyl halide.
  • 4 and R 4a are as described above.
  • the R 4 is preferably hydrogen, a substituted or unsubstituted C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a 3-8 membered heterocycloalkyl group; the C 1-6 When the alkyl group is substituted, it is preferably substituted with 1 to 2 substituents selected from the group consisting of halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl. position;
  • the R 4a is preferably hydrogen or a substituted or unsubstituted C 1-6 alkyl group; when the C 1-6 alkyl group is substituted, it is preferably 1 or 2 selected from a halogen group, a hydroxyl group, Substituents for alkoxy, haloalkyl, haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are substituted at any position;
  • Cy 2 is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is preferably F, Cl, -NH 2 , -CF 3 , - NHCH 3 , -N(CH 3 ) 2 , -NHC 2 H 5 , -N(CH 3 )(C 2 H 5 ),
  • Cy 2 is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is preferably D, -CH 3 , -OCH 3 , or -OCF. 3 ;
  • Cy 2 is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is preferably -CN or -OCHF 2 .
  • Cy 2 is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is preferably F, Cl, or -CF 3 .
  • Cy 2 is preferably substituted at any position by 1 to 2 or 1 substituent, and the substituent is preferably -OH, or
  • the R 2 is preferably H.
  • the R 2 is preferably -Cy 3 .
  • the Cy 3 is preferably a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted C 3-8 cycloalkyl group, or a substituted or unsubstituted group. Substituted 3-12 membered heterocycloalkyl;
  • the Cy 3 is more preferably a substituted or unsubstituted C 3-8 cycloalkyl group, or a substituted or unsubstituted 3-12 membered heterocycloalkyl group;
  • the 5-6 membered heteroaryl group is preferably a substituted or unsubstituted group such as pyridyl, pyridine-2(1H)-keto, pyrimidinyl, Pyridazinyl, pyridazine-3(2H)-keto, pyrazinyl, 1,3,5-triazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, furyl , thienyl, pyrrolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, or tetrazolyl ;
  • the 3-12 membered heterocycloalkyl group is more preferably a substituted or unsubstituted group such as pyrrolidinyl, piperidinyl, piperazinyl, or Zinyl, morpholinyl, homomorpholinyl, azetidinyl, 2,5-diazabicyclo[2.2.1]heptyl;
  • the 3-12 membered heterocycloalkyl group is more preferably a substituted or unsubstituted group such as 5-azaspiro[2.4]heptyl or 6- Azaspiro[3.4]octyl;
  • the 3-12 membered heterocycloalkyl group is more preferably a substituted or unsubstituted group of any one of the following groups: 1-oxa-6-azaspiro[3.4]octyl Or 2-oxa-6-azaspiro[3.4]octyl;
  • the 3-12 membered heterocycloalkyl group is more preferably a substituted or unsubstituted group of any one of the following: a thiazolidinyl group, a 1,1-dithiazolidine group;
  • the 3-12 membered heterocycloalkyl group is more preferably a substituted or unsubstituted group of any one of the following groups: 1-oxa-7-azaspiro[4.4] ⁇ Base, 2-oxa-7-azaspiro[4.4]fluorenyl, 1-oxythiazolidinyl;
  • the C 3-8 cycloalkyl group is more preferably a substituted or unsubstituted group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. ;
  • the C 3-8 cycloalkyl group is more preferably a substituted or unsubstituted group such as a cyclopentenyl group or a cyclohexenyl group;
  • the Cy 3 is preferably unsubstituted
  • the Cy 3 is preferably substituted at any position by 1 to 3, 1 to 2 or 1 substituent, and the substituent is preferably F, Cl, -OH, - CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, aryloxy, substituted or unsubstituted C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; when said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino or C 3-6 cycloalkyl When substituted, the selectivity is 1 to 3, 1 to 2 or 1 selected from -NH 2 , -CN, -OH, D, F, Cl, C 1-3 alkoxy, C 1-3 alkylamine
  • the Cy 3 is more preferably substituted at any position by 1 to 3, 1 to 2 or 1 substituent, and the substituent is more preferably F, Cl or -OH. , substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 1-4 alkoxy, substituted or unsubstituted C 1-4 alkylamino, aryloxy, substituted or unsubstituted C 3 a -6 cycloalkyl group, or a 3-6 membered heterocycloalkyl group; when the C 1-4 alkyl group, the C 1-4 alkoxy group, the C 1-4 alkylamino group or the C 3-6 cycloalkyl group is When substituted, the selectivity is 1 to 3, 1 to 2 or 1 selected from -NH 2 , -OH, D, F, Cl, C 1-3 alkoxy, C 1-3 alkylamino, or halogen Substituents for the C 1-3
  • the 4-aminopyridine derivative (I) is preferably an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, which is a compound of the formula (I-1):
  • Y is N or CR 6 ;
  • X, U, V are each independently CR 6 ;
  • Each R 6 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, decyl, alkyl, cyano, nitro, alkylthio, haloalkyl, haloalkoxy, aminoalkyl, hydroxyalkyl, -OR 4 , -OC(O)R 4 , -OC(O)OR 4 , -OC(O)NR 4 R 4a , -C(O)OR 4 , -C(O)R 4 , -C(O)NR 4 R 4a , -S(O) 0-2 R 4 , -NR 4 R 4a , -NR 4 S(O) 2 R 4a , or -S(O) 2 NR 4 R 4a ;
  • R 1 , R 4 , R 4a , Cy 1 and Cy 3 are as described above.
  • R 1 is H.
  • R 6 is H, D, F, Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -OCHF 2 , or -OH.
  • X is N; Y and U are each CR 6 ; V is N.
  • X is N; Y, U and V are each CR 6 .
  • X, Y, U and V are each independently CR 6 .
  • Cy 1 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
  • Cy 1 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
  • Cy 1 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
  • Cy 3 is selected from any of the following substituted or unsubstituted groups: pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, homomorpholinyl, nitrogen Heterocyclic butyl, 2,5-diazabicyclo[2.2.1]heptyl, 5-azaspiro[2.4]heptyl, or 6-azaspiro[3.4]octyl, 1-oxa-6 - azaspiro[3.4]octyl, 1-oxa-7-azaspiro[4.4]decyl, 2-oxa-7-azaspiro[4.4]decyl, 1-oxathiazolidinyl, or 2-oxa-6-azaspiro[3.4]octyl.
  • Cy 3 when Cy 3 is substituted, it is preferably substituted at any position by one or two substituents selected from D, F, Cl, -OH, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -C(CH 3 ) 2 OH, -CN, phenoxy, Cyclopropyloxy, cyclopropyl, 1-hydroxycyclopropyl, or cyclobutyl.
  • Cy 3 when Cy 3 is substituted, it is preferably substituted at any position by one or two substituents selected from D, F, Cl, -OH, -CH 3 , -OCH 3 , -OCH 2 CH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -C(CH 3 ) 2 OH, -CN, phenoxy, cyclopropyloxy Base, cyclopropyl, 1-hydroxycyclopropyl, cyclobutyl, or morpholin-4-yl.
  • the Cy 3 is more preferably:
  • the carbon atom labeled * is a chiral carbon, and its configuration includes a mixture of R type, S type, or RS configuration.
  • the Cy 3 is more preferably:
  • the 4-aminopyridine derivative (I) is preferably an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, which is a compound of the formula (I-2):
  • R 6 is H, F, Cl, -CN, -CH 3 , -CF 3 , -OCH 3 , -OCF 3 , -OCHF 2 , or -OH.
  • Cy 3 is as described above.
  • the Cy 3 is preferably:
  • the 4-aminopyridine derivative (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the 4-aminopyridine derivative (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the 4-aminopyridine derivative (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the 4-aminopyridine derivative (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the 4-aminopyridine derivative (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the invention further relates to compounds of the formula:
  • R 1 , R 2 , Cy 1 and L are as defined above.
  • the invention also provides a preparation method of the 4-aminopyridine derivative (I), which is any of the following methods:
  • Method 1 in a solvent, a compound of the formula I and a cuprous cyanide are subjected to a substitution reaction to obtain a compound of the formula I,
  • R 1 , R 2 , L and Cy 1 are as defined above.
