WO2022188819A1 - Sos1蛋白水解调节剂及其制备方法和应用 - Google Patents

Sos1蛋白水解调节剂及其制备方法和应用 Download PDF

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WO2022188819A1
WO2022188819A1 PCT/CN2022/080000 CN2022080000W WO2022188819A1 WO 2022188819 A1 WO2022188819 A1 WO 2022188819A1 CN 2022080000 W CN2022080000 W CN 2022080000W WO 2022188819 A1 WO2022188819 A1 WO 2022188819A1
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alkyl
substituted
methyl
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吕彬华
崔大为
庞旭东
刘连军
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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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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a SOS1 proteolysis regulator 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 $54 billion in 2023.
  • 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.).
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.
  • ALK inhibitors such as
  • 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 %vs10%).
  • 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 SOS1GEF activity in KRAS-mutant cancer cells.
  • proteolysis is crucial and strictly regulated in the normal life activities of cells, and its process is mainly completed by the participation of the ubiquitinase system.
  • Proteins to be cleaved are labeled by the E1, E2 and E3 ubiquitin ligase systems, which are then recognized and hydrolyzed by proteases.
  • the proteolytic regulator molecule is a bifunctional active compound. One end of the molecule is tightly bound to the target protein, the other end is bound to E3 ubiquitin ligase, and the two ends are connected by various linking chains. This bifunctional molecule can simultaneously recognize the target protein and E3 ubiquitin ligase in vivo.
  • the target protein and E3 ubiquitin ligase are brought closer together, the target protein is ubiquitinated and then hydrolyzed through the ubiquitin-proteasome pathway. After the target protein is hydrolyzed, this bifunctional molecule can be released to participate in the next cycle of proteolysis, thus having a catalytic effect. Therefore, it can achieve high-efficiency therapeutic effect with less drug administration in clinical practice. .
  • 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 proteolytic modulators 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 type of SOS1 proteolysis regulator and its preparation method and application.
  • the first aspect of the present invention provides a compound having the structure of general formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or pro- medicine:
  • ULM represents a small molecule ligand moiety that can bind to E3 ligase
  • PTM represents a small molecule ligand moiety that can bind to SOS1;
  • L can be a bond or a linking group that can connect the PTM and the ULM.
  • the PTM is selected from PTM1 or PTM2.
  • PTM1 is preferably selected from:
  • each substituent is independently defined as follows:
  • X is selected from the group consisting of: 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 heterocycle base;
  • Z is selected from the group consisting of a substituted or unsubstituted group: a bond, a C 1 -C 18 alkylene group, a deuterated C 1 -C 18 alkylene group, or a halogenated C 1 -C 18 alkylene group;
  • W is selected from the group consisting of substituted or unsubstituted groups: bond, C 1 -C 18 alkylene, 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 substituted or unsubstituted following groups Group: hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 1 , R 2 are each independently selected from the group consisting of bond, hydrogen, deuterium, halogen, cyano, -(CH 2 ) m R 8 , -(CH 2 ) m O(CH 2 ) p R 8 , -( CH 2 ) m O(CH 2 ) p OR 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 8 R 9 , -(CH 2 ) m O(CH 2 ) p R 8 -(CH 2 ) m NR 9 R 10 , -(CH 2 ) m C(O)NR 8 R 9 , -(CH 2 ) m NR 8 C(O)R 9 , -(CH 2 ) m NR 8 C
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 18 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • R 4 and R 5 are independently selected from the group consisting of substituted or unsubstituted groups: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl;
  • substitution refers to being substituted by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl base, halogenated C 1 -C 18 alkylhydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy Oxy group, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamido or Urea group;
  • n are each independently 0, 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4, or 5;
  • q 1 or 2.
  • PTM1 is selected from the following group:
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, W, and n are as defined above.
  • PTM1 is selected from the following group:
  • R 1 , R 2 , R 3 , R 6 , Y, Z, W, and n are defined as described above.
  • PTM1 is selected from the following group:
  • R 13 and R 14 are each independently selected from the group consisting of substituted or unsubstituted 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;
  • 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 2 , R 3 , R 6 , Y and n are defined as above.
  • PTM1-IVA and PTM1-IVB are connected through C ring or through R2 and L, such as:
  • PTM1 is preferably selected from:
  • R 16 and R 17 are each independently selected from the group consisting of substituted or unsubstituted 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;
  • 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 the group consisting of substituted or unsubstituted groups: C 1 -C 18 subgroups Alkyl, C 3 -C 12 cycloalkylene, 4-12 membered heterocyclylene, C 3 -C 12 cycloalkylene C 1 -C 6 alkylene, or 4-12 membered heterocyclylene C 1 -C 6 alkylene;
  • 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;
  • t is 1, 2, 3, 4, 5 or 6;
  • R 1 , R 2 , R 3 , Y and R 6 are as defined above.
  • PTM2 is:
  • the dotted line represents the connection to L
  • 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 of substituted groups: bond, C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene;
  • R 1' substituted or unsubstituted group of the following group: hydrogen, deuterium, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • R 2' are the same or different, each independently selected from the group consisting of -(CH 2 ) p R 7' , -(CH 2 ) m O(CH 2 ) p R 7' , -(CH 2 ) m SR 7' , -(CH 2 ) m COR 7' , -(CH 2 ) m C(O)OR 7' , -(CH 2 ) m S(O) q R 7' , -(CH 2 ) m NR 7' R 8' , -(CH 2 ) m C(O)NR 7' R 8' , -(CH 2 ) m NR 7' C(O)R 8' , -(CH 2 ) m NR 7' C(O) NR 8' R 9' , -(CH 2 ) m S(O) q NR 7' R 8' , -(CH 2 ) m NR 7' S(O) q R 8
  • R 4' , 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;
  • R 6' is selected from: hydrogen, deuterium, halogen, amino, cyano, substituted or unsubstituted C 1 -C 6 alkyl and substituted or unsubstituted C 3 -C 6 cycloalkyl;
  • substitution refers to being substituted by one or more groups selected from the group consisting of 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, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or urea ;
  • n' is 1, 2, 3, 4 or 5;
  • n' is 1, 2, 3, 4 or 5;
  • p' is 0, 1, 2, 3, 4 or 5;
  • q' is 1 or 2.
  • PTM2 is:
  • PTM2 is:
  • PTM2 is:
  • R 13' and R 14' are each independently selected from the group consisting of substituted or unsubstituted H, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, or halo C 1 - C 6 alkyl; or R 13' and R 14' and adjacent C are cyclized together to form a C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl;
  • Ring W' is selected from the group of substituted 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 deuterium, C1 - C18 alkyl, deuterated C1 - C18 alkyl, haloC1- C18 alkyl, halo Substituted C 1 -C 18 alkyl hydroxyl, 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 or urea group;
  • t' is 1, 2, 3, 4, 5 or 6;
  • R 1' , R 2' , R 3' and n' are defined as described above.
  • PTM2 is selected from the following group:
  • ULM is a small molecule ligand part that can bind to a ligase selected from the group consisting of VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP, DCAF15, DCAF16, RNF4, RNF114 and AhR etc.
  • ULM is preferably selected from small molecule VLM, CLM, MLM or ILM that can bind to ligases such as VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), or IAP. Ligand part.
  • ULM is selected from small molecule VLM or CLM ligand part that can be combined with VHL (Von Rippel-Lindau), CRBN (Cereblon) and other ligases, more preferably CRBN (Cereblon) ligase The bound small molecule CLM ligand moiety.
  • the above-mentioned compound of formula I is selected from the following group: PTM-VLM, PTM-CLM, PTM-MLM, PTM-ILM; PTM-L-VLM, PTM-L-CLM, PTM-L-MLM or PTM-L-ILM.
  • the VLM is:
  • the dotted line represents the connection to L
  • n a1 is selected from: 0, 1, 2, 3, or 4;
  • W a1 and W a2 are selected from substituted or unsubstituted following group: -X a3 -X a4 -; wherein X a3 and X a4 are independently selected from substituted or unsubstituted following group: -(CH 2 ) m a1 R a5 -, -(CH 2 ) m a1 O(CH 2 ) m a2 R a5 -, -(CH 2 ) m a1 SR a5 -, -(CH 2 ) m a1 COR a5 -, -(CH 2 ) m a1 C(O)OR a5 -, -(CH 2 ) m a1 S(O) m a3 R a5 -, -(CH 2 ) m a1 NR a5 R a6 -, -(CH 2 ) m a1 C( O)NR a5 R
  • n a1 , m a2 are independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • m a3 is independently selected from 0, 1, or 2;
  • 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.
  • the VLM is:
  • R a8 , R a9 , R a10 are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, halogen, cyano, C 1 -C 18 alkyl or alkylene, C 3 -C 12 cycloalkyl or Cycloalkylene, 4-12-membered heterocyclyl or heterocyclylene, C 6 -C 14 aryl or arylene, 5-20-membered heteroaryl or heteroarylene, -NR a13 R a14 -; wherein R a13 and R a14 are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl;
  • R a11 is independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl;
  • R a12 is independently selected from the group consisting of substituted or unsubstituted groups: C 6 -C 14 aryl, or 5-20-membered heteroaryl;
  • 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.
  • CLM is selected from the following group:
  • each group is independently defined as follows:
  • the dotted line represents the connection to L
  • W b1 is the same or different, independently selected from C ⁇ O, SO 2 , CR b3 R b4 , NR b5 ; wherein R b3 , R b4 are independently selected from substituted or unsubstituted following groups: hydrogen, halogen, cyano base, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6-membered heterocyclic group; R b5 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, C 1 -C 6 alkane base, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • X b1 , X b2 , X b3 are the same or different, and are independently selected from CH2, O or S;
  • Z b1 and Z b2 are the same or different, and are independently selected from CH2, O or S;
  • Y b1 is selected from CH2, O, S or NR b6 ;
  • R b6 is selected from substituted or unsubstituted groups of the following group: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 Membered heterocyclic group, C 6 -C 14 aryl, 5-14 membered heteroaryl;
  • G b1 and G b2 are the same or different, and are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl , C 6 -C 14 aryl, 5-14-membered heteroaryl;
  • a b1 and A b2 are the same or different, and are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4- 6-membered heterocyclic group, C 6 -C 14 aryl, 5-14-membered heteroaryl;
  • R b1 , R b2 , R b3 are the same or different and are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo 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, amide, sulfonamide or urea group;
  • n b1 and n b2 are the same or different, and are independently selected from: 0, 1, 2, 3, or 4;
  • 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.
  • the VLM is preferably selected from:
  • the VLM is selected from the following group:
  • R b1 , R b2 , R b3 , n b1 , n b2 are as described above.
