WO2023078241A1 - Dérivés d'amines aromatiques et leur procédé de préparation et leur utilisation médicale - Google Patents

Dérivés d'amines aromatiques et leur procédé de préparation et leur utilisation médicale Download PDF

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WO2023078241A1
WO2023078241A1 PCT/CN2022/128963 CN2022128963W WO2023078241A1 WO 2023078241 A1 WO2023078241 A1 WO 2023078241A1 CN 2022128963 W CN2022128963 W CN 2022128963W WO 2023078241 A1 WO2023078241 A1 WO 2023078241A1
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alkyl
compound
general formula
aryl
halogen
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PCT/CN2022/128963
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Chinese (zh)
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闫旭
田卫学
陈士柱
殷惠军
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中国医药研究开发中心有限公司
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Priority to CN202280007466.7A priority Critical patent/CN116472047A/zh
Publication of WO2023078241A1 publication Critical patent/WO2023078241A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to aromatic amine derivatives and their preparation method and medical application. Specifically, the present invention relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing it, and its use as a Toll-like receptor (TLR) agonist for treating diseases related to TLR8 activity .
  • TLR Toll-like receptor
  • TLRs Toll-like receptors
  • TLRs are all type I transmembrane glycoproteins, consisting of 16-28 leucine-rich repeat (LRR) extracellular domain, transmembrane domain and cytoplasmic Toll/IL-1 receptor (TIR) structure domain composition. X-ray crystallography analysis confirmed that the TLR and LRR domains were horseshoe-shaped. So far, 11 members have been found in humans, among which TLR1, 2, 4, 5, 6, 10 and 11 are located on the cell surface, and TLR3, 7, 8, and 9 are located on the endosomal membrane. TLR8 and TLR7 are phylogenetically close to each other and have a high degree of sequence homology, and are located on the adjacent X chromosome (Xp22).
  • LRR leucine-rich repeat
  • TIR cytoplasmic Toll/IL-1 receptor
  • TLR8 relies on the MyD88 signaling pathway, induces and activates protease-1 (AP-1) and nuclear factor ⁇ B (NF- ⁇ B) to transfer to the nucleus, induces the expression of related genes in the nucleus, secretes chemokines and inflammatory factors, etc., and plays a role in transcription. role of regulation.
  • MyD88 myeloid differentiation factor 88
  • TLR8 can also activate the mitogen-activated protein kinase (MAPK) signaling pathway, including p38, ERK, and JNK, etc., which are mainly involved in the regulation of cell proliferation, cell differentiation, cell transformation, and apoptosis, and are closely related to inflammation, tumors, etc. A variety of diseases are closely related (Journal of Immunology, 2017, 33, 813).
  • MAPK mitogen-activated protein kinase
  • Hepatitis B virus is a particulate double-stranded DNA virus. Activation of TLR8 can effectively inhibit HBV replication in vivo and in vitro, thus becoming a target for the development of treatments for chronic HBV.
  • TLR8 agonist ssRNA40 can selectively activate perihepatic innate immune cells to produce a large amount of IFN- ⁇ , thereby inhibiting the replication of hepatitis B virus, which has the potential to be used as a treatment for hepatitis virus infection.
  • Stimulation of PBMC with TLR8 agonists was found to induce high levels of IFN- ⁇ and TNF- ⁇ production, thereby inhibiting HBV replication (Current Opinion in Virology, 2018, 30, 9).
  • TLR is not only expressed on immune cells, but also expressed in various tumor cells, participates in tumor immune surveillance, and plays different roles in tumor growth. Among them, the activation of TLR8 enhances the activity of natural killer cells (NK cells), improves antibody-dependent cell-regulated cytotoxicity (ADCC) and induces Th1 polarization. TLR8 agonists serve as potential adjuvants in cancer therapy, aiming to induce specific immune responses against tumor cells and improve the clinical efficacy of approved monoclonal antibody therapies, especially in individuals with reduced ADCC.
  • NK cells natural killer cells
  • ADCC antibody-dependent cell-regulated cytotoxicity
  • TLR-8 agonists In view of the important potential of TLR-8 agonists in the treatment of various diseases, there is an urgent clinical need for new TLR-8 agonists with strong activity and high selectivity.
  • the inventors designed and synthesized a series of arylamine compounds, which exhibit excellent TLR8 agonistic activity, and can be developed as drugs for treating TLR8-related diseases.
  • the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X 1 is CR 1 or N
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N
  • L is selected from a bond, -(CH 2 ) v -, -C(O)(CH 2 ) t - or -(CH 2 ) t C(O)-;
  • R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy;
  • R is selected from hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, -OR a , -SR a , -NR a R b , cycloalkyl, heterocyclyl, aryl and hetero Aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more Q groups;
  • R is selected from hydrogen, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, -OR a , -SR a , -NR a R b , cycloalkyl, heterocyclyl, aryl and hetero Aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more Q groups;
  • R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, haloalkyl, haloalkoxy;
  • R and R are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein the alkyl, alkenyl , alkynyl, cycloalkane Base, heterocyclyl, aryl, heteroaryl is optionally further selected from deuterium, halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, Heteroaryl, -OR a , -SR a , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O) One or more of NR a R b , -NR a C(O)R b , -S(O) n R a , -S(O
  • Q 1 and Q 2 are each independently selected from halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a , -SR a , -(CH 2 ) v -NR a R b , -NR a R b , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O )NR a R b , -NR a C(O)R b , -S(O) n R a , -S(O) n NR a R b and -NR a S(O) n R b , wherein the Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from
  • R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, carboxyl, ester, oxo, Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR c , -SR c , -(CH 2 ) v -OR c , -(CH 2 ) v -NR c R d , -NR c R d , -C(O)R c , -O(O)CR c , -C(O)OR c , -C(O
  • R a and R b form a nitrogen-containing heterocyclic group together with their connected nitrogen atoms, and the nitrogen-containing heterocyclic group optionally further contains one or more heteroatoms selected from N, O, and S in addition to N , the nitrogen-containing heterocyclic group is optionally further selected from halogen, nitro, cyano, oxo, carboxyl, ester, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl group, -OR c , -SR c , -(CH 2 ) v -OR c , -(CH 2 ) v -NR c R d , -NR c R d , -C(O)R c , -O(O )CR c , -C(O)OR c , -C(O)NR c R d , -NR c C(O)R d , -S(O)
  • R and R are each independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, One or more groups in oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted;
  • R c and R d form a nitrogen-containing heterocyclic group together with the nitrogen atom they are connected to, and the nitrogen-containing heterocyclic group optionally further contains one or more heteroatoms selected from N, O, and S in addition to N , the nitrogen-containing heterocyclic group is optionally further selected from halogen, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclic, Aryl and heteroaryl;
  • n 1 or 2;
  • v is an integer from 1 to 6;
  • t 0 to 6.
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II) or their stereoisomers, tautomers, mesomers, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X 1 , X 2 , X 3 , L, R 4 , R 5 , and R 6 are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (III) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • L, R 1 , R 3 , R 4 , R 5 , and R 6 are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IV) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • L, R 1 , R 2 , R 4 , R 5 , and R 6 are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (V) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • L, R 2 , R 4 , R 5 , and R 6 are as defined in general formula (I).
  • L is selected from a bond or -C(O)-; preferably a bond.