  • the conditions and steps of the substitution reaction are the conditions and steps of the conventional substitution reaction in the art, and the present invention particularly preferably the following reaction conditions:
  • the solvent is preferably N-methylpyrrolidone or N,N-dimethyl
  • the acetamide the molar ratio of the cuprous cyanide to the compound of the formula II is preferably from 1.5:1 to 3.5:1
  • the reaction temperature is preferably from room temperature to the boiling point of the solvent, and the reaction temperature is more preferably from 120 to 200 ° C;
  • the time is preferably from 0.5 to 2 hours; the reaction is preferably carried out under microwave conditions.
  • Process 2 a compound of the formula IA and a Lev-Cy 2 -R 2 are subjected to a coupling reaction to obtain a compound of the formula I'.
  • Lev is a leaving group; the Lev is preferably a trimethylstannyl group, a borate ester group, or a boron pinacol ester group; when the Cy 2 is a phenyl group, the Lev is preferably a trimethyl group. a stannic group; when the Cy 2 is a 5- to 6-membered heteroaryl group, Lev is preferably a borate group or a boron pinacol ester group; and R 1 , R 2 and Cy 1 are as defined above. .
  • the conditions and steps of the coupling reaction are the conditions and steps of the conventional coupling reaction in the art, and the following reaction conditions are particularly preferred in the present invention:
  • the compound of the formula IA and the Lev-Cy 2 -R 2 are subjected to a Suzuki coupling reaction to obtain a compound of the formula I', wherein the suzuki coupling reaction conditions are in the field.
  • the solvent is preferably 1,4-dioxane
  • the catalytic system is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride/sodium carbonate aqueous solution system
  • reaction temperature Preferably, the room temperature to the solvent reflux, the reaction time is preferably 3 to 24 hours;
  • the compound of the formula IA and the Lev-Cy 2 -R 2 are obtained by a Stille coupling reaction in a solvent to obtain a compound of the formula I', wherein Stille is coupled.
  • the reaction conditions are common reaction conditions in the art, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably bis(triphenylphosphine)palladium dichloride/tris(2-furyl)phosphorus system, and the reaction temperature is preferred.
  • the reaction time is preferably from 3 to 24 hours at room temperature to reflux of the solvent.
  • Process 3 in a solvent, a compound of the formula IB and a B ring or NHR 4 R 4a are subjected to a substitution reaction under a base to obtain a compound of the formula I'.
  • B ring is a substituted or unsubstituted heterocycloalkyl group
  • R 2 is Or -NR 4 R 4a
  • R 1 , Cy 2 and Cy 1 are as defined above.
  • the conditions and steps of the substitution reaction are the conditions and steps of the conventional substitution reaction in the art, and the present invention particularly preferably the following reaction conditions:
  • the solvent is preferably N,N-dimethylacetamide
  • the base Preferably, N,N-diisopropylethylamine
  • the molar ratio of the N,N-diisopropylethylamine to the compound of the formula IB is preferably from 5:1 to 15:1
  • the reaction temperature is preferably from 80 to
  • the reaction time is preferably from 1 to 10 hours at 120 ° C, and the reaction is preferably carried out in a sealed tube.
  • the compound of the formula II can be synthesized by the route shown in the reaction formulas 4 to 6:
  • a compound of the formula II-1 and N-bromosuccinimide are reacted to give a compound of the formula II.
  • the solvent is preferably N,N-dimethylformamide and/or tetrahydrofuran, and the molar ratio of the N-bromosuccinimide to the compound of the formula II-1 is preferably 0.95:1 to 1.05: 1;
  • the reaction temperature is preferably from 0 ° C to room temperature, and the reaction time is preferably from 5 minutes to 5 hours.
  • A is a leaving group such as F, Cl, Br or methylsulfonyl; and R 1 , R 4 , R 4a , X, Y, U, V and Cy 1 are as defined above.
  • Step 1 a compound of the formula II'-1 and N-bromosuccinimide are reacted in a solvent to give a compound of the formula II'-2.
  • the solvent is preferably N,N-dimethylformamide and/or tetrahydrofuran, and the molar ratio of the N-bromosuccinimide to the compound of the formula II'-1 is preferably 0.95:1 to 1.05.
  • the reaction temperature is preferably from 0 ° C to room temperature, and the reaction time is preferably from 5 minutes to 5 hours.
  • Step 2 In a solvent, a compound of the formula II'-2 and NHR 4 R 4a are reacted under a base to give a compound of the formula II'.
  • the solvent is preferably N,N-dimethylacetamide
  • the base is preferably N,N-diisopropylethylamine
  • the molar ratio of the compound shown is preferably from 5:1 to 15:1; the reaction temperature is preferably from 80 to 120 ° C, and the reaction time is preferably from 1 to 48 hours.
  • the B ring is a substituted or unsubstituted heterocycloalkyl group; and R 1 , X, Y, U, V and Cy 1 are as defined above.
  • a compound of the formula II'-2 and a ring B are reacted under a base to give a compound of the formula II".
  • the solvent is preferably N,N-dimethylacetamide, and the base is preferably N.
  • N-diisopropylethylamine the molar ratio of the N,N-diisopropylethylamine and the compound of the formula II'-2 is preferably 5:1 to 15:1;
  • the reaction temperature is preferably 80 to
  • the reaction time is preferably from 1 to 48 hours at 120 °C.
  • the amino group in the compound represented by the formula IA or IB can be first protected with a tert-butoxycarbonyl group (Boc), and the subsequent deprotection reaction can be carried out in the conventional de Boc protection conditions in the art.
  • Boc protection conditions for example, it is carried out in a p-toluenesulfonic acid/methanol system, a dichloromethane/trifluoroacetic acid system, or a saturated hydrogen chloride diethyl ether solution system.
  • the pharmaceutically acceptable salt of the 4-aminopyridine derivative (I) can be synthesized by a general chemical method.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising a 4-aminopyridine derivative (I), an isomer thereof, the former One or more of a drug, a stable isotope derivative, and a pharmaceutically acceptable salt.
  • the active ingredient may also include other therapeutic agents for cancer or central nervous system diseases.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quatern
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • the present invention also provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the use of the pharmaceutical composition for the preparation of an A2aR antagonist.
  • the present invention also provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for treatment or amelioration of A2aR levels Use in a medicament for causing a related disease; the present invention preferably provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a combination thereof Use in the preparation of a medicament for treating or ameliorating a related disease caused by a disorder of A2aR levels; the diseases include tumors and non-neoplastic diseases. Such diseases include, but are not limited to, cancer, central nervous system diseases, and the like.
  • the present invention still further provides the use of the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition for treating cancer, central nervous system
  • a method of systemic disease comprising: administering to a mammal a dose of a compound of formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition.
  • Said mammal preferably a human.
  • the present invention still further provides the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition may be combined with one or A variety of other types of therapeutic agents and/or treatments are used in combination to treat or ameliorate related disorders caused by A2aR levels.
  • the diseases may include cancer, central nervous system diseases, and the like.
  • the present invention preferably uses the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition may be combined with one or more Other types of therapeutic agents and/or therapeutic methods are used in combination to treat and/or ameliorate a disease associated with a disorder caused by A2aR levels, preferably a cancer.
  • the present invention still further provides a combined preparation comprising a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition and other kinds A combination of therapeutic agents and/or therapeutic methods for treating cancer.
  • the other kinds of therapeutic agents may be combined with the compound of the formula (I) to form a single therapeutic dosage form, or respectively Therapeutic dosage form for administration.
  • the other kinds of therapeutic agents and/or treatment methods for treating cancer may include, but are not limited to, tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antibiotics. Metabolic drugs, hormones and hormone analogues, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies (eg, specific kinase inhibitors), immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors And one or more of the radiotherapy.
  • the other kind of therapeutic agent and/or treatment method for treating cancer is preferably an immunotherapeutic agent.
  • the immunotherapeutic agent and/or treatment method may be selected from, but not limited to, anti-tumor vaccines (eg, synthetic peptides, DNA vaccines, and recombinant viruses), oncolytic viruses, immunostimulatory antibodies, novel adjuvants, cells.