  • MLM is preferably selected from the following group:
  • each group is independently defined as follows:
  • the dotted line represents the connection to L
  • X c1 is selected from the group consisting of O, S, SO, SO2, CR c29 R c30 , NR c31 , wherein R c29 , R c30 are the same or different, and are independently selected from the group consisting of substituted or unsubstituted groups: 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 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 group, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide or
  • Y c1 and Z c1 are independently selected from N or R C32 , wherein R c32 is from the group consisting of substituted or unsubstituted 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;
  • a c1 , A c2 or A c3 is independently selected from N, O, S or CR c33 , or A c1 , A c2 or A c3 wherein two cyclize together to form C 3 -C 8 cycloalkyl, 4-8 membered heterocyclic Cyclic, C 6 -C 14 aryl, 5-14 membered heteroaryl; R c33 substituted or unsubstituted following groups: 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 alkane Oxy, halogenated C 1 -C 18 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocycly
  • R c" is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, halo 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 heterocyclyl;
  • R c1 -R c28 are the same or different and are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo 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, amide, sulfonamido, or ureido; or independently selected from the group consisting of substituted or unsubstituted: -(CH 2 ) m c1 R c34
  • n c1 , m c2 are independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • m c3 is independently selected from 0, 1, or 2;
  • 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.
  • the MLM is:
  • R c37 and R c38 are the same or different, and are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl , C 6 -C 14 aryl, 5-20-membered heteroaryl; or R c37 , R c38 cyclized to form a substituted or unsubstituted 4-20-membered heterocyclic group, or a 5-20-membered heteroaryl;
  • R c39 , R c40 are independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo 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 group, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or urea base;
  • n c4 , m c5 are independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • 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.
  • MLM is selected from the following group:
  • the ILM is selected from the following group:
  • each group is independently defined as follows:
  • R d1 -R d6 are the same or different, and are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo 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, nitro, hydroxyl, cyano, ester, amine, amide, Sulfonamide group or urea group;
  • R d5 and R d6 substituted or unsubstituted 4-20-membered heterocyclic group
  • R d3 and R d6 substituted or unsubstituted 5-20-membered heterocyclic group
  • R d7 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, halo 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 heterocyclyl, halogen, nitro, hydroxyl, cyano, ester, amine, amido, sulfonamide or ureido; or selected from Substituted or unsubstituted groups of the following groups: -(CH 2 ) m d1 R d9 -, -(CH 2 ) m c1 O(CH 2 )
  • n d1 or m d2 is selected from 0, 1, 2, 3, 4, 5, or 6;
  • m d3 is selected from 0, 1, or 2;
  • W d1 is selected from the group consisting of substituted or unsubstituted groups: C 6 -C 14 aryl, 5-20-membered heteroaryl;
  • R d8 is independently selected from the group consisting of substituted or unsubstituted groups: -(CH 2 ) m d1 R d9 -, -(CH 2 ) m d1 O(CH 2 ) m d2 R d9 -, -(CH 2 ) m d1 SR d9 -, -(CH 2 ) m d1 COR d9 -, -(CH 2 ) m d1 C(O)OR d9 -, -(CH 2 ) m d1 S(O) m d3 R d9 -, - (CH 2 ) m d1 NR d9 R d10 -, -(CH 2 ) m d1 C(O)NR d9 R d10 -, -(CH 2 ) m d1 NR d9 C(O)R d10 -, -(CH 2 ) m c
  • n d1 , m d1 , or m d2 is selected from 0, 1, 2, 3, 4, 5, or 6;
  • m d3 is selected from 0, 1, or 2;
  • 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.
  • the ILM is preferably selected from:
  • each group is independently defined as follows:
  • R d" is selected from hydrogen, halogen, cyano, C 1 -C 3 alkyl
  • a d1 or A d2 is independently selected from the group consisting of substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14 membered heteroaryl.
  • L is:
  • P O, C 1 -C 18 alkylene, C 3 -C 20 cycloalkylene, 4-20 membered heterocyclylene, C 6 -C 14 arylene, 5-20 membered heteroarylene, C 1 -C 18 alkylene C 3 -C 20 cycloalkylene, C 1 -C 18 alkylene 4-20 membered heterocyclic group, -(CH 2 ) m L1 O(CH 2 ) m L2 R L7 -, - (CH 2 ) m L1 SR L7 -, -(CH 2 ) m L1 COR L7 -, -(CH 2 ) m L1 C(O)OR L7 -, -(CH 2 ) m L1 S(O) m L3 R L7 -, -(CH 2 ) m L1 NR L7 R L8 -, -(CH 2 ) m L1 C(O)NR L7 R L8 -, -(CH
  • p L1 -p L6 are independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • n L1 or m L2 is independently selected from 0, 1, 2, 3, 4, 5, or 6;
  • n L3 is selected from 0, 1, or 2;
  • 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.
  • ULM is selected from the following group:
  • L is:
  • 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;
  • Each p L1 -p L6 is independently selected from 0, 1, 2, 3, 4, 5, or 6.
  • L can optionally be linked to the PTM or ULM through the R L1 terminal or the R L6 terminal.
  • L is a substituted or unsubstituted group selected from the following group:
  • CH 2 and CH can be independently optionally substituted; and 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, halo C 1 -C 18 alkyl, halo C 1 -C 18 alkyl hydroxyl, 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 heteroaryl Cyclic, halogen, oxo, nitro, hydroxyl, cyano, ester, amine, amide, sulfonamide, or ureido; NH can be independently optionally deuterium, C 1 -C 18 alkyl, Deuterated C
  • two adjacent groups in each R L1 -R L6 group may be independently connected to each other through C, N, O or S atoms, etc.
  • H in CH 2 , CH and NH may be independently optionally substituted; and the substitution refers to substitution 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 alkyl hydroxy, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy base, 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, amido, sulfonamide, or ureido; NH can be independently optionally deuterium, C 1 -C 18 alkyl, deuterated C 1 - C 18
  • PTM, L and ULM are each independently the corresponding part of the compound of the embodiment of the present invention.
  • the compound of the general formula (I) is selected from the compounds prepared in the embodiments of the present invention.
  • the compound of the general formula (I) structure is selected from the following group:
  • a SOS1 proteolysis regulator for preparing the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvents
  • the method of compound or prodrug is selected from following synthetic route:
  • LG 1 , LG 2 , LG 3 , or LG 4 are the same or different, and are leaving groups, each preferably selected from: hydrogen, OH, halogen, OTs, OMs, OTf, B(OH) 2 , etc.;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W, and n are as defined above;
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , Z', W', and n' are as defined above.
  • LG 1 , LG 2 , LG 3 , or LG 4 are the same or different, and are leaving groups, each preferably selected from: hydrogen, OH, halogen, OTs, OMs, OTf, B(OH) 2 , etc.;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W, and n are as defined above
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , Z', W', and n' are as defined above.
  • the third aspect of the present invention provides a pharmaceutical composition, comprising i) one or more compounds of the general formula (I) described in the first aspect of the present invention, its stereoisomers, tautomers, A crystalline form, pharmaceutically acceptable salt, 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 having the structure of general formula (I), its stereoisomers, tautomers, crystal forms and pharmaceutically acceptable salts according to the first aspect of the present invention , hydrate, solvate or prodrug, or use of the pharmaceutical composition according to the third aspect of the present invention, 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, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • the fifth aspect of the present invention provides a method for preventing and/or treating diseases related to the activity or expression of SOS1, comprising the steps of: administering an effective amount of the general formula as described in the first aspect of the present invention to an object in need (I) Compounds, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, or administer the pharmaceutical composition described in the third aspect of the present invention .
  • the subject is a mammal, such as a human, a rat or a mouse.
  • Figure 1 shows the detection of SOS1 and ⁇ -actin contents in H358 cells after treatment with different concentrations of compound Example 26 for 6 hours.
  • alkyl means by itself or as part of another substituent means a straight or branched chain alkane group having the indicated number of carbon atoms, which may contain from 1 to 20 carbon atoms, such as including 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, iso-heptyl 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl base, undecyl, dodecyl, etc.
  • 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 by itself or as part of another substituent refers to a group formed by removing one hydrogen atom from “alkyl”.
  • the alkylene may contain 1-18 carbon atoms, such as 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, including 1-4 rings, each containing 3-30 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 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 by itself or as part of another substituent refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group as described above, such as:
  • 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, which may include 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 ring atoms (including, but not limited to, such as 3-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic systems), at least one heteroatom is present in at least one carbon atom in the ring.
  • 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, such as 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.
  • arylene refers to a group formed by the removal of two hydrogen atoms from the above-mentioned aryl group.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 (eg, 2 or 3) heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and the heterocyclyl may include 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms.
  • 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.
  • 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.
  • heteroarylene refers to a group formed by the removal of two hydrogen atoms from a heteroaryl group as described above.
  • C1-C18 alkoxy refers to a straight or branched chain or cyclic alkyloxy group having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, iso Propoxy and butoxy, etc.
  • it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group or a C1-C4 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 ( 2 H).
  • 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.
  • esters 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.
  • 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.
  • 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. R and R' can be the same or different in the dialkylamine moiety.
  • sulfonamido refers to a group with the structure -SO2NRR ', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclo Alkenyl 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.
  • 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" can be the same or different in the dialkylamine moiety.
  • 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.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'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" can be the same or different in the dialkylamine moiety.
  • 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.
  • 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 substitution may be substituted with one or more substituents selected from the group consisting of, for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4-12 membered heterocyclyl, aryl, heteroaryl, C 1 -C 8 aldehyde group, C 2 -C 10 acyl group, C 2 -C 10 ester group, amine group, C 1 -C 6 alkoxy group, C 1 -C 10 sulfonyl group, and C 1 -C 6 urea group, etc.
  • substituents selected from the group consisting of, for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C 1 -C 6 alkyl, C 2 -C 6 alkenyl
  • 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 to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • module of SOS1 proteolysis and “protease degrader targeting SOS1” are used interchangeably to refer to a protease degrader targeting SOS1 (PROTAC), a compound that utilizes an intracellular "cleaner”— The ubiquitin-proteasome system to degrade SOS1 protein.
  • PROTAC protease degrader targeting SOS1
  • the SOS1 proteolytic modulator is a compound of formula I of the present invention.
  • Targeting ligands are small molecules capable of binding the target protein of interest.
  • the targeting ligand is formed by a small molecule compound targeting SOS1, preferably a PTM1 or PTM2 compound as described above.
  • the E3 ligase ligand moiety (ULM moiety) is used to bind the E3 ligase.
  • the present invention has no special requirements on the type of E3 ligase ligand, and the commonly used molecules or structural fragments of the present invention that can bind to E3 ligase can be used.