  • L is selected from -(CH 2 ) v -; v is 1 or 2, preferably 1.
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in general formula (I).
  • R 3 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl are optionally further substituted by one or more Q groups;
  • Q 2 is selected from halogen, C 1 -C 6 alkyl, 4-6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, -NR a R b , wherein said C 6 - C 10 aryl and 5 to 10 membered heteroaryl are optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl, -(CH 2 ) v -NR c R d ;
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R a and R b form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms.
  • the 4-6 membered nitrogen-containing heterocyclic group optionally further contains a group selected from N, O, One or more heteroatoms of S, the 4-6 membered nitrogen-containing heterocyclic group is optionally further selected from oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 Cycloalkyl, -OR c , -SR c , -(CH 2 ) v -OR c , -NR c R d are substituted by one or more groups;
  • R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R c and R d form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms, and the 4-6 membered nitrogen-containing heterocyclic group may optionally further contain a group selected from N, O, One or more heteroatoms of S, the 4-6 membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl;
  • v is an integer of 1 to 6.
  • R 3 is selected from C 6 -C 10 aryl and 5 to 10 membered heteroaryl, preferably phenyl or 5-6 membered heteroaryl; wherein the C 6 -C 10 aryl and 5 to 10 membered heteroaryl Optionally further substituted by one or more Q2 groups;
  • Q 2 is selected from halogen, C 1 -C 6 alkyl, 4-6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, -NR a R b , wherein said C 6 - C 10 aryl and 5 to 10 membered heteroaryl are optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl;
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R a and R b form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms.
  • the 4-6 membered nitrogen-containing heterocyclic group optionally further contains a group selected from N, O, One or more heteroatoms of S, the 4-6 membered nitrogen-containing heterocyclic group is optionally further selected from oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 Cycloalkyl, -OR c , -SR c , -(CH 2 ) v -OR c , -NR c R d are substituted by one or more groups;
  • R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R c and R d form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms
  • the 4-6 membered nitrogen-containing heterocyclic group may optionally further contain a group selected from N, O, One or more heteroatoms of S
  • the 4-6 membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl, and v is an integer from 1 to 6 , preferably 1 or 2.
  • R is selected from 5 to 10 membered heteroaryl, preferably 5 or 6 membered heteroaryl, more preferably pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridoimidazolyl, pyridopyrrolyl, pyridine Pyrazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl; the heteroaryl is optionally further substituted by one or more Q2 groups;
  • Q 2 is selected from halogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, preferably phenyl, 5 to 10 membered heteroaryl, preferably 5 or 6 membered heteroaryl, wherein the aryl and heteroaryl Optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl.
  • R is selected from 5 to 10 membered heteroaryl, preferably 5 or 6 membered heteroaryl, more preferably pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrrolyl, pyridoimidazolyl, pyridopyrrolyl, pyridine Pyrazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl; the heteroaryl is optionally further substituted by one or more Q2 groups;
  • Q 2 is selected from halogen, C 1 -C 6 alkyl, 4-6 membered heterocyclic group or -NR a R b , preferably -NR a R b ;
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R a and R b form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms.
  • the 4-6 membered nitrogen-containing heterocyclic group optionally further contains a group selected from N, O, One or more heteroatoms of S, the 4-6 membered nitrogen-containing heterocyclic group is optionally further selected from oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 Cycloalkyl, -OR c , -SR c , -(CH 2 ) v -OR c , -NR c R d are substituted by one or more groups;
  • R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R c and R d form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms
  • the 4-6 membered nitrogen-containing heterocyclic group may optionally further contain a group selected from N, O, One or more heteroatoms of S
  • the 4-6 membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl, and v is an integer from 1 to 6 , preferably 1 or 2.
  • R 3 is selected from C 6 -C 10 aryl, preferably phenyl; the aryl is optionally further substituted by Q 2 groups;
  • Q 2 is selected from 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl.
  • R 3 is selected from C 1 -C 6 alkyl, preferably methyl; said C 1 -C 6 alkyl is optionally further substituted by a Q 2 group;
  • Q 2 is selected from C 6 -C 10 aryl, preferably phenyl, wherein the C 6 -C 10 aryl is optionally further substituted by -(CH 2 ) v -NR c R d ;
  • R c and R d form a 4-6 membered nitrogen-containing heterocyclic group together with the nitrogen atom they are connected to.
  • the 4-6 membered nitrogen-containing heterocyclic group may further contain, in addition to N, a group selected from N, O, S One or more heteroatoms, the 4-6 membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl;
  • v is an integer of 1 to 6, preferably 1 or 2.
  • R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, -NR a R b , and the C 1 -C 6 alkyl is optionally further substituted by Q 1 ;
  • Q 1 is selected from C 6 -C 10 aryl, 5 to 10 membered heteroaryl, wherein the C 6 -C 10 aryl and 5 to 10 membered heteroaryl are optionally further selected from halogen, C 1 -C One or more groups of 6 alkyl, -(CH 2 ) v -NR c R d are substituted;
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R c and R d form a 4-6 membered nitrogen-containing heterocyclic group together with their connected nitrogen atoms, and the 4-6 membered nitrogen-containing heterocyclic group may optionally further contain a group selected from N, O, One or more heteroatoms of S, the 4-6 membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl;
  • v is an integer of 1 to 6, preferably 1 or 2.
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl.
  • R 2 is selected from C 1 -C 6 alkyl, preferably methyl; said C 1 -C 6 alkyl is optionally further substituted by a Q 2 group;
  • Q 2 is selected from C 6 -C 10 aryl, preferably phenyl, wherein the C 6 -C 10 aryl is optionally further substituted by -(CH 2 ) v -NR c R d ;
  • R c and R d form a 4-6 membered nitrogen-containing heterocyclic group together with the nitrogen atom they are connected to.
  • the 4-6 membered nitrogen-containing heterocyclic group may further contain, in addition to N, a group selected from N, O, S One or more heteroatoms, the 4-6 membered nitrogen-containing heterocyclic group is optionally further substituted by one or more groups selected from halogen, C 1 -C 6 alkyl;
  • v is an integer of 1 to 6, preferably 1 or 2.
  • R 5 and R 6 are each independently selected from hydrogen and C 1 -C 12 alkyl, and the C 1 -C 12 alkyl is optionally further selected from deuterated, -OR a , -SR a , -NR a R One or more groups of b are substituted;
  • R a is selected from hydrogen, C 1 -C 6 alkyl
  • R b is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 5 to 7 membered heterocyclyl;
  • R 5 is hydrogen
  • R 6 is C 1 -C 12 alkyl
  • the C 1 -C 12 alkyl is optionally further substituted by one or more groups selected from deuterated, -OH.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by the general formula (III-1) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • R 1 , R 3 , R 4 , R 5 , R 6 are as defined in general formula (III-1).
  • the present invention further provides a method for preparing the compound represented by the general formula (IV-1) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • R 1 , R 2 , R 4 , R 5 , R 6 are as defined in general formula (IV-1).