  • anti-tumor vaccines eg, synthetic peptides, DNA vaccines, and recombinant viruses
  • oncolytic viruses e.g, immunostimulatory antibodies, novel adjuvants, cells.
  • factor therapy eg, IL2 and GM-CSF
  • CAR-T chimeric antigen receptor T cell therapy
  • small molecule immunomodulators e.g, tumor microenvironment regulators, and anti-angiogenic factors.
  • the immunostimulatory antibodies can include, but are not limited to, 1) protein antagonists that inhibit T cell activity (eg, immunological checkpoint inhibitors): CTLA4 (eg, ipilimumab and tremelimumab), PD-1 (eg, pembrolizumab and nivolumab) , one or more of PD-L1 (eg, durvalumab, avelumab, and atezolizumab), LAG3, and TIM3; 1) protein agonists that stimulate T cell activity: GITR, OX40, OX40L, 4-1BB (CD137), One or more of CD27 and CD40.
  • the small molecule immunomodulatory agents can include, but are not limited to, IDO inhibitors, TDO inhibitors, TLR8 modulators (agonists/partial agonists), STING agonists, and the like.
  • the cancer includes both metastatic and non-metastatic cancers, as well as family hereditary and sporadic cancers, and may also include solid tumors and non-solid tumors.
  • specific examples of the solid tumor may include, but are not limited to, eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma, neuroblastic cells).
  • Tumor may include ovarian cancer, bladder cancer, cervical cancer, testicular cancer, renal cancer (including adenocarcinoma and nephroblastoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal carcinoma, head and neck
  • non-solid tumor may include, but are not limited to, lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma). , non-Hodgkin's lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), one of myeloid-associated leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia) and AIDs-associated leukemia or A variety.
  • lymphocytic leukemia including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma
  • non-Hodgkin's lymphoma T-cell chronic lymphocytic leukemia
  • B-cell chronic lymphocytic leukemia B-cell chronic lymphocytic
  • the central nervous system diseases include, but are not limited to, neurodegenerative sports diseases (Parkinson's treatment, Huntington's disease), Alzheimer's disease, stroke, hyperactivity disorder (ADHD), anxiety, epilepsy, depression One or more of symptoms, schizophrenia, and drug addiction.
  • neurodegenerative sports diseases Parkinson's treatment, Huntington's disease
  • Alzheimer's disease Huntington's disease
  • stroke hyperactivity disorder
  • ADHD hyperactivity disorder
  • anxiety anxiety
  • epilepsy depression
  • depression depression
  • depression One or more of symptoms, schizophrenia, and drug addiction.
  • the term "optionally substituted by one or more groups at any position" means that any one or more of the hydrogen atoms of the one or more atoms specified on the group are designated by The group is substituted, provided that it does not exceed the normal valence of the specified atom, which is a reasonable substitution that is common in the art at any position.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms.
  • Representative examples of the group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl , mercapto, fluorenyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.
  • alkyl group also includes “alkylene”, and the term “alkylene” refers to an alkyl group which may serve as a linking bond to the other two groups; such as -(CH 2 ) q -.
  • the alkylene group may be straight or branched, and examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-.
  • cycloalkyl refers to a monocyclic or polycyclic group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds).
  • “monocyclic cycloalkyl” is preferably a 3-10 membered monocycloalkyl group, more preferably a 3-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged ring”, “fused cycloalkyl” and “spirocycloalkyl”, and representative examples of “bridged ring” include, but are not limited to, borneol, bicyclo [2.2. 1] heptenyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3. 1] nonylalkyl, bicyclo[4.2.1]nonanyl and adamantyl, and the like.
  • Fused cycloalkyl embraces a cycloalkyl ring fused to a phenyl, cycloalkyl, or heteroaryl group, including but not limited to: benzocyclobutene, 2,3-di Hydrogen-1-H-indole, 2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopentyl[B]thiophene, decalin and the like.
  • a monocyclic cycloalkyl or polycyclic cycloalkyl group can be attached to the parent molecule through any carbon atom on the ring.
  • heterocycloalkyl refers to a non-aromatic cyclic group consisting of a carbon atom and a heteroatom consisting of a hetero atom selected from nitrogen, oxygen or sulfur, including one or two double bonds, which is a cyclic group.
  • the group may be a monocyclic or polycyclic group, and in the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may optionally be Oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • Polycycloheterocycloalkyl includes “fused heterocycloalkyl”, “spiroheterocyclyl” and “bridge heterocycloalkyl”.
  • “Fused heterocycloalkyl” includes a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolyl and the like.
  • “Bridge heterocycloalkyl” includes, but is not limited to, 2-azabicyclo[2.2.1]heptyl, 2-oxabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1 ]heptyl, (1S,5S)-9-oxabicyclo[3.3.1]fluorenyl, (1R,5S)-9-azabicyclo[3.3.1]decyl, (1R,5S)-3- Azabicyclo[3.3.1]fluorenyl, (1R,5S)-8-oxabicyclo[3.2.1]octyl, (1R,5S)-3-oxabicyclo[3.2.1]octyl, 1R,5S)-3-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, quinuclidinyl, 2-azabicyclo[2.2.
  • Spiroheterocyclyl means a cyclic structure formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing one carbon atom, and the spiroheterocyclyl group includes, but is not limited to, 5-azaspiro[ 2.5] Octyl, 6-azaspiro[2.5]octyl, 2-azaspiro[4.4]decyl, 5-azaspiro[2.4]heptyl, 2-azaspiro[3.3]heptyl, 6 -azaspiro[3.4]octyl, 1-oxa-6-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any ring atom on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
  • cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
  • heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. Wait.
  • heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-20.
  • a fused ring (and a ring) structure the monocyclic heteroaryl group is preferably a 5-6 membered heteroaryl group; the fused heteroaryl group is preferably a 9-12 membered fused heteroaryl group, more preferably 9-10 A fused bicyclic heteroaryl group.
  • the number of heteroatoms is preferably 1, 2 or 3, including but not limited to: pyridyl, pyrimidinyl, piperazinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl , pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadi Azyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, anthracene Sulfhydryl, isodecyl, benzofuranyl, benzothienyl, benzo[d][1,3]dioxolanyl, benzothiazolyl, benzoxazolyl,
  • arylalkyl refers to an alkyl linkage between the aryl group and the parent core structure.
  • arylalkyl embraces the definition of alkyl and aryl as defined above.
  • heteroarylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heteroarylalkyl embraces the definitions of alkyl and heteroaryl as defined above.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, a heterocycloalkyloxy group.
  • alkoxy includes the definitions of alkyl, heterocycloalkyl, cycloalkyl as defined above; and the alkoxy includes, but is not limited to, -OCH 3 , -OCH 2 CH 3 ,
  • aryloxy refers to an aryl or heteroaryl group having the number of such ring atoms attached through an oxygen bridge, and includes an aryloxy group and a heteroaryloxy group.
  • aryloxy embraces the definitions of alkyl, aryl and heteroaryl as defined above; the aryloxy includes, but is not limited to, phenoxy.
  • alkoxyalkyl refers to an alkyl linkage between the alkoxy group and the parent core structure. These include, but are not limited to, -CH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 CH 2 OCH 3 . Thus, “alkoxyalkyl” embraces the definition of alkyl and alkoxy as defined above.
  • hydroxyalkyl means an alkyl arbitrary one hydrogen atom is substituted with a hydroxyl group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C (CH 3) 2 OH.
  • alkylthio refers to a cyclic or acyclic alkyl group which is bonded to each other through a sulfur atom and a parent molecule, and includes an alkyl fluorenyl group, a cycloalkyl fluorenyl group, and a heterocycloalkyl fluorenyl group.
  • alkylthio embraces the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl embraces the definitions of the above halo and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy includes the definitions of the above halo and alkoxy.
  • amino refers to -NH 2
  • alkylamino refers to the replacement of at least one hydrogen atom on the amino group by an alkyl group, including but not limited to: -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 .
  • aminoalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 .
  • alkylamino and aminoalkyl embrace the definitions of alkyl and amino groups described above.
  • amino alkyl refers to an alkoxy group between and connected to the core structure through an alkyl group, including, but not limited to, -CH 2 CH 2 NHCH 3, -CH 2 CH 2 N (CH 3) 2, -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 .