  • ULMs are formed by (but are not limited to) small molecule ligands that can bind to ligases selected from the group consisting of: VHL (Von Rippel-Lindau), CRBN (Cereblon), MDM2 (Mouse double-minute homolog2), IAP, Keap1, HSP70, FKBP, DCAF15, DCAF16, RNF4, RNF114 and AhR etc.
  • the ULM is formed from a small molecule ligand selected from the group consisting of VLM, CLM, MLM or ILM.
  • the linking group of the present invention is used to link the target molecule and the E3 ligase ligand.
  • the linking group of the present invention may further contain other various functional groups, such as -OH, -NHR, -SH and other functional groups.
  • the target molecule or E3 ligase ligand contains a functional group such as -OH, -SH, -NH 2 , -NHR, -SOOH or -COOH that can undergo a substitution reaction
  • a linker molecule containing the corresponding reactive functional group can be used. React with it (such as OH/SH/NH2 and -COOH/-COCl, etc.), so as to realize the connection with the target molecule and/or E3 ligase ligand.
  • Functional groups capable of the above-mentioned substitution reaction, and methods of introducing the above-mentioned functional groups on the molecule are known to those skilled in the art.
  • connection direction of the linking group L to the PTM and ULM moieties can be arbitrary, the L group can be connected to PTM on the left and ULM on the right, or the L group can be connected to PTM on the right and ULM on the left,
  • L is -C1 - C4alkyleneCO-
  • -C1 - C4alkyleneCO- and -CO- C1 - C4alkylene- are included.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates of compounds of formula I Substance or prodrug:
  • ULM represents the small molecule ligand moiety that can bind to E3 ligase
  • PTM represents the small molecule ligand part that can bind to SOS1;
  • L can be a bond or a linking group that can connect the PTM and the ULM.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process.
  • the compounds of the present invention may form salts, for example, compound I by reacting with an amount, e.g., an equivalent amount, 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 yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, isomers Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • a compound of formula (PTM1-IA--LG 3 ), (PTM1-IB-L-LG 3 ), or (PTM2-IL-LG 3 ) and formula (LG 4 -ULM) in a base such as DIPEA, TEA) , Py, or DMAP
  • condensing agents such as DCC, EDCI, PyBOP, HATU, or BOP
  • catalysts such as Pd(OAc) 2 , Pd2(dba) 3 , Pd(PPh 3 ) 4 , PdCl 2 (dppf ), CuI, Cu(OAc) 2 , etc.
  • LG 1 , LG 2 , LG 3 , or LG 4 are the same or different, are leaving groups, each independently selected from: hydrogen, OH, halogen, OTs, OMs, OTf, or B(OH) 2 , etc.;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W, and n are as described in claim 3
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , Z', W' and n' are as described in claim 9 .
  • the leaving groups of the two molecules can form at least one small molecule (eg, H 2 O, HCl, TsOH, MsOH). , TfOH, etc.).
  • LG 1 , LG 2 , LG 3 , or LG 4 are the same or different, are leaving groups, each independently selected from: hydrogen, OH, halogen, OTs, OMs, OTf, or B(OH) 2 , etc.;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, W, and n are as defined in claim 3
  • R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , Z', W', and n' are as defined in claim 9 .
  • compositions Use and methods of administration
  • the pharmaceutical composition of the present invention includes the above-mentioned active ingredients and a pharmaceutically acceptable carrier.
  • the compounds of the present invention can reduce the activity and expression level of SOS1, promote the degradation of SOS1 protein and/or reduce the level of SOS1, so as to prevent and/or treat diseases related to the activity or expression level of SOS1.
  • the pharmaceutical composition of the present invention can be used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the cancer is cancer caused by KRAS mutation.
  • the cancer includes (but is not limited to): lung cancer (small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), breast cancer, prostate cancer, esophagus cancer, colorectal cancer, bone cancer Cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • breast cancer breast cancer
  • prostate cancer esophagus cancer
  • colorectal cancer bone cancer Cancer
  • kidney cancer kidney cancer
  • stomach cancer liver cancer
  • colorectal cancer melanoma
  • lymphoma blood cancer
  • brain tumor myeloma
  • soft tissue sarcoma pancreatic cancer
  • pancreatic cancer skin cancer.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel 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 administration .
  • 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 such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting SOS1.
  • the present invention has the following main advantages:
  • the compound can selectively promote the proteolysis of SOS1, thereby preventing and/or treating diseases related to the activity or expression of SOS1 (especially high selectivity for tumor cells), with high activity and good safety;
  • the compound of the present invention can exhibit the effect of inhibiting cell proliferation in a catalytic amount. It can degrade the target protein in the cell cycle, reduce the dosage, prolong the period of administration, and achieve a safe and effective anti-tumor effect;
  • the compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and/or 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.
  • Step 2 (R)-N-(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((1- Preparation of ((methylamino)methyl)cyclopropyl)methoxy)quinazolin-4-amine
  • Step 3 N-(2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-2-(((1-(((( 4-(((R)-1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl) Preparation of oxy)methyl)cyclopropyl)methyl)(methyl)amino)acetamide
  • Example 9 4-((2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1-( ((4-(((R)-1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)oxy)methyl)cyclopropyl)methyl)-N-methylbutanamide formate
  • Example 10 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-((1-( ((4-(((R)-1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazoline-6 -yl)oxy)methyl)cyclopropyl)methyl)-N-methylheptamide formate
  • Example 12 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)ethyl)cyclopropane-1-carboxamide
  • the third step (R)-1-(((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl Preparation of quinazolin-6-yl)oxy)methyl)cyclopropane-1-carboxylic acid
  • the fourth step 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole- Preparation of 4-yl)amino)ethyl)cyclopropane-1-carboxamide
  • Example 13 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)propyl)cyclopropane-1-carboxamide
  • Example 14 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)butyl)cyclopropane-1-carboxamidecarboxylate
  • Example 15 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)pentyl)cyclopropane-1-carboxamide
  • Example 16 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)hexyl)cyclopropane-1-carboxamidecarboxylate
  • Example 17 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)heptyl)cyclopropane-1-carboxamidecarboxylate
  • Example 18 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)octyl)cyclopropane-1-carboxamidecarboxylate
  • reaction solution was stirred at room temperature for 16 hours, and then water and ethyl acetate were added for layer extraction.
  • the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (1.2 g).
  • the third step N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy -2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1, Preparation of 3-Dioxisoindol-4-yl)amino)-N-methylpropionamide formate
  • Example 51 4-(4-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidin-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) ) isoindole-1,3-dione
  • Example 52 4-(4-(((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl)isoindole-1,3-dione
  • Example 54 1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl) ring Propane-1-carboxamide
  • Example 58 4-(4-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7 -Methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) ) isoindole-1,3-dione
  • Example 59 4-(4-(2-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino )-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidin-1-yl)-2-oxoethyl)piperidin-1-yl)-2-(2, 6-Dioxypiperidin-3-yl)isoindole-1,3-dione
  • Example 60 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-1-(1-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxisoindol-4-yl)azetidine-3-yl)-N-methylpiperidine-4-carboxamide
  • Example 61 4-((2-(5-(1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropane-1-carbonyl)hexahydropyrrolyl[3,4-c]pyrrol-2(1H)-yl )-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • Example 62 4-((2-(2-(1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropane-1-carbonyl)-2,7-diaminospiro[3.5]nonan-7-yl) -2-Oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • Example 63 4-((2-(2-(1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropane-1-carbonyl)-2,8-diaminospiro[4.5]decan-8-yl) -2-Oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • Example 64 4-(5-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2- Methylquinazolin-6-yl)oxy)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • Example 65 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-N-methyl-7-((2-(1-methyl-2,6-dioxopiper) pyridin-3-yl)-1,3-dioxoisoindol-4-yl)amino)heptamide
  • Example 69 (3-(4-((7-(((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) Amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)(methyl)amino)-7-oxoheptyl)amino) -1,3-Dioxyisoindol-2-yl)-2,6-dioxopiperidin-1-yl)methyl pivalate
  • Example 70 (1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl quinazolin-6-yl)oxy)methyl)cyclopropyl)methyl 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indol-4-yl)amino)heptanoate
  • Example 72 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-1'-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxisoindol-4-yl)-N-methyl-[1,4'-bipiperidine]-4-carboxamide
  • Example 76 cis-N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxisoindol-4-yl)piperazin-1-yl)-N-methylcyclohexane-1-carboxamide and trans-N-((1-((((4- (((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy )methyl)cyclopropyl)methyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1
  • Example 80 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-2-(5-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxisoindol-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methylacetamide
  • Example 84 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxisoindol-5-yl)amino)-N-methylheptamide
  • Example 96 cis-N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-1-(4-((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindol-4-yl)amino)cyclohexyl)-N-methylpiperidine-4-carboxamide and trans-N-((1-((((4-( ((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy) Methyl)cyclopropyl)methyl)-1-(4-((2-(2,6-dioxopiperidin-3
  • Example 100 4-((6-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 7-Methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidine-3 -yl)isoindole-1,3-dione
  • Example 101 4-((2-(2-(3-((S)-3-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)) ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)pyrrolidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino )-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
  • Example 102 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-2-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxisoindol-4-yl)amino)butoxy)-N,2-dimethylpropionamide
  • Example 104 N1-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-N4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxisoindol-4-yl)amino)cyclohexyl)-N1,N4-dimethylsuccinamide
  • Example 105 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-4-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxisoindol-4-yl)amino)ethoxy)-N-methylbutanamide
  • Example 106 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxisoindol-5-yl)piperazin-1-yl)-N-methylbutanamide
  • Example 109 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxisoindol-5-yl)piperidin-4-yl)piperazin-1-yl)-N-methylacetamide
  • Example 110 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-1-(1-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxisoindol-5-yl)piperidine-4-carbonyl)-N-methylpiperidine-4-carboxamide
  • Example 111 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxisoindol-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-N-methylacetamide
  • Example 112 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-2-(4-(((2-(2,6-dioxopiperidin-3-yl) -1,3-Dioxisoindol-5-yl)amino)methyl)piperidin-1-yl)-N-methylacetamide
  • Example 115 cis-N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxisoindol-5-yl)piperazin-1-yl)-N-methylcyclohexane-1-carboxamide and trans-N-((1-((((4 -(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy (yl)methyl)cyclopropyl)methyl)-4-(4-(2-(2,6-dioxopiperidin-3-y
  • Example 117 cis-N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methyl Oxy-2-methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-4-((4-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindol-4-yl)amino)cyclohexyl)(methyl)amino)-N-methylbutanamide and trans-N-((1-((((4 -(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy yl)methyl)cyclopropyl)methyl)-4-((4-((2-(2,6-dio
  • Example 120 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxisoindol-5-yl)azetidine-3-yl)piperazin-1-yl)-N-methylacetamide
  • Example 126 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-4-((1-(2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxisoindol-5-yl)piperidin-4-yl)oxy)-N-methylcyclohexyl-1-carboxamide
  • Example 135 N-((1-(((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy- 2-Methylquinazolin-6-yl)oxy)methyl)cyclopropyl)methyl)-1-((1s,3s)-3-((2-(2,6-dioxopiperidine) -3-yl)-1,3-dioxisoindol-4-yl)amino)cyclobutyl)-N-methylpiperidine-4-carboxamide and N-((1-((((4- (((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy )methyl)cyclopropyl)methyl)-1-((1r,3r)-3-((2-(2,6-d
  • Step 2 (R)-(3-(1-((7-Hydroxy-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl)amino)ethyl) -Benzyl 5-(trifluoromethyl)phenyl)carbamate
  • Example 137 According to the same synthetic method of Example 137, the following compounds were synthesized with different starting materials.
