WO2022171018A1 - Inhibiteur d'amine de benzopyrimidine ou de pyridopyrimidine substitué, son procédé de préparation et son utilisation - Google Patents

Inhibiteur d'amine de benzopyrimidine ou de pyridopyrimidine substitué, son procédé de préparation et son utilisation Download PDF

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WO2022171018A1
WO2022171018A1 PCT/CN2022/074823 CN2022074823W WO2022171018A1 WO 2022171018 A1 WO2022171018 A1 WO 2022171018A1 CN 2022074823 W CN2022074823 W CN 2022074823W WO 2022171018 A1 WO2022171018 A1 WO 2022171018A1
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substituted
alkyl
group
alkoxy
cycloalkyl
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PCT/CN2022/074823
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Chinese (zh)
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吕彬华
崔大为
张青
柴传柯
梁辉
张冬腾
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Priority claimed from CN202110178999.9A external-priority patent/CN114907324A/zh
Priority claimed from CN202110790488.2A external-priority patent/CN115611865A/zh
Priority claimed from PCT/CN2021/125084 external-priority patent/WO2022083657A1/fr
Application filed by 苏州泽璟生物制药股份有限公司, 上海泽璟医药技术有限公司 filed Critical 苏州泽璟生物制药股份有限公司
Publication of WO2022171018A1 publication Critical patent/WO2022171018A1/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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, in particular to a substituted benzo or pyridopyrimidine amine inhibitor and a preparation method and application thereof.
  • Lung cancer is one of the important causes of human cancer death.
  • Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the global NSCLC market in 2016 was about US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
  • the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
  • chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects.
  • molecularly targeted drugs have gradually become a research hotspot due to their obvious advantages such as high selectivity, relatively small toxic and side effects, and the ability to achieve precise treatment.
  • NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocartetinib, etc.) Ni et al), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimert
  • KRAS mutations occur in 20-40% of lung adenocarcinomas, and this prevalence is higher in Western (vs Asian) populations (26% vs 11%) and in smokers (vs non-smokers) ( 30% vs 10%).
  • the most common mutations occurred in codons 12 and 13, and the most common mutations included G12C, G12V, and G12D. So far, there are still no approved drugs targeting KRAS mutations on the market.
  • the KRAS protein transitions between inactive and activated states.
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • activated state and can activate downstream signaling pathways.
  • GEF guanine nucleotide exchange factor
  • GAP GTPase activating protein
  • SOS proteins are mainly found to be involved in tumors.
  • the SOS protein is widely expressed in vivo and contains two isoforms, SOS1 and SOS2.
  • SOS 1 plays a key role in mutant KRAS activation and oncogenic signaling. Decreased levels of SOS1 resulted in decreased proliferation and survival in KRAS-mutated tumor cells, but not in KRAS wild-type cell lines. The effect of SOS1 deletion could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role for SOS1 GEF activity in KRAS mutant cancer cells (see WO2019122129A1).
  • SOS1 target proteins are pathologically associated with a variety of diseases, there is a need for novel SOS1 inhibitors for clinical treatment.
  • Highly selective and highly active SOS1 inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a substituted benzo or pyridopyrimidine amine compound of general formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, Hydrate, Solvate or Prodrug:
  • X is selected from: CR 6 or N, wherein, R 6 is selected from: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Y is selected from the group consisting of O, NH, NR7 , S, SO, SO2, C ⁇ C, substituted or unsubstituted 4-20 membered heterocyclyl, substituted or unsubstituted C6 - C14 aryl or 5-14-membered heteroaryl, wherein R 7 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Z is selected from the group consisting of substituted or unsubstituted: bond, substituted or unsubstituted C 1 -C 18 alkylene;
  • W is selected from the group consisting of substituted or unsubstituted groups: bond, C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, OR 11 , NR 11 R 12 , SO 2 , NR 12 SO 2 , CO or NR 12 CO;
  • R 11 is independently selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, C 3 -C 20 cycloalkylene C 1 -C 18 alkylene, 4-20 membered heterocyclylene C 1 -C 18 alkylene, C 6 -C 14 aryl or 5-14 membered heteroaryl;
  • R 12 is independently selected from substituted or Unsubstituted groups of the following group: hydrogen, deuterium, C1 - C6 alkyl or C3 - C6 cycloalkyl;
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 18 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, ester group, COOH, CONH 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl group, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkyl-O-, C 1 -C 18 alkoxy, deuterated C 1 -C 18 Alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclyl, 4-20-membered heterocyclyl-O-, Halogen, oxo C 1 -C 6 alkyl, nitro, hydroxyl, cyano, C 2 -C 6 ester, C 1 -C 6 amine, C 1 -C 6 acyl
  • n are each independently 0, 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4, or 5;
  • q 1 or 2;
  • W is C 3 -C 20 cycloalkylene or 4-20 membered heterocyclylene;
  • R 1 is not hydrogen, Deuterium, halogen, cyano, R 8 , O(CH 2 ) p R 8 , COR 8 , -C(O)OR 8 , NR 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O ) R 9 , -NR 8 C(O)NR 9 R 10 .
