WO2022083657A1 - 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 - Google Patents

取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 Download PDF

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WO2022083657A1
WO2022083657A1 PCT/CN2021/125084 CN2021125084W WO2022083657A1 WO 2022083657 A1 WO2022083657 A1 WO 2022083657A1 CN 2021125084 W CN2021125084 W CN 2021125084W WO 2022083657 A1 WO2022083657 A1 WO 2022083657A1
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substituted
alkyl
group
alkoxy
unsubstituted
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PCT/CN2021/125084
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English (en)
French (fr)
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吕彬华
崔大为
张青
柴传柯
梁辉
庞旭东
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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 CN202011128302.9A external-priority patent/CN114380805A/zh
Priority claimed from CN202110178999.9A external-priority patent/CN114907324A/zh
Priority claimed from CN202110790488.2A external-priority patent/CN115611865A/zh
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
Priority to AU2021367089A priority Critical patent/AU2021367089A1/en
Priority to CN202180070062.8A priority patent/CN116323590A/zh
Priority to KR1020237017306A priority patent/KR20230093300A/ko
Priority to EP21882072.8A priority patent/EP4234548A1/en
Priority to CA3196287A priority patent/CA3196287A1/en
Priority to JP2023524477A priority patent/JP2023546248A/ja
Priority to PCT/CN2022/074823 priority patent/WO2022171018A1/zh
Publication of WO2022083657A1 publication Critical patent/WO2022083657A1/zh

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    • 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
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • 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
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    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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;
  • 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;
  • 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, 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 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 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 of formula (VIII):
  • 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.
  • 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 (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 stated, 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.
  • the individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, possess specific activity as a pure or substantially pure optical isomer), 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).
  • Racemic forms can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomers, by separation of 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 of the present invention the compound obtained by successively preparing, isolating and purifying the compound has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the text List.
  • 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 a diastereomeric salt with it, and then the diastereomeric salt 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 tested 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, ofatumuma
  • 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, for example, hydroxymethylcellulose, alginate, 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 glycerol, or
  • 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 dried under vacuum 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
  • Step 1 Dilute 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate (1.2 g), ethyl cyanoformate (0.932 g) and 2M HCl The oxane solution (20 mL) was heated in a sealed tube for 20 hours, then concentrated under reduced pressure. DMF and DBU were added to the residue to dissolve the solid, followed by preparative liquid phase separation to obtain the target product (230 mg, yield: 15%). LC-MS: m/z 323 (M+H) + .

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Abstract

本发明涉及取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用。具体地，本发明化合物具有式(I)所示结构，本发明还公开了所述化合物的制备方法及其作为SOS1抑制剂的用途，本发明化合物对SOS1具有很好的选择性抑制作用且具有更好的药效学、药代动力学性能和更低的毒副作用。

Description

取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 技术领域
本发明属于药物领域，具体涉及一种取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用。
背景技术
肺癌是人类癌症致死的重要原因之一。按照细胞类型肺癌可以分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)，其中NSCLC占所有肺癌患者的85％。据统计2016年全球NSCLC的市场约为209亿美元，其中美国市场占据一半，其次是日本、德国和中国。从现有趋势来看，非小细胞肺癌市场保持着持续增长，预计2023年全球市场将达到540亿美元(Nature，2018；553(7689):446-454)。
目前NSCLC的主要治疗用药分为化疗药物、分子靶向药物以及肿瘤免疫疗法等。其中化疗药物主要包括吉西他滨、紫杉醇以及铂类药物等，但是这类药物普遍具有选择性差、毒性大从而导致比较强烈的毒副作用。近年来，分子靶向药物因其选择性较高、毒副作用相对较小，能够实现精准治疗等明显优势从而逐渐成为研究热点。现有的NSCLC分子靶向药物包括EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Pyrotinib、Rociletinib、Osimertinib等)，ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼等)，以及VEGFR抑制剂(Sorafenib、Regorafenib、Cabozantinib、Sunitinib、多纳非尼等)(Current Medicinal Chemistry,2019,26,1-39)。
KRAS突变发生在20-40％的肺腺癌中，这一患病率在西方(vs亚洲)人群中更高(26％vs 11％)，在吸烟者(vs非吸烟者)中更高(30％vs 10％)。最常见的突变发生在密码子12和13中，最常见的突变包括G12C、G12V和G12D。到目前为止，市场上仍然没有针对KRAS突变的药物被批准上市。
在细胞内，KRAS蛋白在失活和激活状态之间转变，当KRAS与鸟苷二磷酸(GDP)结合时，它处于失活状态，当它与鸟苷三磷酸(GTP)结合时，它处于激活状态，并且可以激活下游信号通路。KRAS在失活与激活状态之间的转换受到两类因子的调节。一类是鸟嘌呤核苷酸交换因子(GEF)，这类蛋白催化KRAS与GTP的结合，从而促进KRAS的激活，其中包括SOS1蛋白。另一类是GTP酶激活蛋白(GAP)，这类蛋白能够促进与KRAS结合的GTP水解成为GDP，从而抑制KRAS的活性。
到目前为止，已经确定了三大类特定于RAS的GEF，在肿瘤中主要发现SOS蛋白参与。SOS蛋白在体内广泛表达，含有两个亚型SOS1和SOS2。已发表的数据表明，在突变KRAS激活和致癌信号中，SOS 1起着关键作用。SOS1水平的降低导致了携带KRAS突变的肿瘤细胞的增殖率和存活率的降低，而KRAS野生型细胞系则未见影响。 SOS1缺失的效果不能通过引入一个在催化位点发生突变的SOS1来挽救，这说明SOS1 GEF活性在KRAS突变癌细胞中的重要作用(参见WO2019122129A1)。
由于不管是突变的还是野生型的KRAS结合GTP都依赖于SOS1，所以选择性的抑制SOS1之后，不管KRAS突变与否，都能阻止SOS1与KRAS的相互作用从而最终抑制KRAS激活。
由于SOS1靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的SOS1抑制剂用于临床治疗。高选择性高活性的SOS1抑制剂可以对KRAS突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。
发明内容
本发明的目的在于提供一类新型的对SOS1有选择性抑制作用和/或更好药效学性能的化合物及其用途。
本发明的第一方面，提供一种通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2021125084-appb-000001
式中，
X选自：CR 6或N，其中，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Y选自下组：O、NH、NR 7、S、SO、SO 2、C≡C、取代或未取代的4-20元杂环基、取代或未取代的C 6-C 14芳基或5-14元杂芳基，其中，R 7选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Z选自取代或未取代的下组基团：键、取代或未取代的C 1-C 18亚烷基；
W选自取代或未取代的下组基团：键、C 3-C 20亚环烷基、4-20元亚杂环基、OR 11、NR 11R 12、SO 2、NR 12SO 2、CO或NR 12CO；R 11独立地选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基、C 3-C 20亚环烷基C 1-C 18亚烷基、4-20元亚杂环基C 1-C 18亚烷基、C 6-C 14芳基或5-14元杂芳基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) m(CH＝CH)R 8、-(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取 代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基或5-14元杂芳基；或者在-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mS(O) qNR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 4、R 5各自独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、酯基、COOH、CONH 2、C 2-C 6烯基、C 2-C 6炔基；
其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-、卤素、氧代C 1-C 6烷基、硝基、羟基、氰基、C 2-C 6酯基、C 1-C 6胺基、C 1-C 6酰基、C 1-C 6酰胺基、C 1-C 6磺酰基、C 1-C 6磺酰胺基或C 1-C 6脲基；其中，所述C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-还可进一步被一个或多个R a取代，其中，R a选自：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代基(＝O)、硝基、羟基、氰基、C 2-C 6酯基、C 1-C 6胺基、C 1-C 6酰胺基、C 1-C 6磺酰胺基或C 1-C 6脲基；或两个位于相同碳原子上的取代基共同构成-(CH 2) n-或＝O；
m、n各自独立地为0、1、2、3、4或5；
p为0、1、2、3、4或5；
q为1或2；
限定条件是当Y选自下组：O、NH或NR 7，且Z为键，W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、卤素、氰基、R 8、O(CH 2) pR 8、COR 8、-C(O)OR 8、NR 8R 9、C(O)NR 8R 9、-NR 8C(O)R 9、-NR 8C(O)NR 9R 10。
在另一优选例中，具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2021125084-appb-000002
式中，
X选自：CR 6或N，其中，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Y选自下组：O、NH、NR 7、S、SO、SO 2、C≡C，其中，R 7选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Z选自取代或未取代的下组基团：键、取代或未取代的C 1-C 18亚烷基(优选为氘代C 1-C 18亚烷基或卤代C 1-C 18亚烷基)；
W选自取代或未取代的下组基团：键、C 3-C 20亚环烷基、4-20元亚杂环基、OR 11、NR 11R 12、SO 2、NR 12SO 2、CO或NR 12CO；R 11独立地选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基、C 3-C 20亚环烷基C 1-C 18亚烷基、4-20元亚杂环基C 1-C 18亚烷基、C 6-C 14芳基或5-14元杂芳基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) m(CH＝CH)R 8、-(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 1-C 18烷氧基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基或5-14元杂芳基；或者在-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mS(O) qNR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 4、R 5各自独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、酯基、COOH、CONH 2、C 2-C 6烯基、C 2-C 6炔基；
其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-、卤素、氧代C 1-C 6烷基、硝基、羟基、氰基、C 2-C 6酯基、C 1-C 6胺基、C 2-C 6酰胺基、C 2-C 6磺酰胺基或C 1-C 6脲基；其中，所述C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-还可进一步被一个或多个R a取代，其中，R a选自：C 1-C 6烷基、氘代C 1-C 6烷基、 卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代C 1-C 6烷基、硝基、羟基、氰基、C 2-C 6酯基、C 1-C 6胺基、C 2-C 6酰胺基、C 2-C 6磺酰胺基或C 1-C 6脲基；或两个位于相同碳原子上的取代基共同构成-(CH 2) n-或＝O；
m、n各自独立地为0、1、2、3、4或5；
p为0、1、2、3、4或5；
q为1或2；
限定条件是当Y选自下组：O、NH或NR 7，且Z为键，W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、卤素、氰基、R 8、O(CH 2) pR 8、COR 8、-C(O)OR 8、NR 8R 9、C(O)NR 8R 9、-NR 8C(O)R 9、-NR 8C(O)NR 9R 10。
在另一优选例中，具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2021125084-appb-000003
式中，
X选自：CR 6或N，其中，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Y选自下组：O、NH、NR 7、S、SO、SO 2、C≡C，其中，R 7选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Z选自取代或未取代的下组基团：键、C 1-C 18亚烷基、氘代C 1-C 18亚烷基或卤代C 1-C 18亚烷基；
W选自取代或未取代的下组基团：键、C 3-C 20亚环烷基、4-20元亚杂环基、OR 11、NR 11R 12、SO 2、NR 12SO 2、CO或NR 12CO；R 11独立地选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基、C 3-C 20亚环烷基C 1-C 18亚烷基或4-20元亚杂环基C 1-C 18亚烷基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) m(CH＝CH)R 8、(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；或者在-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mS(O) qNR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mNR 8S(O) qR 9、 -(CH 2) mNR 8S(O) qNR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 4、R 5各自独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基；
其中，上述取代是指被选自下组的一个或多个(如2、3、4)基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
m、n各自独立地为0、1、2、3、4或5；
p为0、1、2、3、4或5；
q为1或2；
限定条件是当Y选自：O、NH、NR 7，且Z为键，W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、卤素、氰基、R 8、O(CH 2) pR 8、COR 8、-C(O)OR 8、NR 8R 9、C(O)NR 8R 9、-NR 8C(O)R 9、-NR 8C(O)NR 9R 10。
在另一优选例中，具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
Figure PCTCN2021125084-appb-000004
式中：
X选自：CR 6或N，其中，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Y选自下组：O、NH、或NR 7，其中，R 7选自：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
Z选自取代或未取代的下组基团：C 1-C 18亚烷基、氘代C 1-C 18亚烷基、或卤代C 1-C 18亚烷基；
W选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基、OR 11、NR 11R 12、SO 2、NR 12SO 2、CO或NR 12CO；R 11独立地选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基、C 3-C 20亚环烷基C 1-C 18亚烷基、或4-20元亚杂环基C 1-C 18亚烷基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
R 1、R 2独立地选自下组：氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 5R 8、-(CH 2) mC(O)NR 8R 9、 -(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；
R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
R 4、R 5独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基；
其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
m、n各自独立地为0、1、2、3、4或5；
p为0、1、2、3、4或5；
q为1或2。在另一优选例中，R 1选自下组：氢、氘、卤素、氰基、-(CH 2) m1R 8、-(CH 2) m'1(CH＝CH)R 8、-(CH 2) m'1(C≡C)R 8、-(CH 2) m1O(CH 2) p1R 8、-(CH 2) m'1SR 8、-(CH 2) m1COR 8、-(CH 2) m1C(O)OR 8、-(CH 2) m'1S(O) q1R 8、-(CH 2) m1NR 8R 9、-(CH 2) m1C(O)NR 8R 9、-(CH 2) m1NR 8C(O)R 9、-(CH 2) m1NR 8C(O)NR 9R 10、-(CH 2) m'1S(O) q1NR 8R 9、-(CH 2) m'1NR 8S(O) q1R 9、-(CH 2) m'1NR 8S(O) q1NR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；或者在-(CH 2) m1NR 8R 9、-(CH 2) m1C(O)NR 8R 9、-(CH 2) m'1S(O) q1NR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) m1NR 8C(O)R 9、-(CH 2) m1NR 8C(O)NR 9R 10、-(CH 2) m'1NR 8S(O) q1R 9、-(CH 2) m'1NR 8S(O) q1NR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
m1为0、1、2、3、4或5；
m'1为0、1、2、3、4或5；
p1为0、1、2、3、4或5；
q1为1或2；
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，Y选自：O、NH或NR 7，且Z为键，W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、卤素、氰基，且m1不为0。
在另一优选例中，各R 2独立地选自下组：氢、氘、卤素、氰基、-(CH 2) m2R 8、 -(CH 2) m'2(CH＝CH)R 8、-(CH 2) m'2(C≡C)R 8、-(CH 2) m2O(CH 2) p2R 8、-(CH 2) m'2SR 8、-(CH 2) m2COR 8、-(CH 2) m2C(O)OR 8、-(CH 2) m'2S(O) q2R 8、-(CH 2) m2NR 8R 9、-(CH 2) m2C(O)NR 8R 9、-(CH 2) m2NR 8C(O)R 9、-(CH 2) m2NR 8C(O)NR 9R 10、-(CH 2) m'2S(O) q2NR 8R 9、-(CH 2) m'2NR 8S(O) q2R 9、-(CH 2) m'2NR 8S(O) q2NR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；或者在-(CH 2) m2NR 8R 9、-(CH 2) m2C(O)NR 8R 9、-(CH 2) m'2S(O) q2NR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) m2NR 8C(O)R 9、-(CH 2) m2NR 8C(O)NR 9R 10、-(CH 2) m'2NR 8S(O) q2R 9、-(CH 2) m'2NR 8S(O) q2NR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
m2为0、1、2、3、4或5；
m'2为0、1、2、3、4或5；
p2为0、1、2、3、4或5；
q2为1或2；
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(II)所示的结构：
Figure PCTCN2021125084-appb-000005
式中，R 1、R 2、R 3、R 4、X、Y、Z、W、n的定义如上所述。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(III)所示结构：
Figure PCTCN2021125084-appb-000006
式中，R 1、R 2、R 3、X、Y、Z、W、n的定义如上所述。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立 体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(IV)所示结构：
Figure PCTCN2021125084-appb-000007
式中，
R 1、R 2、R 3、R 6、X、Y、Z、W、n的定义如上所述。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有通式(V)所示结构：
Figure PCTCN2021125084-appb-000008
式中，
R 1、R 2、R 3、R 6、Z、W、n的定义如上所述。
在另一优选例中，式I-V中，Z选自取代或未取代的下组基团：键、C 1-C 6亚烷基、氘代C 1-C 6亚烷基或卤代C 1-C 6亚烷基；其中，所述取代是指被选自下组的一个或多个基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，W选自下组：键、取代或未取代C 3-C 12亚环烷基、取代或未取代4-12元亚杂环基、OR 11、NR 11R 12、SO 2、NR 12SO 2、CO或NR 12CO；
其中，R 11选自取代或未取代的下组基团：C 3-C 12亚环烷基、4-12元亚杂环基、C 3-C 12亚环烷基C 1-C 6亚烷基、4-12元亚杂环基C 1-C 6亚烷基、C 6-C 14芳基或5-14元杂芳基；优选地，R 11选自取代或未取代的下组基团：C 3-C 6亚环烷基、4-6元亚杂环基、C 3-C 6亚环烷基C 1-C 3亚烷基、4-6元亚杂环基C 1-C 3亚烷基、C 6-C 14芳基或5-14元杂芳基；
R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
其中，上述取代是指被选自下组的一个或多个(如2、3、4)基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
限定条件是当Z为键，且W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、 卤素、氰基、R 8、O(CH 2) pR 8、COR 8、-C(O)OR 8、NR 8R 9、C(O)NR 8R 9、-NR 8C(O)R 9、-NR 8C(O)NR 9R 10。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(VI)所示结构：
Figure PCTCN2021125084-appb-000009
式中，
R 13和R 14各自独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
环C选自取代或未取代的下组基团：C 3-C 12亚环烷基、4-12元亚杂环基；
R 2相同或不同，独立地自下组：-(CH 2) mO(CH 2) pR 8、-(CH 2) m(CH＝CH) pR 8、(CH 2) m(C≡C) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；m选自1、2、3、4或5；
所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
t为1、2、3、4、5或6；
R 1、R 3、R 6、R 8、R 9、R 10、p、q和n的定义如上所述。
在另一优选例中，式(VI)中，
Figure PCTCN2021125084-appb-000010
部分选自：
Figure PCTCN2021125084-appb-000011
Figure PCTCN2021125084-appb-000012
其中，Y 1和Y 2各自独立地选自：NR b、O；
R m独立地选自：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基；
R b独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、SO 2R 30、COR 30、酯基；
R 30各自独立地选自：氢、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基或取代或未取代4-6元杂环基；
n1为0、1、2、3或4；
n2为1、2、3或4；
其中，上述取代是指被选自下组的一个或多个(如2、3、4)基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(VII)所示结构：
Figure PCTCN2021125084-appb-000013
式中，
R 16和R 17各自独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
R 18选自：OR 11、NR 11R 12、NR 12SO 2R 2、COR 2或NR 12COR 2；R 11独立地选自：取代的C 3-C 12环烷基、取代或未取代4-12元杂环基、取代或未取代C 3-C 12亚环烷基C 1-C 6亚烷基、取代或未取代4-12元亚杂环基C 1-C 6亚烷基、取代或未取代C 6-C 14芳基、取代或未取代5-14元杂芳基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
或者R 18选自：-(CH 2) m(CH＝CH)R 8、-(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自：取代或未取代的C 1-C 18烷基、取代或未取代的C 3-C 20环烷基、取代或未取代的4-20元杂环基；
其中，R 8、R 9和R 10中所述取代是指被选自下组的一个或多个基团取代：C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
t为1、2、3、4、5或6；
其中，若未特别说明，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
R 1、R 2、R 3、R 6、R 8、R 9、R 10、m、p和q的定义如上所述。
在另一优选例中，所述的R 1选自下组：H、氰基、卤素、-(CH 2) mR 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mS(O) qR 8、-(CH 2) m(C≡C)R 8；其中，CH 2中的H可以任选地被取代；R 8选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 1-C 18烷氧基、C 3-C 8环烷基、4-10元杂环基、C 6-C 14芳基或5-14元杂芳基。
在另一优选例中，R 1选自下组：卤素、氰基、-(CH 2) mR 8、-(CH 2) m(C≡CH)、-(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8，优选地R 8为取代或未取代的C 1-C 18烷基(优选地为C 1-C 6烷基)。
在另一优选例中，R 1选自下组：H、氰基、卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 1-C 6烷基O-、氘代C 1-C 6烷基O-、取代或未取代的C 3-C 6环烷基O-、取代或未取代的4-6元杂环基O-、C 1-C 6烷氧基C 1-C 6烷基O-、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的苯基O-、取代或未取代的5-6元杂芳基O-、取代或未取代的C 2-C 6炔基；其中，所述取代是指被选自下组的一个或多个(如2、3、4)基团取代：卤素、C 1-C 6烷基、C 3-C 6环烷基、氧代C 1-C 6烷基、C 2-C 6酯基。
在另一优选例中，式VII中，R 18选自：OR 11、NR 11R 12或NR 12SO 2R 2；其中，R 11独立地选自：取代的C 3-C 12环烷基、取代或未取代4-12元杂环基、取代或未取代C 3-C 12亚环烷基C 1-C 6亚烷基、取代或未取代4-12元亚杂环基C 1-C 6亚烷基、取代或未取代C 6-C 14芳基、取代或未取代5-14元杂芳基；R 12独立地选自下组：氢、氘、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基；
或者R 18选自：-(CH 2) mO(CH 2) pR 8；其中，CH 2中的H可以任选地被取代；R 8选自：取代或未取代的C 1-C 18烷基、取代或未取代的C 3-C 20环烷基、取代或未取代的4-20元杂环基；优选地，R 8为取代或未取代的C 1-C 18烷基(优选地为C 1-C 6烷基)；
上述取代是指被选自下组的一个或多个(如2、3、4)基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，R 3选自：取代的C 6-C 14芳基或取代的5-14元杂芳基；所述取代 是指被选自下组的一个或多个基团取代：R 3a、氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，所述C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-还可进一步被一个或多个R a取代，其中，R a选自：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基，限定条件是至少含有一个R 3a取代基；