  • the first step (3-((1R)-1-((7-((1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo isoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-6-(2-methoxyethoxy)-2-methylquinazoline- 4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate benzyl ester
  • Step 2 5-(4-((4-((4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-( 2-Methoxyethoxy)-2-methylquinazolin-7-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6- Dioxypiperidin-3-yl)isoindole-1,3-dione
  • Example 139 According to the same synthetic method of Example 139, the following compounds were synthesized with different starting materials:
  • Step 2 (R)-(3-(1-((7-([1,4'-bipiperidin]-4-yloxy)-6-(2-methoxyethoxy)- Benzyl 2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate
  • the third step (3-((1R)-1-((7-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -5-yl)-[1,4'-bipiperidin]-4-yl)oxy)-6-(2-methoxyethoxy)-2-methylquinazolin-4-yl) Amino)ethyl)-5-(trifluoromethyl)phenyl)carbamic acid benzyl ester
  • the fourth step 5-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxy (ylethoxy)-2-methylquinazolin-7-yl)oxy)-[1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidine -3-yl)isoindole-1,3-dione
  • Example 141 According to the same synthetic method of Example 141, the following compounds were synthesized with different starting materials:
  • Example 142 5-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-( ((S)-Tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)oxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indole-1,3-dione
  • Table 1 shows the inhibitory activity of the example compounds of the present invention on the binding of KRAS G12C enzyme and SOS1.
  • Example 1 IC50 ( ⁇ M) Example 1 2.6 Example 2 0.391 Example 7 0.681 Example 8 0.18 Example 9 0.1 Example 10 1.0 Example 11 0.141 Example 12 0.073 Example 13 0.183 Example 14 0.176 Example 15 0.452 Example 16 0.515 Example 17 0.813 Example 18 3.0 Example 19 0.266 Example 20 0.335 Example 21 0.036 Example 22 0.149 Example 23 0.253 Example 24 0.145 Example 25 0.164 Example 26 0.455 Example 27 4.56 Example 28 0.109 Example 29 0.104 Example 30 0.04 Example 31 0.02 Example 32 / Example 33 0.044 Example 34 0.026 Example 35 0.067 Example 36 0.063 Example 37 0.012 Example 38 0.015 Example 39 0.019 Example 40 0.005 Example 41 0.028 Example 42 0.019
  • the diluted compounds to be tested were added to a 384-well cell culture plate, and duplicate wells were set up.
  • the positive control group was added with an equal volume of culture medium; the negative control group was added with an equal volume of DMSO, and centrifuged at 1000 rpm for 1 min at room temperature.
  • the cells were inoculated into a) 384 culture plates, the negative control group was added with the same volume of cells, and the positive control group was only added with the same volume of medium. Centrifuge at 1000 rpm for 1 min at room temperature, the final concentration of DMSO of the final compound is 0.5%, and it is placed in a 37°C, 5% CO2 constant temperature incubator for 7 days.
  • the luminescence value was read with an Envision multi-plate reader.
  • IR(%) (1 ⁇ (RLU compound ⁇ RLU blank control)/(RLU vehicle control ⁇ RLU blank control))*100%.
  • the inhibition rates of different concentrations of compounds were calculated in Excel, and then the GraphPad Prism software was used to plot the inhibition curves and calculate the relevant parameters, including the minimum inhibition rate, the maximum inhibition rate and IC 50 .
  • the experimental results are shown in Table 3.
  • Example 9 1.23
  • Example 10 0.11
  • Example 11 1.21
  • Example 12 1.76
  • Example 21 1.97
  • Example 22 2.89
  • Example 24 0.086
  • Example 25 0.33
  • Example 26 0.005
  • Example 28 1.38
  • Example 29 1.66
  • Example 30 0.42
  • Example 31 1.69
  • Example 32 2.45
  • Example 33 0.255
  • Example 38 0.457
  • Example 39 0.373
  • Example 40 / Example 41 1.072
  • Example 42 1.028
  • Example 48 0.422
  • Example 49 0.373 Example 50 1.650 Example 51 0.361 Example 52 0.362 Example 53 0.149 Example 54 0.798 Example 55 0.794 Example 56 0.349 Example 57 1.220 Example 58 0.227 Example 59 0.147 Example 60 0.286 Example 61 / Example 62 0.514 Example 63 2.891 Example 64 2.324 Example 65 1.375 Example 66 0.216 Example 67 0.016 Example 68 0.357 Example 69 0.018 Example 70 0.032 Example 71 2.048 Example 72 1.178 Example 73 0.709 Example 74 0.219 Example 75 0.047 Example 76 Isomer 1 0.434 Example 76 Isomer 2 1.031 Example 77 1.034 Example 78 0.844 Example 79 0.443 Example 80 0.602 Example 81 0.859 Example 82 0.114 Example 83 0.075 Example 84 0.799 Example 85 0.859 Example 86 0.114 Example 87 0.075 Example 88 0.026 Example 89 0.920 Example 90 0.196 Example 91 0.591 Example 92 1.137 Example 93 0.318
  • Inoculate tumor cells such as H358, 5X105 ⁇ 1X06
  • culture them in a petri dish (2D, P100mm dish) for 2-4 days to 70-80% saturation;
  • the cells were cultured for 1-24 hours, and the time curve (1, 2, 4, 6, 8, 24) at the same concentration (0.1 or 1uM) or the dose curve (0.0001, 0.001, 0.01, 0.1, 1, 10uM).
  • Example 26 (Fig. 1), has the effect of targeting and degrading the SOS1 protein.

Abstract

本发明涉及SOS1蛋白水解调节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蛋白水解调节剂的用途，本发明化合物对SOS1水解具有很好的选择性调节作用。

Description

SOS1蛋白水解调节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SOS1蛋白水解调节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。
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)。
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％vs11％)，在吸烟者(vs非吸烟者)中更高(30％vs10％)。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SOS1GEF活性在KRAS突变癌细胞中的重要作用。
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。
蛋白水解在细胞的正常生命活动中是至关重要且被严格调控的，其过程主要是通过泛素化酶***的参与而完成的。待分解的蛋白质通过E1、E2和E3泛素连接酶***标记，进而被蛋白酶识别并水解。蛋白水解调节剂类分子是一种双功能活性化合物，分子的一端与靶蛋白紧密结合，另一端与E3泛素连接酶相结合，两端并通过各种连接链连接。这种双功能分子在体内可以同时识别靶蛋白和E3泛素连接酶，将靶蛋白和E3泛素连接酶拉近后使靶蛋白被泛素化，然后通过泛素-蛋白酶体途径水解。靶蛋白水解后，这个双功能性分子又可以被释放出来参与到下一周期的蛋白水解过程，从而具有催化效果，因此在临床上可以通过较少的药物给药剂量就可以实现高效的治疗作用。
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蛋白水解调节剂可以对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SOS1蛋白水解调节剂及其制备方法和应用。
本发明第一方面，提供了一种具有通式(I)结构的化合物、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：
Figure PCTCN2022080000-appb-000001
式中：
ULM代表一个可以和E3连接酶结合的小分子配体部分；
PTM代表一个可以和SOS1结合的小分子配体部分；
L可以是键或者是可以连接PTM和ULM的连接基团。
在另一优选例中，PTM选自PTM1或PTM2。
在另一优选例中，PTM1优选自：
Figure PCTCN2022080000-appb-000002
式中：
虚线表示与L连接；
在式PTM1-IA和PTM1-IB中，各取代基独立地如下定义：
X选自下组：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：键、O、NH、CR 7、C＝CR 7、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：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 1-C 18亚烷基、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：键、氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mO(CH 2) pOR 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) mO(CH 2) pR 8-(CH 2) mNR 9R 10、-(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：键、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，PTM1选自下组：
Figure PCTCN2022080000-appb-000003
式中：虚线、R 1、R 2、R 3、R 4、X、Y、Z、W、和n的定义如上所述。
在另一优选例中，PTM1选自下组：
Figure PCTCN2022080000-appb-000004
式中：
虚线、R 1、R 2、R 3、R 6、Y、Z、W、和n的定义如上所述。
在另一优选例中，PTM1选自下组：
Figure PCTCN2022080000-appb-000005
式中，各取代基独立地如下定义：
R 13和R 14各自独立地选自取代或未取代的下组基团：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；
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；
虚线、R 1、R 2、R 3、R 6、Y和n的定义如上所述。
在另一优选例中，PTM1-IVA和PTM1-IVB通过C环或者通过R2和L连接，如：
Figure PCTCN2022080000-appb-000006
Figure PCTCN2022080000-appb-000007
在另一优选例中，PTM1优选自：
Figure PCTCN2022080000-appb-000008
式中，各取代基独立地如下定义：
R 16和R 17各自独立地选自取代或未取代的下组基团：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独立地选自取代或未取代的下组基团：C 1-C 18亚烷基、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、或4-12元亚杂环基C 1-C 6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；