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, and hydrates , solvates or prodrugs:
  • X is selected from: CR 6 or N, wherein, R 6 is selected from: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Y is selected from the group consisting of O, NH, NR 7 , S, SO, SO 2 , C ⁇ C, wherein R 7 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Z is selected from the group consisting of substituted or unsubstituted groups: bonds, substituted or unsubstituted C 1 -C 18 alkylene (preferably deuterated C 1 -C 18 alkylene or halogenated C 1 -C 18 alkylene alkyl);
  • W is selected from the group consisting of substituted or unsubstituted groups: bond, C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, OR 11 , NR 11 R 12 , SO 2 , NR 12 SO 2 , CO or NR 12 CO;
  • R 11 is independently selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, C 3 -C 20 cycloalkylene C 1 -C 18 alkylene, 4-20 membered heterocyclylene C 1 -C 18 alkylene, C 6 -C 14 aryl or 5-14 membered heteroaryl;
  • R 12 is independently selected from substituted or Unsubstituted groups of the following group: hydrogen, deuterium, C1 - C6 alkyl or C3 - C6 cycloalkyl;
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 18 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, ester group, COOH, CONH 2 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl group, halogenated C 1 -C 18 alkylhydroxyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkyl-O-, C 1 -C 18 alkoxy, deuterated C 1 -C 18 Alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclyl, 4-20-membered heterocyclyl-O-, Halogen, oxo C 1 -C 6 alkyl, nitro, hydroxyl, cyano, C 2 -C 6 ester, C 1 -C 6 amine, C 2 -C 6 amido,
  • n are each independently 0, 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4, or 5;
  • q 1 or 2;
  • W is C 3 -C 20 cycloalkylene or 4-20 membered heterocyclylene;
  • R 1 is not hydrogen, Deuterium, halogen, cyano, R 8 , O(CH 2 ) p R 8 , COR 8 , -C(O)OR 8 , NR 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O ) R 9 , -NR 8 C(O)NR 9 R 10 .
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, and hydrates , solvates or prodrugs:
  • X is selected from: CR 6 or N, wherein, R 6 is selected from: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Y is selected from the group consisting of O, NH, NR 7 , S, SO, SO 2 , C ⁇ C, wherein R 7 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Z is selected from the group consisting of substituted or unsubstituted groups: bond, C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene or halogenated C 1 -C 18 alkylene;
  • W is selected from the group consisting of substituted or unsubstituted groups: bond, C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, OR 11 , NR 11 R 12 , SO 2 , NR 12 SO 2 , CO or NR 12 CO;
  • R 11 is independently selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, C 3 -C 20 cycloalkylene C 1 -C 18 alkylene or 4-20 membered heterocyclylene C 1 -C 18 alkylene;
  • R 12 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 18 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, and 4-6 membered heterocyclic group;
  • substitution refers to being substituted by one or more (such as 2, 3, 4) groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, Halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl hydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, Halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, oxo, nitro, hydroxyl, cyano, ester group, amine group, amide group, sulfonamide group or urea group;
  • n are each independently 0, 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4, or 5;
  • q 1 or 2;
  • Y is selected from: O, NH, NR 7 , and Z is a bond
  • W is a C 3 -C 20 cycloalkylene group or a 4-20-membered heterocyclic group
  • R 1 is not hydrogen, deuterium, Halogen, cyano, R 8 , O(CH 2 ) p R 8 , COR 8 , -C(O)OR 8 , NR 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9. -NR 8 C(O)NR 9 R 10 .
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, and hydrates , solvates or prodrugs:
  • X is selected from: CR 6 or N, wherein, R 6 is selected from: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Y is selected from the group consisting of O, NH, or NR 7 , wherein R 7 is selected from: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl;
  • Z is selected from the group consisting of substituted or unsubstituted C 1 -C 18 alkylene, deuterated C 1 -C 18 alkylene, or halogenated C 1 -C 18 alkylene;
  • W is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, OR 11 , NR 11 R 12 , SO 2 , NR 12 SO 2 , CO or NR 12 CO;
  • R 11 is independently selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, C 3 -C 20 cycloalkylene C 1 -C 18 alkylene, or 4-20-membered heterocyclylene C 1 -C 18 alkylene;
  • R 12 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 1 , R 2 are independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, -(CH 2 ) m R 8 , -(CH 2 ) m O(CH 2 ) p R 8 , -(CH 2 ) m SR 8 , -(CH 2 ) m COR 8 , -(CH 2 ) m C(O)OR 8 , -(CH 2 ) m S(O) q R 8 , -(CH 2 ) m NR 5 R 8 , -(CH 2 ) m C(O)NR 8 R 9 , -(CH 2 ) m NR 8 C(O)R 9 , -(CH 2 ) m NR 8 C(O)NR 9 R 10 , -( CH 2 ) m S(O) q NR 8 R 9 , -(CH 2 ) m NR 8 S(O) q R 9 , -(CH 2
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 18 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 4 and R 5 are independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl base, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy Oxy group, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamido or Urea group;
  • n are each independently 0, 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4, or 5;
  • q 1 or 2.
  • n1 0, 1, 2, 3, 4 or 5;
  • n'1 0, 1, 2, 3, 4 or 5;
  • p1 is 0, 1, 2, 3, 4, or 5;
  • q1 is 1 or 2;
  • the substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 Alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido , sulfonamide group or urea group.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, hal
  • Y is selected from: O, NH or NR 7 , and Z is a bond, W is a C 3 -C 20 cycloalkylene group or a 4-20-membered heterocyclic group; R 1 is not hydrogen , deuterium, halogen, cyano, and m1 is not 0.