  • the present invention further provides a method for preparing the compound represented by the general formula (V-1) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • Metal-catalyzed cross-coupling e.g. Suzuki coupling
  • boronic acid or boric acid pinacol ester compounds affords compounds of formula C4; deprotection with a suitable acid (e.g. trifluoroacetic acid) then affords Compounds represented by general formula (V-1); catalysts such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ;
  • the compound of formula C7 and boric acid or boric acid pinacol ester compound or R 2 Y compound pass metal-catalyzed cross-coupling reaction (such as Suzuki coupling), obtain the compound shown in general formula (V-1); Catalyst such as Pd ( PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ;
  • R 2 , R 4 , R 5 , R 6 are as defined in general formula (V-1).
  • the present invention further provides a pharmaceutical composition, which comprises the compound of the general formula according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients.
  • the present invention further relates to compounds of the general formula according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or Use of its mixture form, or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it in the preparation of a TLR8 agonist.
  • the present invention further relates to compounds of the general formula according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or Use of its mixture form, or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it in the preparation of a medicament for preventing or treating a TLR8-related disease
  • the disease may be a viral infectious disease or a malignant tumor, and the viral infectious disease
  • the viral infectious disease such as viral hepatitis B, HIV virus infection, the malignant tumors such as breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, Renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck
  • the present invention further relates to a compound of the general formula according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a TLR8 agonist.
  • the present invention further relates to a compound of the general formula according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for preventing or treating a TLR8-related disease
  • the disease may be a viral infectious disease or a malignant tumor, and the viral infectious disease such as Viral hepatitis B, HIV virus infection, the malignant tumors such as breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer Carcinoma, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor
  • the present invention further relates to a method for activating TLR8, which comprises administering an effective amount of the compound of the general formula according to the present invention or its stereoisomers, tautomers, mesoforms, exo Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same.
  • the present invention further relates to a method for preventing or treating TLR8-related diseases, which comprises administering an effective amount of the compound of the general formula according to the present invention or its stereoisomers, tautomers, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same;
  • the disease may be viral infectivity Disease or malignant tumor, the viral infectious disease such as hepatitis B, HIV virus infection, the malignant tumor such as breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer Carcinoma, Oral Cancer, Prostate Cancer, Bone Cancer, Kidney Cancer, Ovarian Cancer, Bladder Cancer, Liver Cancer, Fallopian Tube Tumor, Ovarian Tumor, Peritoneal Tumor, Melanoma, Solid Tumor, Glioma, Glioblastoma, Hepatocyte Carcino
  • the compounds of the present invention can form pharmaceutically acceptable base addition salts or acid addition salts with bases or acids.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
  • the acid includes inorganic acid and organic acid, acceptable inorganic acid includes hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like.
  • Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Wax alcohols (heptadeca ethyl ene oxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with Condensation products of partial esters derived from fatty acids and hexi
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the compounds of this invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention may contain the compound of the general formula, and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 10 carbon atoms, more preferably contain 3 to 8 carbon atoms, most preferably contain 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contain 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • the present invention adopts following synthetic scheme to prepare general formula (I) compound of the present invention.
  • the compound of formula A1 is reacted with a nucleophilic amine to obtain a compound of formula A2; then, under heating conditions, the compound of formula A2 is combined with 2,4-dimethyl Oxybenzylamine reaction to obtain the compound of formula A3; the compound of formula A3 can be cross-coupling reaction (such as Suzuki coupling) by metal catalysis (such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ) Reaction with boric acid or boric acid pinacol ester compound to obtain a compound of formula A4; deprotection with a suitable acid (such as trifluoroacetic acid) to obtain a compound shown in general formula (III-1);
  • a suitable base such as DIEA
  • R 1 , R 3 , R 4 , R 5 , R 6 are as defined in general formula (III-1).
  • the compound of formula A6 reacts with a nucleophilic amine in the presence of a condensing agent (such as BOP) to obtain a compound of the coupled product formula A7;
  • a condensing agent such as BOP
  • the compound of formula A7 can be catalyzed by a metal (such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ) cross-coupling reaction (such as Suzuki coupling) reacts with boric acid or boric acid pinacol ester compound to obtain the compound shown in general formula (III-1);
  • R 1 , R 3 , R 4 , R 5 , R 6 are as defined in general formula (III-1).
  • the compound of formula B1 is reacted with a nucleophilic amine to obtain a compound of formula B2; then, under heating conditions, the compound of formula B2 is combined with 2,4-dimethyl Oxybenzylamine reaction to obtain the compound of formula B3; the compound of formula B3 can be cross-coupling reaction (such as Suzuki coupling) by metal catalysis (such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ) Reaction with boric acid or boric acid pinacol ester compound to obtain a compound of formula B4; deprotection with a suitable acid (such as trifluoroacetic acid) to obtain a compound shown in general formula (IV-1);
  • a suitable base such as DIEA
  • R 1 , R 2 , R 4 , R 5 , R 6 are as defined in general formula (IV-1).
  • the compound of formula B6 reacts with a nucleophilic amine in the presence of a condensing agent (such as BOP) to obtain a compound of the coupled product formula B7;
  • a condensing agent such as BOP
  • the compound of formula B7 can be catalyzed by a metal (such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ) cross-coupling reaction (such as Suzuki coupling) reacts with boric acid or boric acid pinacol ester compound to obtain the compound shown in general formula (IV-1);
  • R 1 , R 2 , R 4 , R 5 , R 6 are as defined in general formula (IV-1).
  • the compound of formula C1 reacts with a nucleophilic amine to obtain a compound of formula C2; then, under heating conditions, the compound of formula C2 reacts with 2,4-dimethyl Oxybenzylamine reaction to give the compound of formula C3; the compound of formula C3 can be cross-coupling reaction (such as Suzuki coupling) by metal catalysis (such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ) Reaction with boric acid or boric acid pinacol ester compound to obtain a compound of formula C4; deprotection with a suitable acid (such as trifluoroacetic acid) to obtain a compound shown in general formula (V-1);
  • a suitable base such as DIEA
  • R 2 , R 4 , R 5 , R 6 are as defined in general formula (V-1).
  • the compound of formula C6 reacts with a nucleophilic amine in the presence of a condensing agent (such as BOP) to obtain a compound of the coupled product formula C7;
  • a condensing agent such as BOP
  • the compound of formula C7 can be catalyzed by a metal (such as Pd(PPh 3 ) 4 , K 2 CO 3 , Cs 2 CO 3 ) cross-coupling reaction (such as Suzuki coupling) reacts with boric acid or boric acid pinacol ester compound to obtain the compound shown in general formula (V-1);
  • R 2 , R 4 , R 5 , R 6 are as defined in general formula (V-1).
  • Figure 1 shows the parameters of the compound of Example 52 in the serum of cynomolgus monkeys.
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a combination of the above methods.
  • For its specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by LC (Waters 2695)/MS (Quattro Premier x E) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • the lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography.
  • Chromatographic column is Daisogel C18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • TLC Thin-layer chromatography
  • Silica gel column chromatography uses Qingdao ocean silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction solution was concentrated under reduced pressure, the resulting brown liquid was added to ice water (1 L), the resulting solid was removed by filtration, extracted by adding ethyl acetate (3 ⁇ 500 mL), the combined organic phases were washed with saturated brine (500 mL), and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • reaction solution was cooled to room temperature, diluted with ice water (30 mL), extracted quickly with ethyl acetate (3 ⁇ 8 mL), the organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate to obtain The ethyl acetate solution of compound 1g was directly used in the next reaction.