t为1、2、3、4、5或6；
虚线、R 1、R 2、R 3、Y和R 6的定义如上所述。
在另一优选例中，
Figure PCTCN2022080000-appb-000009
Figure PCTCN2022080000-appb-000010
Figure PCTCN2022080000-appb-000011
Figure PCTCN2022080000-appb-000012
Figure PCTCN2022080000-appb-000013
Figure PCTCN2022080000-appb-000014
Figure PCTCN2022080000-appb-000015
Figure PCTCN2022080000-appb-000016
Figure PCTCN2022080000-appb-000017
Figure PCTCN2022080000-appb-000018
Figure PCTCN2022080000-appb-000019
Figure PCTCN2022080000-appb-000020
Figure PCTCN2022080000-appb-000021
Figure PCTCN2022080000-appb-000022
Figure PCTCN2022080000-appb-000023
Figure PCTCN2022080000-appb-000024
Figure PCTCN2022080000-appb-000025
Figure PCTCN2022080000-appb-000026
Figure PCTCN2022080000-appb-000027
Figure PCTCN2022080000-appb-000028
Figure PCTCN2022080000-appb-000029
Figure PCTCN2022080000-appb-000030
在另一优选例中，PTM2为：
Figure PCTCN2022080000-appb-000031
式中：
虚线表示与L的连接；
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’选自取代的下组基团：键、C 3-C 20亚环烷基、4-20元亚杂环基；
R 1’取代或未取代的下组基团：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；
R 2’相同或不同，各自独立地选自下组：-(CH 2) pR 7’、-(CH 2) mO(CH 2) pR 7’、-(CH 2) mSR 7’、-(CH 2) mCOR 7’、-(CH 2) mC(O)OR 7’、-(CH 2) mS(O) qR 7’、-(CH 2) mNR 7’R 8’、-(CH 2) mC(O)NR 7’R 8’、-(CH 2) mNR 7’C(O)R 8’、-(CH 2) mNR 7’C(O)NR 8’R 9’、-(CH 2) mS(O) qNR 7’R 8’、-(CH 2) mNR 7’S(O) qR 8’、-(CH 2) mNR 7’S(O) qNR 8’R 9’，其中，CH 2中的H可以任选地被取代；R 7’、R 8’和R 9’各自独立地选自下组：氢、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环基和取代或未取代C 1-C 18烷氧基；或者在-(CH 2) mNR 7’R 8’、-(CH 2) mC(O)NR 7’R 8’、-(CH 2) mS(O) qNR 7’R 8’中，R 7’和R 8’与其相连的N原子环合形成取代或未取代4-20元杂环基；或者在-(CH 2) mNR 7’C(O)R 8’、-(CH 2) mNR 7’C(O)NR 8’R 9’、-(CH 2) mNR 7’S(O) qR 8’、-(CH 2) mNR 7’S(O) qNR 8’R 9’中，R 8’和R 9’与其相连的N原子环合形成取代或未取代4-20元杂环基，或者R 7’和R 8’与其相邻的原子环合形成取代或未取代的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；
R 6’选自：氢、氘、卤素、氨基、氰基、取代或未取代的C 1-C 6烷基和取代或未取代的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基团取代：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’为1、2、3、4或5；
n’为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，PTM2为：
Figure PCTCN2022080000-appb-000032
式中：虚线、R 1’、R 2’、R 3’、R 4’、R 5’、Z’、W’和n’的定义如上所述。
在另一优选例中，PTM2为：
Figure PCTCN2022080000-appb-000033
式中：虚线、R 1’、R 2’、R 3’、R 4’、Z’、W’和n’的定义如上所述。
在另一优选例中，PTM2为：
Figure PCTCN2022080000-appb-000034
式中，
R 13’和R 14’各自独立地选自取代或未取代的下组基团：H、氘、C 1-C 6烷基、氘代C 1-C 6烷基、或卤代C 1-C 6烷基；或者R 13’和R 14’和相邻的C一起环合形成C 3-C 6的环烷基或4-6元杂环基；
环W’选自取代的下组基团：C 3-C 12亚环烷基、4-12元亚杂环基；
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 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；
虚线、R 1’、R 2’、R 3’和n’的定义如上所述。
在另一优选例中，PTM2选自下组：
Figure PCTCN2022080000-appb-000035
Figure PCTCN2022080000-appb-000036
Figure PCTCN2022080000-appb-000037
Figure PCTCN2022080000-appb-000038
Figure PCTCN2022080000-appb-000039
在另一优选例中，ULM为可以和选自下组的连接酶结合的小分子配体部分：VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、IAP、Keap1、HSP70、FKBP、DCAF15、DCAF16、RNF4、RNF114和AhR等。
在另一优选例中，ULM优选自可以和VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、或IAP等连接酶结合的小分子VLM、CLM、MLM或ILM配体部分。
在另一优选例中，ULM选自可以和VHL(Von Rippel-Lindau)、CRBN(Cereblon)等连接酶结合的小分子VLM、或CLM配体部分,更优选地为和CRBN(Cereblon)连接酶结合的小分子CLM配体部分。
在另一优选例中，上述式I化合物选自下组：PTM-VLM、PTM-CLM、PTM-MLM、PTM-ILM；PTM-L-VLM、PTM-L-CLM、PTM-L-MLM或PTM-L-ILM。
在另一优选例中，VLM为：
Figure PCTCN2022080000-appb-000040
式中，
虚线表示与L的连接；
X a1,X a2独立地选自下组：键、O、NR a2、CR a3R a4、C＝O、C＝S、SO、或SO 2；其中R a2、R a3、R a4独立地选自取代或未取代的下组基团：C 1-C 18烷基、C 3-C 12环烷基、4-12元杂环基；
R a1相同或者不同，独立地选自卤素、羟基、C 1-C 3烷基、或者(＝O)；或者不同R a1之间环合形成3-4元环；
n a1选自：0、1、2、3、或4；
W a1和W a2选自取代或未取代的下组基团：-X a3-X a4-；其中X a3、X a4独立地选自取代或未取代的下组基团：-(CH 2) m a1R a5-、-(CH 2) m a1O(CH 2) m a2R a5-、-(CH 2) m a1SR a5-、-(CH 2) m a1COR a5-、-(CH 2) m a1C(O)OR a5-、-(CH 2) m a1S(O) m a3R a5-、-(CH 2) m a1NR a5R a6-、-(CH 2) m a1C(O)NR a5R a6-、-(CH 2) m a1NR a5C(O)R a6-、-(CH 2) m a1NR a5C(O)NR a6R a7-、-(CH 2) m a1S(O) m a3NR a5R a6-、-(CH 2) m a1NR a5S(O) m a3R a6-、-(CH 2) m a1NR a5S(O) m a3NR a6R a7-，其中，CH 2中的H可以任选地被取代；R a5、R a6、R a7独立地选自取代或未取代的下组基团：键、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、5-20元杂芳基；
m a1、 m a2独立地选自0、1、2、3、4、5、或6；
m a3独立地选自0、1、或2；
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，VLM为：
Figure PCTCN2022080000-appb-000041
R a8、R a9、R a10独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 18烷基 或亚烷基、C 3-C 12环烷基或亚环烷基、4-12元杂环基或亚杂环基、C 6-C 14芳基或亚芳基、5-20元杂芳基或亚杂芳基、-NR a13R a14-；其中R a13、R a14独立地选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基；
R a11独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基；
R a12独立地选自取代或未取代的下组基团：C 6-C 14芳基、或5-20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：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。
虚线如上定义。
在另一优选例中，CLM选自下组：
Figure PCTCN2022080000-appb-000042
各式中，各基团独立地如下定义：
虚线表示与L的连接；
W b1相同或不同，独立地选自C＝O、SO 2、CR b3R b4、NR b5；其中R b3、R b4独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基；R b5选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基、C 6-C 14芳基、5-14元杂芳基；
X b1、X b2、X b3相同或不同，独立地选自CH2、O或S；
Z b1、Z b2相同或不同，独立地选自CH2、O或S；
Y b1选自CH2、O、S或NR b6；R b6选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基、C 6-C 14芳基、5-14元杂芳基；
G b1、G b2相同或不同，独立地选自取代或未取代的下组基团：氢、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基、C 6-C 14芳基、5-14元杂芳基；
A b1、A b2相同或不同，独立地选自取代或未取代的下组基团：氢、卤素、氰基、C 1-C 6烷基、C 3-C 6环烷基、或4-6元杂环基、C 6-C 14芳基、5-14元杂芳基；
R b1、R b2、R b3相同或不同，独立地选自取代或未取代的下组基团：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；
n b1、n b2相同或不同，独立地选自：0、1、2、3、或4；
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，VLM优选自：
Figure PCTCN2022080000-appb-000043
虚线、W b1、R b1、R b2、R b3、A b1、A b2、G b2、Y b1、n b1、n b2如上所述。
在另一优选例中，VLM选自下组：
Figure PCTCN2022080000-appb-000044
虚线、R b1、R b2、R b3、n b1、n b2如上所述。
在另一优选例中，MLM优选自下组：
Figure PCTCN2022080000-appb-000045
Figure PCTCN2022080000-appb-000046
各式中，各基团独立地如下定义：
虚线表示与L的连接；
X c1选自下组：O、S、SO、SO2、CR c29R c30、NR c31，其中R c29、R c30相同或不同，且独立地选自取代或未取代的下组基团：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，或者R c29和R c30环合形成3-6元杂环基；R c31选自取代或未取代的下组基团：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；
Y c1和Z c1独立地选自N或R C32，其中R c32自取代或未取代的下组基团：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；
A c1、A c2或A c3独立地选自N、O、S或CR c33，或者A c1、A c2或A c3其中两个环合形成C 3-C 8环烷基、4-8元杂环基、C 6-C 14芳基、5-14元杂芳基；R c33取代或未取代的下组基团：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；
Figure PCTCN2022080000-appb-000047
代表单键或者双键；
R c”选自取代或未取代的下组基团：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；
R c1-R c28相同或不同，独立地选自取代或未取代的下组基团：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；或者独立地选自取代或未取代的下组基团：-(CH 2) m c1R c34-、-(CH 2) m c1O(CH 2) m c2R c34-、-(CH 2) m c1SR c34-、-(CH 2) m c1COR c34-、-(CH 2) m c1C(O)OR c34-、-(CH 2) m c1S(O) m c3R c34-、-(CH 2) m c1NR c34R c35-、-(CH 2) m c1C(O)NR c34R c35-、-(CH 2) m c1NR c34C(O)R c35-、-(CH 2) m c1NR c34C(O)NR c35R c36-、-(CH 2) m c1S(O) m c3NR c34R c35-、-(CH 2) m c1NR c34S(O) m c3R c35-、-(CH 2) m c1NR c34S(O) m c3NR c35R c36-，其中，CH 2中的H可以任选地被取代；R c34、R c35、R c36独立地选自取代或未取代的下组基团：键、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、5-20元杂芳基；或者R c34、R c35、R c36其中任意两者环合形成取代或未取代的4-20元杂环基、或5-20元杂芳基；
m c1、m c2独立地选自0、1、2、3、4、5、或6；
m c3独立地选自0、1、或2；
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，MLM为：
Figure PCTCN2022080000-appb-000048
其中：
R c37、R c38相同或不同，且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、5-20元杂芳基；或者R c37、R c38环合形成取代或未取代的4-20元杂环基、或5-20元杂芳基；
R c39、R c40独立地选自取代或未取代的下组基团：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 c4、m c5独立地选自0、1、2、3、4、5、或6；
虚线、R c”和R c14如权利要求20所述；
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，MLM选自下组：
Figure PCTCN2022080000-appb-000049
在另一优选例中，ILM选自下组：
Figure PCTCN2022080000-appb-000050
各式中，各基团独立地如下定义：
虚线表示与L连接；
R d1-R d6相同或不同，且独立地选自取代或未取代的下组基团：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；
或者R d5和R d6取代或未取代的4-20元杂环基；
或者R d3和R d6取代或未取代的5-20元杂环基；