  • n2 0, 1, 2, 3, 4 or 5;
  • n'2 is 0, 1, 2, 3, 4 or 5;
  • p2 is 0, 1, 2, 3, 4, or 5;
  • q2 is 1 or 2;
  • the substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 Alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido , sulfonamide group or urea group.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, hal
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by general formula (II):
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, W, and n are defined as described above.
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by the general formula (III):
  • R 1 , R 2 , R 3 , X, Y, Z, W, and n are defined as described above.
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by the general formula (IV):
  • R 1 , R 2 , R 3 , R 6 , X, Y, Z, W, and n are as described above.
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by general formula (V):
  • R 1 , R 2 , R 3 , R 6 , Z, W, and n are as described above.
  • Z is selected from the group consisting of substituted or unsubstituted groups: bond, C 1 -C 6 alkylene, deuterated C 1 -C 6 alkylene or halogenated C 1 -C 6 alkylene; wherein, the substitution refers to substitution by one or more groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, Amine group, amide group, s
  • W is selected from the following group: bond, substituted or unsubstituted C 3 -C 12 cycloalkylene, substituted or unsubstituted 4-12-membered heterocyclylene, OR 11 , NR 11 R 12 , SO 2 , NR 12 SO 2 , CO or NR 12 CO;
  • R 11 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 12 cycloalkylene, 4-12-membered heterocyclylene, C 3 -C 12 cycloalkylene C 1 -C 6 alkylene Alkyl, 4-12-membered heterocyclylene C 1 -C 6 alkylene, C 6 -C 14 aryl or 5-14-membered heteroaryl; preferably, R 11 is selected from the group consisting of substituted or unsubstituted Group: C 3 -C 6 cycloalkylene, 4-6 membered heterocyclylene, C 3 -C 6 cycloalkylene C 1 -C 3 alkylene, 4-6 membered heterocyclylene C 1 -C 3 alkylene, C 6 -C 14 aryl or 5-14 membered heteroaryl;
  • R 12 is independently selected from the group consisting of substituted or unsubstituted: hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • substitution refers to being substituted by one or more (such as 2, 3, 4) groups selected from the group consisting of: deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, Amine, amide, sulfonamide or urea group;
  • R 1 is not hydrogen, deuterium, halogen, cyano, R 8 , O(CH 2 ) p R 8 , COR 8 , -C(O)OR 8 , NR 8 R 9 , C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 .
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by formula (VI):
  • R 13 and R 14 are each independently selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, oxo, nitro, Hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups;
  • Ring C is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 12 cycloalkylene, 4-12 membered heterocyclylene;
  • substitution refers to substitution with one or more groups selected from the group consisting of hydrogen, deuterium, C1 - C18 alkyl, deuterated C1 - C18 alkyl, halo C1 - C18 alkyl , halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy base, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido, sulfo amide group or urea group;
  • t is 1, 2, 3, 4, 5 or 6;
  • R 1 , R 3 , R 6 , R 8 , R 9 , R 10 , p, q and n are as defined above.
  • Y 1 and Y 2 are each independently selected from: NR b , O;
  • R m is independently selected from: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- 10-membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide and ureido;
  • R b is independently selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered Heterocyclyl, SO 2 R 30 , COR 30 , ester group;
  • R 30 is each independently selected from: hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted 4-6 membered heterocyclyl;
  • n1 0, 1, 2, 3 or 4;
  • n2 is 1, 2, 3 or 4;
  • substitution refers to being substituted by one or more (such as 2, 3, 4) groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, Halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, Halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclyl, halogen, oxo, nitro, hydroxyl, cyano, ester group, amine group, amide group, sulfonamide group or urea group.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, Halogenated C 1 -C 6
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by formula (VII):
  • R 16 and R 17 are each independently selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, oxo, nitro, Hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups;
  • R 18 is selected from: OR 11 , NR 11 R 12 , NR 12 SO 2 R 2 , COR 2 or NR 12 COR 2 ;
  • R 11 is independently selected from: substituted C 3 -C 12 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl, substituted or unsubstituted C 3 -C 12 cycloalkylene C 1 -C 6 alkylene, substituted or unsubstituted 4-12 membered heterocyclylene C 1 -C 6 alkylene , substituted or unsubstituted C 6 -C 14 aryl, substituted or unsubstituted 5-14-membered heteroaryl;
  • R 12 is independently selected from the group of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • substitution in R 8 , R 9 and R 10 refers to substitution by one or more groups selected from the group consisting of C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclyl, halogen, oxo, Nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea groups;
  • t is 1, 2, 3, 4, 5 or 6;
  • substitution refers to being substituted by one or more groups selected from the following group: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine group, amide group, sulfonamide group or urea group;
  • R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , R 10 , m, p and q are as defined above.
  • the R 1 is selected from the group consisting of H, cyano, halogen, -(CH 2 ) m R 8 , -(CH 2 ) m O(CH 2 ) p R 8 , -( CH 2 ) m SR 8 , -(CH 2 ) m S(O) q R 8 , -(CH 2 ) m (C ⁇ C)R 8 ; wherein, H in CH 2 can be optionally substituted; R 8 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, C 1 -C 18 alkyl, C 1 -C 18 alkoxy, C 3 -C 8 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 14 -aryl or 5-14-membered heteroaryl.