其中，R 3a选自：羟基取代的C 1-C 18烷基、羟基取代的C 1-C 18卤代烷基、羟基取代的C 1-C 18氘代烷基、烷氧基取代的C 1-C 18烷基、烷氧基取代的C 1-C 18卤代烷基、烷氧基取代的C 1-C 18氘代烷基、环烷基氧基取代的C 1-C 18烷基、环烷基氧基取代的C 1-C 18卤代烷基、环烷基氧基取代的C 1-C 18氘代烷基、杂环基氧基取代的C 1-C 18烷基、杂环基氧基取代的C 1-C 18卤代烷基、杂环基氧基取代的C 1-C 18氘代烷基、环烷基取代的C 1-C 18卤代烷基、杂环基取代的C 1-C 18卤代烷基、胺基取代的C 1-C 18卤代烷基、氰基取代的C 1-C 18卤代烷基、酰胺基取代的C 1-C 18卤代烷基、取代的C 3-C 12环烷基、取代的4-12元杂环基、取代或非取代的卤代烷基氧基、取代或非取代的环烷基氧基、取代或非取代的杂环基氧基、取代或非取代的磺酰胺基、取代或非取代的环烷基砜基；上述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(VIII)所示结构：
Figure PCTCN2021125084-appb-000014
式中，R 1、R 2、R 3、R 6和W的定义如上所述。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(IX-A)和(IX-B)所示结构：
Figure PCTCN2021125084-appb-000015
式中，R 2、R 3、R 8、R 9、X、Y、Z、W、n和q的定义如上所述。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(X)所示结构：
Figure PCTCN2021125084-appb-000016
式中，R 8选自取代或未取代的下组基团：C 3-C 20环烷基或4-20元杂环基；
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
R 2、R 3、X、Y、Z、W、n和q的定义如上所述。
在另一优选例中，R 8选自取代或未取代的下组基团：C 3-C 6环烷基或4-6元杂环基；其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
在另一优选例中，Z和W同时为键。
在另一优选例中，Y为O，Z和W为键。
在另一优选例中，R 3选自取代的下组基团：苯基、吡啶基、嘧啶基、哒嗪基；其中，所述取代是指被选自下组的一个或多个(如2、3、4)基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；优选地，所述取代选自卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 1-C 6烷氧基、卤素、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基中的1、2或3个。
在另一优选例中，R 1为甲氧基。
在另一优选例中，
Figure PCTCN2021125084-appb-000017
为
Figure PCTCN2021125084-appb-000018
其中，*表示R或S构型。
优选的，R 3选自：
Figure PCTCN2021125084-appb-000019
在另一优选例中，R 3选自：
Figure PCTCN2021125084-appb-000020
在另一优选例中，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基。
在另一优选例中，R 1、R 2、R 3、R 4、R 5、R 6、X、Y、Z、W和n为实施例中各具体化合物相对应的具体基团。
在另一优选例中，所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，所述化合物选自下组：
Figure PCTCN2021125084-appb-000021
Figure PCTCN2021125084-appb-000022
Figure PCTCN2021125084-appb-000023
Figure PCTCN2021125084-appb-000024
Figure PCTCN2021125084-appb-000025
Figure PCTCN2021125084-appb-000026
Figure PCTCN2021125084-appb-000027
Figure PCTCN2021125084-appb-000028
Figure PCTCN2021125084-appb-000029
Figure PCTCN2021125084-appb-000030
Figure PCTCN2021125084-appb-000031
Figure PCTCN2021125084-appb-000032
Figure PCTCN2021125084-appb-000033
Figure PCTCN2021125084-appb-000034
Figure PCTCN2021125084-appb-000035
Figure PCTCN2021125084-appb-000036
Figure PCTCN2021125084-appb-000037
Figure PCTCN2021125084-appb-000038
Figure PCTCN2021125084-appb-000039
Figure PCTCN2021125084-appb-000040
Figure PCTCN2021125084-appb-000041
Figure PCTCN2021125084-appb-000042
Figure PCTCN2021125084-appb-000043
Figure PCTCN2021125084-appb-000044
Figure PCTCN2021125084-appb-000045
Figure PCTCN2021125084-appb-000046
Figure PCTCN2021125084-appb-000047
Figure PCTCN2021125084-appb-000048
Figure PCTCN2021125084-appb-000049
Figure PCTCN2021125084-appb-000050
Figure PCTCN2021125084-appb-000051
Figure PCTCN2021125084-appb-000052
Figure PCTCN2021125084-appb-000053
Figure PCTCN2021125084-appb-000054
Figure PCTCN2021125084-appb-000055
Figure PCTCN2021125084-appb-000056
Figure PCTCN2021125084-appb-000057
Figure PCTCN2021125084-appb-000058
Figure PCTCN2021125084-appb-000059
Figure PCTCN2021125084-appb-000060
Figure PCTCN2021125084-appb-000061
Figure PCTCN2021125084-appb-000062
Figure PCTCN2021125084-appb-000063
Figure PCTCN2021125084-appb-000064
Figure PCTCN2021125084-appb-000065
Figure PCTCN2021125084-appb-000066
Figure PCTCN2021125084-appb-000067
Figure PCTCN2021125084-appb-000068
Figure PCTCN2021125084-appb-000069
Figure PCTCN2021125084-appb-000070
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
本发明第二方面，提供一种制备通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，包括步骤：
Figure PCTCN2021125084-appb-000071
(i)在第一种碱存在下，式V-1化合物与式V-2化合物反应，得到式V-3化合物；
(ii)在第二种碱以及催化剂(如DMAP)存在下，式V-3化合物与磺酰氯(V-4)反应，得到生成式V-5化合物；
(iii)在第三种碱存在下，式V-5化合物与胺(式V-6)反应，得到式(I)化合物；
式中，
R’选自：卤素、OTs或OMs；
R 1、R 2、R 3、R 4、R 5、X、Y、Z、W和n定义如上所述。
在另一优选例中，第一种碱为碳酸钾或碳酸铯等。
在另一优选例中，第二种碱为TEA或DIPEA等。
在另一优选例中，第三种碱为TEA或DIPEA等。
本发明第三方面，提供一种药物组合物，包含i)一种或多种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。
在另一优选例中，所述药物组合物还包括选自下组的一种或多种治疗剂：PD-1抑制剂(如nivolumab,pembrolizumab,pidilizumab,cemiplimab，JS-001，SHR-120，BGB-A317，IBI-308，GLS-010，GB-226，STW204，HX008,HLX10,BAT 1306,AK105,LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab,atezolizumab,avelumab，CS1001，KN035,HLX20,SHR-1316，BGB-A333，JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab,131I-tositumomab,ibritumomab,90Y-ibritumomab,90In-ibritumomab,ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4，CC-90002，TTI-621，TTI-622,OSE-172，SRF-231，ALX-148，NI-1701，SHR-1603，IBI188，IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
本发明第四方面，提供一种如第一方面所述的化合物、其立体异构体、互变异构体、 晶型、药学上可接受的盐、水合物、溶剂合物或前药，或第三方面所述的药物组合物的用途，用于制备预防和/或治疗与SOS1活性或表达量相关的疾病的药物组合物。
在另一优选例中，所述疾病为癌症。
在另一优选例中，所述癌症选自：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。
本发明第五方面，提供了一种非诊断性、非治疗性地抑制SOS1的方法，其包括步骤：向所需患者施用有效量的第一方面所述的通式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用第三方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类新型的SOS1有选择性抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
术语“烷基”是指直链或支链或环状烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2021125084-appb-000072
戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等等。
术语“C1-C18烷基”指的是直链或支链或环状烷基，包括从1-18个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2021125084-appb-000073
正丁基、叔丁基、异丁基(如
Figure PCTCN2021125084-appb-000074
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、 烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“亚烷基”是指“烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2021125084-appb-000075
)、亚丁基(如
Figure PCTCN2021125084-appb-000076
)、亚戊基(如
Figure PCTCN2021125084-appb-000077
)、亚己基(如
Figure PCTCN2021125084-appb-000078
)、亚庚基(如
Figure PCTCN2021125084-appb-000079
)等。
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选被取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2021125084-appb-000080
Figure PCTCN2021125084-appb-000081
Figure PCTCN2021125084-appb-000082
等。
术语“亚烷基亚环烷基”是指上述的环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义，优选地，C1-C6亚烷基C3-C12亚环烷基，包括但不限于：
Figure PCTCN2021125084-appb-000083
Figure PCTCN2021125084-appb-000084
Figure PCTCN2021125084-appb-000085
等。
术语“杂环基”是指完全饱和的或部分不饱和的环状基团(包含但不限于如3-7元单环，6-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基，其中，环上的任 意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“亚杂环基”是指上述杂环基脱掉两个氢原子所形成的基团，包括但不限于：
Figure PCTCN2021125084-appb-000086
Figure PCTCN2021125084-appb-000087
等。
术语“亚杂环烷基亚烷基”是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“4-20元亚杂环烷基C1-C18亚烷基”或“C1-C18亚烷基4-20元亚杂环烷基”具有相同含义，优选地为4-12元亚杂环烷基C1-6亚烷基，包括但不限于：
Figure PCTCN2021125084-appb-000088
Figure PCTCN2021125084-appb-000089
等。
术语“芳基”是指芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e, P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。
术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。
术语“卤素”或“卤”是指氯、溴、氟、碘。
术语“卤代”是指被卤素取代。
术语“氘代”是指被氘取代。
术语“羟基”是指带有结构OH的基团。
术语“硝基”是指带有结构NO 2的基团。
术语“氰基”是指带有结构CN的基团。
术语“酰基”是指带有结构-COR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。优选地，酰基为“C 2-C 6酰基”(如-COC 1-C 5烷基)。酰基的实例包括但不限：-COCH 3、-COCH 2CH 3、-COCH 2CH 2CH 3、-COCH 2CH(CH 3) 2。
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。优选地，酯基为“C 2-C 6酯基”(如-COOC 1-C 5烷基)。酯基的实例包括但不限：-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3、-COOCH 2CH(CH 3) 2。
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代 的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。优选地，胺基为C 1-C 6胺基(即含有1-6个碳原子的烷胺基，如C 1-C 6烷基NH-)。胺基的实例包括但不限：NH 2、甲胺基、二甲胺基、乙胺基、二乙胺基、丙胺基、二丙胺基、异丙胺基、二异丙胺基、苯胺基、二苯胺基等。
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。优选地，酰胺基为“C 1-C 6酰胺基”(如-CONHC 1-C 5烷基或-CONH 2)。R和R'在二烷基胺片段中可以相同或不同。酰胺基的实例包括但不限于：-CONH 2、-CONHCH 3、-CON(CH 3) 2等。
术语“磺酰胺基”是指带有结构-SO 2NRR'或RSO 2NR'-的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。磺酰胺基的实例包括但不限：-SO 2NH 2、-SO 2NHCH 3、-SO 2N(CH 3) 2、CH 3SO 2NH-、CH 3SO 2NCH 3-等。本发明中，“C 1-C 6磺酰胺基”是指C 1-C 6烷基磺酰胺基，即R和R'的碳原子总数为1-6。
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。脲基的实例包括但不限于：-NHCONH 2、-NHCONHCH 3、-NHCON(CH 3) 2等。本发明中，“C 1-C 6脲基”是指C 1-C 6烷基脲基，即R、R'和R"的碳原子总数为1-6。
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'可以相同或不同。烷基胺基烷基的实例包括但不限于-CH 2NHCH 3、-CH 2CH 2NHCH 3等。
术语"二烷基胺基烷基"是指带有结构-RNR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。二烷基胺基烷基的实例包括但不限于：-CH 2N(CH 3) 2、-CH 2CH 2N(CH 3) 2等。
术语“砜基”是指带有结构-SO 2R'的基团，其中R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。砜基的实例包括但不限于：-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙基、-SO 2-环丁基、-SO 2-环戊基、-SO 2-环己基。
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。杂环基烷基的实例包括但不限于：氮杂环丁基-CH 2-、氧杂环丁基-CH 2-、氮 杂环戊基-CH 2-、氧杂环戊基-CH 2-、氮杂环己基-CH 2-、氧杂环己基-CH 2-、
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对应亚杂环基、烷氧基对应亚烷氧基等。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
所述式I化合物具有如下结构：
Figure PCTCN2021125084-appb-000090
式中，R 1、R 2、R 3、R 4、R 5、X、Y、Z、W、n的定义如上所述。
优选地，所述式I化合物具有通式(II)所示的结构：
Figure PCTCN2021125084-appb-000091
式中，R 1、R 2、R 3、R 4、X、Y、Z、W、n的定义如上所述。
优选地，所述式I化合物具有通式(III)所示结构：
Figure PCTCN2021125084-appb-000092
式中，R 1、R 2、R 3、X、Y、Z、W、n的定义如上所述。
优选地，所述式I化合物具有通式(IV)所示结构：
Figure PCTCN2021125084-appb-000093
式中，
R 1、R 2、R 3、R 6、X、Y、Z、W、n的定义如上所述。
优选地，所述式I化合物具有通式(V)所示结构：
Figure PCTCN2021125084-appb-000094
式中，
R 1、R 2、R 3、R 6、Y、Z、W、n的定义如上所述。
优选地，所述式I化合物具有式(VI)所示结构：
Figure PCTCN2021125084-appb-000095
式中，R 1、R 2、R 3、R 6、R 13、R 14、环C、t和n的定义如上所述。
优选地，所述式I化合物具有式(VII)所示结构：
Figure PCTCN2021125084-appb-000096
式中，
R 1、R 3、R 6、R 16、R 17、R 18和t的定义如上所述。
优选地，所述式I化合物具有式(VIII)所示结构：
Figure PCTCN2021125084-appb-000097
式中，
R 1、R 2、R 3、R 6和W的的定义如上所述。
优选地，所述式I化合物具有式(IX-A)或式(IX-B)所示结构：
Figure PCTCN2021125084-appb-000098
式中，R 1、R 2、R 3、R 8、R 9、X、Y、Z、W、n和q的定义如上所述。
优选地，所述式I化合物具有式(X)所示结构：
Figure PCTCN2021125084-appb-000099
式中，R 1、R 2、R 3、X、Y、Z、W、n和q的定义如上所述。
优选地，式I-VIII中，R 1选自下组：氢、氘、卤素、氰基、-(CH 2) m1R 8、-(CH 2) m'1(CH＝CH)R 8、-(CH 2) m'1(C≡C)R 8、-(CH 2) m1O(CH 2) p1R 8、-(CH 2) m'1SR 8、-(CH 2) m1COR 8、-(CH 2) m1C(O)OR 8、-(CH 2) m'1S(O) q1R 8、-(CH 2) m1NR 8R 9、-(CH 2) m1C(O)NR 8R 9、-(CH 2) m1NR 8C(O)R 9、-(CH 2) m1NR 8C(O)NR 9R 10、-(CH 2) m'1S(O) q1NR 8R 9、-(CH 2) m'1NR 8S(O) q1R 9、-(CH 2) m'1NR 8S(O) q1NR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；或者在-(CH 2) m1NR 8R 9、-(CH 2) m1C(O)NR 8R 9、-(CH 2) m'1S(O) q1NR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) m1NR 8C(O)R 9、-(CH 2) m1NR 8C(O)NR 9R 10、-(CH 2) m'1NR 8S(O) q1R 9、-(CH 2) m'1NR 8S(O) q1NR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
各R 2独立地选自下组：氢、氘、卤素、氰基、-(CH 2) m2R 8、-(CH 2) m'2(CH＝CH)R 8、-(CH 2) m'2(C≡C)R 8、-(CH 2) m2O(CH 2) p2R 8、-(CH 2) m'2SR 8、-(CH 2) m2COR 8、-(CH 2) m2C(O)OR 8、-(CH 2) m'2S(O) q2R 8、-(CH 2) m2NR 8R 9、-(CH 2) m2C(O)NR 8R 9、-(CH 2) m2NR 8C(O)R 9、-(CH 2) m2NR 8C(O)NR 9R 10、-(CH 2) m'2S(O) q2NR 8R 9、-(CH 2) m'2NR 8S(O) q2R 9、-(CH 2) m'2NR 8S(O) q2NR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 3-C 20环烷基或4-20元杂环基；或者在-(CH 2) m2NR 8R 9、-(CH 2) m2C(O)NR 8R 9、-(CH 2) m'2S(O) q2NR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) m2NR 8C(O)R 9、-(CH 2) m2NR 8C(O)NR 9R 10、-(CH 2) m'2NR 8S(O) q2R 9、-(CH 2) m'2NR 8S(O) q2NR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂 环基；
m1为0、1、2、3、4或5；
m'1为0、1、2、3、4或5；
p1为0、1、2、3、4或5；
q1为1或2；
m2为0、1、2、3、4或5；
m'2为0、1、2、3、4或5；
p2为0、1、2、3、4或5；
q2为1或2；
限定条件：当Y选自：O、NH或NR 7，且Z为键，W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、卤素、氰基，且m1不为0；
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰基、酰胺基、磺酰基、磺酰胺基或脲基。
优选地，式I-X中，R 3选自取代或未取代的下组基团：C 3-C 12环烷基、4-12元杂环基、C 6-C 10芳基、5-10元杂芳基；优选地，R 3选自取代的下组基团：苯基、吡啶基、嘧啶基、哒嗪基；更优选地，R 3选自：
Figure PCTCN2021125084-appb-000100
Figure PCTCN2021125084-appb-000101
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 12环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-12元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰基、酰胺基、磺酰基、磺酰胺基或脲基。
优选地，式I中，R 4、R 5独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 12环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-12元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
优选地，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基。
优选地，本发明中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-还可进一步被一个或多个R a取代，其中，R a选自：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰基、酰胺基、磺酰基、磺酰胺基或脲基。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有 的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构 的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
Figure PCTCN2021125084-appb-000102
(i)在第一种碱(如碳酸钾或碳酸铯等)存在下，式V-1化合物与式V-2化合物(其中R’为离去基，如卤素、OTs或OMs等)反应，生成式V-3化合物；
(ii)在第二种碱(如TEA或DIPEA等)以及催化剂(如DMAP)存在下，式V-3化合物用磺酰氯(V-4)保护生成式V-5化合物；
(iii)式V-5化合物与胺(式V-6)在第三种碱(如TEA或DIPEA等)反应生成式(I)化合物；
式中，
R 1、R 2、R 3、R 4、R 5、X、Y、Z、W和n定义如上所述。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当 式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003,KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622,OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组 合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2021125084-appb-000103
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。 活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制SOS1。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物对SOS1具有很好的选择性抑制作用；
(2)所述化合物具有更好的体内外药效学、药代动力学性能和更低的毒副作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道 的文献资料合成的。
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为℃(摄氏度)。
实施例
中间体-1(R)-1-(3-氨基-5-(1-氨基乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000104
第一步：(3-溴-5-碘苯基)氨基甲酸叔丁酯的制备
将3-溴-5-碘苯甲酸(4g,12.2mmol)加入叔丁醇(50mL)中，加入三乙胺(1.85g,18.3mmol)和叠氮磷酸三苯酯(3.7g,13.5mmol)，回流反应过夜，旋干，硅胶柱层析分离，得到目标产物(3.4g，收率：71％)。
LC-MS：m/z 398(M+H) +。
第二步：2-(3-溴-5-((叔丁氧基羰基)氨基)苯基)-2,2-二氟乙酸乙酯的制备
将(3-溴-5-碘苯基)氨基甲酸叔丁酯(3.97g,10mmol)加入二甲基亚砜(30mL)中，加入2-溴-2,2-二氟乙酸乙酯(5.1g,25mmol)和铜粉(1.6g,25mmol)，然后升温到70℃，搅拌反应过夜。倒入水(100mL)中，用乙酸乙酯(300mL)萃取两次，合并有机相，干燥，旋干，硅胶柱层析分离，得到目标产物(3.4g，收率：79％)。
LC-MS：m/z 394(M+H) +。
第三步：(3-溴-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)氨基甲酸叔丁酯的制备
将2-(3-溴-5-((叔丁氧基羰基)氨基)苯基)-2,2-二氟乙酸乙酯(3g,7.6mmol)加入四氢呋喃(30mL)中，0℃下加入甲基溴化镁(10.2mL,30.5mmol)。室温反应1h后，倒入冰(50g)中，用乙酸乙酯(300mL)萃取两次，合并有机相，干燥，旋干，硅胶柱层析分离，得到目标产物(2.8g)。
LC-MS：m/z 380(M+H) +。
第四步：(3-乙酰基-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)氨基甲酸叔丁酯的制备
将(3-溴-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)氨基甲酸叔丁酯(3g,7.9mmol)加入四氢呋喃(30mL)中，-60℃下加入正丁基锂(2.5M，12.6mL，31.6mmol)。加毕，保持这个温度搅拌0.5h后加入N-甲氧基-N-甲基乙酰胺(3.3g,31.6mmol)，缓慢升到室温，搅拌反应过夜，倒入冰(50g)中，用乙酸乙酯(300mL)萃取两次，合并有机相，干燥，旋干，硅胶柱层析分离，得到目标产物(1.1g)。
LC-MS：m/z 344(M+H) +。
第五步：(R，Z)-叔丁基(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)氨基甲酸酯的制备
将(3-乙酰基-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)氨基甲酸叔丁酯(1g,2.9mmol)加入四氢呋喃(20mL)中，再加入(R)-2-甲基丙烷-2-亚磺酰胺(0.53g,4.4mmol)和钛酸四乙酯(2.6g,12mmol)。然后反应液在回流下搅拌过夜，降温，浓缩，硅胶柱层析分离得到目标产物(0.68g，收率：52％)。
LC-MS：m/z 447(M+H) +。
第六步：(3-(1,1-二氟-2-羟基-2-甲基丙基)-5-((R)-1-((R)-1,1-二甲基乙基亚磺酰胺基)乙基)苯基)氨基甲酸叔丁酯的制备
将(R，Z)-叔丁基(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)氨基甲酸酯(0.68g,1.5mmol)加入四氢呋喃/水(8mL/0.16mL)中，0℃下加入硼氢化钠(116mg，3.0mmol)，反应液在室温下搅拌半小时后，加入饱和氯化铵溶液(20mL)，用乙酸乙酯(60mL)萃取2次，合并有机相干燥，浓缩，硅胶柱层析分离，得到目标产物(600mg，收率：88％)。
LC-MS：m/z 449(M+H) +。
第七步：(R)-1-(3-氨基-5-(1-氨基乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
将(3-(1,1-二氟-2-羟基-2-甲基丙基)-5-((R)-1-((R)-1,1-二甲基乙基亚磺酰胺基)乙基)苯基)氨基甲酸叔丁酯(600mg,1.34mmol)加入甲醇(3mL)中，加入4N氯化氢的二氧六环溶液(6mL)，然后反应液在室温搅拌16h。浓缩，粗品制备液相分离，得到目标产物(188mg，收率：50％)。
LC-MS：m/z 245(M+H) +。 1H NMR(400MHz,DMSO)δ8.37(brs,3H),6.82-6.66(m,3H),5.74-4.94(m,2H),4.30-4.16(m,1H),1.46(d,J＝6.8Hz,3H),1.17(s,6H).
中间体-2(R)-1-(2-(1-氨基乙基)吡啶-4-基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000105
第一步：2-(2-氯吡啶-4-基)-2,2-二氟乙酸乙酯的制备
将2-氯-4-碘吡啶(4.0g,16.7mmol)、2-溴-2,2-二氟乙酸乙酯(8.5g,41.8mmol)和活性铜粉(2.7g,41.8mmol)加入二甲亚砜(30mL)中，氮气保护下于55℃搅拌16h。冷却至室温，水/乙酸乙酯(150mL/100mL)稀释，搅拌，过滤除去不溶固体，滤液分层，水相用乙酸乙酯(100mL)萃取。合并乙酸乙酯层用饱和食盐水(50mL)洗涤三次，干燥，旋干，硅胶柱层析分离，得到目标产物(3.5g，收率：86％)。
LC-MS：m/z 236(M+H) +。
第二步：1-(2-氯吡啶-4-基)-1,1-二氟-2-甲基丙烷-2-醇的制备
将2-(2-氯吡啶-4-基)-2,2-二氟乙酸乙酯(3.06g,13.0mmol)加入无水甲苯(30mL)中，置换氮气3次，冰浴下，滴加甲基溴化镁(3M，10mL,30.0mmol)。然后反应液在室温搅拌1h。加入饱和氯化铵溶液(100mL)，用乙酸乙酯(50mL)萃取2次，合并有机相干燥，浓缩，硅胶柱层析分离，得到目标产物(1.8g，纯度：～80％，收率：58％)。
LC-MS：m/z 222(M+H) +。
第三步：1-(2-(1-乙氧基乙烯基)吡啶-4-基)-1,1-二氟-2-甲基丙烷-2-醇的制备
将1-(2-氯吡啶-4-基)-1,1-二氟-2-甲基丙烷-2-醇(1.68g,7.6mmol)加入N,N-二甲基甲酰胺(15mL)中，再加入三丁基(1-乙氧基乙烯基)锡烷(3.29g,9.1mmol)和双三苯基膦二氯化钯(266mg,0.38mmol)，氮气置换。反应液在120℃下搅拌过夜，然后冷却至室温，倒入水/乙酸乙酯(50mL/50mL)中，铺硅藻土抽滤除去絮状黑色固体。滤液分层，水相用乙酸乙酯(30mL)萃取两次。合并有机相，用饱和食盐水(30mL)洗涤三次，干燥，浓缩得到目标产物。无需纯化，直接用于下一步反应。
LC-MS：m/z 258(M+H) +。
第四步：1-(4-(1,1-二氟-2-羟基-2-甲基丙基)吡啶-2-基)乙酮的制备
将上一步得到的1-(2-(1-乙氧基乙烯基)吡啶-4-基)-1,1-二氟-2-甲基丙烷-2-醇(粗品)溶解在四氢呋喃(30mL)中，再加入2M盐酸水溶液(15mL)。然后反应液在室温搅拌1h，用饱和碳酸氢钠调pH到8，再用乙酸乙酯(50mL)萃取两次，合并有机相干燥，浓缩。残留物以硅胶柱层析分离，得到目标产物(1.29g，两步收率：70％)。
LC-MS：m/z 230(M+H) +。
第五步：(R，E)-N-(1-(4-(1,1-二氟-2-羟基-2-甲基-2-甲基丙基)吡啶-2-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备
将1-(4-(1,1-二氟-2-羟基-2-甲基丙基)吡啶-2-基)乙酮(1.07g,4.69mmol)加入四氢呋喃(20mL)中，再加入(R)-2-甲基丙烷-2-亚磺酰胺(850mg,7.03mmol)和钛酸四乙酯(4.3g,18.76mmol)。然后反应液在回流下搅拌1.5h，降温，浓缩，硅胶柱层析分离，得到目标产物(455mg，收率：29％)。
LC-MS：m/z 333(M+H) +。
第六步：(R)-N-((R)-1-(4-(1,1-二氟-2-羟基-2-甲基丙基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备
将(R，E)-N-(1-(4-(1,1-二氟-2-羟基-2-甲基-2-甲基丙基)吡啶-2-基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(455mg,1.37mmol)溶解在四氢呋喃/水(7mL/0.14mL)中，在-50℃分批加入硼氢化钠(78mg，2.06mmol)，然后反应液缓慢升至室温。加半饱和盐水(30mL)，用乙酸乙酯(20mL)萃取3次，合并有机相干燥，浓缩，残留物硅胶柱层析分离，得到目标产物(290mg，收率：56％)。
LC-MS：m/z 335(M+H) +。
第七步：(R)-1-(2-(1-氨基乙基)吡啶-4-基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
将(R)-N-((R)-1-(4-(1,1-二氟-2-羟基-2-甲基丙基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(290mg,0.87mmol)溶解在甲醇(2mL)中，加入氯化氢/二氧六环溶液(4M,4mL)，然后反应液在室温搅拌16h。反应液浓缩干，粗品制备液相分离，得到目标产物(179mg，收率：77％)。
LC-MS：231m/z(M+H) +。 1H NMR(400MHz,DMSO)δ8.73(d,J＝4.8Hz,1H),8.60(brs,3H),7.65(s,1H),7.49(d,J＝5.2Hz,1H),5.52(s,1H),4.60(q,J＝6.4Hz,1H),1.52(d,J＝7.2Hz,3H),1.19(s,6H).