R d7选自取代或未取代的下组基团：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；或者选自取代或未取代的下组基团：-(CH 2) m d1R d9-、-(CH 2) m c1O(CH 2) m d2R d9-、-(CH 2) m d1SR d9-、-(CH 2) m d1COR d9-、-(CH 2) m d1C(O)OR d9-、-(CH 2) m d1S(O) m d3R d9-、-(CH 2) m d1NR d9R d10-、-(CH 2) m d1C(O)NR d9R d10-、-(CH 2) m d1NR d9C(O)R d10-、-(CH 2) m c1NR d9C(O)NR d10R d11-、-(CH 2) m d1S(O) m d3NR d9R d10-、-(CH 2) m d1NR d9S(O) m d3R d10-、-(CH 2) m d1NR d9S(O) m d3NR d10R d11-，其中，CH 2中的H可以任选地被取代；R d9、R d10、R d11独立地选自取代或未取代的下组基团：键、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、5-20元杂芳基；或者R d9、R d10、R d11其中两者环合形成取代或未取代的4-20元杂环基、或5-20元杂芳基；
m d1或m d2选自0、1、2、3、4、5、或6；
m d3选自0、1、或2；
W d1选自取代或未取代的下组基团：C 6-C 14芳基、5-20元杂芳基；
R d8独立地选自取代或未取代的下组基团：-(CH 2) m d1R d9-、-(CH 2) m d1O(CH 2) m d2R d9-、-(CH 2) m d1SR d9-、-(CH 2) m d1COR d9-、-(CH 2) m d1C(O)OR d9-、-(CH 2) m d1S(O) m d3R d9-、-(CH 2) m d1NR d9R d10-、-(CH 2) m d1C(O)NR d9R d10-、-(CH 2) m d1NR d9C(O)R d10-、-(CH 2) m c1NR d9C(O)NR d10R d11-、-(CH 2) m d1S(O) m d3NR d9R d10-、-(CH 2) m d1NR d9S(O) m d3R d10-、-(CH 2) m d1NR d9S(O) m d3NR d10R d11-，其中，CH 2中的H可以任选地被取代；R d9、R d10、R d11独立地选自取代或未取代的下组基团：键、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、5-20元杂芳基；或者R d9、R d10、R d11其中两者环合形成取代或未取代的4-20元杂环基、或5-20元杂芳基；
n d1、m d1、或m d2选自0、1、2、3、4、5、或6；
m d3选自0、1、或2；
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，ILM优选自：
Figure PCTCN2022080000-appb-000051
各式中，各基团独立地如下定义：
R d”选自氢、卤素、氰基、C 1-C 3烷基；
A d1或A d2独立地选自取代或未取代的下组基团：C 6-C 14芳基、5-14元杂芳基。
虚线定义如上所述。
在另一优选例中，L为：
Figure PCTCN2022080000-appb-000052
其中，R L1-R L6相同或不同，且独立地选自取代或未取代的下组基团：键、CH 2、C＝O、C＝C、C≡C、O、NH、SO、SO 2、P＝O、
Figure PCTCN2022080000-appb-000053
C 1-C 18亚烷基、C 3-C 20亚环烷基、4-20元亚杂环基、C 6-C 14亚芳基、5-20元亚杂芳基、C 1-C 18亚烷基C 3-C 20亚环烷基、C 1-C 18亚烷基4-20元亚杂环基、-(CH 2) m L1O(CH 2) m L2R L7-、-(CH 2) m L1SR L7-、-(CH 2) m L1COR L7-、-(CH 2) m L1C(O)OR L7-、-(CH 2) m L1S(O) m L3R L7-、-(CH 2) m L1NR L7R L8-、-(CH 2) m L1C(O)NR L7R L8-、-(CH 2) m d1NR L7C(O)R L8-、-(CH 2) m L1NR L7C(O)NR L8R L9-、-(CH 2) m d1S(O) m L3NR L7R L8-、-(CH 2) m L1NR L7S(O) m L3R L8-、-(CH 2) m L1NR L7S(O) m L3NR L8R L9-，其中，CH 2中的H可以任选地被取代；R L7、R L8、R L9独立地选自取代或未取代的下组基团：键、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、5-20元杂芳基；
p L1-p L6独立地选自0、1、2、3、4、5、或6；
m L1或m L2独立地选自0、1、2、3、4、5、或6；
m L3选自0、1、或2；
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，ULM选自下组:
Figure PCTCN2022080000-appb-000054
Figure PCTCN2022080000-appb-000055
Figure PCTCN2022080000-appb-000056
在另一优选例中，L为：
Figure PCTCN2022080000-appb-000057
其中，R L1-R L6相同或不同，且独立地优选自取代或未取代的下组基团：键、CH 2、C＝O、O、NH、SO、SO 2、P＝O、NHCO、NHSO 2、OCH 2、OCH 2CH 2、CH 2OCH 2、NHCH 2、NMeCH 2、NHCH 2CH 2、NMeCH 2CH 2、CH 2NHCO、NHCOCH 2、
Figure PCTCN2022080000-appb-000058
Figure PCTCN2022080000-appb-000059
Figure PCTCN2022080000-appb-000060
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；
各p L1-p L6独立地选自0、1、2、3、4、5、或6。
L可以任选地通过R L1端或R L6端和PTM或ULM相连接。
在另一优选例中，L为取代或未取代的选自下组的基团：
Figure PCTCN2022080000-appb-000061
Figure PCTCN2022080000-appb-000062
Figure PCTCN2022080000-appb-000063
Figure PCTCN2022080000-appb-000064
Figure PCTCN2022080000-appb-000065
Figure PCTCN2022080000-appb-000066
Figure PCTCN2022080000-appb-000067
Figure PCTCN2022080000-appb-000068
Figure PCTCN2022080000-appb-000069
Figure PCTCN2022080000-appb-000070
Figure PCTCN2022080000-appb-000071
Figure PCTCN2022080000-appb-000072
Figure PCTCN2022080000-appb-000073
Figure PCTCN2022080000-appb-000074
Figure PCTCN2022080000-appb-000075
Figure PCTCN2022080000-appb-000076
Figure PCTCN2022080000-appb-000077
Figure PCTCN2022080000-appb-000078
Figure PCTCN2022080000-appb-000079
Figure PCTCN2022080000-appb-000080
Figure PCTCN2022080000-appb-000081
Figure PCTCN2022080000-appb-000082
Figure PCTCN2022080000-appb-000083
Figure PCTCN2022080000-appb-000084
Figure PCTCN2022080000-appb-000085
Figure PCTCN2022080000-appb-000086
Figure PCTCN2022080000-appb-000087
Figure PCTCN2022080000-appb-000088
Figure PCTCN2022080000-appb-000089
Figure PCTCN2022080000-appb-000090
Figure PCTCN2022080000-appb-000091
Figure PCTCN2022080000-appb-000092
Figure PCTCN2022080000-appb-000093
Figure PCTCN2022080000-appb-000094
另一优选例中，对于式L，各式中，CH 2、CH可以独立任选地被取代；且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；NH可以独立任选地被氘、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烷基酰基、磺酰基取代；p L1-p L6如上所述。
例如：
Figure PCTCN2022080000-appb-000095
可以选自
Figure PCTCN2022080000-appb-000096
在另一优选例中，L中，各R L1-R L6基团中相邻的两个基团，可各自独立地通过C、N、O或S原子等彼此连接。
例如：
Figure PCTCN2022080000-appb-000097
可以选自
Figure PCTCN2022080000-appb-000098
在另一优选例中，
Figure PCTCN2022080000-appb-000099
选自取代或未取代的选自下组的基团：
Figure PCTCN2022080000-appb-000100
Figure PCTCN2022080000-appb-000101
Figure PCTCN2022080000-appb-000102
Figure PCTCN2022080000-appb-000103
Figure PCTCN2022080000-appb-000104
各式中，CH 2、CH和NH中的H可以独立任选地被取代；且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；NH可以独立任选地被氘、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烷基酰基、磺酰基取代。
在另一优选例中，PTM、L和ULM分别独立地为本发明实施例化合物的对应部分。
在另一优选例中，所述通式(I)结构的化合物选自本发明实施例制备的化合物。
在另一优选例中，所述通式(I)结构的化合物选自下组：
Figure PCTCN2022080000-appb-000105
Figure PCTCN2022080000-appb-000106
Figure PCTCN2022080000-appb-000107
Figure PCTCN2022080000-appb-000108
Figure PCTCN2022080000-appb-000109
本发明第二方面，提供了一种制备通式(I)结构的SOS1蛋白水解调节剂、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，选自以下合成路线：
路线一：
Figure PCTCN2022080000-appb-000110
(i)式(PTM1-IA-LG 1)、(PTM1-IB-LG 1)、或(PTM2-I-LG 1)化合物与式(LG 2-L-LG 3)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、或Cu(OAc) 2等)作用下反应分别得到式(PTM1-IA--LG 3)、(PTM1-IB-L-LG 3)、或(PTM2-I-L-LG 3)化合物；
(ii)式(PTM1-IA--LG 3)、(PTM1-IB-L-LG 3)、或(PTM2-I-L-LG 3)化合物与式(LG 4-ULM)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、Cu(OAc) 2等)作用下反应分别得到式(PTM1-IA-L-ULM)、式(PTM1-IB-L-ULM)、或式(PTM2-I-L-ULM)化合物；
LG 1、LG 2、LG 3、或LG 4相同或不同，为离去基团，各自优选自：氢、OH、卤素、OTs、OMs、OTf、B(OH) 2等；
R 1、R 2、R 3、R 4、R 5、X、Y、Z、W、和n的定义如上所述；
R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、Z’、W’、和n’的定义如上所述。
路线二：
Figure PCTCN2022080000-appb-000111
(i)式(LG 4-ULM)化合物与式(LG 2-L-LG 3)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、或Cu(OAc) 2等)作用下反应得到式(LG 2-L-ULM)化合物；
(ii)式(LG 2-L-ULM)化合物与式(PTM1-IA-LG 1)、(PTM1-IB-LG 1)、或(PTM2-I-LG 1)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、或Cu(OAc) 2等)作用下反应分别得到式(PTM1-IA-L-ULM)、式(PTM1-IB-L-ULM)、或式(PTM2-I-L-ULM)化合物；
LG 1、LG 2、LG 3、或LG 4相同或不同，为离去基团，各自优选自：氢、OH、卤素、OTs、OMs、OTf、B(OH) 2等；
R 1、R 2、R 3、R 4、R 5、X、Y、Z、W、和n的定义如上所述
R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、Z’、W’、和n’的定义如上所述。
本发明第三方面，提供了一种药物组合物，包含i)一种或多种本发明第一方面所述通式(I)结构的化合物、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,ibritumomabtiuxetan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，提供了一种如本发明第一方面所述的具有通式(I)结构的化合物、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，或本发明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，所述癌症选自下组：肺癌、乳腺癌、***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，提供了一种预防和/或治疗SOS1活性或表达量相关的疾病的方法，其包括步骤：向有需要的对象施用有效量的如本发明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，或施用本发明第三方面所述的药物组合物。
在另一优选例中，所述对象为哺乳动物，如人、大鼠或小鼠。
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。
附图说明
图1为化合物实施例26不同浓度处理6小时后，H358细胞中，SOS1和β-actin含量的检测。
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针对SOS1的蛋白水解调节剂。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”是指本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烷烃基，可包含1-20个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或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 PCTCN2022080000-appb-000112
正戊基、异戊基、正己基、异己基、正庚基、异庚基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“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、或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”本身或作为另一取代基的一部分是指“烷基”再脱掉一个氢原子所形成的基团，亚烷基可包含1-18个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个碳原子。例如，亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2022080000-appb-000113
)、亚丁基(如