  • Step 7 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-N 2 -(2,4-dimethoxy Preparation of benzyl)pyrido[4,3-d]pyrimidine-2,4-diamine (1i)
  • Step 8 Preparation of (R)-2-((2-aminopyrido[4,3-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (1)
  • the obtained crude product was separated and purified by preparative chromatographic column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min ; Gradient: 18%-35% acetonitrile in 8 minutes; detection wavelength: 220 nm) to obtain compound 1 (3.4 mg, 44%) as a white solid.
  • preparative chromatographic column column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min ; Gradient: 18%-35% acetonitrile in 8 minutes; detection wavelength: 220 nm) to obtain compound 1 (3.4 mg, 44%) as a white solid.
  • compound 2b (961mg, 5.60mmol) was dissolved in N,N-dimethylformamide (DMF) (10mL), and N,N-carbonyldiimidazole (CDI) (3.63g, 22.39mmol) was added successively and 1,8-diazabicycloundec-7-ene (DBU) (2.13 g, 13.99 mmol), and the reaction solution was stirred at 80° C. for 1 hour.
  • DMF N,N-dimethylformamide
  • DBU 1,8-diazabicycloundec-7-ene
  • compound 2d (540 mg, 2.30 mmol) was dissolved in 1,4-dioxane (5 mL), and (R)-1-((tert-butyldimethylsilyl)oxy)-2 was added successively -Methylhexan-2-amine 1e (1.13g, 4.61mmol) and N,N-diisopropylethylamine (2.98g, 23.03mmol), react at room temperature for 1.5 hours.
  • Step 5 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-7-chloro-N 2 -(2,4 Preparation of -dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4-diamine (2f)
  • Step 6 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-N 2 -(2,4-dimethoxy Preparation of benzyl)-7-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)pyrido[4,3-d]pyrimidine-2,4-diamine (2g)
  • compound 2f (204 mg, 0.36 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and 2-(4-methylpiperazin-1-yl) pyrimidine- 5-Boronic acid pinacol ester (CAS: 942922-07-8) (2h) (264mg, 1.05mmol), potassium carbonate (148mg, 1.07mmol) and [1,1'-bis(diphenylphosphoryl) di Ferrocene]palladium dichloride (Pd(dppf) Cl2 ) (26mg, 0.036mmol). The reaction was stirred overnight at 95°C under a nitrogen atmosphere.
  • Step 7 (R)-2-((2-Amino-7-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)pyrido[4,3-d]pyrimidine-4 Preparation of -yl)amino)-2-methylhexan-1-alcohol (2)
  • the preparation method is the same as in Example 2, except that the compound 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (2h) is replaced by 2-(4-methylpiperazine- 1-yl) pyridine-5-boronic acid pinacol ester (CAS: 918524-63-7) (3b), the obtained crude product was separated and purified by preparative chromatographic column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm ; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 6%-17% acetonitrile in 8 minutes; detection wavelength: 220nm), obtain the formic acid of compound 3 Salt.
  • reaction solution was diluted with water (20mL), and then extracted with ethyl acetate (2 ⁇ 20mL).
  • the resulting aqueous phase was concentrated under reduced pressure, and the crude product was separated and purified by reverse-phase column chromatography (column type: Agel C18 column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%-20% acetonitrile in 10 minutes; detection wavelength: 220/254nm), to obtain off-white Solid compound 4b (370mg, 85.04%).
  • the preparation method is the same as in Example 2, except that the compound 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (2h) is replaced by 6-(pyrrolidin-1-yl) Pyridine-3-boronic acid (CAS: 1150114-75-2) (5b), the obtained crude product was separated and purified by preparative chromatographic column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase A: water (0.1 % formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 7%-21% acetonitrile in 8 minutes; detection wavelength: 220nm), the formate salt of compound 5 was prepared.
  • preparative chromatographic column column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase A: water (0.1 % formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient:
  • the preparation method is the same as in Example 2, except that the compound 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (2h) is replaced by 2-(piperidin-1-yl) Pyridine-5-boronic acid pinacol ester (CAS: 852228-08-1) (6b), the obtained crude product was separated and purified by preparative chromatographic column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase A : water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 13%-29% acetonitrile in 8 minutes; detection wavelength: 220nm), the formate salt of compound 6 was obtained.
  • preparative chromatographic column column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase A : water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL
  • the preparation method is the same as in Example 2, except that the compound 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (2h) is replaced by 6-(4-hydroxypiperidine-1 -yl) pyridine-3-boronic acid pinacol ester (CAS: 1251948-86-3) (7b), the obtained crude product was separated and purified by preparative chromatographic column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 10%-32% acetonitrile in 8 minutes; detection wavelength: 254nm), obtained the formic acid of compound 7 Salt.
  • the preparation method is the same as in Example 2, except that the compound 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (2h) is replaced by imidazo[1,2-a]pyridine -6-boronic acid pinacol ester (CAS: 1204742-76-6) (8b), the obtained crude product was separated and purified by preparative chromatographic column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase A: Water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 7%-15% acetonitrile in 8 minutes; detection wavelength: 254nm), the formate salt of compound 8 was obtained.
  • preparative chromatographic column column (column type: SunFire Prep C18 OBD column, 5um, 19*150mm; mobile phase A: Water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient
  • 6-chloropyridine-3-boronic acid pinacol ester 50 mg, 0.209 mmol was dissolved in dimethyl sulfoxide (1 mL), and 1-cyclopropylpiperazine (52.69 mg, 0.418 mmol), stirred at 150° C. for 3 hours under nitrogen atmosphere. After the reaction was complete, add water (20 mL) to quench the reaction, add ethyl acetate (3 ⁇ 20 mL) to the system for extraction, wash the combined organic phase with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , to obtain brown solid compound 9d (72 mg, crude product), which was directly used in the next step without purification.
  • Step 4 (R)-2-((2-Amino-7-(6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl)pyrido[4,3-d]pyrimidine- Preparation of 4-yl)amino)-2-methylhexan-1-ol (9)
  • the preparation method was the same as in Example 9, except that 1-cyclopropylpiperazine was replaced by 1-methylpiperazin-2-one, to prepare compound 10.
  • the preparation method was the same as that of Example 9, except that the compound 1-cyclopropylpiperazine was replaced by 1-ethylpiperazine to prepare compound 11.
  • the preparation method was the same as that of Example 9, except that compound 1-cyclopropylpiperazine was replaced by 1-isopropylpiperazine to prepare compound 12.
  • the preparation method was the same as that of Example 9, except that the compound 1-cyclopropylpiperazine was replaced by 1-(2-methoxyethyl)piperazine to prepare compound 13.
  • the preparation method was the same as in Example 9, except that the compound 1-cyclopropylpiperazine was replaced by 1,2-dimethylpiperazine to prepare compound 14.
  • the preparation method is the same as in Example 9, except that the compound 6-chloropyridine-3-boronic acid pinacol ester is replaced by 4-methyl-6-chloropyridine-3-boronic acid pinacol ester, and 1-cyclopropane Substituting 1-methylpiperazine for 1-methylpiperazine yielded compound 15.
  • the preparation method is the same as in Example 9, except that the compound 6-chloropyridine-3-boronic acid pinacol ester is replaced by 2-methyl-6-chloropyridine-3-boronic acid pinacol ester, and 1-cyclopropane Substituting 1-methylpiperazine for 1-methylpiperazine yielded compound 16.