按照中间体-2相同方法，以不同起始原料合成以下化合物：
中间体-3(R)-1-(6-(1-氨基乙基)吡啶-2-基)-1,1-二氟-2-甲基丙-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000106
LC-MS：231m/z(M+H) +。 1H NMR(400MHz,DMSO)δ8.61(s,3H),8.04-8.00(m,1H),7.70(d,J＝8.0Hz,1H),7.59(d,J＝7.6Hz,1H),5.28(s,1H),4.54(m,1H),1.56(d,J＝6.8Hz,3H),1.24(s,6H).
中间体-4(R)-1-(4-(1-氨基乙基)吡啶-2-基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐 的制备
Figure PCTCN2021125084-appb-000107
LC-MS：231m/z(M+H) +。 1H NMR(400MHz,DMSO)δ8.86(brs,3H),8.70(d,J＝5.2Hz,1H),7.77(s,1H),7.73(d,J＝5.2Hz,1H),4.54-4.50(m,1H),1.53(d,J＝6.8Hz,3H),1.23(s,6H).
中间体-5(R)-1-(5-(1-氨基乙基)吡啶-3-基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000108
LC-MS：231m/z
中间体-6(R)-1-(3-(1-氨基乙基)-4-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000109
第一步：2-溴-1-氟-4-碘苯的制备
将3-溴-4-氟苯胺(5g,26.5mmol)加入乙腈/水(50mL/8mL)中，0℃下加入浓盐酸(11mL)和亚硝酸钠(2g,29.1mmol)，反应半小时后，加入碘化钾(6.6g,39.8mmol)/水(15mL)溶液，室温搅拌反应3h后，倒入水(100mL)中，用乙酸乙酯(300mL)萃取两次，合并有机相，干燥，旋干，硅胶柱层析分离得到目标产物(15.8g，收率：100％)。
第二步：2-(3-溴-4-氟苯基)-2,2-二氟乙酸乙酯的制备
将2-溴-1-氟-4-碘苯(15.8g,52.7mmol)加入二甲基亚砜(110mL)中，加入2-溴-2,2-二氟乙酸乙酯(26.8g,131.6mmol)和铜粉(8.4g,131.6mmol)，然后升温到70℃，搅拌反应过夜。倒入水(300mL)中，用乙酸乙酯(800mL)萃取两次，合并有机相，干 燥，旋干，硅胶柱层析分离得到目标产物(9.8g，收率：63％)。
1H NMR(400MHz,CDCl 3)δ7.83(dd,J＝6.4Hz,2.0Hz；1H),7.61-7.51(m,1H),7.20(t,J＝8.4Hz；1H),4.32(q,J＝7.2Hz；2H),1.32(t,J＝6.8Hz；3H).
第三步：1-(3-溴-4-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
将2-(3-溴-4-氟苯基)-2,2-二氟乙酸乙酯(9.8g,33mmol)加入四氢呋喃(150mL)中，0℃下加入甲基溴化镁(33mL,99mmol)。室温反应1h后，倒入冰(100g)中，用乙酸乙酯(400mL)萃取两次，合并有机相，干燥，旋干，硅胶柱层析分离，得到目标产物(9g，收率：97％)。
1H NMR(400MHz,CDCl 3)δ7.74(dd,J＝6.4Hz,2.0Hz；1H),7.54-7.43(m,1H),7.16(t,J＝8.4Hz；1H),1.32-1.29(m,6H).第四步：1-(3-(1-乙氧基乙烯基)-4-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
将1-(3-溴-4-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇(9.3g,32.9mmol)加入氮，氮-二甲基甲酰胺(100mL)中，加入三丁基(1-乙氧基乙烯基)锡烷(14.2g，39.4mmol)和双三苯基磷二氯化钯(1.2g,1.65mmol)。加毕，氮气保护，升温到120℃搅拌反应16h。反应毕，降温，倒入水(300mL)中，用乙酸乙酯(600mL)萃取两次，合并有机相，干燥，旋干，得到目标产物，直接用于下一步反应。
第五步：1-(5-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙酮的制备
将1-(3-(1-乙氧基乙烯基)-4-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇(粗品)加入四氢呋喃(60mL)中，再加入盐酸水溶液(20mL,4mol/L)，室温搅拌1h后，用饱和碳酸氢钠水溶液调pH＝7.0～8.0,用乙酸乙酯(600mL)萃取两次，合并有机相，干燥，旋干，硅胶柱层析分离得到目标产物(6.6g，两步收率：81％)。
LC-MS：m/z 247(M+H) +。
第六步：(R，Z)-N-(1-(5-(1,1-二氟-2-羟基-2-甲基-2-甲基丙基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备
将1-(5-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙酮(6.6g,26.8mmol)加入四氢呋喃(70mL)中，再加入(R)-2-甲基丙烷-2-亚磺酰胺(4.9g,40.2mmol)和钛酸四乙酯(23.9g,107mmol)。然后反应液在60℃下搅拌过夜，降温，浓缩，硅胶柱层析分离，得到目标产物(6.4g，收率：68％)。
LC-MS：m/z 350(M+H) +。
第七步：(R)-N-((R)-1-(5-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备
将(R，Z)-N-(1-(5-(1,1-二氟-2-羟基-2-甲基-2-甲基丙基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(6.3g,18.1mmol)加入四氢呋喃/水(80mL/1.6mL)中，0℃下加入硼氢化钠(1.4g，36.2mmol)，反应液在室温下搅拌半小时后，加入饱和氯化铵溶液(100mL)，用乙酸乙酯(300mL)萃取2次，合并有机相干燥，浓缩，硅胶柱层析 分离，得到目标产物(4.1g，收率：64％)。
LC-MS：m/z 352(M+H) +。
第八步：(R)-1-(3-(1-氨基乙基)-4-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
将(R)-N-((R)-1-(5-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(4g,11.4mmol)加入甲醇(20mL)中，加入4N氯化氢的二氧六环溶液(20mL)，然后反应液在室温搅拌16h。浓缩，残余物制备液相分离，得到目标产物(2.32g)，收率：82％。
LC-MS：m/z 248(M+H) +。 1H NMR(400MHz,DMSO)δ8.70(brs,3H),7.79(dd,J＝7.2Hz,2.4Hz；1H),7.56-7.49(m,1H),7.37(t,J＝9.6Hz；1H),5.33(s,1H),4.63(q,J＝6.4Hz；1H),1.53(d,J＝6.8Hz,3H),1.18(s,6H).
按照中间体-6相同方法，以不同起始原料合成以下化合物：
中间体-7(R)-1-(3-(1-氨基乙基)-5-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000110
LC-MS：m/z 248(M+H) +。 1H NMR(400MHz,DMSO)δ8.72(s,3H),7.62(d,J＝9.7Hz,1H),7.49(s,1H),7.27(d,J＝9.4Hz,1H),4.52-4.47(m,1H),1.53(d,J＝6.8Hz,3H),1.18(s,6H).
中间体-8(R)-1-(5-(1-氨基乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
Figure PCTCN2021125084-appb-000111
LC-MS：m/z 248(M+H) +。 1H NMR(400MHz,DMSO)δ8.57(brs,3H),7.72(s,1H),7.62-7.60(m,1H),7.35(dd,J＝10.8Hz,8.8Hz,1H),5.38(s,1H),4.50-4.44(m,1H),1.51(d,J＝6.8Hz,3H),1.21(s,6H).
中间体-9(R)-1-(3-(1-氨基乙基)-5-甲氧基苯基)-1,1-二氟-2-甲基丙醇-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000112
LC-MS：m/z 260(M+H) +。 1H NMR(400MHz,DMSO)δ8.67(s,3H),7.36(s,1H),7.18(s,1H),6.98(s,1H),5.31(brs,1H),4.44-4.40(m,1H),3.81(s,3H),1.53(d,J＝6.8Hz,3H),1.18(s,6H).
中间体-10(R)-1-(3-(1-氨基乙基)-2-氯苯基)-1,1-二氟-2-甲基丙-2-醇盐酸盐的制备
Figure PCTCN2021125084-appb-000113
LC-MS：m/z 264(M+H) +。 1H NMR(400MHz,DMSO)δ8.74(brs,3H),7.90(dd,J＝8.8Hz,3.2Hz,1H),7.65-7.54(m,2H),5.45(s,1H),4.63(q,J＝8.8Hz,1H),1.54(d,J＝8.8Hz,3H),1.27(s,6H).
中间体-11(R)-1-(3-(1-氨基乙基)-2-甲基苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
Figure PCTCN2021125084-appb-000114
LC-MS：m/z 244(M+H) +。 1H NMR(400MHz,DMSO)δ8.49(brs,3H),7.69(d,J＝7.2Hz,1H),7.41-7.34(m,2H),4.71-4.65(m,1H),3.57(s,1H),2.46(s,3H),1.48(d,J＝6.8Hz,3H),1.22(s,6H).
中间体-12(R)-3-(1-氨基乙基)-5-(1,1-二氟-2-羟基-2-甲基丙基)苯甲腈的制备
Figure PCTCN2021125084-appb-000115
LC-MS：m/z 255(M+H) +。 1H NMR(400MHz,DMSO)δ7.97(s,1H),7.81(s,1H),7.72(s,1H),5.40(s,1H),4.14(q,J＝6.6Hz,1H),1.28(d,J＝6.6Hz,3H),1.17(s,6H).
中间体-13 2-(1-氨基乙基)-6-(1-甲基环丙基)吡啶-4-胺的制备
Figure PCTCN2021125084-appb-000116
第一步：2-溴-6-(丙-1-烯-2-基)吡啶-4-胺的制备
氮气保护下，2,6-二溴吡啶-4-胺(19.0g,75.4mmol,1.00eq)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧硼杂环戊烷(25.4g,151mmol,2.00eq)的二氧六环(150mL)和H 2O(30mL)的溶液中加入K 2CO 3(31.3g,226mmol,3.00eq)和Pd(PPh 3) 2Cl 2(3.71g,5.28mmol,0.07eq)。反应液在80℃反应16h。得到的反应液用水(500mL)淬灭后用EtOAc(500mL*2)萃取。合并的有机相用饱和食盐水(300mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标产物(8.00g,37.6mmol,收率49.8％)。
LC-MS：m/z 213(M+H) +。
第二步：(2-溴-6-(丙-1-烯-2-基)吡啶-4-基)(叔-丁氧羰基)氨基甲酸叔丁酯的制备
2-溴-6-(丙-1-烯-2-基)吡啶-4-胺(8.00g,37.6mmol,1.00eq)的DCM(80mL)溶液中加入(Boc) 2O(32.8g,150mmol,34.5mL,4.00eq)和DMAP(1.38g,11.3mmol,0.30eq)。反应液在25℃反应16h，然后减压浓缩。残余物用硅胶柱层析分离，得到目标产物(8.00g,19.4mmol,收率51.6％)。
LC-MS：m/z 413(M+H) +。
第三步：(2-溴-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯的制备
氮气保护下，在0℃下二乙基锌(1.00M,38.7mL,4.00eq)的DCM(20mL)中加入TFA(4.41g,38.7mmol,2.87mL,4.00eq)。反应液在0℃反应15mins。随后在0℃下滴加入CH 2I 2(10.4g,38.7mmol,3.12mL,4.00eq)的DCM(20mL)溶液。反应液在0℃反应20mins。随后在0℃加入(2-溴-6-(丙-1-烯-2-基)吡啶-4-基)(叔-丁氧羰基)氨基甲酸叔丁酯(4.00g,9.68mmol,1.00eq)的DCM(20mL)溶液。反应液在20℃反应5h。得到的反应液用水(200mL)淬灭后用DCM(100mL*2)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(1.08g,2.64mmol,收率17.0％,纯度80.0％)。
LC-MS：m/z 327(M+H) +。
第四步：(2-乙酰基-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯的制备
氮气保护下，(2-溴-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯(1.05g,3.21mmol,1.00eq)的二氧六环(5mL)溶液中加入三丁基(1-乙氧基乙烯基)锡(1.43g,3.96mmol,1.34mL,1.24eq)、TEA(649mg,6.42mmol,893uL,2.00eq)和Pd(PPh 3) 2Cl 2(113mg,160umol,0.05eq)。反应液在60℃反应16h。得到的反应液用1N HCl(50mL)淬灭后用EtOAc(200mL)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(560mg,1.93mmol,收率60.1％)。
LC-MS：m/z 291(M+H) +。
第五步：(E)-(2-(1-((叔丁基亚磺酰)亚胺)乙基)-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯的制备
(2-乙酰基-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯(0.56g,1.93mmol,1.00eq)和 叔丁基亚磺酰胺(351mg,2.90mmol,1.50eq)的THF(5mL)中加入Ti(OEt) 4(1.10g,4.82mmol,999μL,2.50eq)。反应液在80℃反应16h，然后减压浓缩。残余物用硅胶柱层析分离，得到目标产物(440mg,1.01mmol,收率52.1％,纯度90.0％)。
LC-MS：m/z 394(M+H) +。
第六步：(2-(1-((叔丁基亚磺酰)胺基)乙基)-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯的制备
在0℃下，(E)-(2-(1-((叔丁基亚磺酰)亚胺)乙基)-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯(440mg,1.12mmol,1.00eq)的THF(5mL)和H 2O(0.1mL)的溶液中加入NaBH 4(46.5mg,1.23mmol,1.10eq)。反应液在25℃反应1h。得到的反应液用水(20mL)淬灭后用EtOAc(100mL)萃取。合并的有机相用饱和食盐水(30mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(300mg,758μmol,收率67.8％)。
LC-MS：m/z 396(M+H) +。
第七步：2-(1-氨基乙基)-6-(1-甲基环丙基)吡啶-4-胺的制备
在0℃下，(2-(1-((叔丁基亚磺酰)胺基)乙基)-6-(1-甲基环丙基)吡啶-4-基)氨基甲酸叔丁酯(300mg,758umol,1.00eq)的二氧六环(1mL)溶液中加入HCl/dioxane(1mL)。反应液在25℃反应16h然后过滤。滤饼真空干燥，得到白色固体状的目标产物(165mg,647umol,收率85.4％,纯度89.3％)。
LC-MS：m/z 192(M+H) +。 1H NMR(400MHz,CD 3OD)δ6.91(d,J＝2.3Hz,1H),6.78(d,J＝2.2Hz,1H),4.78-4.65(m,1H),4.78-4.65(m,1H),1.75-1.71(m,1H),1.75-1.71(m,1H),1.73(d,J＝7.0Hz,4H),1.54-1.50(m,1H),1.51(s,3H),1.15-1.10(m,2H),1.01-0.95(m,2H).
中间体-14 2-(1-氨基乙基)-6-(1-氟环丙基)吡啶-4-胺的制备
Figure PCTCN2021125084-appb-000117
第一步：2-氯-6-(1-氟环丙基)-4-硝基吡啶的制备
2-氯-4-硝基吡啶(16.0g,101mmol,1.00eq)、1-氟环丙烷-1-甲酸(13.7g,131mmol, 1.30eq)和AgNO 3(3.43g,20.2mmol,0.200eq)的ACN(50.0mL)和H 2O(65.0mL)的混合物加热至80℃.，随后加入(NH 4) 2S 2O 8(46.0g,202mmol,43.9mL,2.00eq)的H 2O(65.0mL)溶液。反应液在80℃反应48h。得到的反应液用2M NaOH溶液(500mL)淬灭后用EtOAc(500mL)萃取。合并的有机相用无水MgSO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(2.50g,11.5mmol,收率11.4％)。
1H NMR(400MHz,CDCl 3)δ8.55-8.62(m,1H)7.45(d,J＝5.25Hz,1H)1.48-1.55(m,2H)0.87-0.95(m,2H)。
第二步：2-(1-乙氧基乙烯基)-6-(1-氟环丙基)-4-硝基吡啶的制备
氮气保护下，2-氯-6-(1-氟环丙基)-4-硝基吡啶(2.37g,11.0mmol,1.00eq)、三丁基(1-乙氧基乙烯基)锡(7.00g,19.4mmol,6.54mL,1.75eq)和Pd(PPh 3) 2Cl 2(778mg,1.11mmol,0.100eq)的二氧六环(25.0mL)溶液在110℃反应16h。得到的反应液用H 2O(60mL)淬灭后用EtOAc(60mL)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(1.66g,6.58mmol,收率59.4％)。
1H NMR(400MHz,CDCl 3)δ8.77(dd,J＝5.13,1.25Hz,1H)7.49(d,J＝5.13Hz,1H)4.51-4.69(m,2H)3.94(q,J＝7.00Hz,2H)1.30-1.38(m,5H)0.77-0.85(m,2H)。
第三步：1-(6-(1-氟环丙基)-4-硝基吡啶-2-基)乙烷-1-酮的制备
2-(1-乙氧基乙烯基)-6-(1-氟环丙基)-4-硝基吡啶(1.63g,6.46mmol,1.00eq)的THF(5.00mL)溶液中加入HCl水溶液(2.00M,4.85mL,1.50eq)。反应液在25℃反应1h。得到的反应液用H 2O(30mL)淬灭后用EtOAc(50mL)萃取。合并的有机相用饱和食盐水(100mL)洗涤，经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(1.44g,6.26mmol,收率96.8％,纯度97.4％)。
1H NMR(400MHz,CDCl 3)δ(dd,J＝5.14,1.38Hz,1H)7.69(d,J＝5.27Hz,1H)2.74(s,3H)1.45-1.55(m,2H)0.77-0.86(m,2H)。
第四步：(E)-N-(1-(6-(1-氟环丙基)-4-硝基吡啶-2-基)乙烯)-2-甲基丙烷-2-磺酰亚胺的制备
1-(6-(1-氟环丙基)-4-硝基吡啶-2-基)乙烷-1-酮(1.24g,5.53mmol,1.00eq)和叔丁基亚磺酰胺(1.01g,8.30mmol,1.50eq)的THF(15.0mL)中加入Ti(OEt) 4(5.05g,22.1mmol,4.59mL,4.00eq)。反应液在80℃反应16h。得到的反应液用H 2O(200mL)淬灭后用EtOAc(300mL)萃取。合并的有机相经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离，得到目标产物(750mg,2.44mmol,收率44.1％)。
1H NMR(400MHz,CDCl 3)δ8.89(dd,J＝5.02,1.00Hz,1H)7.57-7.70(m,1H)2.65-2.87(m,3H)1.40-1.55(m,2H)1.31(d,J＝12.30Hz,9H)0.84(dd,J＝9.03,2.51Hz,2H)。
第五步：N-(1-(6-(1-氟环丙基)-4-硝基吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备
(E)-N-(1-(6-(1-氟环丙基)-4-硝基吡啶-2-基)乙烯)-2-甲基丙烷-2-磺酰亚胺(730mg, 2.23mmol,1.00eq)的THF(8.00mL)and H 2O(0.100mL)溶液中加入NaBH 4(126mg,3.34mmol,1.50eq)。反应液在0℃反应0.5h。在0℃，得到的反应液用水(20mL)淬灭后用EtOAc(20mL)萃取。合并的有机相经无水Na 2SO 4干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到黄色固体状的目标产物(0.300g,911μmol,收率40.8％)。
1H NMR(400MHz,CDCl 3)δ8.80(br s,1H)7.40(br s,1H)5.35(br d,J＝6.50Hz,1H)4.90(br d,J＝9.01Hz,1H)1.62(br s,5H)1.26(br s,9H)0.82-0.99(m,2H)。
第六步：N-(1-(4-氨基-6-(1-氟环丙基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备
在氮气氛围下，N-(1-(6-(1-氟环丙基)-4-硝基吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(200mg,607μmol,1.00eq)和Boc 2O(159mg,729umol,167μL,1.20eq)的MeOH(2.00mL)溶液中加入Pd/C(607μmol,2.00mL,纯度10.0％,1.00eq)。在氢气氛围下反应液在25℃反应2h，然后减压浓缩。残余物用硅胶柱层析分离，得到目标产物(140mg,468μmol,收率77.0％)。
LC-MS：m/z 300(M+H) +。
第七步：2-(1-氨基乙基)-6-(1-氟环丙基)吡啶-4-胺的制备
N-(1-(4-氨基-6-(1-氟环丙基)吡啶-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺(120mg,401μmol,1.00eq)的二氧六环(1.00mL)溶液中加入HCl/dioxane(1.80mL)。反应液在25℃反应0.5h，然后减压浓缩得到目标产物(52.0mg,259μmol,收率64.6％,纯度97.1％)。
LC-MS：m/z 196(M+H) +。 1H NMR(400MHz,DMSO)δ9.02-9.39(m,3H)8.23(d,J＝6.85Hz,1H)6.99(d,J＝6.85Hz,1H)5.20(br d,J＝5.50Hz,1H)1.68(br d,J＝6.85Hz,3H)1.56-1.66(m,2H)1.27-1.39(m,1H)0.95(br s,1H)。
中间体-15(R)-5-(7-溴-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-8-氟-2-甲基喹唑啉-6-基)-1-甲基吡啶-2(1H)-酮的制备
Figure PCTCN2021125084-appb-000118
第一步：2-氨基-4-溴-3-氟-5-碘苯甲酸的制备
2-氨基-4-溴-3-氟苯甲酸(2.00g,8.55mmol,1.00eq)的DMF(20.0mL)溶液中加入NIS(2.12g,9.40mmol,1.10eq)。得到的混合物在80℃反应2h，然后用水(100mL)淬灭 后过滤。滤饼收集干燥得到目标产物(2.20g,产率67.2％)。无需纯化直接用于下一步反应。
LC-MS：m/z 360(M+H) +。
第二步：7-溴-8-氟-6-碘-2-甲基喹唑啉-4-醇的制备
2-氨基-4-溴-3-氟-5-碘苯甲酸(5.20g,14.5mmol,1.00eq)的Ac 2O(50mL)溶液在138℃反应12h，然后减压浓缩。残余物在EtOH(50mL)和NH 3.H 2O(50mL)的混合溶剂中在80℃反应5h，然后过滤。滤饼收集干燥得到目标产物(4.00g,产率69.6％)。无需纯化直接用于下一步反应。
LC-MS：m/z 383(M+H) +。
第三步：(R)-1-(3-(1-((7-溴-8-氟-6-碘-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
7-溴-8-氟-6-碘-2-甲基喹唑啉-4-醇(1.60g,4.18mmol,1.00eq)的DMF(16mL)溶液中加入PyBOP(4.35g,8.36mmol,2.00eq)和TEA(2.11g,20.9mmol,2.91mL,5.00eq),反应液在室温反应0.5h,随后加入(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇盐酸盐(1.54g,5.43mmol,1.30eq)。得到的混合物在25℃反应16h，随后加入EtOAc(50mL)和H 2O(50mL)。有机相分离后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用制备液相分离得到目标产物(1.10g,产率43.2％)。
LC-MS：m/z 612(M+H) +。 1H NMR(400MHz,DMSO)δ8.93(s,1H)8.78(br d,J＝7.21Hz,1H)7.59(br t,J＝6.54Hz,1H)7.29-7.36(m,1H)7.19-7.26(m,1H)5.76(t,J＝7.09Hz,1H)5.33(s,1H)2.36(s,3H)1.58(d,J＝7.09Hz,3H)1.22(br d,J＝10.27Hz,6H).