  • alkylaminoalkyl includes the definitions of the above alkyl and alkylamine groups.
  • nitro refers to -NO 2 .
  • cyano refers to -CN.
  • hydroxy refers to -OH.
  • mercapto refers to -SH.
  • Root temperature as used herein means 15-30 °C.
  • the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
  • prodrug is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
  • “Pharmaceutically acceptable salts” as described herein are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,
  • the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • “isomer” means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention.
  • a compound of the formula I or a salt thereof, in stereoisomeric form is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention.
  • the invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers.
  • the invention includes all combinations and subsets of stereoisomers of all the specific groups defined above.
  • the invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
  • the reagents and starting materials used in the present invention are commercially available.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • the chiral compound or intermediate of the present invention can be separated and analyzed by high performance liquid chromatography.
  • the chiral resolution was performed using preparative high performance liquid chromatography (prep-HPLC) HPLC-Gilson GX-281 Method Station, flow rate: 50 mL/min, and column temperature of 35 °C.
  • the detection wavelength is 214 and / or 254 nM.
  • Chiral column CHIRALPAK IE 20 ⁇ 250 mm, 10 um (Daicel), mobile phase was n-hexane (0.1% diethylamine) / ethanol (0.1% diethylamine) 70 / 30, injection amount: 0.5 mL.
  • Chiral analysis was performed using an analytical high performance liquid chromatography (analytical-HPLC) Agilent 1200 at a flow rate of 1.0 mL/min and a column temperature of 40 °C. The detection wavelength is 214 and / or 254 nM.
  • Chiral column CHIRALPAK IE 4.6 x 100 mm, 5 um (Daicel), mobile phase was n-hexane (0.1% diethylamine) / ethanol (0.1% diethylamine) 70 / 30, injection amount: 8 mL.
  • All of the compounds of the present invention can be separated by high performance liquid chromatography or flash column chromatography.
  • Preparative high performance liquid chromatography was prepared using Shimadzu LC-20 preparative liquid chromatography column: waters xbridge Pre C18, 10 um, 19 mm * 250 mm.
  • Acidic preparation conditions mobile phase A: 0.05% aqueous hydrochloric acid (percentage by volume), mobile phase B: acetonitrile; gradient elution conditions: 25-75% solvent B and 75%-25% solvent A; basic preparation conditions: Mobile phase A: 10 mM aqueous solution of ammonium hydrogencarbonate; mobile phase B: acetonitrile; gradient elution conditions: 30-75% solvent B and 70%-25% solvent A.
  • Flash column chromatography flash system/Cheetah TM
  • Agela Technologies MP200 the separation column used is a normal phase flash columm Silica-CS (80 g), elution system: ethyl acetate / petroleum Ether; reverse phase C-18 column, elution system: 0.1% aqueous ammonium bicarbonate / acetonitrile or 0.1% aqueous trifluoroacetic acid / acetonitrile.
  • the thin layer chromatography is Yantai Xinnuo Chemical Co., Ltd.
  • the coating thickness is 0.2 ⁇ 0.03mm and the specification is 20 ⁇ 20cm.
  • the hydrogen atmosphere means that the reaction apparatus is connected to a hydrogen balloon having a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • Microwave reaction Initiator+Microwave System EU 356006 microwave reactor.
  • Step 1 To a solution of 1-N-Cbz-3-pyrrolidone (1.2 g, 5.47 mmol) in tetrahydrofuran (80 mL) was added cesium chloride (5 g, 29.7 mmol), and the system was cooled under nitrogen to -78 ° C, then Cyclopropylmagnesium bromide (18.6 mL, 18.6 mmol) was slowly added dropwise to the above system. The reaction was slowly warmed to room temperature and stirred for 2 hr. EtOAc was evaporated. The organic phase was washed with brine, dried over anhydrous sodium sulfate Cyclopropyl-3-hydroxypyrrolidine (500 mg, yield: 35%) was a colorless liquid.
  • Step 2 The product of Step 1 (500 mg, 1.91 mmol) was dissolved in THF (20 mL) and then palladium carbon (200 mg, 5%). The reaction system was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the ⁇
  • Step 1 6-Boc-2-oxo-6-azaspiro[3.4]octane (400 mg, 1.78 mmol) was added to methanol (10.0 mL), and sodium borohydride (101 mg, 2.67 mmol), the resulting mixture was stirred at 0 ° C for 0.5 h. The reaction was quenched with EtOAc (EtOAc)EtOAc. 2) Purification afforded 6-Boc-2-hydroxy-6-azaspiro[3.4]octane (380 mg, yield: 94%) as a colorless oil.
  • Step 2 The product of Step 1 (380 mg, 1.67 mmol) was dissolved in dichloromethane (4.0 mL), and THF (4M, 4.0 mL) Stir at room temperature overnight. Direct concentration under reduced pressure gave Intermediate 2 (200 mg, yield: 94%).
  • Step 2 The product from Step 1 (8 g, 34.9 mmol) was dissolved in dichloromethane (20 mL). EtOAc EtOAc. The reaction mixture was stirred at this temperature for 2 hr.
  • Step 1 1,3-dibromobenzene (5.0 g, 21.20 mmol), (R)-3-methoxypyrrolidine (1.85 g, 21.20 mmol), tris(dibenzylideneacetone)dipalladium (0.97 g) , 1.06 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.33 g, 0.53 mmol) and potassium t-butoxide (57 mg, 0.08 mmol) were dispersed in a toluene solution (60 mL). The mixture was refluxed under reduced pressure of EtOAc (EtOAc)EtOAc. Alcohol (1.68 g, yield: 33%) was obtained as a brown oil. m/z: [M+H] + 242.0.
  • the intermediate 5 is obtained by substituting the (R)-3-methoxypyrrolidine in the first step to the intermediate 3 by the synthesis method of the intermediate 4. m/z: [M+H] + 332.2.
  • Step 2 According to the synthesis method of the intermediate 4 step 2, the product of the step 1 is used to obtain the intermediate 7. m/z: [M+H] + 357.2.
  • Step 2 Step 1 product (30.0 mg, 0.12 mmol), hexamethylditin (46 mg, 0.14 mmol) and bistriphenylphosphine palladium dichloride (7.0 mg, 0.01 mmol) were added to 1,4-dioxane. In a six-ring (15 mL), the reaction was stirred at 120 ° C for 3 hours. Concentration under reduced pressure afforded Intermediate 8 (40 mg, 100%) m/z: [M+H] + 345.0.
  • Step 1 2,6-Dibromo-4-aminopyridine (500 mg, 1.98 mmol) and 2-tributylstannylthiazole (1.64 g, 4.36 mmol) were dissolved in 1,4-dioxane (10 mL) Then, bistriphenylphosphine palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ) (140 mg, 0.20 mmol) and tris(2-furyl)phosphorus ligand (TFP) (23 mg, 0.10 mmol) were added. The reaction system was heated to 120 ° C under nitrogen for a night. After the reaction mixture was cooled to room temperature, the mixture was evaporated. mjjjjjjjj , Yield: 97%) as a pale yellow solid. m/z: [M+H] + 261.0.
  • Step 2 The product of Step 1 (500 mg, 0.38 mmol) was added to N,N-dimethylformamide (5.0 mL). N-bromosuccinimide (102 mg, 0.57 mmol) . The reaction was stirred at room temperature overnight.
  • Step 1 2,6-Dibromo-4-aminopyridine (3.5 g, 13.8 mmol), sodium ethoxide (1.28 g, 15.2 mmol), cesium carbonate (6.74 g, 20.7 mmol) was added to dimethyl sulfoxide ( In 30.0 mL), the mixture was stirred at room temperature for 1 hour, and then heated to 80 ° C and stirred overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. 6/1) Purification afforded 2-bromo-6-(ethylthio)pyridin-4-amine (2.90 g, yield: 91%) as pale yellow solid. m/z: [M+H] + 233.0.
  • Step 2 Step 1 product (1 g, 4.31 mmol), 2-(tri-n-butylstannyl)thiazole (1.94 g, 5.17 mmol), Pd(PPh 3 ) 2 Cl 2 (301.8 mg, 0.43 mmol) and TFP ( 50 mg, 0.22 mmol) was dissolved in 1,4-dioxane (15.0 mL). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. mjjjjjjjjjjj 4-amine (680 mg, yield: 67%) was obtained as a pale yellow solid. m/z: [M+H] + 238.0.