  • reaction solution was diluted with water (10 mL), and then extracted with ethyl acetate (2 ⁇ 10 mL), and the obtained aqueous phase was concentrated under reduced pressure to obtain brown solid compound 17c (150 mg, crude product), which was directly used in the following step.
  • the preparation method was the same as in Example 9, except that 1-cyclopropylpiperazine was replaced by 4-dimethylaminopiperidine, to obtain compound 18.
  • the preparation method was the same as in Example 9, except that 1-cyclopropylpiperazine was replaced by N-hydroxyethylpiperazine to prepare compound 19.
  • the preparation method was the same as in Example 20, except that 1-n-propylpiperazine dibromide was replaced by 1-(2,2-difluoroethyl)piperazine hydrochloride to prepare compound 21.
  • the preparation method is the same as in Example 22, except that 1-(2-fluoroethyl)piperazine dihydrochloride is replaced by 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride to obtain Compound 23.
  • Compound 24 was prepared in the same manner as in Example 22, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 4-n-propylpiperidine hydrochloride.
  • Compound 25 was prepared in the same manner as in Example 22, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 3-ethoxyazetidine hydrochloride.
  • Compound 26 was prepared in the same manner as in Example 22, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 4-ethoxypiperidine.
  • the preparation method was the same as in Example 22, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by N,N-dipropylazetidin-3-amine to prepare compound 27.
  • the preparation method was the same as in Example 9, except that 1-cyclopropylpiperazine was replaced by 4-diethylaminopiperidine, to obtain compound 28.
  • Compound 29 was prepared in the same manner as in Example 22, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 3-(diethylamino)azetidine dihydrochloride.
  • Compound 31 was prepared in the same manner as in Example 30, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 1-n-propylpiperazine dibromide.
  • Compound 32 was prepared in the same manner as in Example 30, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 1-isopropylpiperazine.
  • Compound 33 was prepared in the same manner as in Example 30, except that 1-(2-fluoroethyl)piperazine dihydrochloride was replaced by 4-dimethylaminopiperidine.
  • the preparation method is the same as that of Example 9, except that 2-(4-cyclopropylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester (9d) is replaced by (1-methylpiperidine-4 -yl)-1H-pyrazole-4-boronic acid pinacol ester (CAS: 1323919-64-7) (35a), to obtain compound 35.
  • the preparation method is the same as in Example 9, except that 2-(4-cyclopropylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester (9d) is replaced by 1-(tetrahydropyran-4- base)-1H-pyrazole-4-boronic acid pinacol ester (CAS: 1040377-03-4) (36a), to obtain compound 36.
  • Step 1 (R)-4-(5-(2-amino-4-((1-hydroxy-2-methylhex-2-yl)amino)pyrido[4,3-d]pyrimidine-7- yl)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester (38b)
  • Step 2 (R)-2-((2-Amino-7-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)amino ) Preparation of -2-methylhexan-1-ol (38)
  • 3-pyridineboronic acid 500.09 mg, 4.069 mmol
  • 5-bromo-2-iodopyridine 1050 mg, 3.699 mmol
  • potassium carbonate 1533.49mg, 11.097mmol
  • tetrakis(triphenylphosphine)palladium 427.39mg, 0.37mmol
  • reaction solution was diluted with water (30 mL), then extracted with ethyl acetate (3 ⁇ 30 mL), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the preparation method was the same as in Example 39, except that 3-pyridineboronic acid was replaced by 4-pyridineboronic acid to prepare compound 40.
  • the preparation method was the same as that of Example 39, except that compound 3-pyridineboronic acid was replaced by 6-methylpyridine-3-boronic acid to prepare compound 41.
  • the preparation method was the same as that of Example 39, except that compound 5-bromo-2,3'-bipyridine (39a) was replaced by 5-bromo-2,2'-bipyridine (42a), to prepare compound 42.
  • Step 1 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-7-(4-chlorobenzyl)-N
  • 2- (2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4-diamine 43a
  • compound 2f 150 mg, 0.26 mmol was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and 4-chlorobenzylboronic acid pinacol ester (CAS: 475250-49 -8) (43b) (264mg, 1.05mmol), potassium carbonate (255mg, 1.83mmol) and tetrakis(triphenylphosphine)palladium (60mg, 0.052mmol). The reaction solution was stirred at 95° C. for 3 hours under nitrogen atmosphere.
  • Step 2 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-N 2 -(2,4-dimethoxy Preparation of benzyl)-7-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrido[4,3-d]pyrimidine-2,4-diamine (43c)
  • compound 43a (92 mg, 0.14 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and (1-pyrrolidinylmethyl) potassium trifluoroborate (37 mg, 0.19mmol), potassium carbonate (57.8mg, 0.41mmol) and XPhos Pd G3 (11.7mg, 0.014mmol). The reaction solution was stirred overnight at 100° C. under a nitrogen atmosphere.
  • Step 3 (R)-2-((2-Amino-7-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrido[4,3-d]pyrimidin-4-yl)amino) - Preparation of 2-methylhexan-1-ol (43)
  • Step 2 Preparation of N 4 -propylpyrido[3,4-d]pyrimidine-2,4-diamine (44)
  • compound 44b (40mg, 0.247mmol) was dissolved in N,N-dimethylformamide (3mL), and Carter’s condensing agent (BOP) (218mg, 0.494mmol), 1,8-diazepine Dicycloundec-7-ene (DBU) (75.1 mg, 0.494 mmol), n-propylamine (29.2 mg, 0.494 mmol), and the reaction liquid were reacted at room temperature for 4 hours under nitrogen atmosphere. After the reaction was completed, it was quenched by adding water (10 mL), and extracted with ethyl acetate (3 ⁇ 20 mL). The organic phases were combined and washed with saturated brine (2 ⁇ 20 mL).
  • BOP condensing agent
  • DBU 1,8-diazepine Dicycloundec-7-ene
  • n-propylamine 29.2 mg, 0.494 mmol
  • the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified with a preparative reverse-phase chromatographic column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min ; Gradient: 47%-53% acetonitrile in 8 minutes; detection wavelength: 254/220nm) to give compound 44 (10.2 mg, 20.8%) as a white solid.
  • the preparation method was the same as that of Example 44, except that n-propylamine was replaced by n-butylamine, and compound 45 was prepared.
  • Compound 46 was prepared in the same manner as in Example 44, except that n-propylamine was replaced by n-pentylamine.
  • Compound 49 was prepared in the same manner as in Example 44, except that n-propylamine was replaced by (R)-2-amino-2-methylbutan-1-ol (49a).
  • Compound 50 was prepared in the same manner as in Example 44, except that n-propylamine was replaced by (R)-2-amino-2-methylpentan-1-ol (50a).
  • Compound 51 was prepared in the same manner as in Example 44, except that n-propylamine was replaced by (R)-2-amino-2-methylheptan-1-ol (51a).
  • Example 52 and Example 53 (R)-2-((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (52) and Preparation of (S)-2-((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (53)
  • Step 1 (R)-N-((1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-2-chloropyrido[3,4-d ] Preparation of pyrimidine-4-amine (52b)
  • 2,4-Dichloropyrido[3,4-d]pyrimidine 52a (100 mg, 0.50 mmol) was dissolved in 1,4-dioxane (2.0 mL) at room temperature.