第四步：(R)-5-(7-溴-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-8-氟-2-甲基喹唑啉-6-基)-1-甲基吡啶-2(1H)-酮的制备
在氮气保护下，(R)-1-(3-(1-((7-溴-8-氟-6-碘-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇(1g,1.63mmol,1eq)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼环戊烷-2-基)吡啶-2(1H)-酮(461mg,1.96mmol,1.2eq)、Pd(dppf)Cl 2(120mg,163umol,0.1eq)、和K 3PO 4(1.04g,4.90mmol,3eq)的dioxane(5mL)、MeCN(5mL)和H 2O(5mL)的混合物在90℃反应6h。然后加入EtOAc(20mL)和H 2O(20mL)。有机相分离后用无水MgSO4干燥后过滤。滤液减压浓缩，残余物用制备液相分离得到目标产物(750mg,产率77.4％)。
LC-MS：m/z 593(M+H) +。 1H NMR(400MHz,DMSO)δ8.71(br d,J＝7.28Hz,1H)8.34(s,1H)8.00(d,J＝2.51Hz,1H)7.57-7.65(m,2H)7.29-7.36(m,1H)7.18-7.26(m,1H)6.53(d,J＝9.29Hz,1H)5.81(br t,J＝7.15Hz,1H)5.34(s,1H)3.54(s,3H)2.40(s,3H)1.58(d,J＝7.03Hz,3H)1.23(br d,J＝10.04Hz,6H).
实施例1 1,1-二氟-1-(2-氟-3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇的制备
Figure PCTCN2021125084-appb-000119
第一步：(S)-2-(氯甲基)-1-甲基吡咯啉的制备
将N-甲基-L-脯氨醇(500.0mg,4.34mmol)溶于甲苯(5mL)中，再加入二氯亚砜(2.0mL)。得到的反应液在100℃下搅拌2.0h，然后减压浓缩。得到的粗品无需进一步纯化，直接投下一步。
第二步：(S)-7-甲氧基-2-甲基-6-((1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4(3H)-酮的制备
将6-羟基-7-甲氧基-2-甲基喹唑啉-4(3H)-酮(120mg,0.58mmol)加入N，N-二甲基甲酰胺(10mL)中，随后加入上一步得到的(S)-2-(氯甲基)-1-甲基吡咯啉(77.8mg,0.58mmol)和碳酸钾(402.2mg,2.91mmol)。得到的反应液在100℃下搅拌3.0h，然后冷却至室温。混合物通过制备液相制备得到目标产物(39mg，收率：22％)。
LC-MS：m/z 304(M+H) +。
第三步:(S)-7-甲氧基-2-甲基-6-((1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-基2,4,6-三异丙基苯磺酸酯的制备
将(S)-7-甲氧基-2-甲基-6-((1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4(3H)-酮(38.0mg,0.13mmol)加入二氯甲烷(4mL)中，再加入2,4,6-三异丙基磺酰氯(45.5mg,0.15mmol)、三乙胺(25.4mg,0.25mmol)和4-二甲氨基吡啶(1.5mg,0.013mmol)。得到的反应液在室温下搅拌过夜，随后倒入水中，再用二氯甲烷(10mL)萃取。有机相干燥后减压浓缩，得到的残余物用硅胶柱层析(PE:EA＝5:1)得到目标产物(14.0mg，收率：20％)。
LC-MS：m/z 570(M+H) +。
第四步:1,1-二氟-1-(2-氟-3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇的制备
将(S)-7-甲氧基-2-甲基-6-((1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-基2,4,6-三异丙基苯磺酸酯(31.0mg,0.054mmol)加入二甲基亚砜(2mL)中，再加入(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇(20.2mg,0.082mmol)和三乙胺(0.4mL)。得到的反应液在微波120℃下反应2.0h，然后降至室温用水淬灭，再用乙酸乙酯(10mL)萃取。 有机相干燥后减压浓缩，得到的残余物用制备液相分离，得到目标化合物(4mg，收率：13.9％)。
LC-MS：m/z 533(M+H) +。 1H NMR(400MHz,DMSO)δ8.07(m,1H),7.81(m,1H),7.57(d,J＝6.3Hz,1H),7.30(t,J＝7.1Hz,1H),7.25–7.17(m,1H),7.02(d,J＝3.0Hz,1H),5.79(m,1H),5.34(m,1H),4.10–3.97(m,1H),3.87(m,3H),2.43(m,2H),2.34–2.17(m,5H),2.13–1.94(m,2H),1.82–1.66(m,2H),1.58(m,3H),1.24(m,9H).
按照实施例1的方法以不同的起始原料合成了以下化合物：
实施例2 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000120
LC-MS：m/z 490(M+H) +。
实施例3 N-((R)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000121
LC-MS：m/z 471(M+H) +。
实施例4 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000122
LC-MS：m/z 460(M+H) +。
实施例5 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7-二甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基))喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000123
LC-MS：m/z 474(M+H) +。
实施例6(S)-5-(((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧)甲基)-1-甲基吡咯啉-2-酮的制备
Figure PCTCN2021125084-appb-000124
LC-MS：m/z 504(M+H) +。 1H NMR(400MHz,DMSO)δ14.28(brs,1H),9.71(d,J＝7.6Hz,1H),8.04(s,1H),7.17(m,3H),6.88(d,J＝4.3Hz,2H),6.76(s,1H),5.81–5.61(m,1H),4.33(m,1H),4.15(m,1H),3.97(m,4H),2.80(s,3H),2.59(s,3H),2.45(m,1H),2.27–2.13(m,2H),1.91(m,1H),1.64(d,J＝7.0Hz,3H).
实施例7(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-环丙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000125
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.93(d,1H),7.71(s,1H),7.03(s,1H),6.86(d,1H),6.69(s,1H),5.57-5.53(m,3H),4.22-4.18(m,2H),3.91-3.84(m,5H),3.44-3.39(m,1H),2.35(s,3H),1.55-1.53(d,3H),0.54-0.44(m,4H).
实施例8(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-(环丙基(甲基)氨基)乙氧基)-7-甲氧基-2-甲基喹啉-4-胺的制备
Figure PCTCN2021125084-appb-000126
LC-MS：m/z 490(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝8.0Hz,1H),7.69(s,1H),7.02(s,1H),6.87(d,J＝11.5Hz,2H),6.70(s,1H),5.64–5.44(m,3H),4.23–4.07(m,2H),3.86(s,3H),2.96(t,J＝5.9Hz,2H),2.39(s,3H),2.35(s,3H),1.87–1.74 (m,1H),1.52(d,J＝8.0Hz,3H),0.51–0.40(m,2H),0.37–0.24(m,2H).
实施例9(R)-1-(3-(1-((6-(2-((环丁基甲基)(甲基)氨基)乙氧基)-7-甲氧基-2-甲基喹啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
Figure PCTCN2021125084-appb-000127
LC-MS：m/z 561(M+H) +。 1H NMR(400MHz,DMSO)δ8.03(d,J＝7.4Hz,1H),7.74(s,1H),7.58(t,J＝6.7Hz,1H),7.30(t,J＝6.7Hz,1H),7.20(t,J＝7.7Hz,1H),7.02(s,1H),5.80(p,J＝7.0Hz,1H),5.31(s,1H),4.16(m,2H),3.86(s,3H),2.78(t,J＝6.0Hz,2H),2.27(d,J＝10.1Hz,6H),2.08–1.95(m,2H),1.93–1.73(m,3H),1.66(m,2H),1.58(d,J＝7.0Hz,3H),1.22(m,8H).
实施例10(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-((环丁基甲基)(甲基)氨基)乙氧基)-7-甲氧基-2-甲基喹啉-4-胺的制备
Figure PCTCN2021125084-appb-000128
LC-MS：m/z 518(M+H) +。 1H NMR(400MHz,DMSO)δ7.93(d,J＝8.0Hz,1H),7.69(s,1H),7.02(s,1H),6.87(d,J＝11.0Hz,2H),6.69(s,1H),5.63–5.46(m,3H),4.13(m,2H),3.86(s,3H),2.76(t,J＝6.0Hz,2H),2.47(m,2H),2.34(s,3H),2.25(s,3H),2.00(m,2H),1.90–1.71(m,3H),1.70–1.59(m,2H),1.55(d,J＝7.0Hz,3H).
实施例11(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-((1-((二甲基氨基)甲基)环丙基)甲氧基)-7-甲氧基-2-甲基喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000129
LC-MS：m/z 504(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝8.0Hz,1H),7.64(d,J＝9.6Hz,1H),7.02(s,1H),6.86(d,J＝10.4Hz,2H),6.69(s,1H),5.62–5.46(m,3H),3.96(m,2H),3.88(s,3H),2.39–2.10(m,11H),1.54(d,J＝7.1Hz,3H),0.67(s,2H),0.48(s,2H).
实施例12(R)-1-(3-(1-((6-((1-((二甲基氨基)甲基)环丙基)甲氧基)-7-甲氧基-2-甲基喹 啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000130
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.67(s,1H),7.58(t,J＝6.6Hz,1H),7.30(t,J＝6.6Hz,1H),7.21(m,1H),7.01(s,1H),5.79(m,1H),5.31(s,1H),3.98(m,2H),3.89(s,3H),2.26(m,8H),1.58(d,J＝7.0Hz,3H),1.32–1.12(m,9H),0.68(m,2H),0.48(m,2H).
实施例13(R)-N-(2-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)氧)乙基)-N-甲基甲烷磺酰胺的制备
Figure PCTCN2021125084-appb-000131
LC-MS：m/z 528(M+H) +。 1H NMR(400MHz,DMSO)δ7.99(d,J＝7.7Hz,1H),7.74(s,1H),7.05(s,1H),6.86(d,J＝10.6Hz,2H),6.69(s,1H),5.61–5.43(m,3H),4.20(t,J＝19.3Hz,2H),3.87(s,3H),3.59(t,J＝5.5Hz,2H),2.99(s,3H),2.92(s,3H),2.34(s,3H),1.52(t,J＝17.4Hz,3H).
实施例14 1-((S)-2-(((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)氧)甲基)吡咯-1-基)乙烷-1-酮的制备
Figure PCTCN2021125084-appb-000132
LC-MS：m/z 518(M+H) +。 1H NMR(400MHz,DMSO)δ7.92(d,J＝7.4Hz,1H),7.79(s,1H),7.02(s,1H),6.87(d,J＝14.3Hz,2H),6.69(s,1H),5.53(m,3H),4.32(m,2H),4.05(m,3H),3.88(s,3H),2.34(m,3H),2.17(m,2H),1.99(m,5H),1.54(d,J＝7.0Hz,3H).
实施例15(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((1-(吗啡啉甲基)环丙基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000133
LC-MS：m/z 546(M+H) +。 1H NMR(400MHz,DMSO)δ7.92(d,J＝7.9Hz,1H),7.64(s,1H),7.01(s,1H),6.87(m,2H),6.70(s,1H),5.66–5.44(m,3H),4.28–3.93(m,2H),3.87(s,3H),3.60–3.48(m,4H),2.66–2.56(m,1H),2.50(s,3H),2.35(m,4H),2.07–1.95(m,1H),1.56(t,J＝8.6Hz,3H),0.63(m,2H),0.50(m,2H).
实施例16(S)-2-(((4-(((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)氧)甲基)吡咯啉-1-甲酸叔丁酯
Figure PCTCN2021125084-appb-000134
LC-MS：m/z 579(M+H) +。 1H NMR(400MHz,DMSO)δ8.10(m,1H),7.77(m,2H),7.63(t,J＝7.1Hz,1H),7.34(t,J＝7.8Hz,1H),7.03(s,1H),5.75(m,1H),4.07(m,3H),3.87(s,3H),2.30(s,3H),1.91(m,4H),1.62(d,J＝7.1Hz,3H),1.40(m,11H).
实施例17 N-((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-吡咯啉-2-基)甲氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000135
LC-MS：m/z 479(M+H) +。 1H NMR(400MHz,DMSO)δ8.14(t,J＝8.6Hz,1H),7.84–7.70(m,2H),7.62(t,J＝6.9Hz,1H),7.35(t,J＝7.8Hz,1H),7.03(s,1H),5.85–5.67(m,1H),4.23–3.92(m,2H),3.87(s,3H),3.56(m,1H),2.91(m,2H),2.30(s,3H),2.12–1.67(m,4H),1.62(d,J＝7.1Hz,3H).
实施例18 N-((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-1-甲基吡咯啉-2-基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000136
LC-MS：m/z 493(M+H) +。 1H NMR(400MHz,DMSO)δ14.61(brs,1H),10.00(s,1H),8.21(d,J＝19.4Hz,1H),7.92(t,J＝7.2Hz,1H),7.72(t,J＝7.0Hz,1H),7.43(t,J＝7.8Hz,1H),7.28(s,1H),5.93(m,1H),4.66(d,J＝9.6Hz,1H),4.54–4.37(m,1H),4.23(m,1H),3.98(s,3H),3.71(m,2H),3.03(s,3H),2.54(s,3H),2.37(m,1H),2.25–1.90(m,3H),1.73(t,J＝10.3Hz,3H).
实施例19(R)-1-(3-(1-((6-(2-(((3,3-二氟环丁基)甲基)(甲基)氨基)乙氧基)-7-甲氧基-2-甲基喹啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
Figure PCTCN2021125084-appb-000137
LC-MS：m/z 597(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.74(s,1H),7.58(t,J＝6.7Hz,1H),7.31(m,1H),7.20(t,J＝7.7Hz,1H),7.02(s,1H),5.79(m,1H),5.34(s,1H),4.36(t,J＝5.1Hz,2H),3.83(s,3H),2.83(t,J＝5.7Hz,2H),2.75(d,J＝10.4Hz,2H),2.68–2.56(m,4H),2.39–2.15(m,7H),1.58(d,J＝7.0Hz,3H),1.20(m,6H).
实施例20 N-((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-1-(甲砜基)吡咯啶-2-基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000138
LC-MS：m/z 557(M+H) +。 1H NMR(400MHz,DMSO)δ8.15(d,J＝6.9Hz,1H),7.79(t,J＝7.1Hz,1H),7.74(s,1H),7.63(t,J＝7.0Hz,1H),7.35(t,J＝7.8Hz,1H),7.04(s,1H),5.75(p,J＝6.9Hz,1H),4.15(d,J＝10.8Hz,2H),4.08–3.95(m,1H),3.87(s,3H),3.32–3.24(m,2H),3.02(s,3H),2.28(s,3H),1.99(m,4H),1.62(d,J＝7.0Hz,3H).
实施例21(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-(((1-氟环丙基)甲基)(甲基)氨基)乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000139
LC-MS：m/z 522(M+H) +。 1H NMR(400MHz,DMSO)δ8.21–7.98(brs,1H),7.75(s,1H),7.04(s,1H),6.88(m,2H),6.71(s,1H),5.64–5.49(m,3H),4.21(m,2H),3.88(s,3H),2.91(m,4H),2.46(s,3H),2.36(s,3H),1.57(d,J＝7.0Hz,3H),0.99(m 2H),0.70(m,2H).
实施例22(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-(((3,3-二氟环丁基)甲基)(甲基)氨基)乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000140
LC-MS：m/z 554(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝7.9Hz,1H),7.70(s,1H),7.02(s,1H),6.86(m,2H),6.69(s,1H),5.62–5.48(m,3H),4.14(m,2H),3.86(s,3H),2.80(m,2H),2.75(m,1H),2.69–2.59(m,3H),2.58–2.54(m,2H),2.35(s,3H),2.27(s,3H),2.20(m,1H),1.55(d,J＝7.0Hz,3H).
实施例23 1,1-二氟-1-(2-氟-3-((R)-1-((7-甲氧基-2-甲基-6-(((R)-吗啡啉-2-基)甲氧基)喹唑啉-4-基)氨基)乙氧基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000141
LC-MS：m/z 535(M+H) +。 1H NMR(400MHz,DMSO)δ9.02(brs,1H),7.96(s,1H),7.63(t,J＝6.9Hz,1H),7.36(t,J＝6.9Hz,1H),7.26(t,J＝7.8Hz,1H),7.11(s,1H),5.96–5.81(m,1H),5.35(s,1H),4.32–4.10(m,3H),4.06(m,1H),3.94(s,3H),3.80(m,1H),3.50–3.38(m,2H),3.26(m,1H),3.05(m,2H),2.45(s,3H),1.64(d,J＝6.9Hz,3H),1.22(d,J＝7.5Hz,6H).
实施例24 1,1-二氟-1-(2-氟-3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-吗啡啉-2-基)甲氧基)喹唑啉-4-基)氨基)乙氧基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000142
LC-MS：m/z 535(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.73(s,1H),7.65–7.51(m,1H),7.30(t,J＝6.7Hz,1H),7.20(t,J＝7.7Hz,1H),7.02(s,1H),5.80(m,1H),5.33(s,1H),4.14–3.94(m,2H),3.87(s,3H),3.78(m,2H),3.51(m,1H),2.97(m,1H),2.68(m,2H),2.60–2.52(m,2H),2.28(s,3H),1.58(d,J＝7.0Hz,3H),1.20(t,J＝17.2Hz,6H).
实施例25 1,1-二氟-1-(2-氟-3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-4-甲基吗啡啉-2-基)甲氧基)喹唑啉-4-基)氨基)乙氧基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000143
LC-MS：m/z 549(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.74(s,1H),7.58(t,J＝6.6Hz,1H),7.30(t,J＝6.6Hz,1H),7.20(t,J＝7.7Hz,1H),7.03(s,1H),5.80(t,J＝7.1Hz,1H),5.32(s,1H),4.25–3.98(m,2H),3.85(m,5H),3.59(m,1H),2.87(m,1H),2.72–2.56(m,1H),2.28(s,3H),2.22(s,3H),2.04(m,1H),1.94(m,1H),1.58(d,J＝7.0Hz,3H),1.22(d,J＝11.3Hz,6H).
实施例26 1-(3-((R)-1-((6-(((S)-1,4-二氧六环-2-基)甲氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000144
LC-MS：m/z 536(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.3Hz,1H),7.74(s,1H),7.58(t,J＝6.9Hz,1H),7.30(t,J＝6.7Hz,1H),7.20(t,J＝7.7Hz,1H),7.03(s,1H),5.88–5.70(m,1H),5.32(s,1H),4.17–4.02(m,2H),4.01–3.84(m,5H),3.80(m,1H),3.74–3.62(m,2H),3.60–3.41(m,2H),2.28(s,3H),1.58(d,J＝7.0Hz,3H),1.20(t,J＝17.3Hz,6H).
实施例27 1-(3-((R)-1-((6-(((R)-1,4-二氧六环-2-基)甲氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000145
LC-MS：m/z 536(M+H) +。 1H NMR(400MHz,DMSO)δ8.05(d,J＝7.2Hz,1H),7.76(d,J＝10.9Hz,1H),7.58(t,J＝6.8Hz,1H),7.30(t,J＝6.7Hz,1H),7.20(t,J＝7.7Hz,1H),7.03(s,1H),5.88–5.72(m,1H),5.33(s,1H),4.09(m,2H),4.01–3.84(m,5H),3.80(m,1H),3.76–3.63(m,2H),3.50(m,2H),2.29(s,3H),1.58(d,J＝7.0Hz,3H),1.22(d,J＝11.0Hz,7H).
实施例28 6-(((S)-1,4-二氧六环-2-基)甲氧基)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000146
LC-MS：m/z 493(M+H) +。 1H NMR(400MHz,DMSO)δ8.05(d,J＝7.1Hz,1H),7.73(s,1H),7.04(s,1H),6.87(d,J＝10.7Hz,2H),6.70(s,1H),5.56(brs,2H),4.15–4.01(m,2H),4.01–3.84(m,5H),3.79(m,1H),3.74–3.60(m,2H),3.58–3.44(m,3H),2.36(s,3H),1.56(d,J＝6.9Hz,3H).
实施例29 1,1-二氟-1-(2-氟-3-((R)-1-((7-甲氧基-2-甲基-6-(((S)-4-(甲磺酰基)吗啡啉-2-基)甲氧基)喹唑啉-4-基)氨基)乙氧基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000147
LC-MS：m/z 613(M+H) +。 1H NMR(400MHz,DMSO)δ8.13(s,1H),7.79(s,1H),7.58(t,J＝6.8Hz,1H),7.30(t,J＝6.7Hz,1H),7.21(t,J＝7.7Hz,1H),7.04(s,1H),5.81(t,J＝7.1Hz,1H),5.33(s,1H),4.30–4.08(m,2H),4.09–3.94(m,2H),3.88(s,3H),3.76–3.56(m,2H),3.41(m,1H),3.06–2.72(m,5H),2.29(s,3H),1.58(d,J＝7.0Hz,3H),1.20(t,J＝14.5Hz,6H).
实施例30 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-5-甲基-5-氮杂螺[2.4]庚烷-6-基)甲氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000148
LC-MS：m/z 516(M+H) +。 1H NMR(400MHz,DMSO)δ7.98(d,J＝7.9Hz,1H),7.71(s,1H),7.02(s,1H),6.85(t,J＝11.2Hz,2H),6.69(s,1H),5.64–5.45(m,3H),4.14–3.98(m,2H),3.86(s,3H),2.91(m,1H),2.61(m,1H),2.53(m,1H),2.42(s,3H),2.35(s,3H),2.13(dd,J＝12.6,8.2Hz,1H),1.67–1.44(m,4H),0.63–0.39(m,4H).
实施例31 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(((S)-4,4-二氟-1-甲基吡咯烷-2-基)甲氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000149
LC-MS：m/z 526(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝8.0Hz,1H),7.73(s,1H),7.04(s,1H),6.86(d,J＝10.1Hz,2H),6.69(s,1H),5.66–5.46(m,3H),4.11(d,J＝5.2Hz,2H),3.87(s,3H),3.45–3.34(m,1H),3.05(t,J＝5.3Hz,1H),2.80–2.56(m,2H),2.43(s,3H),2.35(s,3H),2.30–2.12(m,1H),1.56(t,J＝7.2Hz,3H).