Figure PCTCN2022080000-appb-000114
)、亚戊基(如
Figure PCTCN2022080000-appb-000115
)、亚己基(如
Figure PCTCN2022080000-appb-000116
)、亚庚基(如
Figure PCTCN2022080000-appb-000117
)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3-30个碳原子，如包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18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、或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”本身或作为另一取代基的一部分是指上述环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2022080000-appb-000118
Figure PCTCN2022080000-appb-000119
Figure PCTCN2022080000-appb-000120
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 PCTCN2022080000-appb-000121
Figure PCTCN2022080000-appb-000122
Figure PCTCN2022080000-appb-000123
等。
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团，可包括3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个环原子(包含但不限于如3-7元单环，6-11元双环，或8-16元三环***)，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、***啉基、硫代***啉基、硫代***啉亚砜基、硫代***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，如包括但不限于：
Figure PCTCN2022080000-appb-000124
Figure PCTCN2022080000-appb-000125
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 PCTCN2022080000-appb-000126
Figure PCTCN2022080000-appb-000127
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。
术语“亚芳基”是指上述芳基脱掉两个氢原子所形成的基团。
术语“杂芳基”指包含1-4(如2或3个)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，杂环基可包括5、6、7、8、9、10、11、12、13或14个环原子。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“亚杂芳基”是指上述杂芳基脱掉两个氢原子所形成的基团。
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基氧基，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烷氧基或C1-C4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( 2H)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“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。
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。
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。R和R'在二烷基胺片段中可以相同或不同。
术语“磺酰胺基”是指带有结构-SO 2NRR'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。
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。
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。
术语"二烷基胺基烷基"是指带有结构-RNHR'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。
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。
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。优选地，如无特别说明，取代可为被选自下组的一个或多个取代基取代：例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、4-12元杂环基、芳基、杂芳基、C 1-C 8醛基、C 2-C 10酰基、C 2-C 10酯基、胺基、C 1-C 6烷氧基、C 1-C 10磺酰基、及C 1-C 6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、杂环基对亚杂环基、烷氧基对应亚烷氧基等。
SOS1蛋白水解调节剂
如本文所用，“SOS1蛋白水解调节剂”和“靶向SOS1的蛋白酶降解剂”可互换使用，指 靶向SOS1的蛋白酶降解剂(PROTAC),该化合物利用了细胞内的“清洁工”—泛素-蛋白酶体***来降解SOS1蛋白。
优选地，所述SOS1蛋白水解调节剂为本发明的式I化合物。
靶向配体
靶向配体(或靶蛋白部分或靶蛋白配体或配体)是能够结合目标靶蛋白的小分子。
本发明中，所述靶向配体(PTM部分)由靶向SOS1的小分子化合物形成，优选由如上所述的PTM1或PTM2化合物形成。
E3连接酶配体
在本发明中，E3连接酶配体部分(ULM部分)用于结合E3连接酶。本发明对E3连接酶配体种类没有特别要求，可使用本发明常用的能与E3连接酶结合的分子或结构片段。
典型地，ULM由可以和选自下组的连接酶结合的小分子配体形成(但并不限于)：VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、IAP、Keap1、HSP70、FKBP、DCAF15、DCAF16、RNF4、RNF114和AhR等。
优选地，所述ULM由选自下组的小分子配体形成：VLM、CLM、MLM或ILM。
连接基团(如本文中所述的L)
本发明的连接基团用于连接靶标分子和E3连接酶配体。
优选地，所述靶标分子(部分)或E3连接酶配体(部分)可以通过-O-、-S-、-NH-、-NR-、-(C＝O)-、-(C＝O)O-、-(C＝O)NR-、-SO 2-、-SO 2NR-等基团与连接基团连接。
在本发明的连接基团上，还可进一步含有其它各种官能团，例如-OH、-NHR、-SH等官能团。
典型地，靶标分子或E3连接酶配体上含有例如-OH、-SH、-NH 2、-NHR、-SOOH或-COOH等可发生取代反应的官能团时，可使用含有对应反应官能团的连接分子与其反应(如OH/SH/NH2与-COOH/-COCl等)，从而实现与靶标分子和/或E3连接酶配体的连接。能够发生上述取代反应的官能团，以及在分子上引入上述官能团的方法对于本领域技术人员而言是已知的。
在本发明中，连接基团L与PTM和ULM部分的连接方向可以是任意的，L基团可以左边与PTM连接而右边与ULM连接，或者L基团右边与PTM连接而左边与ULM连接，例如，当L为-C 1-C 4亚烷基CO-时，包括-C 1-C 4亚烷基CO-和-CO-C 1-C 4亚烷基-。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括式I化合物的立体异构体、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 PCTCN2022080000-appb-000128
式中：
ULM代表可以和E3连接酶结合的小分子配体部分；
PTM代表可以和SOS1结合的小分子配体部分；
L可以是键或者是可以连接PTM和ULM的连接基团。
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。
路线一：
Figure PCTCN2022080000-appb-000129
(i)式(PTM1-IA-LG 1)、(PTM1-IB-LG 1)、或(PTM2-I-LG 1)化合物与式(LG 2-L-LG 3)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl2(dppf)、CuI、或Cu(OAc) 2等)作用下反应分别得到式(PTM1-IA--LG 3)、(PTM1-IB-L-LG 3)、或(PTM2-I-L-LG 3)化合物；
(ii)式(PTM1-IA--LG 3)、(PTM1-IB-L-LG 3)、或(PTM2-I-L-LG 3)化合物与式(LG 4-ULM)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、Cu(OAc) 2等)作用下反应分别得到式(PTM1-IA-L-ULM)、式(PTM1-IB-L-ULM)、式(PTM2-I-L-ULM)化合物；
LG 1、LG 2、LG 3、或LG 4相同或不同，为离去基团，各自独立地选自：氢、OH、卤素、OTs、OMs、OTf、或B(OH) 2等；
R 1、R 2、R 3、R 4、R 5、X、Y、Z、W、n的定义如权利要求3所述
R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、Z’、W’、n’的定义如权利要求9所述。
分别含有至少一个LG 1、LG 2、LG 3、或LG 4基团的两个分子反应时，两个分子的离去基团可形成至少一个小分子(如H 2O、HCl、TsOH、MsOH、TfOH等)。
路线二：
Figure PCTCN2022080000-appb-000130
(i)式(LG 4-ULM)化合物与式(LG 2-L-LG 3)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl2(dppf)、CuI、Cu(OAc) 2等)作用下反应得到式(LG 2-L-ULM)化合物；
(ii)式(LG 2-L-ULM)化合物与式(PTM1-IA-LG 1)、(PTM1-IB-LG 1)、或(PTM2-I-LG 1)在碱(如DIPEA、TEA、Py、或DMAP)、缩合剂(如DCC、EDCI、PyBOP、HATU、或BOP)或者在催化剂(如Pd(OAc) 2、Pd 2(dba) 3、Pd(PPh 3) 4、PdCl 2(dppf)、CuI、或Cu(OAc) 2等)作用下反应分别得到式(PTM1-IA-L-ULM)、式(PTM1-IB-L-ULM)、式(PTM2-I-L-ULM)化合物；
LG 1、LG 2、LG 3、或LG 4相同或不同，为离去基团，各自独立地选自：氢、OH、卤素、OTs、OMs、OTf、或B(OH) 2等；
R 1、R 2、R 3、R 4、R 5、X、Y、Z、W、和n的定义如权利要求3所述
R 1’、R 2’、R 3’、R 4’、R 5’、R 6’、Z’、W’、和n’的定义如权利要求9所述。
药物组合物、用途和施用方法
本发明的药物组合物包括上述活性成分及药学上可接受的载体。
本发明的化合物可以降低SOS1的活性、表达量、促进SOS1蛋白降解和/或降低SOS1水平，从而可以用于预防和/或治疗SOS1活性或表达量相关的疾病。本发明所述的药物组合物可用于预防和/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。
在另一优选例中，所述癌症为KRAS突变导致的癌症。
在另一优选例中，所述癌症包括(但并不限于)：肺癌(小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC))、乳腺癌、***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。
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、ibritumomabtiuxetan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 PCTCN2022080000-appb-000131
)、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***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)所述化合物能够选择性的促进SOS1蛋白水解，从而预防和/或治疗SOS1活性或表达量相关的疾病(尤其对肿瘤细胞选择性高)，活性高，安全性好；
(2)本发明的化合物可以催化量发挥抑制细胞增殖的效果。细胞内能够循环发挥降解靶蛋白的作用，实现减少给药剂量，延长给药周期，达到安全有效的抗肿瘤效果；
(3)所述化合物具有更好的体内外药效学、药代动力学性能和/或更低的毒副作用。
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)、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 5micron C18 100x 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
实施例1 N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)-2-(((1-(((4-(((R)-1-(2-氟-3-(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)环丙基)甲基)(甲基)氨基)乙酰胺的制备
Figure PCTCN2022080000-appb-000132
第一步：(R)-(1-(((4-((1-(2-氟-3-(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)环丙基)甲基4-甲基苯磺酸酯的制备
在圆底烧瓶中依次加入(R)-4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-酚(100mg，0.25mmol)、环丙烷-1,1-二基二(亚甲基)二(对甲苯磺酸酯)(519mg，1.26mmol)、碳酸钾(140mg，1.01mmol)和乙腈(5mL)。反应物加热至60℃反应2小时然后减压浓缩。残余物用制备色谱分离得到目标化合物(100mg，产率：63.1％)。
LC-MS：m/z 634(M+H) +。
第二步：(R)-N-(1-(2-氟-3-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((1-((甲基氨基)甲基)环丙基)甲氧基)喹唑啉-4-胺的制备
在圆底烧瓶中依次加入(R)-(1-(((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基对甲苯磺酸酯(90mg，0.14mmol)、甲胺盐酸盐(96mg，1.42mmol)、碳酸钾(196mg，1.42mmol)和乙腈(5mL)。反应物加热至60℃反应4小时然后减压浓缩。残余物用制备色谱分离得到目标化合物(50mg，产率：72.6％)。
LC-MS：m/z 493(M+H) +。
第三步:N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)-2-(((1-(((4-(((R)-1-(2-氟-3-(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)环丙基)甲基)(甲基)氨基)乙酰胺的制备
在圆底烧瓶中依次加入(R)-N-(1-(2-氟-3-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((1-((甲基氨基)甲基)环丙基)甲氧基)喹唑啉-4-胺(7.7mg，0.015mmol)、2-氯-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)乙酰胺(11mg，0.03mmol)、碳酸钾(7mg，0.045mmol)和乙腈(1mL)。反应物加热至60℃反应2小时然后减压浓缩。残余物用制备色谱分离得到目标化合物(3mg，产率：24.8％)。
LC-MS：m/z 806(M+H) +。 1H NMR(400MHz，DMSO)δ10.62-10.54(m,1H),8.70-8.62(m,1H),7.95-7.93(m,1H),7.81-7.71(m,2H),7.62-7.57(m,2H),7.48-7.43(m,1H),7.29(m,1H),6.60(s,1H),5.65-5.60(m,1H),4.73-4.69(m,1H),4.30-4.25(m,1H),3.87-3.81(m,1H),3.53-3.49(m,3H),2.68-2.58(m,2H),2.44-2.39(m,4H),2.33-2.26(m,2H),2.19-1.99(m,6H),1.56(d,J＝6.8Hz,3H),0.70-0.56(m,4H).