  • (R)-1-((tert-butyldimethylsilyl)oxy)-2-methylhexan-2-amine (1e) (123mg, 0.50mmol) and N,N-di Isopropylethylamine (0.26 ⁇ L, 1.49 mmol) stirred at room temperature for 2 hours. After the reaction is complete, cool to room temperature. The reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3 ⁇ 20 mL).
  • Step 2 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-N 2 -(2,4-dimethoxy Preparation of benzyl)pyrido[3,4-d]pyrimidine-2,4-diamine (52c)
  • Step 3 Preparation of (R)-2-((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (52d)
  • Step 4 (R)-2-((2-Aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (52) and (S)-2 Preparation of -((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (53)
  • 3-chloro-2-fluoroisonicotinic acid (55a) (1.0g, 5.70mmol) was dissolved in N,N-dimethylformamide (15mL), and cesium carbonate (5.57g, 17.1mmol) was added successively ), guanidine carbonate (1.03g, 5.72mmol), cuprous iodide (217mg, 1.14mmol), and the reaction solution was stirred at 110°C for 4 hours under a nitrogen atmosphere.
  • Step 2 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-8-fluoropyrido[3,4-d ] Preparation of pyrimidine-2,4-diamine (55c)
  • compound 55b (30 mg, 0.167 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (R)-1-((tert-butyldimethylsilyl)oxy) was added successively -2-Methylhex-2-amine (1e) (122mg, 0.50mmol), 1,8-diazabicycloundec-7-ene (76.1mg, 0.50mmol), Carter condensing agent (110mg, 0.25 mmol), and the reaction solution was stirred overnight at room temperature under a nitrogen atmosphere.
  • Step 3 Preparation of (R)-2-((2-amino-8-fluoropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (55)
  • Aqueous ammonia (30 mL) was added to methyl 3-amino-5-fluoroisonicotinate (56a) (900 mg, 5.29 mmol) at room temperature.
  • the reaction was stirred at 60°C for 3 hours.
  • Step 4 (R)-N-((1-((tert-Butyldimethylsilyl)oxy)-2-methylhex-2-yl)-2-chloro-5-fluoropyrido[3 ,4-d] Preparation of pyrimidin-4-amine (56e)
  • reaction solution was diluted with water (15 mL), extracted with ethyl acetate (3 ⁇ 10 mL), and the combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 5 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-N 2 -(2,4-dimethoxy Preparation of benzyl)-5-fluoropyrido[3,4-d]pyrimidine-2,4-diamine (56f)
  • Step 6 Preparation of (R)-2-((2-amino-5-fluoropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (56)
  • the obtained crude product was purified with a preparative chromatographic column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; Gradient: 25%-45% acetonitrile in 8 minutes; detection wavelength: 254/220nm) to give compound 56 (7.30 mg, 43.7%) as a white solid.
  • a preparative chromatographic column column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min; Gradient: 25%-45% acetonitrile in 8 minutes; detection wavelength: 254/220nm) to give compound 56 (7.30 mg, 43.7%) as a white solid.
  • 5-Amino-2-fluoro-4-pyridinecarboxylic acid 57a (1.50 g, 9.62 mmol) was dissolved in thionyl chloride (20 mL) at room temperature. The reaction was refluxed at 80°C for 1 hour. After the reaction was complete, it was directly concentrated under reduced pressure, and the resulting brown oily liquid compound was dissolved in tetrahydrofuran (5 mL), and slowly added dropwise into ammonia water (15 mL) at 0°C, and the reaction solution was stirred at 0°C for 1 hour.
  • Step 1 Preparation of 2-fluoro-5-iodo-4-aminopyridine (58b) and 2-fluoro-3-iodo-4-aminopyridine (58c)
  • Step 1 Preparation of 4-amino-6-fluoro-nicotinic acid methyl ester (59a)
  • Step 1 Preparation of 5-amino-2-chloroisonicotinic acid methyl ester (60b)
  • 5-amino-2-chloropyridine-4-carboxylic acid 60a (25 g, 145 mmol) was dissolved in methanol (300 mL), and then thionyl chloride (100 mL) was added dropwise to the above solution (keep the reaction system The inner temperature is 20-25°C), after the dropwise addition, the temperature was raised to 70°C and stirred overnight. The reaction system was cooled to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was slurried twice with aqueous sodium bicarbonate solution, filtered, and the filter cake was dried to obtain compound 60b (16 g, 59.1%) as a yellow solid.
  • compound 60b (3.0g, 16.1mmol), chloroformamidine hydrochloride (3.7g, 32.2mmol), and dimethyl sulfone (10g) were sequentially added to a 100mL glass bottle, and the reaction solution was heated to 150°C and stirred for 4 Hour. After the reaction was completed, the reaction liquid was diluted with water (100 mL), filtered, and the obtained filter cake was rinsed with water twice, and the obtained filter cake was dried to obtain yellow solid compound 60c (3.7 g, crude product).
  • Step 3 Preparation of 2-((2-amino-6-chloropyridin[3,4-d]pyrimidin-4-yl)amino)hexan-1-ol (60d)
  • Step 4 Preparation of 2-((2-amino-6-(4-chlorobenzyl)pyridin[3,4-d]pyrimidin-4-yl)amino)hexan-1-ol (60e)
  • Step 1 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-6-chloropyrido[3,4-d ] Preparation of pyrimidine-2,4-diamine (61a)
  • compound 60c 300 mg, 1.52 mmol was mixed with (R)-1-((tert-butyldimethylsilyl)oxy)-2-methylhexan-2-amine (1e) (749 mg, 3.05 mmol) was dissolved in N,N-dimethylformamide (2mL), then Carter condensing agent (810mg, 1.83mmol) and 1,8-diazabicycloundec-7-ene (697mg, 4.57mmol ) into the system in turn. The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), and then extracted with ethyl acetate (3 ⁇ 30 mL).
  • Step 2 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-6-(4-chlorobenzyl)pyrido Preparation of [3,4-d]pyrimidine-2,4-diamine (61b)
  • Step 3 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-6-(4-(pyrrolidine-1- Preparation of methyl)benzyl)pyrido[3,4-d]pyrimidine-2,4-diamine (61c)
  • the obtained crude product was separated and purified by preparative chromatographic column (column type: XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase A: water (0.05% ammonia water), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 30%-65% acetonitrile within 8 minutes; detection wavelength: 220 nm), to obtain compound 61 (1.2 mg, 8.3%) as a white solid.
  • Step 1 Preparation of (R)-2-((2-amino-6-chloropyridin[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (62a)
  • compound 60c (300mg, 1.56mmol), (R)-2-amino-2-methylhexan-1-ol (300mg, 2.27mmol), Carter condensing agent (810mg, 1.83mmol), 1,8 - Diazabicycloundec-7-ene (697 mg, 4.59 mmol) was dissolved in N,N-dimethylformamide (5 mL). The reaction was stirred at room temperature for 12 hours.