  • Step 3 The product of Step 2 (150 mg, 0.63 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (110 mg) was slowly added dropwise to the reaction solution under ice bath. , 0.62 mmol) of a solution of N,N-dimethylformamide (1 mL). After the reaction mixture was stirred at this temperature for 1 hour, the mixture was evaporated, evaporated, evaporated, evaporated. m/z: [M+H] + 316.0.
  • Step 1 Add sodium hydrogen (794 mg, 19.8) to a solution of 2,6-dibromo-4-aminopyridine (2 g, 7.94 mmol) in N,N-dimethylformamide (20 mL). After the addition was completed, stirring was continued at this temperature for 0.5 hour, then 4-methoxybenzyl chloride (2.6 mL, 19.8 mmol) was added and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. Purification afforded 2,6-dibromo-N,N-bis(4-methoxybenzyl)pyridin-4-amine (3.6 g, yield: 92%) as a brown solid. m/z: [M+H] + 493.0.
  • Step 2 Step 1 product (2.16 g, 4.39 mmol), cyclopentylamine (355 mg, 4.17 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (56.0 mg, 0.09 mmol), three (Dibenzylideneacetone) dipalladium (40.0 mg, 0.04 mmol) and sodium tert-butoxide (464.0 mg, 4.83 mmol) were added to dimethyl sulfoxide (20.0 mL) and stirred at 80 ° C overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature.
  • Step 3 Step 2 product (1.54 g, 3.11 mmol), 2-(tri-n-butylstannyl) thiazole (1.4 g, 3.73 mmol), Pd (PPh 3 ) 2 Cl 2 (218 mg, 0.31 mmol) and TFP ( 36 mg, 0.15 mmol) was dissolved in 1,4-dioxane (15 mL).
  • Step 5 The product of Step 4 (75 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), and N-bromosuccinimide (50 mg, 0.28 mmol) of tetrahydrofuran (1 mL) was slowly added dropwise to the reaction mixture under ice-water bath. ) solution. The reaction mixture was stirred at rt mp EtOAc (EtOAc)EtOAc. m/z: [M+H] + 339.0.
  • Step 1 Intermediate 12 (400 mg, 1.56 mmol), hexamethylditin (614 mg, 1.87 mmol) and bis(triphenylphosphine)palladium dichloride (55 mg, 0.08 mmol) dissolved in 1,4-dioxane In a six-ring (30 mL) solution, the mixture was stirred under reflux with nitrogen overnight. The reaction mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 2-(thiazol-2-yl)-6-(trimethylstannyl)pyridin-4-amine (460 mg, yield: 87%) was pale yellow solid.
  • Step 2 Step 1 product (460 mg, 1.35 mmol), 2,6-dibromopyridine (320 mg, 1.35 mmol), bis(triphenylphosphine)palladium dichloride (95 mg, 0.14 mmol) and TFP (16 mg, 0.07) Methyl) was dissolved in a solution of 1,4-dioxane (30 mL) and refluxed overnight under nitrogen. The reaction mixture was concentrated under reduced pressure and purified purified mjjjjjjjjjjj ]-4-amine (200 mg, yield: 44%) was a pale yellow solid.
  • Step 3 The product of Step 2 (700 mg, 2.1 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (0.41) was slowly added dropwise to the reaction mixture in an ice water bath. g, 2.3 mmol) of N,N-dimethylformamide (2.0 mL).
  • Step 1 2-(4-Methoxypyrimidin-2-yl)-6-(thiazol-2-yl)-pyridin-4-amine (in the synthesis of intermediate 14 steps 1 to 2, in step 2 The 2,6-dibromopyridine was replaced by 2-iodo-4-methoxypyrimidine (0.16 g, 0.56 mmol) dissolved in a hydrobromic acid solution (5.0 mL) and stirred at 100 ° C for 3 hours.
  • Step 2 A catalytic amount of N,N-dimethylaniline was added to a solution of the product of Step 1 (0.16 g, 0.22 mmol) in chlorobenzene (5OmL), and the mixture was stirred at 100 ° C for 4 hours. The reaction mixture was cooled to room temperature, and the mixture was diluted with EtOAc EtOAc EtOAc (EtOAc) The organic layer was dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness.
  • EtOAc EtOAc EtOAc
  • Step 3 The product of Step 2 (0.10 g, 0.35 mmol) was dissolved in N,N-dimethylformamide (6.0 mL), and N-bromosuccinimide was slowly added dropwise to the reaction solution in an ice water bath. (62 mg, 0.35 mmol) of N,N-dimethylformamide (2.0 mL). After the reaction mixture was stirred at this temperature for 1 hour, the mixture was evaporated, evaporated, evaporated, evaporated. Filtration and concentration of the filtrate under reduced pressure.
  • 2,6-dichloro-4-(difluoromethoxy)pyridine 2,6-dichloro-4-hydroxypyridine (900 mg, 5.49 mmol), ethyl difluoroacetate (2.23 g, 11.0)
  • a mixture of potassium carbonate (1.52 g, 11.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 40 ° C for 5 hours.
  • Step 1 Substituting 2,6-dibromopyridine for 3,5-dichloro-2-methylpyrazine to obtain 2-(6-chloro-3methylpyrazine) using the synthesis method of Intermediate 14 Step 2.
  • a mixture of 4-amines, the above mixture was separated by prep-HPLC (basic conditions, 30-65% mobile phase B) to give 2-(6-chloro-3-methylpyrazin-2-yl)-6- ( Thiazol-2-yl)pyridin-4-amine (peak time: 17.5 to 18 minutes) and 2-(6-chloro-5-methylpyrazin-2-yl)-6-(thiazol-2-yl) Pyridyl-4-amine (peak time: 19.5-20 minutes).
  • Step 2 using the synthesis method of the intermediate 14 step 3, respectively using 2-(6-chloro-3-methylpyrazin-2-yl)-6-(thiazol-2-yl)pyridin-4-amine and 2 -(6-Chloro-5-methylpyrazin-2-yl)-6-(thiazol-2-yl)pyridin-4-amine is reacted to give intermediate 26 and intermediate 27.
  • the intermediate 12 in the step 1 is replaced with 2-bromo-6-(4-chloro-1H-pyrazol-1-yl)pyridin-4-amine by the synthesis method of the intermediate 14, 2 in the step 2,
  • the 6-dibromopyridine is replaced by 2,6-dibromopyrazine to give intermediate 28.
  • intermediate 12 is carried out by the reaction of 4-methyl-2-(tri-n-butylstannyl)thiazole to give 2-bromo-6-(4-methylthiazol-2-yl)pyridin-4-amine.
  • Step 1 2-(2-(Methylthio)pyrimidin-4-yl)-6-(thiazol-2-yl)pyridin-4-amine (using the synthesis method of Intermediate 14 Step 2, the step 2 2,6-dibromopyridine was replaced by 4-iodo-2-(methylthio)pyrimidine) (150 mg, 0.50 mmol). Dissolved in acetic acid (0.5 mL) and tetrahydrofuran (15.0 mL). A solution of peroxybenzoic acid in tetrahydrofuran (345 mg, 2.0 mmol) was stirred at room temperature for 4 hours. The reaction was quenched with aq.
  • EtOAc EtOAc (EtOAc (EtOAc (EtOAc) -(2-(Methanesulfonyl)pyrimidin-4-yl)-6-(thiazol-2-yl)pyridin-4-amine (120 mg, yield: 75%) m/z: [M+H] + 334.0.
  • Step 2 The product of Step 1 (120 mg, 0.36 mmol) was dissolved in tetrahydrofuran (20.0 mL), and N-bromosuccinimide (64.0 mg, 0.36 mmol) of tetrahydrofuran was slowly added dropwise to the reaction mixture in an ice water bath. (4.0 mL) solution. After the reaction mixture was stirred at this temperature for 1 hour, it was concentrated under reduced pressure. EtOAc m.