  • R 1 is selected from the group consisting of halogen, cyano, -(CH 2 ) m R 8 , -(CH 2 ) m (C ⁇ CH), -(CH 2 ) m (C ⁇ C ) R 8 , -(CH 2 ) m O(CH 2 ) p R 8 , preferably R 8 is substituted or unsubstituted C 1 -C 18 alkyl (preferably C 1 -C 6 alkyl).
  • R 1 is selected from the group consisting of H, cyano, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, Halogenated C 1 -C 6 alkyl O-, deuterated C 1 -C 6 alkyl O-, substituted or unsubstituted C 3 -C 6 cycloalkyl O-, substituted or unsubstituted 4-6 membered hetero Cyclic O-, C 1 -C 6 alkoxy C 1 -C 6 alkyl O-, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted benzene base O-, substituted or unsubstituted 5-6-membered heteroaryl O-, substituted or unsubstituted C 2 -C 6 alkynyl; wherein, the substitution
  • R 18 is selected from: OR 11 , NR 11 R 12 or NR 12 SO 2 R 2 ; wherein, R 11 is independently selected from: substituted C 3 -C 12 cycloalkyl , substituted or unsubstituted 4-12 membered heterocyclyl, substituted or unsubstituted C 3 -C 12 cycloalkylene C 1 -C 6 alkylene, substituted or unsubstituted 4-12 membered heterocyclylene C 1 - C6 alkylene, substituted or unsubstituted C6 - C14 aryl, substituted or unsubstituted 5-14 membered heteroaryl; R12 is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl;
  • R 18 is selected from: -(CH 2 ) m O(CH 2 ) p R 8 ; wherein, H in CH 2 can be optionally substituted; R 8 is selected from: substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 3 -C 20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocyclic group; preferably, R 8 is substituted or unsubstituted C 1 -C 18 alkyl (preferably is C 1 -C 6 alkyl);
  • substitution refers to substitution by one or more (eg 2, 3, 4) groups selected from the group consisting of deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, halogenated C1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine , amide group, sulfonamide group or urea group.
  • groups selected from the group consisting of deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, halogenated C1 -C 6 alkyl,
  • R 8 is selected from: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, deuterium Substituted C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, 4-12 membered heterocyclyl, deuterated 4-12 membered heterocyclyl, halogenated 4-12 membered heterocyclyl.
  • R 8' is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, deuterated C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, 4-12 membered heterocyclyl, deuterated 4 -12-membered heterocyclyl, halogenated 4-12-membered heterocyclyl, C6 - C14 -aryl or substituted or unsubstituted 5-14-membered heteroaryl; the above substitution refers to one or more selected from the group below One (eg 2, 3, 4) group substitution: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C
  • R 3 is selected from: substituted C 6 -C 14 aryl or substituted 5-14-membered heteroaryl; the substitution refers to being substituted by one or more groups selected from the following group : R 3a , hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl hydroxyl, C 3 - C 20 cycloalkyl, C 3 -C 20 cycloalkyl-O-, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 -aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclyl, 4-20-membered heterocyclyl-O-, halogen, oxo, nitro, hydroxyl, cyano, ester
  • R 3a is selected from: C 1 -C 18 alkyl substituted by hydroxy, C 1 -C 18 haloalkyl substituted by hydroxy, C 1 -C 18 deuterated alkyl substituted by hydroxy, C 1 -C 18 substituted by alkoxy C 18 alkyl, alkoxy substituted C 1 -C 18 haloalkyl, alkoxy substituted C 1 -C 18 deuterated alkyl, cycloalkyloxy substituted C 1 -C 18 alkyl, cycloalkane C 1 -C 18 haloalkyl substituted by yloxy, C 1 -C 18 deuterated alkyl substituted by cycloalkyloxy, C 1 -C 18 alkyl substituted by heterocyclyloxy, heterocyclyloxy Substituted C 1 -C 18 haloalkyl, heterocyclyloxy substituted C 1 -C 18 deuterated alkyl, cycloalkyl substituted C 1 -C
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by formula (VIIA):
  • R 16a , R 16b , R 17a , R 17b are each independently selected from: H, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogen, oxygen substituted group, nitro group, hydroxyl group, cyano group, ester group, amine group, amide group, sulfonamide group or urea group;
  • R s6 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl , deuterated C 3 -C 20 cycloalkyl, halogenated C 3 -C 20 cycloalkyl, 4-20-membered heterocyclyl, deuterated 4-20-membered heterocyclyl, halogenated 4-20-membered heterocyclyl ;
  • substitution refers to substitution by one or more (eg 2, 3, 4) groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide group, sulfonamide group or urea group;
  • R 1 , R 3 , and R 6 are as defined above.
  • R s6 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 12 -cycloalkyl, deuterated C 3 -C 12 -cycloalkyl, halogenated C 3 -C 12 -cycloalkyl, 4-12-membered heterocyclyl, deuterated 4-12-membered heterocyclyl, halogenated 4-12 membered heterocyclyl;
  • substitution refers to substitution by one or more (eg 2, 3, 4) groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl, 4-6-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide group, sulfonamide group or urea group.
  • groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by formula (VIIB):
  • R s1 , R s2 , R s3 , or R s4 are the same or different, each independently selected from: H, D, halogen, NH 2 , NHCOH, or NHCOCH 3 ;
  • R s5 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl , deuterated C 3 -C 20 cycloalkyl, halogenated C 3 -C 20 cycloalkyl, 4-20-membered heterocyclyl, deuterated 4-20-membered heterocyclyl, halogenated 4-20-membered heterocyclyl ;
  • R s6 is defined as above;
  • substitution refers to substitution by one or more (eg 2, 3, 4) groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl, 4-6-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide group, sulfonamide group or urea group.
  • groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6
  • R s5 is selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 12 -cycloalkyl, deuterated C 3 -C 12 -cycloalkyl, halogenated C 3 -C 12 -cycloalkyl, 4-12-membered heterocyclyl, deuterated 4-12-membered heterocyclyl, halogenated 4-12 membered heterocyclyl;
  • substitution refers to substitution by one or more (eg 2, 3, 4) groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5-10-membered heteroaryl, 4-6-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide group, sulfonamide group or urea group.
  • groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halogenated C 1 -C 6
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure of formula (VIII):
  • n, R 1 , R 2 , R 3 , R 6 and W are as defined above.
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which have the structures shown in formula (IX-A) and (IX-B):
  • R 2 , R 3 , R 8 , R 9 , X, Y, Z, W, n and q are as defined above.
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug, which has the structure represented by formula (X):
  • R 8 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkyl or 4-20-membered heterocyclic group;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 Alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido , sulfonamide group or urea group;
  • R 2 , R 3 , X, Y, Z, W, n and q are as defined above.
  • R 8 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 6 cycloalkyl or 4-6 membered heterocyclic group; wherein, the substitution refers to being selected from the group Substituted with one or more groups of: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl Hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-6 membered heterocyclyl, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido.
  • Z and W are both bonds.
  • Y is O
  • Z and W are bonds.
  • R 3 is selected from the group of substituted groups: phenyl, pyridyl, pyrimidinyl, pyridazinyl; wherein, the substitution refers to one or more selected from the group (such as 2, 3, 4) Group substitution: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 1 -C6alkoxy, deuterated C1 - C6alkoxy, halogenated C1 - C6alkoxy , halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide group, sulfonamide group or ureido group; preferably, the substitution is selected from halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 1 -C 6 alkoxy
  • R 1 is methoxy
  • * represents R or S configuration.
  • R is selected from:
  • R 3 is selected from:
  • R 6 is selected from: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, Z, W and n are specific groups corresponding to each specific compound in the embodiment.
  • substituted benzo- or pyrido-pyrimidine amine compounds having the structure of general formula (I), their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug selected from the group consisting of:
  • the compound is preferably the compound prepared in the examples.
  • the second aspect of the present invention provides a substituted benzo or pyridopyrimidine amine compound of general formula (I) structure, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, A method of hydrate, solvate or prodrug comprising the steps of:
  • R' is selected from: halogens, OTs or OMs;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W and n are as defined above.
  • the first base is potassium carbonate or cesium carbonate or the like.
  • the second base is TEA or DIPEA or the like.
  • the third base is TEA or DIPEA or the like.
  • the third aspect of the present invention provides a pharmaceutical composition, comprising i) one or more of the compounds described in the first aspect, their stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable salts , hydrate, solvate or prodrug; and ii) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further includes one or more therapeutic agents selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltu), CD20 antibodies
  • the fourth aspect of the present invention provides a compound as described in the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Or the use of the pharmaceutical composition in the third aspect for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of SOS1.
  • the disease is cancer.
  • the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophagus cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain cancer tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the fifth aspect of the present invention provides a non-diagnostic and non-therapeutic method for inhibiting SOS1, comprising the steps of: administering an effective amount of the compound of general formula (I) described in the first aspect, its stereotaxic Isomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administer the pharmaceutical composition of the third aspect.
  • Figure 1 shows the plasma concentration-time profiles of compounds in rats.
  • Figure 2 shows the plasma concentration-time profiles of compounds in cynomolgus monkeys.
  • the present inventors unexpectedly discovered a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl groups, including from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl n-butyl, tert-butyl, isobutyl (such as ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • alkylene refers to a group formed by removing one hydrogen atom from “alkyl”, such as methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as )Wait.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group comprising 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaromatic ring), fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclic or fused aryl ring, the above cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted. Any two or more atoms on the ring can be further cyclolinked with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • cycloalkylene refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as: Wait.
  • alkylenecycloalkylene refers to the above-mentioned cycloalkylalkyl or alkylcycloalkyl group formed by removing two hydrogen atoms, wherein "C1-C18 alkylene C3-C20 alkylene”"Cycloalkyl” or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning, preferably, C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to: Wait.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, such as 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic systems), wherein At least one heteroatom is present in a ring with at least one carbon atom.
  • Each heterocyclic ring containing a heteroatom may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur may be oxidized or the nitrogen may Quaternized.
  • a heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepanyl gene, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms on the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further cyclically connected; the heterocyclic group can be substituted or unsubstituted, and when substituted,
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate, where
  • heterocyclylene refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclyl, including but not limited to:
  • heterocycloalkylene alkylene refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl group or an alkylcycloalkyl group, wherein "4-20 membered heterocycloalkylene C1-C18 "Alkylene” or "C1-C18 alkylene 4-20 membered heterocycloalkylene” have the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to: Wait.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclyl or fused ring aryl, the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • C1-C18 alkoxy refers to a straight or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropyl oxy and butoxy, etc. Preferably it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group.
  • C1-C18 alkyleneoxy refers to a group obtained by removing one hydrogen atom from "C1-C18 alkoxy”.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo refers to substitution with halogen.