  • Step 3 (R)-2-((2-amino-6-(4-((dimethylamino)methyl)benzyl)pyridin[3,4-d]pyrimidin-4-yl)amino)-2 - Preparation of methylhexan-1-ol (62)
  • compound 62b (20 mg, 0.05 mmol), potassium (dimethylaminomethyl) trifluoroborate (165 mg, 0.08 mmol), cesium carbonate (49 mg, 0.15 mmol), 2-dicyclohexylphosphine-2,4 , 6-triisopropylbiphenyl (5 mg, 0.01 mmol), palladium acetate (1 mg, 0.005 mmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). The reaction solution was replaced with nitrogen three times, and stirred at 100° C. for 12 hours.
  • the preparation method was the same as that of Example 63, except that the compound trimethylboroxine was replaced by ethyl boroxane to obtain compound 64.
  • compound 62a 40 mg, 0.129 mmol
  • dimethylamine hydrochloride 15.79 mg, 0.194 mmol
  • cesium carbonate 168.27 mg, 0.516 mmol
  • Pd-PEPPSI-IPent Cl -o-picoline CAS1612891-29-8, 10.85 mg, 0.013 mmol
  • 1,4-dioxane 1.5 mL
  • reaction solution was diluted with water (20 mL), extracted with ethyl acetate (3 ⁇ 20 mL), the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained crude product was separated and purified by preparative chromatographic column (column type: XBridge Prep C18 OBD column, 5um, 19*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25mL/min ; gradient: 25%-40% acetonitrile in 8 minutes; detection wavelength: 254/220nm).
  • the product was collected and lyophilized to obtain compound 65 (2.3 mg, 5.43%) as a yellow-green solid.
  • Step 1 (R)-N-((1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-2,6,8-trichloropyrimido[ Preparation of 5,4-d]pyrimidin-4-amine (66b)
  • Step 3 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-6-chloro-N 2 -(2,4 -dimethoxybenzyl)pyrimido[5,4-d]pyrimidine-2,4-diamine (66d) and (R)-N 8 -(1-((tert-butyldimethylsilyl) Oxy)-2-methylhex-2-yl)-6-chloro-N 2 -(2,4-dimethoxybenzyl)pyrimido[5,4-d]pyrimidine-2,8-di Preparation of amine (67a)
  • compound 66c (300mg, 0.675mmol) was dissolved in 1,4-dioxane (3mL), and N,N-diisopropylethylamine (174mg, 1.35mmol) and 2,4- Dimethoxybenzylamine (113 mg, 0.675 mmol).
  • the reaction system was stirred at 100°C for 3 hours.
  • water (20 mL) was added to quench the reaction
  • ethyl acetate (3 ⁇ 20 mL) was added to the system for extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 4 (R)-N 4 -(1-((tert-butyldimethylsilyl)oxy)-2-methylhex-2-yl)-N 2 -(2,4-dimethoxy benzyl)pyrimido[5,4-d]pyrimidine-2,4-diamine (66e) and (R)-N 8 -(1-((tert-butyldimethylsilyl)oxy)- Preparation of 2-methylhex-2-yl)-N 2 -(2,4-dimethoxybenzyl)pyrimido[5,4-d]pyrimidine-2,8-diamine (67b)
  • Step 5 (R)-2-((2-aminopyrimido[5,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (66) and (R)-2 Preparation of -((6-aminopyrimido[5,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (67)
  • compound 68a (2.4 g, 12.68 mmol) was dissolved in dry tetrahydrofuran (80 mL), the reaction solution was cooled to -78 ° C, and boron trifluoride ether solution (3.3 mL) was slowly added dropwise under nitrogen atmosphere, Keep at -78°C for 1.5 hours. Then a solution of n-butylmagnesium chloride in tetrahydrofuran (13.5 mL, 2 mol/L) was slowly added dropwise, and the reaction was maintained at -78°C for 2 hours.
  • Step 3 Preparation of (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexa-1,1-dideutero-1-ol (68c)
  • Step 5 (R)-2-((2-Aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexan-1,1-dideutero-1-ol (68 ) preparation
  • compound 68d (90mg, 0.67mmol) and 2-aminopyridin[3,4-d]pyrimidin-4(3H)-one (44b) (100mg, 0.62mmol) were dissolved in N,N-dimethyl Add formamide (2 mL), add Carter's condensing agent (327 mg, 0.74 mmol) and 1,8-diazabicycloundec-7-ene (282 mg, 1.85 mmol), and react at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), and then extracted with ethyl acetate (3 ⁇ 8 mL).
  • Step 1 Preparation of (R)-3-ethyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (69a)
  • compound 69a (2.3 g, 11.32 mmol) was dissolved in dry tetrahydrofuran (75 mL), the reaction solution was cooled to -78 ° C, and boron trifluoride ether solution (3.0 mL) was slowly added dropwise under nitrogen atmosphere, Keep at -78°C for 1.5 hours. Then a solution of n-butylmagnesium chloride in tetrahydrofuran (11.9 mL, 2 mol/L) was slowly added dropwise, and the reaction was maintained at -78°C for 2 hours.
  • Step 3 Preparation of (R)-2-ethyl-2-(((R)-2-hydroxy-1-phenylethyl)amino)hexan-1-ol (69c)
  • Step 5 Preparation of (R)-2-((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol (69)
  • compound 69d (202mg, 1.39mmol) and 2-aminopyridin[3,4-d]pyrimidin-4(3H)-one (44b) (150mg, 0.93mmol) were dissolved in N,N-dimethyl Add formamide (3 mL), add Carter's condensing agent (491 mg, 1.11 mmol) and 1,8-diazabicycloundec-7-ene (422 mg, 2.78 mmol), and react at room temperature for 16 hours.
  • reaction solution was diluted with water (10 mL), extracted with ethyl acetate (3 ⁇ 8 mL), the organic phases were combined, washed with saturated brine (3 ⁇ 15 mL), and dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure, and the obtained crude product was separated and purified by preparative chromatographic column (column type: XBridge Shield RP18OBD Column, 5um, 19*150mm; mobile phase A: water (0.05% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL/min; gradient: 25%-50% acetonitrile in 8 minutes; detection wavelength: 254/220 nm), the product 69 was obtained as a white solid (16.3 mg, 6.0%).
  • Test Example 1 The agonistic activity of the compound of the present invention on hTLR8 and hTLR7
  • HEK-Blue TM hTLR8 cells and HEK-Blue TM hTLR7 cells purchased from Invivogen were used.
  • the cells were co-transfected with hTLR8 or hTLR7 gene and a reporter gene of secreted alkaline phosphatase (SEAP) in HEK293 cells.
  • SEAP secreted alkaline phosphatase
  • the SEAP gene is placed downstream of the IFN- ⁇ minimal promoter, and the IFN- ⁇ minimal promoter is composed of five NF- ⁇ B and AP-1 binding sites.
  • Stimulators of hTLR8 or hTLR7 will activate NF- ⁇ B and AP-1 promoters to produce SEAP, and evaluate the effect of compounds by detecting SEAP levels.
  • Compound plate preparation starting from 2 mM, the compound to be tested was diluted 3 times with DMSO and diluted 10 gradients. Take 2 ⁇ L of diluted compound and add 38 ⁇ L HEK-BlueTM detection reagent for 20-fold intermediate dilution. Wells with cells plus 0.5% DMSO served as negative control wells for low readings. Cells were added with 1 ⁇ M GS-9688 (refer to WO2016141092A1 synthesis route) wells as positive control wells with high readings.
  • Activity % (compound reading - negative well reading) / (positive well reading - negative well reading) x 100.