  • Step 1 Intermediate 12 (400 mg, 1.56 mmol), (3-cyano-5-fluorophenyl)boronic acid (309 mg, 1.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (57 mg, 0.08 mmol) was dispersed in 1,4-dioxane solution (30 mL), followed by aqueous sodium carbonate (2.34 mL, 4.68 mmol). The reaction mixture was stirred with EtOAc EtOAc (EtOAc)EtOAc. Pyridin-2-yl)-5-fluorobenzonitrile (315 mg, yield: 68%) was an off-white solid. m/z: [M+H] + 297.0.
  • Steps 2 & 3 Using the steps 2 to 3 of Example 62 and the synthesis method, the product of Step 1 was reacted to give Intermediate 63. m/z: [M+H] + 442.0.
  • Intermediates 74 to 82 are obtained by the reaction of the intermediate 37, using the corresponding starting material 1 and starting material 2 ( intermediate 3):
  • Step 1 2-Bromo-6-(trifluoromethyl)pyridine (320 mg, 1.03 mmol), hexamethylditin (560 mg, 1.71 mmol) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol) dissolved In a solution of 1,4-dioxane (4 mL), reflux under nitrogen overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc m. 6-(Trimethylstannyl)pyridine (350 mg, yield: 100%) was obtained as a black oil.
  • Step 2 Step 1 product (350 mg, 1.03 mmol), 4-amino-2,6-dibromopyridine (150 mg, 0.59 mmol), bis(triphenylphosphine)palladium dichloride (46 mg, 0.06 mmol)
  • a solution of TFP (10 mg, 0.04 mmol) in 1,4-dioxane (5 mL) was stirred under reflux overnight.
  • the reaction mixture was concentrated under reduced pressure and purified title crystallilililililililililililililililililililililililililililililililili "-Tripyridyl]-4'-amine (30 mg, yield: 13%) was a yellow solid.
  • Step 3 The product of Step 2 (120 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (53 mg) was slowly added dropwise to the reaction solution in an ice water bath. , 0.29 mmol) of a solution of N,N-dimethylformamide (5 mL). After the reaction mixture was stirred at this temperature for 1 hour, the reaction was quenched with ice water (30 mL), EtOAc (EtOAc) The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated,363363363363363363363363363363363363363363363363363363363363363363363363 . . m/z: [M+H] + 463.0.
  • Step 1 2-Tri-n-butylstannylpyridine (1.92 g, 5.22 mmol), 4-amino-2,6-dibromopyridine (600 mg, 2.38 mmol), bis(triphenylphosphine)palladium dichloride A solution of (168 mg, 0.23 mmol) and EtOAc (EtOAc m. The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjjjjjjjjjjjjjj Yield: 100%) as a yellow solid. m/z: [M+H] + 249.0.
  • Step 2 The product of Step 1 (240 mg, 0.96 mmol) was dissolved in N,N-dimethylformamide (13 mL), and N-bromosuccinimide (146 mg) was slowly added dropwise to the reaction solution in an ice water bath. , 0.92 mmol) of a solution of N,N-dimethylformamide (10 mL). After the reaction mixture was stirred at this temperature for 0.5 hr, the mixture was evaporated to dryness (30 mL), EtOAc (EtOAc) The sodium was dried, filtered, and the filtrate was evaporated evaporated. m/z: [M+H] + 327.0.
  • Step 1 Toluene solution of ethyl glyoxylate (5 g, 49 mol, 50%) and 2-acetylpyrazine (12 g, 98 mmol) were dissolved in methanol (163 mL) and stirred for 5 min under nitrogen. Subsequently, 15% aqueous potassium hydroxide solution (22 mL, 58.8 mmol) and aqueous ammonia (16.3 mL, 425 mmol) were slowly added to the above reaction mixture, and stirred at room temperature for 3 days.
  • Step 2 2,6-bis(pyrazin-2-yl)isonicotinic acid (1 g, 3.58 mmol), triethylamine (1.1 g, 10.7 mmol), diphenyl azide (1.4 g, 5.01 mmol) And tert-butanol (557 mg, 7.52 mmol) was dissolved in toluene (23 mL). The reaction mixture was stirred under a nitrogen atmosphere at 95 ° C under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc m.
  • Step 3 Step 2
  • the product (816 mg, 2.33 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj : 22%) is a pale yellow solid. m/z: [M+H] + 251.2.
  • Step 4 2,6-bis(pyrazin-2-yl)pyridin-4-amine (127 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (1 mL). A solution of N-bromosuccinimide (127 mg, 0.7 mmol) in N,N-dimethylformamide (1 mL) was slowly added dropwise. After the reaction mixture was stirred at this temperature for 5 minutes, the reaction was quenched with ice water (2 mL). : 37%) is a pale yellow solid. m/z: [M+H] + 329.0.
  • Step 1 2,6-Dibromo-4-aminopyridine (0.63 g, 2.50 mmol), pyrimidine-5-boronic acid (0.77 g, 6.25 mmol), [1,1'-bis(diphenylphosphine) dioxin Iron] palladium dichloride dichloromethane complex (0.1 g, 0.13 mmol) and sodium carbonate (1.06 g, 0.01 mol) were dispersed in a solution of 1,4-dioxane (40 mL) and water (20 mL). Stir under reflux overnight under nitrogen.
  • Step 2 The product of step 1 (125 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (9 mL) and tetrahydrofuran (5 mL). N-bromobutane was slowly added dropwise to the reaction mixture in an ice water bath. A solution of the imide (98 mg, 0.55 mmol) in N,N-dimethylformamide (5 mL). After the reaction mixture was stirred at this temperature for 1 hour, the mixture was evaporated, evaporated, evaporated, evaporated. Filtration and concentrating of the filtrate under reduced pressure. EtOAc EtOAc m. m/z: [M+H] + 329.0.
  • Step 2 Diisopropylamine (7.9 g, 77.4 mmol) was dissolved in tetrahydrofuran (120 mL), and a n-butyllithium solution (22.1 mL, 77.4 mmol) was slowly added dropwise to the reaction mixture at -78 °C. The reaction mixture was stirred at this temperature for 1 hour. A solution of the product of Step 1 (10.0 g, 22.1 mmol) in tetrahydrofuran (40 mL) was then added dropwise to the mixture.
  • Step 3 Step 2 product (4.5 g, 9.95 mmol), 2-(tri-n-butylstannyl)thiazole (4.47 g, 11.94 mmol), bis(triphenylphosphine)palladium dichloride (698 mg, 0.99 mmol) And TFP (460 mg, 1.99 mmol) was dissolved in 1,4-dioxane (200 mL).
  • Step 4 The mixture obtained in Step 3 (2.3 g, 5.04 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was concentrated under reduced pressure to give 4-amino-2-bromo-6-(thiazol-2-yl)nicotinic acid and 4-amino-6-bromo-2-(thiazol-2-yl)nicotinic acid (1.5 g. Rate: 100%) as a yellow oil. m/z: [M+H] + 300.0.
  • Step 5 The mixture obtained in Step 4 (1.5 g, 5.04 mmol), ammonium chloride (2.7 g, 50.4 mmol), N,N-diisopropylethylamine (13 g, 101 mmol), 1-hydroxybenzotriene Azole (2.1 g, 50.4 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.9 g, 15.1 mmol) were dissolved in N,N-dimethylformamide (50 mL) The solution was stirred at room temperature overnight, then added with water (200 mL).
  • Step 6 To a solution of the mixture obtained in Step 5 (0.95 g, 3.17 mmol) in THF (60 mL), hexane (18 mL), and then trifluoromethanesulfonic acid anhydride (4.5 mL) The mixture was stirred at room temperature for 2 hours. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. Purification afforded 4-amino-6-bromo-2-(thiazol-2-yl)nicotinonitrile (0.4 g, yield: 44%, less polar) and intermediate 95 (0.18 g, yield: 20%, Large polarity), all light yellow solids. m/z: [M+H] + 281.0.
  • Step 1 N-methylimidazole (8.2 g, 99.6 mmol) was dissolved in tetrahydrofuran (150.0 mL), and a solution of n-butyllithium in tetrahydrofuran (39.8 mL, 99.55 mmol) was slowly added dropwise to the reaction mixture at -78 °C. . The reaction solution was stirred at this temperature for 1 hour, and a solution of zinc chloride in tetrahydrofuran (79.6 mL, 160 mmol) was added dropwise to the mixture. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour.