  • deuterated refers to substitution with deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2.
  • cyano refers to a group with the structure CN.
  • acyl refers to a group with the structure -COR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • the acyl group is a "C 2 -C 6 acyl group” (eg -COC 1 -C 5 alkyl).
  • Examples of acyl groups include, but are not limited to : -COCH3, -COCH2CH3 , -COCH2CH2CH3 , -COCH2CH ( CH3 ) 2 .
  • ester refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • the ester group is a "C 2 -C 6 ester group” (eg -COOC 1 -C 5 alkyl).
  • ester groups include, but are not limited to : -COOCH3, -COOCH2CH3 , -COOCH2CH2CH3 , -COOCH2CH ( CH3 ) 2 .
  • amino refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • R and R' can be the same or different in the dialkylamine moiety.
  • the amine group is a C 1 -C 6 amine group (ie, an alkylamine group containing 1-6 carbon atoms, such as a C 1 -C 6 alkyl NH-).
  • amine groups include, but are not limited to: NH2 , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, aniline, diisopropylamine Aniline, etc.
  • amido refers to a group with the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • the amido group is a "C 1 -C 6 amido group” (eg -CONHC 1 -C 5 alkyl or -CONH 2 ).
  • R and R' can be the same or different in the dialkylamine moiety. Examples of amide groups include, but are not limited to: -CONH2 , -CONHCH3, -CON( CH3 )2 , and the like.
  • sulfonamido refers to a group having the structure -SO2NRR ' or RSO2NR'- , where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • C 1 -C 6 sulfonamide group refers to C 1 -C 6 alkylsulfonamide group, that is, the total number of carbon atoms of R and R' is 1-6.
  • ureido refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" may be the same or different in the dialkylamine moiety. Examples of ureido groups include, but are not limited to: -NHCONH 2 , -NHCONHCH 3 , -NHCON(CH 3 ) 2 , etc. In the present invention, "" C 1 -C 6 ureido” refers to a C 1 -C 6 alkyl ureido group, that is, the total number of carbon atoms in R, R' and R" is 1-6.
  • alkylaminoalkyl refers to a group with the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different. Examples of alkylaminoalkyl groups include, but are not limited to, -CH2NHCH3 , -CH2CH2NHCH3 , and the like.
  • dialkylaminoalkyl refers to a group with the structure -RNR'R", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" may be the same or different in the dialkylamine moiety. Examples of dialkylaminoalkyl groups include, but are not limited to: -CH2N ( CH3 ) 2 , -CH2CH2N ( CH 3 ) 2 etc.
  • sulfone refers to a group having the structure -SO2R ', wherein R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • examples of sulfone groups include, but are not limited to: -SO2CH3 , -SO2CH2CH3 , -SO2 - cyclopropyl, -SO2 - cyclobutyl, -SO2 - cyclopentyl, -SO2 -Cyclohexyl.
  • heterocyclylalkyl refers to a group bearing the structure -RR', where R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R' represents heterocycle or substituted heterocycle.
  • heterocyclylalkyl groups include, but are not limited to: azetidine-CH2-, oxetanyl-CH2-, azetyl -CH2-, oxetanyl - CH2 -, azacyclohexyl-CH 2 -, oxane-CH 2 -,
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, and alkoxy corresponds to Alkyleneoxy, etc.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.
  • the compound of formula I has the following structure:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W, and n are defined as described above.
  • the compound of formula I has the structure shown in general formula (II):
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, W, and n are defined as described above.
  • the compound of formula I has the structure shown in general formula (III):
  • R 1 , R 2 , R 3 , X, Y, Z, W, and n are defined as described above.
  • the compound of formula I has the structure shown in general formula (IV):
  • R 1 , R 2 , R 3 , R 6 , X, Y, Z, W, and n are as described above.
  • the compound of formula I has a structure represented by general formula (V):
  • R 1 , R 2 , R 3 , R 6 , Y, Z, W, and n are as described above.
  • the compound of formula I has the structure shown in formula (VI):
  • R 1 , R 2 , R 3 , R 6 , R 13 , R 14 , ring C, t and n are as defined above.
  • the compound of formula I has the structure shown in formula (VII):
  • R 1 , R 3 , R 6 , R 16 , R 17 , R 18 and t are as defined above.
  • the compound of formula I has the structure shown in formula (VIIA):
  • R 1 , R 3 , R 6 , R 16a , R 16b , R 17a , R 17b , and R s6 are as defined above.
  • the compound of formula I has the structure shown in formula (VIIB):
  • R s1 , R s2 , R s3 , R s4 , R s5 , and R s6 are defined as described above.
  • the compound of formula I has the structure shown in formula (VIII):
  • R 1 , R 2 , R 3 , R 6 and W are as described above.
  • the compound of formula I has the structure represented by formula (IX-A) or formula (IX-B):
  • R 1 , R 2 , R 3 , R 8 , R 9 , X, Y, Z, W, n and q are as defined above.
  • the compound of formula I has a structure represented by formula (X):
  • R 1 , R 2 , R 3 , X, Y, Z, W, n and q are as defined above.