实施例32 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-1-(甲砜基)吡咯啶-2-基)甲氧基)喹唑啉-4-胺的制备
Figure PCTCN2021125084-appb-000150
LC-MS：m/z 554(M+H) +。 1H NMR(400MHz,DMSO)δ7.99(t,J＝13.1Hz,1H),7.71(s,1H),7.06(d,J＝10.1Hz,1H),6.87(d,J＝9.9Hz,2H),6.70(s,1H),5.64–5.45(m,3H),4.09(t,J＝12.0Hz,2H),3.99(m,1H),3.88(s,3H),2.99(s,3H),2.36(s,3H),2.02(m,4H),1.56(d,J＝7.0Hz,3H).
实施例33(R)-N-(2-((4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧)乙基)-N-甲基甲烷磺酰胺
Figure PCTCN2021125084-appb-000151
LC-MS：m/z 571(M+H) +。 1H NMR(400MHz,DMSO)δ8.13(d,J＝6.8Hz,1H),7.79(d,J＝15.0Hz,1H),7.60(t,J＝6.7Hz,1H),7.38–7.25(m,1H),7.21(t,J＝7.7Hz,1H),7.04(d,J＝10.1Hz,1H),5.81(p,J＝6.8Hz,1H),5.33(s,1H),4.27(t,J＝5.0Hz,2H),3.87(s,3H),3.61(t,J＝5.4Hz,2H),3.01(s,3H),2.95(s,3H),2.29(s,3H),1.59(d,J＝7.0Hz,3H),1.22(d,J＝11.1Hz,6H).
实施例34(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-((1-(二甲基氨基)环丙基)甲氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000152
LC-MS：m/z 490(M+H) +。 1H NMR(400MHz,DMSO)δ7.93(d,J＝8.0Hz,1H),7.65(s,1H),7.03(s,1H),6.86(d,J＝10.5Hz,2H),6.69(s,1H),5.57(d,J＝11.2Hz,3H),4.19–4.02(m,2H),3.87(s,3H),2.42(s,6H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),0.70(q,J＝6.8Hz,4H).
实施例35(R)-N-(1-(5-氨基-2-氟-3-(三氟甲基)苯基)乙基)-6-(2-环丙氧基乙基氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000153
LC-MS：m/z 495(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝7.2Hz,1H),7.77(s,1H),7.04(s,1H),6.89–6.79(m,1H),6.70(dd,J＝5.4,2.7Hz,1H),5.67(p,J＝6.9Hz,1H),5.33(s,2H),4.35–4.11(m,2H),3.87(m,5H),3.43(m,1H),2.31(s,3H),1.55(d,J＝7.0Hz,3H),0.62–0.35(m,4H).
实施例36(R)-6-(2-环丙氧基乙基氧基)-7-甲氧基-2-甲基-N-(1-(4-(三氟甲基)吡啶-2-基)乙基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000154
LC-MS：m/z 463(M+H) +。 1H NMR(400MHz,DMSO)δ8.81(d,J＝4.8Hz,1H),8.14(d,J＝7.1Hz,1H),7.78(d,J＝18.9Hz,2H),7.63(d,J＝4.3Hz,1H),7.04(s,1H),5.68(m,1H),4.22(d,J＝4.4Hz,2H),3.87(m,5H),3.46–3.40(m,1H),2.30(s,3H),1.65(d,J＝6.9Hz,3H),0.49(m,4H).
实施例37(R)-6-(2-环丙氧基乙基氧基)-7-甲氧基-2-甲基-N-(1-(2-(三氟甲基)吡啶-2-基)乙基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000155
LC-MS：m/z 463(M+H) +。 1H NMR(400MHz,DMSO)δ8.70(d,J＝4.6Hz,1H),8.12(d,J＝6.9Hz,1H),7.95(s,1H),7.73(s,2H),7.05(s,1H),5.69–5.51(m,1H),4.23(d,J＝3.8Hz,2H),3.88(s,5H),3.50–3.39(m,1H),2.30(s,3H),1.63(d,J＝6.9Hz,3H),0.64–0.30(m,4H).
实施例38(R)-N-(1-(6-氨基-4-(三氟甲基)吡啶-2-基)乙基)-6-(2-环丙氧基乙基氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000156
LC-MS：m/z 478(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.7Hz,1H),7.73(s, 1H),7.04(s,1H),6.76(s,1H),6.56(s,1H),6.50(s,2H),5.46(m,1H),4.29–4.13(m,2H),3.95–3.80(m,5H),3.42(m,1H),2.32(s,3H),1.55(d,J＝7.1Hz,3H),0.50(m,4H).
实施例39 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-2-基)甲氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000157
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝8.0Hz,1H),7.70(s,1H),7.03(s,1H),6.86(d,J＝10.1Hz,2H),6.69(s,1H),5.57(m,3H),4.31–4.16(m,1H),4.04(d,J＝5.3Hz,2H),3.93–3.76(m,4H),3.71(m,1H),2.35(s,3H),2.13–2.00(m,1H),2.00–1.81(m,2H),1.79–1.67(m,1H),1.55(d,J＝7.0Hz,3H).
实施例40 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((R)-四氢呋喃-2-基)甲氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000158
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝8.0Hz,1H),7.70(s,1H),7.03(s,1H),6.86(d,J＝10.2Hz,2H),6.69(s,1H),5.65–5.44(m,3H),4.33–4.18(m,1H),4.04(m,2H),3.94–3.78(m,4H),3.71(m,1H),2.35(s,3H),2.13–2.04(m,1H),2.02–1.81(m,2H),1.81–1.67(m,1H),1.55(d,J＝7.0Hz,3H).
实施例41(R)-N-(1-(2-氨基-6-(三氟甲基)吡啶-4-基)乙基)-6-(2-环丙氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000159
LC-MS：m/z 478(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝8.0Hz,1H),7.72(s,1H),7.05(s,1H),6.99(s,1H),6.66(s,1H),6.49(s,2H),5.48(m,1H),4.29–4.16(m,2H),3.92–3.77(m,5H),3.41(m,1H),2.34(s,3H),1.55(d,J＝7.1Hz,3H),0.64–0.40(m,4H).
实施例42(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000160
LC-MS：m/z 451(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.9Hz,1H),7.72(s,1H),7.03(s,1H),6.87(d,J＝10.9Hz,2H),6.69(s,1H),5.56(m,3H),4.30–4.14(m,2H),3.89(s,3H),3.73(m,2H),3.32(s,3H),2.35(s,3H),1.55(d,J＝7.0Hz,3H).
实施例43(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((3-(甲氧基甲基)氧杂环丁烷-3-基)甲氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000161
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ7.99(d,J＝7.9Hz,1H),7.81(s,1H),7.06(s,1H),6.88(d,J＝8.1Hz,2H),6.71(s,1H),5.71–5.43(m,3H),4.50(m,4H),4.28(m,2H),3.89(s,3H),3.71(s,2H),3.34(s,3H),2.37(s,3H),1.57(d,J＝7.0Hz,3H).
实施例44(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000162
LC-MS：m/z 493(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝7.9Hz,1H),7.72(s,1H),7.04(s,1H),6.86(d,J＝10.5Hz,2H),6.69(s,1H),5.65–5.43(m,3H),4.75–4.60(m,3H),4.44(m,2H),4.28–4.14(m,2H),3.88(s,3H),3.80(t,J＝4.5Hz,2H),2.35(s,3H),1.55(d,J＝7.0Hz,3H).
实施例45(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-环丙氧基乙氧基)-2-甲基-7-(三氟甲基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000163
LC-MS：m/z 515(M+H) +。 1H NMR(400MHz,DMSO)δ8.61(d,J＝6.7Hz,1H),8.06(s,1H),7.85(s,1H),7.80(t,J＝7.0Hz,1H),7.69–7.59(m,1H),7.35(t,J＝7.7Hz,1H),5.76(m,1H),4.34(t,J＝14.1Hz,2H),3.87(m,2H),3.44(m,1H),2.33(s,3H),1.66(d,J＝7.1Hz,3H),0.56–0.40(m,4H).
实施例46(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((1-甲氧基环丙基)甲氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000164
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝7.9Hz,1H),7.71(s,1H),7.04(s,1H),6.88(d,J＝8.6Hz,2H),6.70(s,1H),5.66–5.43(m,3H),4.20(q,J＝11.1Hz,2H),3.89(s,3H),3.34(s,3H),2.36(s,3H),1.56(d,J＝7.0Hz,3H),0.95–0.85(m,2H),0.75(t,J＝5.4Hz,2H).
实施例47 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((S)-2-甲氧基丙基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000165
LC-MS：m/z 465(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝7.7Hz,1H),7.70(s,1H),7.03(s,1H),6.86(d,J＝10.4Hz,2H),6.69(s,1H),5.56(m,3H),4.04(m,2H),3.87(s,3H),3.75(m,1H),3.36(s,3H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),1.24(d,J＝6.3Hz,3H).
实施例48 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((R)-2-甲氧基丙基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000166
LC-MS：m/z 465(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝7.9Hz,1H),7.70(s,1H),7.03(s,1H),6.86(d,J＝10.3Hz,2H),6.69(s,1H),5.69–5.42(m,3H),4.09(m,1H),3.99(m,1H),3.87(s,3H),3.75(m,1H),3.36(s,3H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),1.24(d,J＝6.3Hz,3H).
实施例49(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-环丁氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000167
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ7.97(d,J＝7.9Hz,1H),7.73(s,1H),7.04(s,1H),6.88(d,J＝10.2Hz,2H),6.71(s,1H),5.68–5.40(m,3H),4.32–4.13(m,2H),4.08–3.96(m,1H),3.88(s,3H),3.70(t,J＝4.8Hz,2H),2.36(s,3H),2.24–2.10(m,2H),1.95–1.78(m,2H),1.69–1.35(m,5H).
实施例50(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-(2-(2-甲氧基乙氧基)乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000168
LC-MS：m/z 495(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.9Hz,1H),7.72(s,1H),7.03(s,1H),6.86(d,J＝10.9Hz,2H),6.69(s,1H),5.64–5.38(m,3H),4.28–4.14(m,2H),3.94–3.77(m,5H),3.69–3.57(m,2H),3.48(m,2H),3.25(s,3H),2.35(s,3H),1.55(d,J＝7.0Hz,3H).
实施例51(R)-N-(1-(6-氨基-4-(三氟甲基)吡啶-2-基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000169
LC-MS：m/z 452(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.7Hz,1H),7.74(s,1H),7.04(s,1H),6.77(s,1H),6.55(m,1H),6.49(s,2H),5.48(m,1H),4.30–4.14(m,2H),3.88(s,3H),3.75(t,J＝4.6Hz,2H),3.35(d,J＝3.1Hz,3H),2.33(s,3H),1.56(d,J＝7.1Hz,3H).
实施例52(R)-N-(1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000170
LC-MS：m/z 452(M+H) +。 1H NMR(400MHz,DMSO)δ7.98(d,J＝7.8Hz,1H),7.77(s,1H),7.05(s,1H),6.76(d,J＝1.7Hz,1H),6.70(s,1H),6.49(s,2H),5.49(p,J＝7.0Hz,1H),4.29–4.17(m,2H),3.88(s,3H),3.76(t,J＝4.6Hz,2H),3.35(s,3H),2.34(s,3H),1.56(d,J＝7.1Hz,3H).
实施例53(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3-环丙氧基丙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000171
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ7.99(d,J＝7.8Hz,1H),7.71(s,1H),7.03(s,1H),6.87(d,J＝11.3Hz,2H),6.69(s,1H),5.57(m,3H),4.23–4.05(m,2H),3.87(s,3H),3.70–3.58(m,2H),3.29(m,1H),2.35(s,3H),2.02(p,J＝6.1Hz,2H),1.55(d,J＝7.0Hz,3H),0.55–0.36(m,4H).
实施例54(R)-N-(1-(2-氟-3-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((1-((甲基胺基)甲基)环丙基)甲氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000172
LC-MS：m/z 493(M+H) +。 1H NMR(400MHz,DMSO)δ8.00(s,1H),7.90(t,J＝7.2Hz,1H),7.72(t,J＝7.1Hz,1H),7.48(d,J＝8.0Hz,1H),7.24(s,1H),7.11(d,J＝7.9Hz,1H),5.93(t,J＝7.0Hz,1H),4.09(m,2H),3.98(s,3H),3.08(m,2H),2.63(s,3H),2.54(s,3H),1.70(d,J＝7.0Hz,3H),0.91–0.73(m,4H).
实施例55(R)-(1-(((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)胺基)-7-甲氧基-2-甲基喹唑啉-6-基)氧)甲基)环丙基)甲醇
Figure PCTCN2021125084-appb-000173
LC-MS：m/z 480(M+H) +。 1H NMR(400MHz,DMSO)δ8.10(d,J＝6.9Hz,1H),7.83–7.73(m,1H),7.70(s,1H),7.62(t,J＝6.9Hz,1H),7.35(t,J＝7.7Hz,1H),7.03(d,J＝8.2Hz,1H),5.83–5.68(m,1H),4.68(brs,1H),4.03(m,2H),3.87(s,3H),3.45(m,2H),2.26(s,3H),1.61(d,J＝7.0Hz,3H),0.58(s,4H).
实施例56(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((1-(甲氧基甲基)环丙基)甲氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000174
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝7.9Hz,1H),7.67(s, 1H),7.02(s,1H),6.86(d,J＝10.2Hz,2H),6.69(s,1H),5.64–5.46(m,3H),3.97(dd,J＝36.2,9.9Hz,2H),3.88(s,3H),3.36(dd,J＝19.9,6.9Hz,2H),3.26(s,3H),2.35(s,3H),1.54(d,J＝7.0Hz,3H),0.63(t,J＝12.3Hz,4H).
实施例57(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-(2-(甲氧基-d3)乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000175
LC-MS：m/z 454(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.8Hz,1H),7.72(s,1H),7.03(s,1H),6.87(d,J＝10.5Hz,2H),6.70(s,1H),5.67–5.40(m,3H),4.27–4.09(m,2H),3.87(s,3H),3.79–3.68(m,2H),2.36(s,3H),1.55(d,J＝7.0Hz,3H).
实施例58(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-(环丙基甲氧基)乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000176
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ7.75(d,J＝7.9Hz,1H),7.54(s,1H),6.84(s,1H),6.68(d,J＝10.3Hz,2H),6.51(s,1H),5.45–5.21(m,3H),4.09–3.94(m,2H),3.68(s,3H),3.62(t,J＝4.8Hz,2H),3.16(m,2H),2.17(s,3H),1.36(d,J＝7.0Hz,3H),0.37–0.20(m,2H),0.01(m,2H).
实施例59(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-((1,3-二甲氧基丙烷-2-基)氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000177
LC-MS：m/z 495(M+H) +。 1H NMR(400MHz,DMSO)δ8.07(s,1H),7.85(s,1H),7.04(s,1H),6.86(d,J＝12.9Hz,2H),6.70(s,1H),5.67–5.46(m,3H),4.98–4.77(m,1H),3.87(s,3H),3.67–3.49(m,4H),3.32(s,6H),2.37(s,3H),1.55(d,J＝7.0Hz,3H).
实施例60(R)-N-(1-(6-氨基-4-(三氟甲基)吡啶-2-基)乙基)-7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000178
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝7.7Hz,1H),7.74(s,1H),7.05(s,1H),6.77(s,1H),6.57(s,1H),6.48(s,2H),5.57–5.40(m,1H),4.70(d,J＝4.5Hz,3H),4.46(d,J＝5.4Hz,2H),4.23(d,J＝5.0Hz,2H),3.89(s,3H),3.80(t,J＝4.6Hz,2H),2.33(s,3H),1.56(d,J＝7.1Hz,3H).
实施例61(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(2-((3-甲基氧杂环丁烷-3-基)氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000179
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝7.9Hz,1H),7.73(s,1H),7.04(s,1H),6.87(d,J＝10.6Hz,2H),6.70(s,1H),5.56(m,3H),4.58(d,J＝6.5Hz,2H),4.32(d,J＝6.6Hz,2H),4.22(dd,J＝10.0,5.0Hz,2H),3.87(s,3H),3.79(t,J＝5.0Hz,2H),2.36(s,3H),1.62–1.41(m,6H).
实施例62(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(2-(吡啶-3-基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000180
LC-MS：m/z 514(M+H) +。 1H NMR(400MHz,DMSO)δ8.37(s,1H),8.21(d,J＝3.5Hz,1H),8.12(s,1H),7.82(s,1H),7.50(dd,J＝8.4,1.8Hz,1H),7.37(dd,J＝8.3,4.6Hz,1H),7.06(s,1H),6.87(d,J＝10.1Hz,2H),6.70(s,1H),5.76–5.47(m,3H),4.60–4.34(m,4H),3.87(s,3H),2.38(s,3H),1.56(d,J＝7.0Hz,3H).
实施例63 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-(1-(1-(甲氧基甲基)环丙基)乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000181
LC-MS：m/z 505(M+H) +。 1H NMR(400MHz,DMSO)δ8.01(s,1H),7.76(d,J＝3.3Hz,1H),7.02(s,1H),6.97–6.77(m,2H),6.70(s,1H),5.68–5.48(m,3H),4.57(dd,J＝19.7,6.3 Hz,1H),3.86(s,3H),3.52(t,J＝9.7Hz,1H),3.24(m,4H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),1.26(m,3H),0.62(m,2H),0.47(m,2H).
实施例64(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(2-(1-甲基环丁氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000182
LC-MS：m/z 505(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝8.0Hz,1H),7.72(s,1H),7.03(s,1H),6.86(d,J＝10.9Hz,2H),6.69(s,1H),5.56(d,J＝11.3Hz,3H),4.18(dd,J＝10.6,5.2Hz,2H),3.87(s,3H),3.67(t,J＝5.2Hz,2H),2.35(s,3H),2.17–2.03(m,2H),1.82(t,J＝8.9Hz,2H),1.71–1.47(m,5H),1.33(s,3H).
实施例65 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((1-(1-甲氧基乙基)环丙基)甲氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000183
LC-MS：m/z 505(M+H) +。
实施例65A和65B经手性分离得到两个异构体N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((1-((R)-1-甲氧基乙基)环丙基)甲氧基)-2-甲基喹唑啉-4-胺甲酸盐和N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-((1-((S)-1-甲氧基乙基)环丙基)甲氧基)-2-甲基喹唑啉-4-胺甲酸盐
Figure PCTCN2021125084-appb-000184
实施例65A
LC-MS：m/z 505(M+H) +。 1H NMR(400MHz,DMSO)δ8.28(s,1H),7.94(d,J＝7.9Hz,1H),7.64(s,1H),7.02(s,1H),6.86(d,J＝9.7Hz,2H),6.69(s,1H),5.66–5.40(m,3H),4.11(m,1H),3.88(m,4H),3.29(s,3H),3.13(m,2H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),1.20(d,J＝6.4Hz,3H),0.76–0.42(m,4H).
实施例65B
LC-MS：m/z 505(M+H) +。 1H NMR(400MHz,DMSO)δ8.23(s,1H),7.95(d,J＝7.8Hz, 1H),7.64(s,1H),7.02(s,1H),6.86(d,J＝10.9Hz,2H),6.69(s,1H),5.65–5.44(m,3H),4.17(d,J＝10.2Hz,1H),3.87(s,3H),3.81(d,J＝10.2Hz,1H),3.28(s,3H),3.11(m,2H),2.33(s,3H),1.54(d,J＝7.0Hz,3H),1.21(d,J＝6.4Hz,3H),0.73–0.46(m,4H).
实施例66 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(2-(((S)-四氢呋喃-3-基)氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000185
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝8.0Hz,1H),7.72(s,1H),7.03(s,1H),6.86(d,J＝11.3Hz,2H),6.69(s,1H),5.56(d,J＝10.7Hz,3H),4.32–4.09(m,3H),3.87(s,3H),3.81(d,J＝4.3Hz,2H),3.77–3.61(m,4H),2.35(s,3H),1.95(m,2H),1.54(d,J＝7.0Hz,3H).
实施例67 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(2-(((R)-四氢呋喃-3-基)氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000186
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝8.0Hz,1H),7.72(s,1H),7.03(s,1H),6.86(d,J＝10.8Hz,2H),6.69(s,1H),5.55(d,J＝13.1Hz,3H),4.33–4.08(m,3H),3.87(s,3H),3.81(d,J＝4.7Hz,2H),3.70(dt,J＝9.9,6.4Hz,4H),1.95(m,2H),1.54(d,J＝7.0Hz,3H).
实施例68 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((R)-2-(氧杂环丁烷-3-基氧基)丙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000187
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.9Hz,1H),7.69(s,1H),7.04(s,1H),6.86(d,J＝10.1Hz,2H),6.70(s,1H),5.68–5.44(m,3H),4.79(d,J＝5.9Hz,1H),4.75–4.62(m,2H),4.44(dd,J＝9.5,5.9Hz,2H),4.02(dd,J＝8.9,2.6Hz,2H),3.88(s,4H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),1.23(d,J＝6.3Hz,3H).
实施例69 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((S)-2-(氧杂环丁烷-3-基氧基)丙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000188
LC-MS：m/z 507(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(d,J＝7.9Hz,1H),7.68(s,1H),7.04(s,1H),6.87(d,J＝9.8Hz,2H),6.70(s,1H),5.56(dd,J＝14.5,6.7Hz,3H),4.86–4.75(m,1H),4.69(dd,J＝14.7,6.7Hz,2H),4.44(dd,J＝9.5,5.9Hz,2H),4.01(dd,J＝9.5,5.6Hz,2H),3.89(d,J＝7.1Hz,4H),2.35(s,3H),1.55(d,J＝7.0Hz,3H),1.23(d,J＝6.3Hz,3H).
实施例70(R)-N-(1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙基)-7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000189
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ8.10(s,1H),7.79(s,1H),7.06(s,1H),6.84–6.65(m,2H),6.49(s,2H),5.58–5.38(m,1H),4.77–4.65(m,3H),4.45(d,J＝5.5Hz,2H),4.22(d,J＝2.6Hz,2H),3.90(s,3H),3.80(t,J＝4.5Hz,2H),2.36(s,3H),1.57(d,J＝7.1Hz,3H).
实施例71(S)-1,1-二氟-1-(2-氟-3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇甲酸盐
Figure PCTCN2021125084-appb-000190
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ8.23(s,1H),8.05(d,J＝7.4Hz,1H),7.76(s,1H),7.58(t,J＝6.6Hz,1H),7.30(t,J＝6.6Hz,1H),7.22(m,1H),7.03(s,1H),5.80(p,J＝6.9Hz,1H),5.34(s,1H),4.24(m,2H),3.87(s,3H),3.77(t,J＝4.6Hz,2H),3.36(s,3H),2.28(s,3H),1.58(d,J＝7.0Hz,3H),1.22(d,J＝11.3Hz,6H).
实施例72(R)-1,1-二氟-1-(2-氟-3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000191
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ8.10(d,J＝7.2Hz,1H),7.81(s,1H),7.64(t,J＝6.5Hz,1H),7.36(t,J＝6.8Hz,1H),7.28(m,1H),7.09(s,1H),6.00–5.77(m,1H),5.39(s,1H),4.30(d,J＝3.4Hz,2H),3.93(s,3H),3.82(t,J＝4.2Hz,2H),3.41(s,3H),2.34(s,3H),1.64(d,J＝6.9Hz,3H),1.28(d,J＝11.1Hz,6H).