  • TLR8/TLR7 The agonistic activity of the compounds of the present invention on TLR8/TLR7 is shown in Table 1 below.
  • the compound of the present invention can selectively activate TLR8.
  • Test Example 2 Research on the absorption mechanism of the compound of Example 52
  • Dilute Caco-2 cells (American Type Culture Collection, HTB-37) with culture medium to 6.86 ⁇ 105 cells/mL, and add 50 ⁇ L of cell suspension to a 96-well Transwell plate (Cat.No.3391) in the filter hole.
  • the cell culture plates were incubated for 14-18 days in a cell culture incubator at 37°C, 5% CO 2 , 95% relative humidity. Change the cell culture medium every other day.
  • Transepithelial electrical resistance (TEER) across the monolayer was measured using the Millicell Epithelial Volt-Ohm measurement system (Millipore, USA). Return the plate to the incubator after the measurement is complete.
  • the TEER value is calculated according to the following formula:
  • TEER measurement value (ohms) x membrane area (cm 2 ) TEER value (ohm ⁇ cm 2 )
  • the TEER value is greater than 230ohm ⁇ cm 2 , indicating that the Caco-2 monolayer film is qualified and can be used for subsequent tests.
  • Example 52 The compound of Example 52 was accurately weighed, dissolved in DMSO to prepare a stock solution with a concentration of 2 mM, and diluted with HBSS (Gibico, 10 mM HEPES, pH 7.4) to obtain a 10 ⁇ M working solution. Metoprolol and digoxin were used as control compounds.
  • the monolayer was washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4) before the experiment. The plates were then incubated at 37°C for 30 minutes.
  • the plates were incubated at 37°C for 2 hours. At the end of the incubation, pipette 50 ⁇ L of the solution from the donor side (Ap ⁇ Bl's apical compartment, Bl ⁇ Ap's basolateral compartment) and the recipient side (Ap ⁇ Bl's basolateral compartment and Bl ⁇ Ap's apical compartment). The samples were transferred to the wells of a new 96-well plate, and then 200 ⁇ L of acetonitrile containing IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) was added.
  • acetonitrile containing IS 100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide
  • P app is the apparent permeability (cm/s ⁇ 10 -6 )
  • dQ/dt is the rate of drug transport (pmol/s)
  • A is the surface area of the membrane (cm 2 )
  • D0 is the initial donor concentration (nM ; pmol/cm 3 )
  • P app(BA) represents the apparent permeability coefficient from the basolateral to the apex direction
  • P app(AB) represents the apparent permeability coefficient from the apex to the basolateral direction
  • the compound of Example 52 has a good permeability coefficient, and the risk of efflux transporter substrate is low.
  • the compound in Example 4 of WO2018045144A1 has low permeability and high efflux ratio, and is likely to be an efflux transporter substrate.
  • the in vitro Caco-2 test results of the compound Example 52 of the present invention show better permeability than the compound of Example 4 of WO2018045144A1.
  • This experiment aims to evaluate the pharmacokinetic behavior of the compound of Example 52 after intravenous infusion or gavage administration in rats.
  • Intravenous infusion the test compound is prepared as a clear solution of 0.5 mg/ml, and the solvent is 2% ethanol/40% polyethylene glycol 300/58% 0.01 molar hydrochloric acid;
  • intragastric administration the test compound is prepared as 0.5 mg/ml clear solution in 2% ethanol/40% polyethylene glycol 300/58% 0.01 molar hydrochloric acid.
  • Plasma concentrations of test compounds were determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma and tissue concentrations were processed using the non-compartmental model of the pharmacokinetic software WinNonlin TM Version 8.3 (Pharsight, Mountain View, CA), and pharmacokinetic parameters were calculated using the linear log trapezoidal method.
  • Table 5 below shows the intestinal bioavailability of the compound of Example 52 at a dose of 5 mg/kg in rats and the relevant parameters of the liver first-pass study.
  • the compound of Example 52 has low systemic oral bioavailability, but high intestinal bioavailability, can be specifically enriched in liver tissue, and is mainly excreted through the intestinal tract.
  • the purpose of this test is to evaluate the pharmacodynamics of the compound of Example 52 after oral administration in male cynomolgus monkeys.
  • test compound was formulated at 10 mg/mL, and the vehicle was 10% ethanol, 40% polyethylene glycol 300, and 50% deionized water. Weigh an appropriate amount of the test compound in an appropriate amount of ethanol, and dissolve the mixture completely under stirring and/or ultrasonication. An appropriate volume of polyethylene glycol 300 is then added with stirring. Finally, the appropriate volume of deionized water is added with stirring to obtain the final concentration of the formulation. Formulations will be stirred at room temperature for at least 10 minutes prior to and during dosing.
  • MSD GOLD Read Buffer B add 150 ⁇ L MSD GOLD Read Buffer B to each well, and use MSD reader (model: MESO SECTOR S600) to read the U-PLEX 96 microwell plate.
  • Figure 1 shows the parameters of the compound of Example 52 in the serum of cynomolgus monkeys.

Abstract

L'invention concerne des dérivés d'amines aromatiques, leur procédé de préparation et leur utilisation médicale. En particulier, l'invention concerne un composé représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'agoniste du récepteur de type Toll (TLR) pour le traitement de maladies liées à l'activité de TLR8. Les définitions de chaque groupe dans la formule générale (I) sont telles que définies dans la description.
PCT/CN2022/128963 2021-11-05 2022-11-01 Dérivés d'amines aromatiques et leur procédé de préparation et leur utilisation médicale WO2023078241A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107108615A (zh) * 2015-03-04 2017-08-29 吉利德科学公司 Toll样受体调节性4,6‑二氨基‑吡啶并[3,2‑D]嘧啶化合物
CN108069963A (zh) * 2017-11-17 2018-05-25 清华大学 吡啶并嘧啶衍生物或其盐及其制法、药物组合物和用途
CN109923106A (zh) * 2016-09-02 2019-06-21 吉利德科学公司 toll样受体调节剂化合物
WO2020007275A1 (fr) * 2018-07-03 2020-01-09 江苏恒瑞医药股份有限公司 Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation médicale
WO2020057604A1 (fr) * 2018-09-19 2020-03-26 正大天晴药业集团股份有限公司 Agoniste de tlr8
WO2020078455A1 (fr) * 2018-10-19 2020-04-23 南京明德新药研发有限公司 Agoniste tlr8

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107108615A (zh) * 2015-03-04 2017-08-29 吉利德科学公司 Toll样受体调节性4,6‑二氨基‑吡啶并[3,2‑D]嘧啶化合物
CN109923106A (zh) * 2016-09-02 2019-06-21 吉利德科学公司 toll样受体调节剂化合物
CN108069963A (zh) * 2017-11-17 2018-05-25 清华大学 吡啶并嘧啶衍生物或其盐及其制法、药物组合物和用途
WO2020007275A1 (fr) * 2018-07-03 2020-01-09 江苏恒瑞医药股份有限公司 Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation médicale
WO2020057604A1 (fr) * 2018-09-19 2020-03-26 正大天晴药业集团股份有限公司 Agoniste de tlr8
WO2020078455A1 (fr) * 2018-10-19 2020-04-23 南京明德新药研发有限公司 Agoniste tlr8

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