  • n1 0, 1, 2, 3, 4 or 5;
  • n'1 0, 1, 2, 3, 4 or 5;
  • p1 is 0, 1, 2, 3, 4, or 5;
  • q1 is 1 or 2;
  • n2 0, 1, 2, 3, 4 or 5;
  • n'2 is 0, 1, 2, 3, 4 or 5;
  • p2 is 0, 1, 2, 3, 4, or 5;
  • q2 is 1 or 2;
  • W is a C 3 -C 20 cycloalkylene group or a 4-20-membered heterocyclic group;
  • R 1 is not hydrogen, deuterium, Halogen, cyano, and m1 is not 0;
  • the substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 Alkyl, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 Alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-20-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, acyl, Amido, sulfonyl, sulfonamide or urea.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 12 cycloalkyl, 4-12 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered Heteroaryl; preferably, R is selected from the group of substituted groups: phenyl, pyridyl, pyrimidinyl, pyridazinyl; more preferably, R is selected from:
  • the substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 12 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 Alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-12-membered heterocyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, acyl, Amido, sulfonyl, sulfonamide or urea.
  • R 4 and R 5 are independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl ;
  • the substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 12 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 Alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-12-membered heterocyclyl, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido , sulfonamide group or urea group.
  • groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkyl
  • R 6 is selected from: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl.
  • the substitution refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-O-, C 1 -C 6 alkoxy, deuterium Substituted C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-6-membered heterocyclyl, 4-6-membered heterocycle Cyclic-O-, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido; C 1 -C 6 alkyl, de
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to produce the compound, salt or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compound of formula V-5 reacts with an amine (formula V-6) in a third base (such as TEA or DIPEA, etc.) to generate the compound of formula (I);
  • a third base such as TEA or DIPEA, etc.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W and n are as defined above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) slow solvents such as paraffin; (f) absorption Accelerators, eg, quaternary amine compounds; (g) wetting agents, eg, cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting SOS1.
  • the present invention has the following main advantages:
  • the compound has a good selective inhibitory effect on SOS1;
  • the compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • the first step the preparation of (3-bromo-5-iodophenyl) tert-butyl carbamate
  • the second step preparation of ethyl 2-(3-bromo-5-((tert-butoxycarbonyl)amino)phenyl)-2,2-difluoroacetate
  • tert-butyl (3-bromo-5-iodophenyl)carbamate (3.97 g, 10 mmol) was added to dimethyl sulfoxide (30 mL), and ethyl 2-bromo-2,2-difluoroacetate (5.1 g, 25 mmol) and copper powder (1.6 g, 25 mmol), then the temperature was raised to 70°C, and the reaction was stirred overnight. Pour into water (100 mL), extract twice with ethyl acetate (300 mL), combine the organic phases, dry, spin dry, and separate by silica gel column chromatography to obtain the target product (3.4 g, yield: 79%).
  • the third step the preparation of (3-bromo-5-(1,1-difluoro-2-hydroxy-2-methylpropyl) phenyl) tert-butyl carbamate
  • the fourth step the preparation of (3-acetyl-5-(1,1-difluoro-2-hydroxy-2-methylpropyl) phenyl) tert-butyl carbamate
  • the sixth step (3-(1,1-Difluoro-2-hydroxy-2-methylpropyl)-5-((R)-1-((R)-1,1-dimethylethyl) Preparation of tert-butyl sulfinamido)ethyl)phenyl)carbamate
  • the seventh step preparation of (R)-1-(3-amino-5-(1-aminoethyl)phenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride
  • the first step preparation of 2-(2-chloropyridin-4-yl)-2,2-difluoroethyl acetate
  • the second step preparation of 1-(2-chloropyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol
  • the third step preparation of 1-(2-(1-ethoxyvinyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol
  • the fourth step the preparation of 1-(4-(1,1-difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethanone
  • the 1-(2-(1-ethoxyvinyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol (crude product) obtained in the previous step was dissolved in tetrahydrofuran (30 mL) ), and then 2M aqueous hydrochloric acid (15 mL) was added. Then the reaction solution was stirred at room temperature for 1 h, adjusted to pH 8 with saturated sodium bicarbonate, extracted twice with ethyl acetate (50 mL), and the organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to obtain the target product (1.29 g, two-step yield: 70%).
  • the seventh step preparation of (R)-1-(2-(1-aminoethyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride
  • the first step the preparation of 2-bromo-1-fluoro-4-iodobenzene
  • the second step preparation of ethyl 2-(3-bromo-4-fluorophenyl)-2,2-difluoroacetate
  • the third step preparation of 1-(3-bromo-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol
  • the fifth step the preparation of 1-(5-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone
  • Step 7 (R)-N-((R)-1-(5-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)- Preparation of 2-methylpropane-2-sulfinamide
  • the eighth step preparation of (R)-1-(3-(1-aminoethyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride
  • the first step the preparation of 2-bromo-6-(prop-1-en-2-yl)pyridin-4-amine
  • the second step preparation of (2-bromo-6-(prop-1-en-2-yl)pyridin-4-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester
  • the third step the preparation of (2-bromo-6-(1-methylcyclopropyl) pyridin-4-yl) tert-butyl carbamate
  • tert-butyl (2-bromo-6-(prop-1-en-2-yl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (4.00 g, 9.68 mmol, 1.00 eq) was added at 0°C ) in DCM (20 mL).
  • the reaction solution was reacted at 20°C for 5h.
  • the resulting reaction solution was quenched with water (200 mL) and extracted with DCM (100 mL*2).
  • the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the target product (1.08 g, 2.64 mmol, yield 17.0%, purity 80.0%).