实施例73(R)-N-(1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙基)-7-甲氧基-2-甲基-6-(2-(1-甲基环丁基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000192
LC-MS：m/z 506(M+H) +。 1H NMR(400MHz,DMSO)δ7.99(d,J＝7.5Hz,1H),7.79(s,1H),7.06(s,1H),6.73(d,J＝22.6Hz,2H),6.49(s,2H),5.57–5.37(m,1H),4.58(d,J＝6.2Hz,2H),4.32(d,J＝6.3Hz,2H),4.23(s,2H),3.88(s,3H),3.80(s,2H),2.34(s,3H),1.56(d,J＝6.9Hz,3H),1.51(s,3H).
实施例74(R)-1-(3-氨基-5-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000193
LC-MS：m/z 491(M+H) +。 1H NMR(400MHz,DMSO)δ8.14(s,1H),7.77(s,1H),7.04(s,1H),6.70(d,J＝10.8Hz,2H),6.56(s,1H),5.67–5.46(m,1H),5.19(s,2H),5.08(s,1H),4.30–4.14(m,2H),3.88(s,3H),3.81–3.69(m,2H),3.35(s,3H),2.38(s,3H),1.55(d,J＝7.0Hz,3H),1.12(s,6H).
实施例75(R)-1,1-二氟-1-(2-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000194
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ8.63(d,J＝5.0Hz,1H),8.09(d,J＝7.5Hz,1H),7.75(s,1H),7.51(s,1H),7.31(d,J＝4.0Hz,1H),7.02(s,1H),5.61(t,J＝7.2Hz,1H),5.38(s,1H),4.21(d,J＝2.7Hz,2H),3.87(s,3H),3.75(t,J＝4.6Hz,2H),3.35(s,3H),2.29(s,3H),1.64(d,J＝7.1Hz,3H),1.10(d,J＝6.5Hz,6H).
实施例76(R)-1,1-二氟-1-(6-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基) 氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000195
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.86(t,J＝7.8Hz,1H),7.74(s,1H),7.52(d,J＝7.8Hz,1H),7.45(d,J＝7.7Hz,1H),7.04(s,1H),5.62(t,J＝7.2Hz,1H),5.28(s,1H),4.29–4.19(m,2H),3.88(s,3H),3.82–3.69(m,2H),3.36(s,3H),2.29(s,3H),1.62(d,J＝7.1Hz,3H),1.18(d,J＝7.7Hz,6H).
实施例77(R)-1,1-二氟-1-(5-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000196
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ8.77(s,1H),8.51(d,J＝1.6Hz,1H),8.15(s,1H),7.92(s,1H),7.73(s,1H),7.03(s,1H),5.69–5.51(m,1H),5.40(s,1H),4.28–4.10(m,2H),3.87(s,3H),3.80–3.68(m,2H),3.35(s,3H),2.33(s,3H),1.66(d,J＝7.1Hz,3H),1.14(d,J＝9.2Hz,6H).
实施例78(R)-1,1-二氟-1-(4-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000197
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ8.56(d,J＝5.0Hz,1H),8.06(d,J＝7.4Hz,1H),7.72(s,1H),7.65(s,1H),7.52(d,J＝4.3Hz,1H),7.04(s,1H),5.58(t,J＝7.2Hz,1H),5.26(s,1H),4.22(d,J＝2.8Hz,2H),3.88(s,3H),3.76(t,J＝4.7Hz,2H),3.36(s,3H),2.30(s,3H),1.61(d,J＝7.1Hz,3H),1.18(d,J＝5.4Hz,6H).
实施例79(R)-1,1-二氟-1-(4-氟-3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000198
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.3Hz,1H),7.75(s, 1H),7.65–7.52(m,1H),7.37–7.31(m,1H),7.23(t,J＝9.4Hz,1H),7.02(s,1H),5.75(t,J＝7.1Hz,1H),5.20(s,1H),4.29–4.15(m,2H),3.87(s,3H),3.80–3.71(m,2H),3.36(s,3H),2.29(s,3H),1.61(d,J＝7.0Hz,3H),1.08(s,3H),0.99(s,3H).
实施例80(R)-1,1-二氟-1-(3-氟-5-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000199
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ7.98(d,J＝7.7Hz,1H),7.69(s,1H),7.44–7.32(m,2H),7.10(d,J＝9.3Hz,1H),7.03(s,1H),5.60(t,J＝7.2Hz,1H),5.30(s,1H),4.22(dd,J＝5.3,3.5Hz,2H),3.87(s,3H),3.82–3.73(m,2H),3.35(s,3H),2.32(s,3H),1.60(d,J＝7.0Hz,3H),1.12(d,J＝5.5Hz,6H).
实施例81(R)-1,1-二氟-1-(2-氟-5-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000200
LC-MS：m/z 494(M+H) +。 1H NMR(400MHz,DMSO)δ7.97(d,J＝7.7Hz,1H),7.68(s,1H),7.55(m,2H),7.21(dd,J＝11.1,8.6Hz,1H),7.02(s,1H),5.59(t,J＝7.2Hz,1H),5.27(s,1H),4.24–4.16(m,2H),3.87(s,3H),3.81–3.72(m,2H),3.35(s,3H),2.34(s,3H),1.59(d,J＝7.1Hz,3H),1.15(s,6H).
实施例82 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-(2,2-二氟环丙基氧基)乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000201
LC-MS：m/z 513(M+H) +。 1H NMR(400MHz,DMSO)δ7.94(t,J＝18.5Hz,1H),7.75(s,1H),7.04(s,1H),6.85(t,J＝16.3Hz,2H),6.70(s,1H),5.56(dd,J＝16.5,9.2Hz,3H),4.35–4.19(m,2H),4.08–3.92(m,3H),3.88(s,3H),2.36(s,3H),1.82–1.47(m,5H).
实施例83(R)-N-(1-(3-氨基-5-(三氟甲氧基)苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000202
LC-MS：m/z 467(M+H) +。 1H NMR(400MHz,DMSO)δ7.88(d,J＝8.0Hz,1H),7.71(s,1H),7.03(s,1H),6.60(s,1H),6.47(d,J＝16.9Hz,1H),6.32(d,J＝11.2Hz,1H),5.59–5.40(m,3H),4.28–4.14(m,2H),3.87(s,3H),3.75(t,J＝4.7Hz,2H),3.34(d,J＝12.2Hz,3H),2.35(s,3H),1.51(t,J＝11.5Hz,3H).
实施例84(R)-3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯磺酰胺
Figure PCTCN2021125084-appb-000203
LC-MS：m/z 447(M+H) +。 1H NMR(400MHz,DMSO)δ8.05(d,J＝7.7Hz,1H),7.93(s,1H),7.79–7.61(m,3H),7.52(t,J＝7.7Hz,1H),7.32(s,2H),7.03(s,1H),5.67(m,1H),4.22(dd,J＝7.1,4.2Hz,2H),3.87(s,3H),3.75(t,J＝4.7Hz,2H),3.35(s,3H),2.35(s,3H),1.61(d,J＝7.1Hz,3H).
实施例85(R)-2,2-二氟-2-(3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000204
LC-MS：m/z 448(M+H) +。 1H NMR(400MHz,DMSO)δ8.01(d,J＝7.9Hz,1H),7.72(s,1H),7.66–7.52(m,2H),7.51–7.33(m,2H),7.03(s,1H),5.63(m,2H),4.22(d,J＝2.5Hz,2H),3.94–3.71(m,7H),3.35(s,3H),2.35(s,3H),1.60(d,J＝7.1Hz,3H).
实施例86(R)-1-(3-(1-((6,7-bis(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000205
LC-MS：m/z 538(M+H) +。 1H NMR(400MHz,DMSO)δ8.31(s,1H),7.85(s,1H),7.62(t,J＝6.8Hz,1H),7.27(dt,J＝15.5,7.3Hz,2H),7.06(s,1H),5.91–5.77(m,1H),5.32(s,1H),4.31–4.17(m,4H),3.83–3.66(m,4H),3.38(m,6H),2.32(s,3H),1.60(d,J＝7.0Hz, 3H),1.23(d,J＝10.7Hz,6H).
实施例87(R)-1,1-二氟-1-(3-甲氧基-5-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000206
LC-MS：m/z 506(M+H) +。 1H NMR(400MHz,DMSO)δ7.97(d,J＝7.9Hz,1H),7.72(s,1H),7.15(d,J＝13.3Hz,2H),7.04(s,1H),6.87(s,1H),5.68–5.53(m,1H),5.22(s,1H),4.29–4.12(m,2H),3.88(s,3H),3.75(d,J＝7.3Hz,5H),3.36(s,3H),2.35(s,3H),1.61(d,J＝7.0Hz,3H),1.14(s,6H).
实施例88(R)-1-(2-氯-3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000207
LC-MS：m/z 510(M+H) +。H NMR(400MHz,DMSO)δ8.13(d,J＝7.1Hz,1H),7.79(s,1H),7.63(d,J＝6.6Hz,1H),7.43–7.27(m,2H),7.02(s,1H),5.95(t,J＝7.0Hz,1H),5.30(s,1H),4.26(dd,J＝9.7,4.7Hz,2H),3.87(s,3H),3.77(t,J＝4.6Hz,2H),3.37(s,3H),2.25(s,3H),1.55(d,J＝7.0Hz,3H),1.26(d,J＝13.6Hz,6H).
实施例89(R)-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-甲腈
Figure PCTCN2021125084-appb-000208
LC-MS：m/z 489(M+H) +。 1H NMR(400MHz,DMSO)δ8.52(d,J＝7.1Hz,1H),8.07(s,1H),8.04(s,1H),7.59(t,J＝6.6Hz,1H),7.32(t,J＝6.7Hz,1H),7.22(t,J＝7.7Hz,1H),5.79(p,J＝6.8Hz,1H),5.30(s,1H),4.40(dd,J＝5.0,2.9Hz,2H),3.89–3.75(m,2H),3.39(s,3H),2.33(s,3H),1.62(d,J＝7.0Hz,3H),1.22(d,J＝10.4Hz,6H).
实施例90(R)-1,1-二氟-1-(3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000209
LC-MS：m/z 490(M+H) +。 1H NMR(400MHz,DMSO)δ8.07(d,J＝7.4Hz,1H),7.75(s,1H),7.60(d,J＝7.2Hz,1H),7.30–7.14(m,2H),7.01(s,1H),5.79(t,J＝7.1Hz,1H),5.24(s,1H),4.32–4.18(m,2H),3.86(s,3H),3.76(t,J＝4.6Hz,2H),3.36(s,3H),2.63(s,3H),2.30(s,3H),1.52(d,J＝6.9Hz,3H),1.22(d,J＝10.1Hz,6H).
实施例91(R)-3-(1,1-二氟-2-羟基-2-甲基丙烷)-5-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯腈
Figure PCTCN2021125084-appb-000210
LC-MS：m/z 501(M+H) +。 1H NMR(400MHz,DMSO)δ8.03(d,J＝10.3Hz,2H),7.87(s,1H),7.70(d,J＝11.1Hz,2H),7.03(s,1H),5.58(dd,J＝14.1,7.0Hz,1H),5.41(s,1H),4.22(dd,J＝5.5,3.6Hz,2H),3.87(s,3H),3.82–3.71(m,2H),3.36(s,3H),2.31(s,3H),1.62(d,J＝7.1Hz,3H),1.12(d,J＝10.2Hz,6H).
实施例92(R)-1,1-二氟-1-(2-氟-3-(1-((7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000211
LC-MS：m/z 536(M+H) +。 1H NMR(400MHz,DMSO)δ8.04(d,J＝7.4Hz,1H),7.76(s,1H),7.59(s,1H),7.29(d,J＝6.7Hz,1H),7.21(d,J＝7.7Hz,1H),7.04(s,1H),5.80(s,1H),5.33(s,1H),4.76–4.62(m,3H),4.46(dd,J＝5.7,3.6Hz,2H),4.24(dd,J＝8.0,4.2Hz,2H),3.88(s,3H),3.81(t,J＝4.6Hz,2H),2.29(s,3H),1.58(d,J＝7.0z,3H),1.22(d,J＝11.2Hz,6H).
实施例93(R)-1-(3-(1-((6-(2-环丙基氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000212
LC-MS：m/z 520(M+H) +。 1H NMR(400MHz,DMSO)δ8.02(d,J＝7.4Hz,1H),7.75(s,1H),7.58(s,1H),7.29(d,J＝6.7Hz,1H),7.21(d,J＝7.7Hz,1H),7.03(s,1H),5.81(d,J＝7.2 Hz,1H),5.32(s,1H),4.23(dd,J＝7.5,4.4Hz,2H),3.86(d,J＝6.5Hz,5H),3.43(td,J＝5.9,3.0Hz,1H),2.28(s,3H),1.57(d,J＝7.0Hz,3H),1.22(d,J＝11.0Hz,6H).
实施例94(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000213
LC-MS：m/z 464(M+H) +。 1H NMR(400MHz,DMSO)δ8.21(d,J＝7.3Hz,1H),7.84(d,J＝2.4Hz,1H),7.59(t,J＝6.6Hz,1H),7.53(d,J＝9.1Hz,1H),7.38(dd,J＝9.1,2.5Hz,1H),7.30(t,J＝6.6Hz,1H),7.21(d,J＝7.7Hz,1H),5.80(t,J＝7.1Hz,1H),5.32(s,1H),4.25(d,J＝3.1Hz,2H),3.75(t,J＝4.5Hz,2H),3.36(s,3H),2.30(s,3H),1.59(d,J＝7.0Hz,3H),1.22(d,J＝11.3Hz,6H).
实施例95(R)-1-(3-(1-((7-溴-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000214
LC-MS：m/z 542(M+H) +。 1H NMR(400MHz,DMSO)δ8.39(d,J＝7.0Hz,1H),7.93(s,1H),7.86(s,1H),7.59(t,J＝6.6Hz,1H),7.31(t,J＝6.6Hz,1H),7.21(t,J＝7.7Hz,1H),5.80(t,J＝7.1Hz,1H),5.31(s,1H),4.34(dd,J＝7.2,4.1Hz,2H),3.81(t,J＝4.6Hz,2H),3.40(s,3H),2.31(s,3H),1.60(d,J＝7.0Hz,3H),1.22(d,J＝10.6Hz,6H).
实施例96(R)-4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-醇
Figure PCTCN2021125084-appb-000215
LC-MS：m/z 480(M+H) +。 1H NMR(400MHz,DMSO)δ7.71(d,J＝7.1Hz,1H),7.59(d,J＝11.6Hz,2H),7.28(t,J＝6.7Hz,1H),7.18(t,J＝7.7Hz,1H),6.67(s,1H),5.91–5.60(m,1H),4.20(d,J＝4.0Hz,2H),3.75(t,J＝4.5Hz,2H),3.35–3.19(m,3H),2.19(s,3H),1.54(d,J＝6.9Hz,3H),1.22(d,J＝11.8Hz,6H).
实施例97(R)-1,1-二氟-1-(2-氟-3-(1-((7-氘代甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000216
LC-MS：m/z 497(M+H) +。 1H NMR(400MHz,DMSO)δ8.03(d,J＝7.4Hz,1H),7.75(s,1H),7.58(s,1H),7.29(d,J＝6.8Hz,1H),7.21(d,J＝7.7Hz,1H),7.02(s,1H),5.84–5.76(m,1H),5.42–5.20(m,1H),4.24(dd,J＝7.6,4.3Hz,2H),3.76(t,J＝4.6Hz,2H),3.36(s,3H),2.28(s,3H),1.58(d,J＝7.0Hz,3H),1.22(d,J＝11.0Hz,6H).
实施例98(R)-1-(3-(1-((7-乙氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000217
LC-MS：m/z 508(M+H) +。 1H NMR(400MHz,DMSO)δ8.03(d,J＝7.4Hz,1H),7.76(s,1H),7.58(t,J＝6.5Hz,1H),7.30(t,J＝6.6Hz,1H),7.20(t,J＝7.7Hz,1H),7.00(s,1H),5.79(t,J＝7.1Hz,1H),5.32(s,1H),4.28–4.21(m,2H),4.14(q,J＝6.9Hz,2H),3.77(t,J＝4.7Hz,2H),3.38(s,3H),2.28(s,3H),1.58(d,J＝7.0Hz,3H),1.38(t,J＝6.9Hz,3H),1.22(d,J＝11.2Hz,6H).
实施例99(R)-1,1-二氟-1-(2-氟-3-(1-((7-异丙氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000218
LC-MS：m/z 522(M+H) +。 1H NMR(400MHz,DMSO)δ8.03(d,J＝7.4Hz,1H),7.77(s,1H),7.58(t,J＝6.5Hz,1H),7.30(t,J＝6.6Hz,1H),7.20(t,J＝7.7Hz,1H),7.01(s,1H),5.79(t,J＝7.2Hz,1H),5.31(s,1H),4.79–4.67(m,1H),4.24(dd,J＝6.0,3.4Hz,2H),3.76(t,J＝4.7Hz,2H),3.38(s,3H),2.28(s,3H),1.57(d,J＝7.0Hz,3H),1.32(dd,J＝5.6,4.9Hz,6H),1.22(d,J＝11.3Hz,6H).
实施例100(R)-1,1-二氟-1-(2-氟-3-(1-((7-环丙氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000219
LC-MS：m/z 520(M+H) +。
实施例101(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(吡啶-3-基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙基-2-醇
Figure PCTCN2021125084-appb-000220
LC-MS：m/z 541(M+H) +。 1H NMR(400MHz,DMSO)δ8.82(d,J＝2.3Hz,1H),8.61–8.56(m,1H),8.32(d,J＝7.4Hz,1H),8.08–8.01(m,1H),7.95(s,1H),7.65–7.58(m,2H),7.49(dd,J＝7.9,4.8Hz,1H),7.32(t,J＝6.9Hz,1H),7.22(t,J＝7.7Hz,1H),5.87–5.79(m,1H),5.32(s,1H),4.38–4.27(m,2H),3.72(t,J＝4.7Hz,2H),3.30(s,3H),2.33(s,3H),1.62(d,J＝7.0Hz,3H),1.24(s,3H),1.22(s,3H).
实施例102(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(1-甲基-1H-吡唑-4-基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙基-2-醇
Figure PCTCN2021125084-appb-000221
LC-MS：m/z 544(M+H) +。 1H NMR(400MHz,DMSO)δ8.30(s,1H),8.21(d,J＝7.4Hz,1H),8.10(s,1H),7.85(s,2H),7.64–7.57(m,1H),7.35–7.27(m,1H),7.21(t,J＝7.7Hz,1H),5.88–5.76(m,1H),5.32(s,1H),4.42–4.29(m,2H),3.92–3.85(m,5H),3.43(s,3H),2.31(s,3H),1.61(d,J＝7.1Hz,3H),1.24(s,3H),1.22(s,3H).
实施例103(R)-1,1-二氟-1-(2-氟-3-(1-(6-(2-甲氧基乙氧基)-2-甲基-7-(氧乙基-3-氨基)喹唑啉-4-基)氨基乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000222
LC-MS：m/z 536(M+H) +。 1H NMR(400MHz,DMSO)δ8.13(s,1H),7.83(s,1H),7.60(s,1H),7.28(d,J＝6.5Hz,1H),7.19(t,J＝7.7Hz,1H),6.63(s,1H),5.78(d,J＝7.0Hz,1H),5.42–5.30(m,1H),4.99(t,J＝6.4Hz,2H),4.58(dd,J＝12.2,5.1Hz,2H),4.27(d,J＝2.5Hz, 2H),3.79(t,J＝4.7Hz,2H),3.39(s,4H),2.26(s,3H),1.57(d,J＝6.9Hz,3H),1.22(d,J＝11.0Hz,6H).
实施例104(R)-3-(4-(1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氮杂环丁烷-1-羧酸叔丁酯
Figure PCTCN2021125084-appb-000223
LC-MS：m/z 635(M+H) +。 1H NMR(400MHz,DMSO)δ8.09(d,J＝7.4Hz,1H),7.84(s,1H),7.59(t,J＝6.6Hz,1H),7.31(d,J＝6.9Hz,1H),7.21(t,J＝7.7Hz,1H),6.77(s,1H),5.88–5.72(m,1H),5.10(s,1H),4.63(d,J＝6.1Hz,1H),4.44–4.21(m,4H),3.81(dd,J＝13.2,8.4Hz,4H),3.40(s,3H),2.30(s,3H),1.59(d,J＝7.0Hz,3H),1.40(d,J＝5.9Hz,9H),1.23(d,J＝11.2Hz,6H).
实施例105(R)-1-(3-(1-((7-(氮杂环丁烷-3-基氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000224
LC-MS：m/z 535(M+H) +。
实施例106(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-((1-甲基氮杂环丁烷-3-基)氧基)喹唑啉-4-喹唑啉)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000225
LC-MS：m/z 549(M+H) +。
实施例107(R)-1-(3-((4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)氮杂环丁烷-1-基)乙烷-1-酮
Figure PCTCN2021125084-appb-000226
LC-MS：m/z 577(M+H) +。
实施例108(R)-1,1-二氟-1-(2-氟-3-(1-(6-(2-甲氧基乙氧基)-2-甲基-7-(吡啶-3-氧基)喹唑啉-4-基)氨基乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000227
LC-MS：m/z 557(M+H) +。 1H NMR(400MHz,DMSO)δ8.52–8.37(m,1H),8.24(d,J＝16.4Hz,1H),8.02(s,1H),7.60(s,1H),7.45(s,2H),7.31(s,1H),7.23(s,1H),7.05(s,1H),5.79(s,1H),5.32(s,1H),4.26(s,2H),3.62(s,2H),3.22(s,3H),2.28(s,3H),1.59(s,3H),1.21–1.14(m,6H).
实施例109(R)-1,1-二氟-1-(2-氟-3-(1-((7-氟-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000228
LC-MS：m/z 482(M+H) +。 1H NMR(400MHz,DMSO)δ8.28(d,J＝8.0Hz,1H),8.02(d,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.33-7.30(m,1H),7.21(d,J＝8.0Hz,1H),5.80(m,1H),5.33(s,1H),4.36-4.33(m,2H),3.79(t,J＝4.0Hz,2H),3.34(s,3H),2.31(s,3H),1.60(d,J＝8.0Hz,3H),1.24(s,3H),1.21(s,3H).
实施例110(R)-1-(3-(1-((7-氯-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000229
LC-MS：m/z 498(M+H) +。 1H NMR(400MHz,DMSO)δ8.41(d,J＝8.0Hz,1H),7.99(s,1H),7.69(s,1H),7.60(d,J＝6.0Hz,1H),7.33-7.30(m,1H),7.24-7.20(m,1H),5.80(m,1H),5.34(s,1H),4.36-4.33(m,2H),3.81(t,J＝4.0Hz,2H),3.39(s,3H),2.51(s,3H),1.61(d,J＝7.2Hz,3H),1.24(s,3H),1.21(s,3H)。
实施例111(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(三氟甲基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000230
LC-MS：m/z 532(M+H) +。
实施例112(R)-1,1-二氟-1-(2-氟-3-(1-((氟-6-(2-甲氧基乙氧基)-2-甲基-7-(三氟甲氧基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000231
LC-MS：m/z 548(M+H) +。
实施例113(R)-1-(3-氨基-5-(1-((6,7-双(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000232
LC-MS：m/z 535(M+H) +。 1H NMR(400MHz,DMSO)δ7.89(d,J＝8.0Hz,1H),7.73(s,1H),7.03(s,1H),6.70(d,J＝12.1Hz,2H),6.56(d,J＝4.9Hz,1H),5.61–5.47(m,1H),5.15(s,3H),4.27–4.14(m,4H),3.83–3.62(m,4H),3.36(s,3H),3.34(s,3H),2.34(s,3H),1.53(d,J＝7.0Hz,3H),1.12(s,6H).