  • N-Boc-4-amino-2,6-dibromonicotinic acid tert-butyl ester (9.0 g, 19.91 mmol) and four-three were added dropwise.
  • Phenylphosphine palladium (1.84 g, 1.59 mmol) in tetrahydrofuran.
  • EtOAc EtOAc EtOAc
  • Steps 2 & 3 Using the synthesis of Steps 5 & 5 of Example 95, using N-Boc-4-amino-2-bromo-6-(1-methyl-1H-imidazol-2-yl)nicotinic acid tert-butyl ester (3.0 g The reaction gave 4-amino-2-bromo-6-(1-methyl-1H-imidazol-2-yl)nicotinamide (850 mg) as a yellow solid. m/z: [M+H] + 296.0.
  • Step 4 4-amino-2-bromo-6-(1-methyl-1H-imidazol-2-yl)nicotinamide (850 mg, 2.87 mmol) and pyridine (20 mL) in tetrahydrofuran Trifluoromethanesulfonic anhydride (6 mL) was slowly added dropwise to the solution (60 mL), and stirred at 0 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. Purification afforded intermediate 96 (750 mg, yield: 94%) as pale yellow solid. m/z: [M+H] + 278.0.
  • Step 1 2-Chloro-6-fluoro-4-methoxypyridine (190 mg, 1.18 mmol) was dissolved in 1,4-dioxane (7 mL), followed by the addition of bis-boronic acid pinacol ester ( 389 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (98 mg, 0.12 mmol), potassium acetate (232 mg, 2.36 mmol). The reaction system was heated to 110 ° C under nitrogen for 2 hours.
  • Step 2 Intermediate 96 (200 mg, 0.72 mmol), 2-fluoro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan 2-yl)pyridine (273 mg, 1.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (50 mg, 60 ⁇ mol), saturated aqueous sodium carbonate (8.0 mL) was dissolved in a solution of 1,4-dioxane (60 mL). The reaction mixture was stirred with EtOAc (EtOAc)EtOAc. m/z: [M+H] + 325.2.
  • Step 1 To a solution of N-BOC-3-pyrrolidone (2.8 g, 15 mmol) in tetrahydrofuran (30 mL) was added (trifluoromethyl)trimethylsilane (2.6 mL) and tetrabutyl fluoride, respectively. Ammonium (528 mg, 1.7 mmol). The system was stirred to room temperature under nitrogen for 12 hours. Aqueous saturated ammonium chloride (24 mL) was added and stirred for 15 min. The organic phases were combined and washed with brine. The residue was dried over anhydrous sodium sulfate, filtered, and evaporated. Pyrrolidine (3.1 g, yield: 82%) was a white solid.
  • Step 2 To a solution of the title compound (57 mg, 0.22 mmol. The reaction system was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc m. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate
  • Step 1 To a solution of (S)-(+)-3-hydroxytetrahydrofuran (197 mg, 2.24 mmol) in THF (7 mL) 2-Bromo-6-bromomethylpyridine (301 mg, 1.20 mmol) was added to the above reaction system, stirred at room temperature for 12 hours, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate (50mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated. Tetrahydrofuran-3-yl)oxy)methyl)pyridine (226 mg, yield: 72%) was obtained as a colorless liquid. m/z: [M+H] + 258.0.
  • Step 2 Synthesis of intermediate 99 by reaction of (S)-2-bromo-6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridine (60 mg, 0.23 mmol). (80 mg) was a grey solid. m/z: [M+H] + 344.0.
  • Step 1 2,6-Dichloropyrazine (300 mg, 2.0 mmol) and 3-methylpyrrolidin-3-ol (204 mg, 2.0 mmol) were dissolved in acetonitrile (20 mL), then N, N- Isopropylethylamine (388 mg, 3.0 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc m.) Alkanol-3-ol (320 mg, yield: 75%) was obtained as a pale yellow oil. m/z: [M+H] + 214.2.
  • Step 2 The product of Step 1 (150 mg, 0.70 mmol) was dissolved in 1,4-dioxane (10 mL), then bis-boronic acid pinacol ester (213 mg, 0.84 mmol), palladium acetate (16 mg, 0.07 mmol), tricyclohexylphosphine (20 mg, 0.07 mmol) and potassium acetate (172 mg, 1.75 mmol).
  • the reaction system was heated to 110 ° C under nitrogen for 1 hour.
  • the reaction solution containing the intermediate 101 can be directly subjected to the next reaction without post-treatment.
  • the 3-methylpyrrolidin-3-ol in the step 1 is replaced with the intermediate 3 to obtain a reaction liquid containing the intermediate 102, and the next reaction can be directly carried out without post-treatment.
  • Step 1 To a solution of 3-bromopyrazole (1.0 g, 6.81 mmol) in tetrahydrofuran (15 mL), EtOAc (EtOAc, EtOAc. After an hour, 2-(trimethylsilyl)ethoxymethyl chloride (1.36 g, 8.16 mmol) was added dropwise and stirred at room temperature overnight. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. 3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.2 g, yield: 64%) was obtained as a yellow oil. m/z: [M+H] + 277.0.
  • Step 2 Step 1 product (1.2g, 4.33mmol), 3-hydroxy-3-methylpyrrolidine (650mg, 6.50mmol), cuprous iodide (825mg, 4.33mmol), potassium carbonate (3.6g, 26.0mmol) And L-valine (100 mg, 0.87 mmol) was added to dimethyl sulfoxide (10 mL), the reaction system was replaced with nitrogen, and the mixture was heated to 120 ° C overnight in a sealed tube. The reaction solution was cooled to room temperature, then water (15 mL), EtOAc (EtOAc)EtOAc.
  • Step 3 To a solution of the product of Step 2 (300 mg, 1.01 mmol) in THF (20 mL), THF (10 mL), and the mixture was heated to 80 ° C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj m/z: [M+H] + 168.2.
  • Step 1 Intermediate 24 (120 mg, 0.28 mmol) and cuprous cyanide (125 mg, 1.40 mmol) were dissolved in N,N-dimethylacetamide (2.0 mL) and reacted at 130 ° C for 80 min under microwave conditions. The reaction solution was cooled to room temperature, and then aqueous ammonia (5 mL) and saturated aqueous sodium hydrogen sulfate (5 mL) was evaporated.
  • Step 2 4-Amino-6'-chloro-4'-(difluoromethoxy)-6-(thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile (90.0 mg, 0.24 mmol), 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride (199 mg, 1.20 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.02 mmol). N-dimethylacetamide (2.0 mL) was reacted in a sealed tube at 120 ° C for 4 hours.
  • the compound 54 is reacted with Intermediate 80 to give compound 54 as 4-amino-6-(4-chloro-1H-pyrazol-1-yl)-2-(6-(3-(2-hydroxypropyl).
  • -2-yl)pyrrolidin-1-yl)pyrazin-2-yl)nicotinonitrile and 4-amino-2-(4-chloro-1H-pyrazol-1-yl)-6-(6-(3) A mixture of -(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrazin-2-yl)nicotinonitrile.
  • the compound 54 in the step 1 was replaced with the compound 60 by the synthesis method of the compound 55, and purified by prep-HPLC (acidic conditions) to give 4-amino-6'-(3-(2-hydroxypropan-2-yl)pyrrole.
  • Alkyl-1-yl)-6-(1H-pyrazol-1-yl)-[2,2'-dipyridine]-3-carbonitrile hydrochloride (Compound 61) was obtained as a white solid.
  • the intermediate 24 in the step 1 is replaced with the intermediate 31, and the (R)-pyrrolidin-3-ol in the step 2 is replaced with 3-methylpyrrolidin-3-ol to obtain 4- Amino-6'-(3-hydroxy-3-methylpyrrolidin-1-yl)-6-(thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile hydrochloride (compound) 66, prep-HPLC: acidic conditions) as a white solid. m/z: [M+H] + 379.2; 1 H NMR (400 MHz, DMSO-d 6 ): ⁇ 8.