  • the fourth step the preparation of (2-acetyl-6-(1-methylcyclopropyl) pyridin-4-yl) tert-butyl carbamate
  • the sixth step preparation of (2-(1-((tert-butylsulfinyl)amino)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamic acid tert-butyl ester
  • the seventh step the preparation of 2-(1-aminoethyl)-6-(1-methylcyclopropyl)pyridin-4-amine
  • tert-butyl (2-(1-((tert-butylsulfinyl)amino)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate To a solution of 300 mg, 758 umol, 1.00 eq) in dioxane (1 mL) was added HCl/dioxane (1 mL). The reaction solution was reacted at 25°C for 16h and then filtered. The filter cake was vacuum-dried to obtain the target product (165 mg, 647 umol, yield 85.4%, purity 89.3%) as a white solid.
  • the first step the preparation of 2-chloro-6-(1-fluorocyclopropyl)-4-nitropyridine
  • the second step preparation of 2-(1-ethoxyvinyl)-6-(1-fluorocyclopropyl)-4-nitropyridine
  • the third step preparation of 1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethane-1-one
  • the fourth step (E)-N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethene)-2-methylpropane-2-sulfonimide preparation
  • the fifth step preparation of N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
  • the sixth step preparation of N-(1-(4-amino-6-(1-fluorocyclopropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide
  • N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide 200 mg, To a solution of 607 ⁇ mol, 1.00 eq) and Boc 2 O (159 mg, 729 umol, 167 ⁇ L, 1.20 eq) in MeOH (2.00 mL) was added Pd/C (607 ⁇ mol, 2.00 mL, purity 10.0%, 1.00 eq). The reaction solution was reacted at 25 °C for 2 h under a hydrogen atmosphere, and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target product (140 mg, 468 ⁇ mol, yield 77.0%).
  • the seventh step the preparation of 2-(1-aminoethyl)-6-(1-fluorocyclopropyl)pyridin-4-amine
  • the first step the preparation of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid
  • the second step the preparation of 7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-ol
  • the third step (R)-1-(3-(1-((7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-yl)amino)ethyl)-2- Preparation of fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol
  • the first step preparation of (S)-2-(chloromethyl)-1-methylpyrroline
  • N-methyl-L-prolinol (500.0 mg, 4.34 mmol) was dissolved in toluene (5 mL) and thionyl chloride (2.0 mL) was added. The resulting reaction solution was stirred at 100° C. for 2.0 h, and then concentrated under reduced pressure. The obtained crude product was directly put into the next step without further purification.
  • the fourth step 1,1-difluoro-1-(2-fluoro-3-((R)-1-((7-methoxy-2-methyl-6-(((S)-1- Preparation of Methylpyrrolin-2-yl)methoxy)quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol

Abstract

La présente invention concerne un inhibiteur d'amine de benzopyrimidine ou de pyridopyrimidine substitué, son procédé de préparation et son utilisation. Plus particulièrement, le composé de la présente invention a une structure telle que représentée dans la formule (I). La présente invention concerne en outre un procédé de préparation du composé et son utilisation en tant qu'inhibiteur de SOS1. Le composé de la présente invention présente un bon effet inhibiteur sélectif sur SOS1 et présente de bonnes propriétés pharmacodynamiques et pharmacocinétiques et de faibles effets secondaires toxiques.
PCT/CN2022/074823 2021-02-09 2022-01-28 Inhibiteur d'amine de benzopyrimidine ou de pyridopyrimidine substitué, son procédé de préparation et son utilisation WO2022171018A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202110178999.9A CN114907324A (zh) 2021-02-09 2021-02-09 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用
CN202110178999.9 2021-02-09
CN202110790488.2A CN115611865A (zh) 2021-07-13 2021-07-13 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用
CN202110790488.2 2021-07-13
PCT/CN2021/125084 WO2022083657A1 (fr) 2020-10-20 2021-10-20 Inhibiteur d'amine benzo ou pyridopyrimidine substitué, son procédé de préparation et son application
CNPCT/CN2021/125084 2021-10-20

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CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
CN112105419A (zh) * 2018-11-09 2020-12-18 豪夫迈·罗氏有限公司 稠环化合物
WO2021092115A1 (fr) * 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations
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WO2017091661A1 (fr) * 2015-11-25 2017-06-01 Strovel Jeffrey William Inhibiteurs de bromodomaines bet bicycliques et leurs utilisations
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2018134685A2 (fr) * 2017-01-17 2018-07-26 Liverpool School Of Tropical Medicine Composés
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
CN112105419A (zh) * 2018-11-09 2020-12-18 豪夫迈·罗氏有限公司 稠环化合物
WO2021092115A1 (fr) * 2019-11-08 2021-05-14 Revolution Medicines, Inc. Composés hétéroaryles bicycliques et leurs utilisations
WO2021203768A1 (fr) * 2020-04-08 2021-10-14 江苏恒瑞医药股份有限公司 Dérivé pyrimido dicyclo, son procédé de préparation et son utilisation en médecine
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HILLIG ROMAN C; SAUTIER BRICE; SCHROEDER JENS; MOOSMAYER DIETER; HILPMANN ANDRÉ; STEGMANN CHRISTIAN M; WERBECK NICOLAS D; BRIEM HA: "Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 116, no. 7, 12 February 2019 (2019-02-12), pages 2551 - 2560, XP055841142, ISSN: 0027-8424, DOI: 10.1073/pnas.1812963116 *

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