实施例114(R)-N-(1-(6-氨基-4-(三氟甲基)吡啶-2-基)乙基)-6,7-双(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000233
LC-MS：m/z 496(M+H) +。 1H NMR(400MHz,DMSO)δ7.95(d,J＝7.8Hz,1H),7.76(s,1H),7.05(s,1H),6.77(s,1H),6.57(s,1H),6.46(s,2H),5.54–5.36(m,1H),4.23(dt,J＝10.2,5.2Hz,4H),3.74(dt,J＝11.1,4.5Hz,4H),3.36(s,3H),3.34(s,3H),2.32(s,3H),1.56(d,J＝7.1Hz,3H).
实施例115(R)-1-(3-氨基-5-(1-(7-甲氧基-2-甲基-6-(2-(吡啶-3-氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000234
LC-MS：m/z 554(M+H) +。 1H NMR(400MHz,DMSO)δ8.37(d,J＝2.9Hz,1H),8.20(dd,J＝4.6,1.1Hz,1H),7.93(d,J＝8.0Hz,1H),7.80(s,1H),7.50(dd,J＝8.4,1.7Hz,1H),7.36(dd,J＝8.4,4.6Hz,1H),7.04(s,1H),6.70(d,J＝10.3Hz,2H),6.55(s,1H),5.60–5.48(m,1H),5.18(s,2H),4.47(dd,J＝20.2,3.9Hz,4H),3.86(s,3H),2.35(s,3H),1.54(d,J＝7.0Hz,3H),1.12(s,6H).
实施例116(R)-1-(3-氨基-5-(1-((6-(2-环丙氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙基-2-醇
Figure PCTCN2021125084-appb-000235
LC-MS：m/z 517(M+H) +。1H NMR(400MHz,DMSO)δ7.89(d,J＝8.0Hz,1H),7.71(s,1H),7.02(s,1H),6.74–6.66(m,2H),6.56(t,J＝1.9Hz,1H),5.59–5.47(m,1H),5.16(s,2H),5.08(s,1H),4.19(dd,J＝5.9,4.0Hz,2H),3.87(s,3H),3.92–3.81(m,2H),3.46–3.38(m,1H),2.35(s,3H),1.54(d,J＝7.0Hz,3H),1.12(s,6H),0.56–0.41(m,4H).
实施例117(R)-1-(3-氨基-5-(1-((7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙基-2-醇
Figure PCTCN2021125084-appb-000236
LC-MS：m/z 533(M+H) +。1H NMR(400MHz,DMSO)δ7.90(d,J＝8.1Hz,1H),7.72(s,1H),7.03(s,1H),6.74–6.66(m,2H),6.56(t,J＝1.9Hz,1H),5.59–5.47(m,1H),5.17(s,2H),5.09(s,1H),4.76–4.62(m,3H),4.50–4.40(m,2H),4.20(dd,J＝5.8,3.8Hz,2H),3.88(s,3H),3.79(dd,J＝5.8,3.7Hz,2H),2.35(s,3H),1.54(d,J＝7.0Hz,3H),1.12(s,6H).
实施例118 1-(3-氨基-5-(1R)-1-(6-(2-(2,2-二氟环丙氧基)乙氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000237
LC-MS：m/z 553(M+H) +。 1H NMR(400MHz,DMSO)δ7.89(d,J＝8.0Hz,1H),7.72(s,1H),7.03(s,1H),6.69(d,J＝11.5Hz,2H),6.55(s,1H),5.62–5.46(m,1H),5.16(s,2H),5.07(s,1H),4.23(d,J＝4.5Hz,2H),4.11–3.95(m,3H),3.87(s,3H),2.34(s,3H),1.81–1.44(m,5H),1.19–1.07(m,6H).
实施例119(R)-1-(3-氨基-5-(1-(7-甲氧基-6-(2-(2-甲氧基乙氧基)乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000238
LC-MS：m/z 535(M+H) +。 1H NMR(400MHz,DMSO)δ7.89(d,J＝8.0Hz,1H),7.72(s,1H),7.02(s,1H),6.70(d,J＝11.6Hz,2H),6.55(s,1H),5.59–5.42(m,1H),5.16(s,2H),4.20(t,J＝4.8Hz,2H),3.92–3.77(m,5H),3.63(dd,J＝5.6,3.9Hz,2H),3.48(dd,J＝5.6,3.8Hz,2H),3.26(s,3H),2.34(s,4H),1.53(d,J＝7.0Hz,3H),1.10(d,J＝10.9Hz,6H).
实施例120(R)-N-(3-(1,1-二氟-2-羟基-2-甲基丙基)-5-(1-(7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基氨基)乙基)苯乙酰胺
Figure PCTCN2021125084-appb-000239
LC-MS：m/z 533(M+H) +。 1H NMR(400MHz,DMSO)δ10.01(s,1H),8.03(s,1H),7.75(d,J＝12.1Hz,2H),7.61(s,1H),7.26(s,1H),7.04(s,1H),5.65–5.51(m,1H),5.19(s,1H),4.27–4.15(m,2H),3.88(s,3H),3.81–3.70(m,2H),3.37(s,3H),2.35(s,3H),2.02(s,3H),1.60(d,J＝7.1Hz,3H),1.14(s,6H).
实施例121(R)-(3-(1,1-二氟-2-羟基-2-甲基丙基)-5-(1-(7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基氨基)乙基)苯基氨基甲酸甲酯
Figure PCTCN2021125084-appb-000240
LC-MS：m/z 549(M+H) +。 1H NMR(400MHz,DMSO)δ9.70(s,1H),7.98(d,J＝7.7Hz,1H),7.72(s,1H),7.64(s,1H),7.50(s,1H),7.21(s,1H),7.02(s,1H),5.65–5.51(m,1H),5.17(s,1H),4.30–4.15(m,2H),3.87(s,3H),3.79–3.71(m,2H),3.64(s,3H),2.34(s,3H),1.58(d,J＝7.0Hz,3H),1.12(s,6H).
实施例122(R)-1-(3-氨基-5-(1-(7-甲氧基-6-(2-(2-甲氧基乙氧基)乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000241
LC-MS：m/z 535(M+H) +。 1H NMR(400MHz,DMSO)δ7.90(d,J＝8.0Hz,1H),7.84(s,1H),7.03(s,1H),6.72(d,J＝12.9Hz,2H),6.58(s,1H),5.56(d,J＝7.3Hz,1H),5.16(s,2H),5.06(s,1H),4.96–4.83(m,1H),3.88(s,3H),3.69–3.52(m,4H),3.30(s,6H),2.36(s,3H),1.55(d,J＝7.0Hz,3H),1.13(d,J＝2.7Hz,6H).
实施例123(R)-1-(3-氨基-5-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(1H-吡唑基-3- 基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000242
LC-MS：m/z 527(M+H) +。 1H NMR(400MHz,DMSO)δ13.05(s,1H),8.14(s,2H),7.82(d,J＝23.4Hz,2H),6.98(s,1H),6.73(d,J＝10.4Hz,2H),6.57(s,1H),5.64–5.50(m,1H),5.16(s,2H),5.08(s,1H),4.34(s,2H),3.85(s,2H),3.39(s,3H),2.39(s,3H),1.58(d,J＝6.9Hz,3H),1.13(s,6H).
实施例124(R)-4-((1-(3-氨基-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-氰
Figure PCTCN2021125084-appb-000243
LC-MS：m/z 486(M+H) +。 1H NMR(400MHz,DMSO)δ8.41(d,J＝7.9Hz,1H),8.06(s,1H),8.00(s,1H),6.74–6.66(m,2H),6.57(t,J＝1.9Hz,1H),5.60–5.50(m,1H),5.19(s,2H),5.10(s,1H),4.41–4.33(m,2H),3.83–3.76(m,2H),3.38(s,3H),2.39(s,3H),1.57(d,J＝7.0Hz,3H),1.12(s,6H).
实施例125(R)-1-(5-氨基-2-氟-3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000244
LC-MS：m/z 509(M+H) +。
实施例126(R)-1-(5-氨基-3-(1-((6-(2-环丙氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000245
LC-MS：m/z 535(M+H) +。
实施例127(R)-1-(5-氨基-2-氟-3-(1-((7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000246
LC-MS：m/z 551(M+H) +。
实施例128(R)-1-(5-氨基-2-氯-3-(1-((7-甲氧基-2-甲基-6-(2-甲氧基乙氧基)2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000247
LC-MS：m/z 525(M+H) +。
实施例129(R)-1-(5-氨基-2-氯-3-(1-((6-(2-环丙氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000248
LC-MS：m/z 535(M+H) +。
实施例130(R)-1-(5-氨基-2-氯-3-(1-((7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000249
LC-MS：m/z 567(M+H) +。
实施例131(R)-1,1-二氟-1-(3-(1-((7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000250
LC-MS：m/z 476(M+H) +。
实施例132(R)-1-(3-(1-((6-(2-环丙氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000251
LC-MS：m/z 502(M+H) +。
实施例133(R)-1,1-二氟-1-(3-(1-((7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000252
LC-MS：m/z 518(M+H) +。
实施例134 N-(1-(4-氨基-6-(1-甲基环丙基)吡啶-2-基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000253
LC-MS：m/z 438(M+H) +。 1H NMR(400MHz,DMSO)δ7.86(d,J＝7.9Hz,1H),7.63(s,1H),7.04(s,1H),6.37(s,1H),6.29(s,1H),5.79(s,2H),5.38–5.34(m,1H),4.23–4.21(m,2H),3.88(s,3H),3.76–3.74(m,2H),3.35(s,3H),2.35(s,3H),1.50(d,J＝6.9Hz,3H),1.38(s,3H),1.24-1.12(m,2H),0.65(m,2H).
实施例135 N-(1-(4-氨基-6-(1-甲基环丙基)吡啶-2-基)乙基)-6-(2-环丙氧基乙氧基)-7-甲氧基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000254
LC-MS：m/z 464(M+H) +。 1H NMR(400MHz,DMSO)δ7.86(d,J＝7.9Hz,1H),7.63(s,1H),7.04(s,1H),6.37(d,J＝1.6Hz,1H),6.29(s,1H),5.79(s,2H),5.46–5.17(m,1H),4.28–4.13(m,2H),3.95–3.78(m,5H),3.46–3.35(m,1H),2.35(s,3H),1.50(d,J＝6.9Hz,3H),1.38(s,3H),1.15(m 2H),0.65(m,2H),0.56–0.36(m,4H).
实施例136 N-(1-(4-氨基-6-(1-甲基环丙基)吡啶-2-基)乙基)-7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000255
LC-MS：m/z 480(M+H) +。 1H NMR(400MHz,DMSO)δ7.88(m,1H),7.64(s,1H),7.05(s,1H),6.37(s,1H),6.29(s,1H),5.79(s,2H),5.37(m,1H),4.72–4.69(m,3H),4.46–4.42(m,2H),4.22(m,2H),3.89(s,3H),3.81–3.79(m,2H),2.35(s,3H),1.49(d,J＝8.0Hz,3H),1.38(s,3H),1.19(m,2H),0.66(m,2H).
实施例137 N-(1-(4-氨基-6-(1-氟环丙基)吡啶-2-基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000256
LC-MS：m/z 442(M+H) +。 1H NMR(400MHz,DMSO)δ7.96-7.94(m,2H),7.74(s,1H),6.97(s,1H),6.52(d,J＝8.0Hz,1H),6.24(d,J＝8.0Hz,1H),6.14(s,2H),4.19(m,2H),3.85(s,3H),3.74–3.72(m,2H),3.35(s,3H),2.28(s,3H),1.88(m,1H),1.62-1.57(m,2H),1.48(d,J＝8.0Hz,3H),0.93(m,1H).
实施例138(R)-N-(1-(3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000257
LC-MS：m/z 480(M+H) +。
实施例139(R)-N-(1-(3-(2-环丙基氧基-1,1-二氟乙基)-2-氟苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000258
LC-MS：m/z 506(M+H) +。
实施例140(R)-N-(1-(3-(1,1-二氟-2-(氧杂环丁烷-3-基氧基)乙基)-2-氟苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000259
LC-MS：m/z 522(M+H) +。
实施例141 N-((1R)-1-(3-(二氟(四氢呋喃-2-基)甲基)-2-氟苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺(异构体A和异构体B)
Figure PCTCN2021125084-appb-000260
异构体A
LC-MS：m/z 506(M+H) +。 1H NMR(400MHz,DMSO)δ8.04-8.01(m,1H),7.75(s,1H), 7.64-7.60(m,1H),7.40-7.37(m,1H),7.25-7.22(m,1H),7.03(s,1H),5.81-5.75(m,1H),4.54-4.48(m,1H),4.26-4.23(m,2H),3.87(s,3H),3.78-3.74(m,4H),3.36(s,3H),2.29(s,3H),2.03-1.94(m,2H),1.85-1.82(m,2H),1.59(d,J＝4Hz,2H)
异构体B
LC-MS：m/z 506(M+H) +。 1H NMR(400MHz,DMSO)δ8.03-8.01(m,1H),7.75(s,1H),7.64-7.60(m,1H),7.40-7.37(m,1H),7.25-7.22(m,1H),7.03(s,1H),5.81-5.75(m,1H),4.54-4.48(m,1H),4.26-4.23(m,2H),3.87(s,3H),3.76-3.74(m,4H),3.36(s,3H),2.29(s,3H),2.03-1.94(m,2H),1.86-1.82(m,2H),1.59(d,J＝4Hz,2H)
实施例142 N-((1R)-1-(3-(二氟(4-甲基吗啡啉-2-基)甲基)-2-氟苯基)乙基)-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000261
LC-MS：m/z 536(M+H) +。
实施例143(R)-1,1-二氟-1-(2-氟-3-(1-((8-氟-7-甲氧基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000262
LC-MS：m/z 512(M+H) +。
实施例144(R)-1-(3-(1-((6-(2-环丙氧基乙氧基)-8-氟-7-甲氧基-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000263
LC-MS：m/z 538(M+H) +。
实施例145(R)-1,1-二氟-1-(2-氟-3-(1-((8-氟-7-甲氧基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000264
LC-MS：m/z 554(M+H) +。
实施例146-148的制备
Figure PCTCN2021125084-appb-000265
第一步：将2-氨基-4-甲氧基-5-(2-甲氧基乙氧基)苯甲酸甲酯(1.2g)、氰基甲酸乙酯(0.932g)和2M HCl的二氧六环溶液(20mL)在封管中加热反应20小时，然后减压浓缩。残余物中加入DMF和DBU使固体溶解，然后通过制备液相分离，得到目标产物(230mg，产率：15％)。LC-MS：m/z 323(M+H) +。
第二步：将4-羟基-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-2-甲酸乙酯(230mg)溶于DMF(5mL)中，加入DBU(540mg)，冰水浴中缓慢加入BOP(628mg)，室温搅拌1小时后，加入(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺(201mg)。混合物100℃下搅拌反应16小时。然后通过制备液相分离得到目标产物(150mg，产率：39％)。LC-MS：m/z 540(M+H) +。
第三步：将4-羟基-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-2-甲酸乙酯(20mg，0.04mmol)加入到乙醇(5mL)和水(2mL)中，依次加入氯化铵(42mg，080mmol)和铁粉(23mg，040mmol)，混合物加热到80℃搅拌反应3小时，然后通过制备液相分离得到目标产物。
实施例146(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-2-甲酸乙酯
Figure PCTCN2021125084-appb-000266
LC-MS：m/z 495(M+H) +。 1H NMR(400MHz,DMSO)δ8.29(d,J＝7.5Hz,1H),7.81(s,1H),7.27(s,1H),6.88(m,2H),6.71(s,1H),5.56(m,3H),4.28(d,J＝6.6Hz,4H),3.93(s,3H),3.77(m,2H),3.36(s,3H),1.58(d,J＝6.6Hz,3H),1.30(t,J＝6.9Hz,3H).
实施例147(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-2-甲酸
Figure PCTCN2021125084-appb-000267
LC-MS：m/z 467(M+H) +。 1H NMR(400MHz,DMSO)δ8.39(d,J＝7.4Hz,1H),7.83(s,1H),7.29(s,1H),6.90(s,1H),6.86(s,1H),6.71(s,1H),5.80–5.67(m,1H),5.54(s,2H),4.27(d,J＝4.5Hz,2H),3.92(s,3H),3.77(t,J＝4.4Hz,2H),3.51(s,3H),1.58(d,J＝7.0Hz,3H).
实施例148(R)-4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-2-甲酰胺
Figure PCTCN2021125084-appb-000268
LC-MS：m/z 466(M+H) +。 1H NMR(400MHz,DMSO)δ8.22(d,J＝8.0Hz,1H),7.82(s,2H),7.46(s,1H),7.23(s,1H),6.91(s,1H),6.86(s,1H),6.70(s,1H),5.73–5.58(m,1H),5.51(s,2H),4.27(d,J＝4.1Hz,2H),3.92(s,3H),3.77(t,J＝4.5Hz,2H),3.36(s,3H),1.57(d,J＝7.1Hz,3H).
实施例149(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-环丙基-6,7-二甲氧基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000269
第一步：2-氨基-5-羟基-4-甲基苯甲酸甲酯的制备
将5-羟基-4-甲氧基-2-硝基苯甲酸甲酯(10g)分散到MeOH(100mL)中，加入钯碳(10％wt，1.5g)，置换氢气三次，室温搅拌过夜。反应液中加入THF溶解固体，通过硅藻土过滤，滤液减压浓缩得到目标产物(8.0g，收率：92％)。无需纯化，直接用于下一 步反应。LC-MS：m/z 198(M+H) +。
第二步：2-环丙基-7-甲氧基喹唑啉-4,6-二醇的制备
将2-氨基-5-羟基-4-甲基苯甲酸甲酯(6g)、环丙腈(6.1g)和4M HCl二氧六环溶液(100mL)的混合物加热至110℃搅拌过夜。得到的反应液冷却，过滤，滤饼收集后空气干燥得到目标产物(6.0g，收率：85％)。无需纯化，直接用于下一步反应。LC-MS：m/z 233(M+H) +。
第三步：2-环丙基-6,7-二甲氧基喹唑啉-4-醇的制备
将2-环丙基-7-甲氧基喹唑啉-4,6-二醇(400mg)、对甲苯磺酸甲酯(500mg)、碳酸钾(476mg)和DMF(5mL)的混合物加热至100℃搅拌过夜。得到的混合物用中压过柱机柱分离得到目标产物(50mg，收率：12％)。LC-MS：m/z 247(M+H) +。
第四步：(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-环丙基-6,7-二甲氧基喹唑啉-4-胺的制备
将2-环丙基-6,7-二甲氧基喹唑啉-4-醇(50mg)溶于DMF(5mL)中，加入DBU(152mg)，随后在冰水浴冷却下缓慢加入BOP(177mg)。得到的混合物在室温搅拌1小时后，随后加入(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺(49mg)。反应混合物在100℃下搅拌反应16小时然后冷却，通过制备色谱分离得到目标产物(21mg，收率：26％)。LC-MS：m/z 433(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝6.9Hz,1H),7.68(s,1H),6.98(s,1H),6.83(s,1H),6.79–6.76(m,1H),6.68(s,1H),5.49(s,2H),5.39–5.22(m,1H),3.90(s,3H),3.86(s,3H),1.86(dd,J＝8.2,3.6Hz,1H),1.54(d,J＝7.0Hz,3H),0.98(d,J＝4.6Hz,1H),0.85–0.55(m,3H).
按实施例149同样方法以不同起始原料合成以下化合物：
实施例150(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-环丙基-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000270
LC-MS：m/z 477(M+H) +。 1H NMR(400MHz,DMSO)δ7.93(d,J＝7.1Hz,1H),7.70(s,1H),6.99(s,1H),6.83(s,1H),6.79(s,1H),6.68(s,1H),5.49(s,2H),5.30(t,J＝7.0Hz,1H),4.21(dd,J＝8.5,4.3Hz,2H),3.87(s,3H),3.75(t,J＝4.6Hz,2H),1.86(m,1H),1.53(d,J＝7.0Hz,3H),0.98(m,1H),0.84–0.57(m,3H).
实施例151(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-(3,3-二氟环丁基)-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000271
LC-MS：m/z 527(M+H) +。 1H NMR(400MHz,DMSO)δ8.38(s,1H),7.90(s,1H),7.09(s,1H),6.87(d,J＝14.5Hz,2H),6.69(s,1H),5.59–5.35(m,3H),4.27(dd,J＝9.9,4.8Hz,2H),3.89(s,3H),3.76(t,J＝4.6Hz,2H),3.35(s,4H),2.91–2.72(m,4H),1.60(d,J＝7.0Hz,3H).
实施例152(R)-1-(3-氨基-5-(1-((2-(3,3-二氟环丁基)-7-甲氧基-6-(2-甲氧基乙氧基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000272
LC-MS：m/z 567(M+H) +。 1H NMR(400MHz,DMSO)δ8.06(d,J＝7.3Hz,1H),7.75(s,1H),7.07(s,1H),6.69(s,2H),6.56(s,1H),5.58–5.38(m,1H),5.13(s,2H),5.05(s,1H),4.22(d,J＝5.3Hz,2H),3.89(s,3H),3.81–3.70(m,2H),3.37(s,3H),3.26–3.20(m,1H),2.94–2.72(m,4H),1.56(d,J＝7.0Hz,3H),1.09(s,6H).
实施例153(R)-1-(3-(1-(7-乙炔基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
Figure PCTCN2021125084-appb-000273
第一步：(R)-1,1-二氟-1-(2-氟-3-(1-(6-(2-甲氧基乙氧基)-2-甲基-7-(三甲基硅基乙炔基)喹唑啉-4-基氨基乙基)苯基)-2-甲基丙烷-2-醇的制备
在氩气保护下，将(R)-1-(3-(1-(7-溴-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇(100mg,0.18mmol)加入到二氧六环中(5mL),室温下加入三乙胺(56mg,0.55mmol)、碘化亚铜(20mg)、Pd(PPh 3) 2Cl 2(20mg)、和乙炔基三甲基硅烷(54mg,0.55mmol)。反应液微波加热到80度反应2小时，然后减压浓缩，得到目标产物(120mg)。无需纯化直接用于下一步反应。
第二步：(R)-1-(3-(1-(7-乙炔基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇的制备
室温下，将上一步得到的(R)-1,1-二氟-1-(2-氟-3-(1-(6-(2-甲氧基乙氧基)-2-甲基-7-(三甲基硅基乙炔基)喹唑啉-4-基氨基乙基)苯基)-2-甲基丙烷-2-醇(120mg,0.21mmol)加入到甲醇中(5mL)，随后加入氟化钾(38mg,0.64mmol)。得到的反应液在室温搅拌1小时，然后减压浓缩。残留物用制备液相分离得到目标产物(65mg，收率：64％)。
LC-MS：m/z 488(M+H) +。 1H NMR(400MHz,DMSO)δ8.32(d,J＝7.2Hz,1H),7.85(s,1H),7.72–7.52(m,3H),7.31(t,J＝6.6Hz,1H),7.23(dd,J＝24.6,16.9Hz,1H),5.79(t,J＝7.1Hz,1H),5.31(s,1H),4.48(s,1H),4.38–4.22(m,2H),3.79(t,J＝4.7Hz,2H),3.39(s,3H),2.30(s,3H),1.60(d,J＝7.0Hz,3H),1.22(d,J＝10.9Hz,6H).