  • Step 1 A solution of intermediate 35 (60 mg, 0.14 mmol) in N,N-dimethylacetamide (5mL) The reaction mixture was stirred at 110 ° C for 2 hours, then the reaction was quenched with EtOAc EtOAc. Amino-6'-bromo-4'-fluoro-6-(thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile (60 mg, yield: 100%) was obtained as a yellow solid. m/z: [M+H]+376.0.
  • Step 2 To a solution of the product of Step 1 (96 mg, 0.26 mmol) in THF (29 mL), 4-dimethylaminopyridine (41 mg, 0.34 mmol) and di-tert-butyl dicarbonate (109 mg, 0.50 mmol).
  • Step 3 To a solution of the product from Step 2 (54 mg, EtOAc, EtOAc, EtOAc. Naphthalene-2,2'-bisdiphenylphosphine (24mg, 0.04mmol), palladium acetate (6mg, 0.03mmol), cesium carbonate (90mg, 0.28mmol), the reaction system is reacted in the microwave at 110 ° C for 0.5 hours, the reaction mixture is directly Concentration under reduced pressure, and the residue was purified by prep-HPLC to give N,N-di-Boc-4-amino-4'-fluoro-6'-(3-hydroxy-3-methylpyrrolidin-1-yl)-6- (thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile (50 mg, yield: 67%) was obtained as a yellow solid. m/z: [M+H] + 597.2.
  • Step 4 The product of Step 3 (50 mg, 0.08 mmol) was dissolved in a mixture of dichloromethane (2mL) and trifluoroacetic acid (2mL), and the reaction mixture was reacted at room temperature for 3 hours, then concentrated under reduced pressure. -HPLC (acidic conditions) purification affords 4-amino-4'-fluoro-6'-(3-hydroxy-3-methylpyrrolidin-1-yl)-6-(thiazol-2-yl)-[2, 2'-Dipyridine]-3-carbonitrile hydrochloride (Compound 74, 3.8 mg, yield: 10%) was obtained as a yellow solid.
  • the intermediate 24 in the step 1 is replaced with the intermediate 31, and the (R)-pyrrolidin-3-ol in the step 2 is replaced with 4-(pyrrolidin-3-yl)morpholine.
  • 4-amino-6'-(3-morpholinopyrrolidin-1-yl)-6-(thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile (Compound 78, prep-HPLC : Basic condition) is a white solid.
  • Trifluoroacetic acid (2 mL) was added dropwise to a solution of Compound 82 (EtOAc, m.
  • the reaction mixture was concentrated under reduced pressure and purified and purified to purified crystals eluted elute Thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile (Compound 83, 18.6 mg, Yield: 44%) was obtained as a yellow solid.
  • Step 2 Sodium borohydride (7.0 mg, 0.192 mmol) was added portionwise to a mixture of compound 89 (15 mg, 0.038 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL). Stir under 1 hour. The reaction was quenched by the addition of ice water, and the mixture was evaporated. mjjjjjjjjjj '-Methoxy-6-(thiazol-2-yl)-[2,2'-bipyridine]-3-carbonitrile (Compound 90, 2.29 mg, yield: 16%) as a white solid.
  • Step 2 Intermediate 103 (51.8 mg, 0.31 mmol), Step 1 product (30 mg, 0.062 mmol) and N,N-diisopropylethylamine (0.2 mL). (2 mL), reacted in a sealed tube at 160 ° C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced vacuo. Pyrazol-1-yl)-6-(thiazol-2-yl)nicotinonitrile (Compound 91, 1.22 mg, yield: 5%) was obtained as a yellow solid.
  • the compounds disclosed herein determine the ability of a compound of the invention to bind to a human A2a receptor by measuring the binding of the adenosine A2a receptor antagonist to the human A2a receptor under in vitro conditions.
  • the experimental method is as follows:
  • Test compounds were first prepared in DMSO as stock solutions, followed by a gradient dilution of the buffer (purchased from Cisbio, Cat. No. 08B) to the desired concentration for the test, starting at a test concentration of 1 [mu]M and 11 concentration points per compound.
  • use 3000 purchased from Invitrogen, Cat. No. 1816990
  • Transfer the pHALO-adenosine A2a receptor plasmid purchased from Cisbio, Cat. PHTA2A
  • HaloTag- -Tb purchased from Cisbio, item number SHALOTBC 2nmoles
  • a HEK293 cell suspension expressing a human A2a receptor and labeled was prepared using a buffer, and a 10 uL/well cell suspension (5000 cells/well) was added to a 384-well plate (purchased from Greiner, Cat. No. 784075). Subsequently, 5 ⁇ L of the test compound was added to each test well, and 5 ⁇ L of DMSO was added to the wells of the control group, and a duplicate well control was set. Add 5 ⁇ L to each well.
  • Adenosine A2a receptor red antagonist purchasedd from Cisbio, article number: L0058RED
  • was mixed and sealed with a sealing film purchased from Perkin Elmer, Cat. No. 6050185
  • %Activity (test well value - positive control well value) / (negative control well value - positive control well value) ) *100.
  • Ki IC 50 /(1 + adenosine A2a receptor antagonist concentration / Kd), where Kd is the dissociation constant of the adenosine A2a receptor antagonist.
  • Drugs and reagents The test compound is formulated into a clear solution with 20% sulfobutyl- ⁇ -cyclodextrin aqueous solution. If the test compound cannot form a clear solution in 20% sulfobutyl- ⁇ -cyclodextrin aqueous solution, it can be dripped. A small amount of 0.01 M hydrochloric acid or aqueous oxalic acid solution was added until the test compound solution was clarified.
  • the reagents used were of analytical grade:
  • Test animals male SPF grade SD rats (6 in each group) were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., all animals were fasted for 10-14 hours before administration, and returned to food 4 hours after administration. .
  • Pharmacokinetic test The test compounds were administered to SD male rats by oral and intravenous administration respectively. Blood samples were collected by jugular vein puncture. Each sample was collected about 0.20 mL. Heparin sodium was anticoagulated. The time of blood collection was as follows: Blood collection time in the intravenous administration group: before administration, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after administration. Blood collection time in the oral administration group: before administration, 0.25 h after administration, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h.
  • Plasma samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis. Plasma samples were analyzed by LC-MS/MS (API5500). Pharmacokinetic parameters of the test samples were calculated using the pharmacokinetic calculation software WinNonlin5.2 non-compartmental model according to the blood concentration data of the drug. Concentration, peak time, half-life, area under the drug time curve, mean residence time) and bioavailability average (BA%).
  • the compound of the present invention can significantly improve the pharmacokinetic properties of SD rats, prolong the mean residence time (MRT) of drugs, and prolong the half-life of drugs (t1/2). Significantly increase the area under the curve (AUC), and thus improve the oral bioavailability of the drug (BA%):
  • Ref. A (positive control) in Biological Examples 1 and 2 was 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidine-4-amine synthesized according to the experimental method of Example 1 of CN102892761A ;
  • Ref. B (positive control) in Biological Example 2 is (R)-4-amino-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(6-(3) -Methoxypyrrolidin-1-yl)pyridin-2-ylpyrimidine-5-carbonitrile, synthesized according to the experimental procedure of Example 6 of CN106749190A.

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Abstract

L'invention concerne un dérivé de 4-aminopyridine, une composition pharmaceutique contenant celui-ci, un procédé de préparation associé et une utilisation correspondante. Le dérivé de 4-aminopyridine (I) selon la présente invention, et un isomère, un promédicament, un dérivé isotopique stable ou un sel pharmaceutiquement acceptable de celui-ci ont la structure suivante. Le dérivé de 4-aminopyridine selon la présente invention a une bonne action antagoniste du récepteur A2a de l'adénosine, et peut traiter ou soulager de manière efficace des maladies apparentées provoquées par un niveau anormal du récepteur A2a de l'adénosine, tels que des cancers, des maladies du système nerveux central, etc. (I)
PCT/CN2018/109300 2017-10-11 2018-10-08 Dérivé de 4-aminopyridine, composition pharmaceutique contenant celui-ci, procédé de préparation associé et utilisation correspondante Ceased WO2019072143A1 (fr)

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WO2024223373A1 (fr) 2023-04-24 2024-10-31 Basf Se Composés de pyrimidine pour la lutte contre les invertébrés nuisibles
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