按实施例153同样方法以不同起始原料合成以下化合物：
实施例154(R)-1,1-二氟-1-(2-氟-3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(丙-1-炔-1-基)喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000274
LC-MS：m/z 502(M+H) +。
实施例155(R)-1-(3-(1-((7-(环丙基乙炔基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000275
LC-MS：m/z 528(M+H) +。
实施例156(R)-1-(3-(1-((6-(2-环丙氧基乙氧基)-7-乙炔基-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000276
LC-MS：m/z 514(M+H) +。 1H NMR(400MHz,DMSO)δ8.32(d,J＝7.2Hz,1H),7.84(s,1H),7.64(s,1H),7.59(t,J＝6.6Hz,1H),7.31(t,J＝6.7Hz,1H),7.21(t,J＝7.7Hz,1H),5.78(dd,J＝14.1,7.0Hz,1H),5.30(s,1H),4.48(s,1H),4.28(t,J＝6.7Hz,2H),3.89(t,J＝4.6Hz,2H),3.49(m,1H),2.30(s,3H),1.60(d,J＝7.0Hz,3H),1.22(d,J＝10.8Hz,6H),0.65–0.39(m,4H).
实施例157(R)-1-(3-(1-((7-乙炔基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000277
LC-MS：m/z 530(M+H) +。 1H NMR(400MHz,DMSO)δ8.34(d,J＝8Hz,1H),7.85(s,1H),7.65(s,1H),7.59(m,1H),7.31(m,1H),7.23-7.21(m,1H),5.79(m,1H),5.37(brs,1H),4.74-4.72(m,3H),4.53(s,1H),4.48–4.46(m,2H),4.31–4.30(m,2H),3.84(t,J＝4.0Hz,2H),2.30(s,3H),1.60(d,J＝8.0Hz,3H),1.22(d,J＝8.0Hz,6H).
实施例158 1-(3-((R)-1-((7-乙炔基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000278
LC-MS：m/z 500(M+H) +。 1H NMR(400MHz,DMSO)δ8.32(d,J＝6.5Hz,1H),7.83(s,1H),7.66(s,1H),7.58(t,J＝6.6Hz,1H),7.31(t,J＝6.6Hz,1H),7.22(t,J＝7.7Hz,1H),5.80(t,J＝7.1Hz,1H),5.30(d,J＝8.2Hz,1H),5.28(m,1H),4.49(s,1H),4.04(dd,J＝10.2,4.6Hz,1H),3.97–3.77(m,3H),2.43–2.24(m,4H),2.11–1.97(m,1H),1.61(d,J＝7.0Hz,3H),1.22(d,J＝10.5Hz,6H).
实施例159(R)-1-(3-(1-((7-乙炔基-2-甲基-6-(2-(吡啶-3-基氧基)乙氧基)喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000279
LC-MS：m/z 551(M+H) +。
实施例160(R)-N-(2-((4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-7-乙炔基-2-甲基喹唑啉-6-基)氧基)乙基)-N-甲基甲磺酰胺
Figure PCTCN2021125084-appb-000280
LC-MS：m/z 565(M+H) +。
实施例161(R)-5-(4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-7-乙炔基-2-甲基喹唑啉-6-基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021125084-appb-000281
LC-MS：m/z 521(M+H) +。
实施例162(R)-1-(4-(4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-7-乙炔基-2-甲基喹唑啉-6-基)-4-甲氧基哌啶-1-基)乙烷-1-酮
Figure PCTCN2021125084-appb-000282
LC-MS：m/z 569(M+H) +。
实施例163(R)-1-(3-氨基-5-(1-((7-乙炔基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000283
LC-MS：m/z 485(M+H) +。 1H NMR(400MHz,DMSO)δ8.18(d,J＝8Hz,1H),7.81(s,1H),7.63(s,1H),6.71-6.68(m,2H),6.56(s,1H),5.56-5.52(m,1H),5.17(s,2H),5.06(s,1H),4.45(s,1H),4.28–4.26(m,2H),3.78–3.76(m,2H),3.38(s,3H),2.36(s,3H),1.56(d,J＝4.0Hz,3H),1.12(s,6H).
实施例164 1-(3-氨基-5-((R)-1-((7-乙炔基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-基)氨基)乙基)苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000284
LC-MS：m/z 497(M+H) +。 1H NMR(400MHz,DMSO)δ8.22(m,1H),7.79(s,1H),7.64(s,1H),6.71(s,1H),6.68(s,1H),6.56(s,1H),5.57(m,1H),5.23-5.20(m,3H),5.08(s,1H),4.00(m,1H),3.92-3.82(m,3H),2.37(s,3H),2.32-2.30(m,1H),1.56(d,J＝8.0Hz,3H),1.11(s,6H).
实施例165(R)-1-(3-(1-((7-乙炔基-8-氟-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇
Figure PCTCN2021125084-appb-000285
LC-MS：m/z 506(M+H) +。
实施例166(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-乙炔基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000286
LC-MS：m/z 445(M+H) +。
实施例167 N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-乙炔基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000287
LC-MS：m/z 457(M+H) +。
实施例168(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-环丙氧基乙氧基)-7-乙炔基-2-甲基喹唑啉-4-胺
Figure PCTCN2021125084-appb-000288
LC-MS：m/z 471(M+H) +。
实施例169(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-乙炔基-2-甲基-6-(2-(氧杂环丁烷-3-基氧基)乙氧基)喹唑啉-4-胺
Figure PCTCN2021125084-appb-000289
LC-MS：m/z 487(M+H) +。
实施例170(R)-5-(4-((1-(3-(1,1-二氟-2-羟基-2-甲基丙基)-2-氟苯基)乙基)氨基)-7-乙炔基-8-氟-2-甲基喹唑啉-6-基)-1-甲基吡啶-2(1H)-酮
Figure PCTCN2021125084-appb-000290
LC-MS：m/z 539(M+H) +。 1H NMR(400MHz,DMSO)δ8.67(d,J＝7.3Hz,1H),8.27(s,1H),8.07(d,J＝2.4Hz,1H),7.74(dd,J＝9.4,2.6Hz,1H),7.60(t,J＝6.7Hz,1H),7.32(t,J＝6.8Hz,1H),7.21(t,J＝7.7Hz,1H),6.52(d,J＝9.4Hz,1H),5.81(t,J＝7.1Hz,1H),5.32(s,1H),4.81(s,1H),3.54(s,3H),2.39(s,3H),1.58(d,J＝7.0Hz,3H),1.22(d,J＝10.0Hz,6H).
实施例171 生物学测试评价
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。
化合物对KRAS  G12C和SOS1结合的抑制实验。
实验步骤
(1)待测化合物梯度稀释：将10mM母液(溶解于100％DMSO)加入384孔测试板中，DMSO最终含量为0.25％。
(2)将5ul Tag1-SOS1溶液加入测试板中，对照组加入5ul稀释缓冲液。
(3)向测试板中加入5ul Tag2-KRAS G12C溶液。
(4)将10ul Anti-Tag1-Tb3+和Anti-Tag2-XL665检测液加入测试板中。1000rpm离心1分钟，室温孵育2hr。
(5)读板
(6)最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线。
本发明中实施例化合物对KRAS  G12C酶和SOS1结合的抑制活性见表1。
表1本发明中实施例化合物抑制活性
IC 50 (nM)
实施例1 4.6
实施例2 8.5
实施例6 13
实施例7 3.3
实施例8 1.9
实施例9 3.4
实施例10 2.9
实施例11 3.6
实施例12 8.3
实施例13 2.5
实施例14 16
实施例15 6.9
实施例16 1089
实施例17 70
实施例18 36
实施例19 9.4
实施例20 121
实施例21 4.7
实施例22 7.0
实施例23 7.9
实施例24 7.7
实施例25 3.9
实施例26 9.2
实施例27 8.5
实施例28 7.9
实施例29 4.7
实施例30 /
实施例31 /
实施例32 31
实施例33 7.5
实施例34 5.4
实施例35 17
实施例36 >1000
实施例37 >1000
实施例38 33
实施例39 21
实施例40 8.2
实施例41 252
实施例42 5.6
实施例43 5.2
实施例44 4.4
实施例45 167
实施例46 10
实施例47 7.4
实施例49 4.6
实施例50 4.2
实施例51 24
实施例52 31
实施例53 3.7
实施例54 15
实施例55 16
实施例56 9.6
实施例57 5.2
实施例58 5.1
实施例59 4.7
实施例60 18
实施例61 3.7
实施例62 5.3
实施例63 12
实施例64 8.7
实施例65 16
实施例65A 18
实施例65B 7.3
实施例66 7.0
实施例67 4.2
实施例68 6.2
实施例69 6.2
实施例70 24
实施例71 314
实施例72 3.2
实施例73 15
实施例74 3.1
实施例75 40
实施例76 188
实施例77 924
实施例78 /
实施例79 19
实施例80 6.2
实施例81 /
实施例82 4.5
实施例83 15
实施例84 18
实施例85 4.1
实施例86 4.4
实施例87 170
实施例88 20
实施例89 6.7
从表1可以看出：
本发明实施例化合物对于KRAS G12C和SOS1的结合显示出了很好的抑制活性。
实施例172 化合物对H358细胞增殖的抑制实验
实验步骤
1.细胞培养
(a)复苏细胞于T75细胞培养瓶中：
表2 H358细胞的培养
编号 细胞系 培养基(Medium) 传代#T75
1 NCI-H358 RPMI 1640+10％FBS+1％PS 2～3x10 6
(b)当细胞融合度达到80-90％，对细胞进行传代。
2.细胞增殖检测
实验步骤
利用纳升移液系统将稀释好的待测化合物加入384孔细胞培养板中,设置复孔。阳性对照组加入等体积的培养基；阴性对照组加入等体积的DMSO，1000rpm室温离心1min。
将细胞接种到a)384培养板中，阴性对照组加入等量等体积细胞，阳性对照组仅加入等体积的培养基。1000rpm室温离心1min，最终化合物的DMSO终浓度为0.5％，放置于37℃，5％CO2恒温培养箱孵育7天。
加入20μL/well的
Figure PCTCN2021125084-appb-000291
3D至b)384孔细胞培养板中，避光320rpm震荡20min，避光室温孵育2hrs。
用Envision多功能酶标仪读取发光值。
3.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(1–(RLU化合物–RLU空白对照)/(RLU溶媒对照–RLU空白对照))*100％。在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC 50。实验结果如表3所示。
表3本发明中实施例化合物H358细胞增殖抑制活性
IC 50 (nM)
实施例44 25
实施例72 16.6
实施例74 6.5
实施例79 419
实施例80 53
实施例82 33
实施例83 187
实施例85 39
实施例86 11.8
实施例89 130
实施例90 48.6
实施例91 >10000
实施例92 18.24
实施例93 40.93
实施例97 15.5
实施例98 12.8
实施例99 19.97
实施例101 15.48
实施例102 13.26
实施例103 23.5
实施例113 10.40
实施例115 9.92
实施例116 4.29
实施例117 2.65
实施例118 2.65
实施例119 11.47
实施例122 15.63
实施例123 32.83
实施例153 34.71
实施例157 15.85
实施例163 14.5
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，灌胃给予10mg/kg本发明化合物的溶液[CMC/TW80为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12，24、36和48h采血，用LC/MS/MS测定血浆中本发明化合物的浓度。
由检测结果看出，本发明化合物具有良好的药代动力学特性。
抗肿瘤药效学评价
将100uL含5x10 6MIA PaCa-2肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW 2，其中L、W分别代表肿瘤长、宽。肿瘤长至～100mm 3，对小鼠进行随机分组。小鼠每天两次灌胃给予相应剂量(50mg/Kg)化合物的CMC-Na悬液，同时对其一般状态进行监测。肿瘤每周测量3次，体重每周测量两次。测试结果如表4所示。
参照化合物BI3406结构：
Figure PCTCN2021125084-appb-000292
表4抗肿瘤活性药效学测试评价
Figure PCTCN2021125084-appb-000293
Figure PCTCN2021125084-appb-000294
由检测结果看出，本发明化合物相对于参照化合物BI3406具有较优的抗肿瘤效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (14)

  1. 具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：
    Figure PCTCN2021125084-appb-100001
    式中，
    X选自：CR 6或N，其中，R 6选自：氢、氘、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
    Y选自下组：O、NH、NR 7、S、SO、SO 2、C≡C、取代或未取代的4-20元杂环基、取代或未取代的C 6-C 14芳基或5-14元杂芳基，其中，R 7选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基或4-6元杂环基；
    Z选自取代或未取代的下组基团：键、取代或未取代的C 1-C 18亚烷基；
    W选自取代或未取代的下组基团：键、C 3-C 20亚环烷基、4-20元亚杂环基、OR 11、NR 11R 12、SO 2、NR 12SO 2、CO或NR 12CO；R 11独立地选自取代或未取代的下组基团：C 3-C 20亚环烷基、4-20元亚杂环基、C 3-C 20亚环烷基C 1-C 18亚烷基、4-20元亚杂环基C 1-C 18亚烷基、C 6-C 14芳基或5-14元杂芳基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
    R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) m(CH＝CH)R 8、-(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自取代或未取代的下组基团：氢、C 1-C 18烷基、C 1-C 18烷氧基、C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基或5-14元杂芳基；或者在-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mS(O) qNR 8R 9中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10中，R 8和R 9与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 9和R 10与其相邻的原子环合形成取代或未取代的4-8元杂环基；
    R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基、5-14元杂芳基；
    R 4、R 5各自独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基、4-6元杂环基、酯基、COOH、CONH 2、C 2-C 6烯基、C 2-C 6炔基；
    其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-、卤素、氧代C 1-C 6烷基、硝基、羟基、氰基、C 2-C 6酯基、C 1-C 6胺基、C 2-C 6酰基、C 1-C 6酰胺基、C 1-C 6磺酰基、C 1-C 6磺酰胺基或C 1-C 6脲基；其中，所述C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-还可进一步被一个或多个R a取代，其中，R a选自：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代C 1-C 6烷基、硝基、羟基、氰基、C 2-C 6酯基、C 1-C 6胺基、C 2-C 6酰胺基、C 1-C 6磺酰胺基或C 1-C 6脲基；或两个位于相同碳原子上的取代基共同构成-(CH 2) n-或＝O；
    m、n各自独立地为0、1、2、3、4或5；
    p为0、1、2、3、4或5；
    q为1或2；
    限定条件是当Y选自下组：O、NH或NR 7，且Z为键，W为C 3-C 20亚环烷基或4-20元亚杂环基时；R 1不为氢、氘、卤素、氰基、R 8、O(CH 2) pR 8、COR 8、-C(O)OR 8、NR 8R 9、C(O)NR 8R 9、-NR 8C(O)R 9、-NR 8C(O)NR 9R 10。
  2. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(III)所示结构：
    Figure PCTCN2021125084-appb-100002
    式中，R 1、R 2、R 3、X、Y、Z、W、n的定义如权利要求1所述。
  3. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有通式(IV)所示结构：
    Figure PCTCN2021125084-appb-100003
    式中，R 1、R 2、R 3、R 6、X、Y、Z、W、n的定义如权利要求1所述。
  4. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VI)所示结构：
    Figure PCTCN2021125084-appb-100004
    式中，
    R 13和R 14各自独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    环C选自取代或未取代的下组基团：C 3-C 12亚环烷基、4-12元亚杂环基；
    各R 2相同或不同，且独立地自下组：-(CH 2) mO(CH 2) pR 8、-(CH 2) m(CH＝CH) pR 8、(CH 2) m(C≡C) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；
    m为1、2、3、4或5；
    t为1、2、3、4、5或6；
    其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    R 1、R 3、R 6、R 8、R 9、R 10、p、q和n的定义如权利要求1所述。
  5. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VII)所示结构：
    Figure PCTCN2021125084-appb-100005
    式中，
    R 16和R 17各自独立地选自：H、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    R 18选自：OR 11、NR 11R 12、NR 12SO 2R 2、COR 2或NR 12COR 2；R 11独立地选自：取代的 C 3-C 12环烷基、取代或未取代4-12元杂环基、取代或未取代C 3-C 12亚环烷基C 1-C 6亚烷基、取代或未取代4-12元亚杂环基C 1-C 6亚烷基、取代或未取代C 6-C 14芳基、取代或未取代5-14元杂芳基；R 12独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基或C 3-C 6环烷基；
    或者R 18选自：-(CH 2) m(CH＝CH)R 8、-(CH 2) m(C≡C)R 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mSR 8、-(CH 2) mCOR 8、-(CH 2) mC(O)OR 8、-(CH 2) mS(O) qR 8、-(CH 2) mNR 8R 9、-(CH 2) mC(O)NR 8R 9、-(CH 2) mNR 8C(O)R 9、-(CH 2) mNR 8C(O)NR 9R 10、-(CH 2) mS(O) qNR 8R 9、-(CH 2) mNR 8S(O) qR 9、-(CH 2) mNR 8S(O) qNR 9R 10，其中，CH 2中的H可以任选地被取代；R 8、R 9、R 10各自独立地选自：取代或未取代的C 1-C 18烷基、取代或未取代的C 3-C 20环烷基、取代或未取代的4-20元杂环基；
    其中，R 8、R 9和R 10中所述取代是指被选自下组的一个或多个基团取代：C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    t为1、2、3、4、5或6；
    其中，若未特别说明，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    R 1、R 2、R 3、R 6、m、p和q的定义如权利要求1所述。
  6. 如权利要求5所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R 18选自：OR 11、NR 11R 12或NR 12SO 2R 2；其中，R 11独立地选自：取代的C 3-C 12环烷基、取代或未取代4-12元杂环基、取代或未取代C 3-C 12亚环烷基C 1-C 6亚烷基、取代或未取代4-12元亚杂环基C 1-C 6亚烷基、取代或未取代C 6-C 14芳基、取代或未取代5-14元杂芳基；R 12独立地选自下组：氢、氘、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基；
    或者R 18选自：-(CH 2) mO(CH 2) pR 8；其中，CH 2中的H可以任选地被取代；R 8选自：取代或未取代的C 1-C 18烷基、取代或未取代的C 3-C 20环烷基、取代或未取代的4-20元杂环基；优选地R 8为取代或未取代的C 1-C 18烷基(优选地为C 1-C 6烷基)；
    上述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    在另一优选例中，R 3选自：取代的C 6-C 14芳基或取代的5-14元杂芳基；所述取代是指被选自下组的一个或多个基团取代：R 3a、氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元 杂环基-O-、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；其中，所述C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 3-C 20环烷基-O-、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、4-20元杂环基-O-还可进一步被一个或多个R a取代，其中，R a选自：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 3-C 6环烷基-O-、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、4-6元杂环基-O-、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；限定条件是至少含有一个R 3a取代基；
    其中，R 3a选自：羟基取代的C 1-C 18烷基、羟基取代的C 1-C 18卤代烷基、羟基取代的C 1-C 18氘代烷基、烷氧基取代的C 1-C 18烷基、烷氧基取代的C 1-C 18卤代烷基、烷氧基取代的C 1-C 18氘代烷基、环烷基氧基取代的C 1-C 18烷基、环烷基氧基取代的C 1-C 18卤代烷基、环烷基氧基取代的C 1-C 18氘代烷基、杂环基氧基取代的C 1-C 18烷基、杂环基氧基取代的C 1-C 18卤代烷基、杂环基氧基取代的C 1-C 18氘代烷基、环烷基取代的C 1-C 18卤代烷基、杂环基取代的C 1-C 18卤代烷基、胺基取代的C 1-C 18卤代烷基、氰基取代的C 1-C 18卤代烷基、酰胺基取代的C 1-C 18卤代烷基、取代的C 3-C 12环烷基、取代的4-12元杂环基、取代或非取代的卤代烷基氧基、取代或非取代的环烷基氧基、取代或非取代的杂环基氧基、取代或非取代的磺酰胺基、取代或非取代的环烷基砜基；上述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 10芳基、5-10元杂芳基、4-6元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。
  7. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VIII)所示结构：
    Figure PCTCN2021125084-appb-100006
    式中，R 1、R 2、R 3、R 6和W的定义如权利要求1所述。
  8. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(IX-A)或式(IX-B)所示结构：
    Figure PCTCN2021125084-appb-100007
    式中，R 2、R 3、R 8、R 9、X、Y、Z、W、n和q的定义如权利要求1所述。
  9. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(X)所示结构：
    Figure PCTCN2021125084-appb-100008
    式中，R 8选自取代或未取代的下组基团：C 3-C 20环烷基或4-20元杂环基；
    其中，所述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、氧代基、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；
    R 2、R 3、X、Y、Z、W、n和q的定义如权利要求1所述。
  10. 如权利要求1所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，R 3选自：
    Figure PCTCN2021125084-appb-100009
    Figure PCTCN2021125084-appb-100010
  11. 如权利要求1-10中任一项所述的具有通式(I)结构的取代苯并或吡啶并嘧啶胺类化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2021125084-appb-100011
    Figure PCTCN2021125084-appb-100012
    Figure PCTCN2021125084-appb-100013
    Figure PCTCN2021125084-appb-100014
    Figure PCTCN2021125084-appb-100015
    Figure PCTCN2021125084-appb-100016
    Figure PCTCN2021125084-appb-100017
    Figure PCTCN2021125084-appb-100018
    Figure PCTCN2021125084-appb-100019
    Figure PCTCN2021125084-appb-100020
    Figure PCTCN2021125084-appb-100021
    Figure PCTCN2021125084-appb-100022
    Figure PCTCN2021125084-appb-100023
    Figure PCTCN2021125084-appb-100024
    Figure PCTCN2021125084-appb-100025
    Figure PCTCN2021125084-appb-100026
    Figure PCTCN2021125084-appb-100027
    Figure PCTCN2021125084-appb-100028
    Figure PCTCN2021125084-appb-100029
    Figure PCTCN2021125084-appb-100030
    Figure PCTCN2021125084-appb-100031
    Figure PCTCN2021125084-appb-100032
    Figure PCTCN2021125084-appb-100033
    Figure PCTCN2021125084-appb-100034
    Figure PCTCN2021125084-appb-100035
    Figure PCTCN2021125084-appb-100036
    Figure PCTCN2021125084-appb-100037
    Figure PCTCN2021125084-appb-100038
    Figure PCTCN2021125084-appb-100039
    Figure PCTCN2021125084-appb-100040
    Figure PCTCN2021125084-appb-100041
    Figure PCTCN2021125084-appb-100042
    Figure PCTCN2021125084-appb-100043
    Figure PCTCN2021125084-appb-100044
    Figure PCTCN2021125084-appb-100045
    Figure PCTCN2021125084-appb-100046
    Figure PCTCN2021125084-appb-100047
    Figure PCTCN2021125084-appb-100048
    Figure PCTCN2021125084-appb-100049
    Figure PCTCN2021125084-appb-100050
    Figure PCTCN2021125084-appb-100051
    Figure PCTCN2021125084-appb-100052
    Figure PCTCN2021125084-appb-100053
    Figure PCTCN2021125084-appb-100054
    Figure PCTCN2021125084-appb-100055
    Figure PCTCN2021125084-appb-100056
    Figure PCTCN2021125084-appb-100057
    Figure PCTCN2021125084-appb-100058
    Figure PCTCN2021125084-appb-100059
    Figure PCTCN2021125084-appb-100060
  12. 一种制备如权利要求1-11中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的方法，其特征在于，包括步骤：
    Figure PCTCN2021125084-appb-100061
    (i)在第一种碱存在下，式V-1化合物与式V-2化合物反应，得到式V-3化合物；
    (ii)在第二种碱以及催化剂存在下，式V-3化合物与磺酰氯(V-4)反应，得到生成式V-5化合物；
    (iii)在第三种碱存在下，式V-5化合物与胺(式V-6)反应，得到式(I)化合物；
    式中，
    R’选自：卤素、OTs或OMs；
    R 1、R 2、R 3、R 4、R 5、X、Y、Z、W和n定义如权利要求1所述。
  13. 一种药物组合物，其特征在于，包含i)一种或多种权利要求1-11中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。
  14. 一种如权利要求1-11中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或如权利要求13所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与SOS1活性或表达量相关的疾病的药物组合物。
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