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-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)-2-(((1-(((4-(((R)-1-(2-氟-3-(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)环丙基)甲基)(甲基)氨基)乙酰胺的制备
Figure PCTCN2022080000-appb-000133
LC-MS：m/z 806(M+H) +。 1H NMR(400MHz，DMSO)δ10.19(s,1H),8.05-7.98(m,2H),7.86(s,1H),7.80(t,J＝7.2Hz,1H),7.63-7.59(m,3H),7.38-7.30(m,2H),6.73(d,J＝9.6Hz,1H),5.76-5.69(m,1H),5.12-5.03(m,1H),4.14-3.99(m,2H),3.69(d,J＝7.2Hz,3H),3.33-3.27(m,2H),2.92-2.84(m,1H),2.67-2.55(m,2H),2.43(s,3H),2.22(s,3H),2.14-1.98(m,2H),1.63-1.61(m,3H),0.67-0.54(m,4H).
实施例3 2-(((1-(((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)氧基)甲基)环丙基)甲基)(甲基)氨基)-N-(2-(2,6-二氧哌啶-3-基)1,3-二氧异吲哚-4-基)乙酰胺的制备
Figure PCTCN2022080000-appb-000134
LC-MS：m/z 803(M+H) +。
实施例4 2-(((1-(((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)氧基)甲基)环丙基)甲基)(甲基)氨基)-N-(2-(2,6-二氧哌啶-3-基)1,3-二氧异吲哚-3-基)乙酰胺的制备
Figure PCTCN2022080000-appb-000135
LC-MS：m/z 803(M+H) +。
实施例5 N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-3-(((1-(((4-(((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)(甲基)氨基)丙酰胺的制备
Figure PCTCN2022080000-appb-000136
LC-MS:m/z 820(M+H) +。
实施例6 N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-3-(((1-(((4-(((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)(甲基)氨基)丙酰胺的制备
Figure PCTCN2022080000-appb-000137
LC-MS:m/z 820(M+H) +。
实施例7 2-(2,6-二氧哌啶-3-基)-4-(((1-(((4-(((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)氨基)异吲哚-1,3-二酮的制备
Figure PCTCN2022080000-appb-000138
LC-MS:m/z 735(M+H) +。1H NMR(400MHz，DMSO)δ8.47(brs,1H),7.87-7.78(m,1H),7.66-7.61(m,1H),7.48-7.42(m,1H),7.38-7.18(m,2H),7.07-6.93(m,3H),6.53-6.50(m,1H),5.81-5.78(m,1H),5.34-5.04(m,1H),4.29-4.04(m,1H),3.98-3.84(m,4H),3.06-2.98(m,1H),2.78-2.56(m,2H),2.33-2.23(m,3H),2.13-1.91(m,3H),1.64-1.59(m,3H),0.87-0.58(m,4H).
实施例8 2-(2,6-二氧哌啶-3-基)-5-(((1-(((4-(((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)氨基)异吲哚-1,3-二酮的制备
Figure PCTCN2022080000-appb-000139
LC-MS:m/z 735(M+H) +。 1H NMR(400MHz,DMSO)δ8.16(m,1H),7.85(m,1H),7.79–7.66(m,1H),7.65–7.51(m,2H),7.41(m,1H),7.14–7.06(m,1H),7.05–6.96(m,1H),6.96–6.84(m,1H),6.68(m,2H),5.91–5.76(m,1H),5.34–5.04(m,1H),4.10–3.88(m,5H),2.95–2.73(m,2H),2.73–2.61(m,1H),2.50(m,1H),2.36(s,3H),2.19–1.97(m,2H),1.70(t,J＝8.0Hz,3H),0.88(m,2H),0.67(m,2H).
实施例9 4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)胺基)-N-((1-(((4-(((R)-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)甲基)-N-甲基丁酰胺甲酸盐
Figure PCTCN2022080000-appb-000140
LC-MS:m/z 834(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.27(s,1H),8.03(m,1H),7.75(d,J＝6.9Hz,1H),7.69–7.52(m,2H),7.30(t,J＝7.5Hz,1H),7.18(m,1H),7.01(t,J＝13.6Hz,1H),6.84(m,1H),6.73–6.53(m,1H),6.42(d,J＝8.1Hz,1H),5.71(m,1H),5.04(m,1H),3.99–3.78(m,6H),3.13–2.97(m,3H),2.99–2.78(m,4H),2.56(m,2H),2.44(m,2H),2.37–2.21(m,5H),2.02(m,1H),1.71–1.51(m,5H),0.67(m,4H).
实施例10 7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)胺基)-N-((1-(((4-(((R)-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)甲基)-N-甲基庚酰胺甲酸盐
Figure PCTCN2022080000-appb-000141
LC-MS:m/z 876(M+H)+。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.23(s,1H),8.04(t,J＝7.1Hz,1H),7.76(s,1H),7.66–7.42(m,3H),7.32(t,J＝7.4Hz,1H),7.11–6.77(m,3H),6.38(m,1H),5.72(m,1H),5.05(m,1H),4.02–3.76(m,5H),3.45(m,2H),3.08(m,2H),3.03–2.75(m,5H),2.66–2.51(m,2H),2.37–2.12(m,5H),2.12–1.86(m,1H),1.60(d,J＝7.0Hz,3H),1.38–1.18(m,4H),0.97(m,4H),0.69(m,4H).
实施例11 3-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)胺基)乙氧基)乙氧基)-N-((1-(((4-(((R)-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)甲基)-N-甲基丙酰胺甲酸盐
Figure PCTCN2022080000-appb-000142
LC-MS:m/z 908(M+H)+。 1H NMR(400MHz,DMSO)δ11.11(d,J＝12.0Hz,1H),8.28(s,1H),8.05(d,J＝6.9Hz,1H),7.77(d,J＝6.5Hz,1H),7.69–7.49(m,3H),7.33(t,J＝7.5Hz,1H),7.16–6.95(m,3H),6.55(m,1H),5.74(m,1H),5.05(m,1H),3.99–3.78(m,5H),3.49–3.24(m,10H),3.05(m,1H),2.94–2.77(m,3H),2.60(m,4H),2.47(s,3H),2.27(t,J＝5.1Hz,3H),2.01(m,1H),1.60(d,J＝6.9Hz,3H),0.65(m,4H).
实施例12 1-(((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)氧基)甲基)-N-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙基)环丙烷-1-甲酰胺
Figure PCTCN2022080000-appb-000143
第一步：(R)-1-(((7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)甲基)环丙烷-1-甲酸乙酯的制备
在圆底烧瓶中依次加入化合物(R)-7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基) 乙基)氨基)喹唑啉-6-醇(450mg，1.07mmol)、1-(碘甲基)环丙基-1-甲酸乙酯(300mg，1.17mmol)、碳酸钾(442mg，3.20mmol)和乙腈(10mL)。反应液加热至80℃反应16小时，然后减压浓缩。残余物用硅胶柱层析分离得到目标化合物(500mg，85％收率)。
LC-MS:m/z 549(M+H) +。
第二步：(R)-1-(((7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)甲基)环丙烷-1-甲酸的制备
在圆底烧瓶中依次加入化合物(R)-1-(((7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)甲基)环丙烷-1-甲酸乙酯(500mg，0.91mmol)、氢氧化钠(73mg，1.82mmol)、四氢呋喃(10mL)和水(2mL)。反应液加热至60℃反应20小时，然后减压浓缩得到目标产物(474mg)。无需纯化直接用于下一步反应。
LC-MS:m/z 521(M+H) +。
第三步：(R)-1-(((4-((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)氧基)甲基)环丙烷-1-甲酸的制备
氮气保护下，在圆底烧瓶中依次加入化合物(R)-1-(((7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)甲基)环丙烷-1-甲酸(474mg，0.91mmol)、10％Pd/C(50mg)和甲醇(10mL)。得到的反应液在氢气氛围下在室温反应16小时然后过滤。滤液减压浓缩得到目标产物(650mg)。无需纯化直接用于下一步反应。
LC-MS:m/z 491(M+H) +。
第四步：1-(((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)氧基)甲基)-N-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙基)环丙烷-1-甲酰胺的制备
在圆底烧瓶中依次加入化合物(R)-1-(((4-((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)氧基)甲基)环丙烷-1-甲酸(45mg，0.09mmol)、4-((2-氨基乙基)氨基-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮盐酸盐(33mg，0.09mmol)、吡啶(29mg，0.37mmol)和N,N-二甲基甲酰胺(1mL)。混合物搅拌溶解，随后分批加入EDCI(26mg，0.14mmol)。加完后反应液在室温反应3小时，然后用制备液相分离得目标化合物(25mg，35％收率)。
LC-MS:m/z 789(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.18(s,1H),7.93(t,J＝8.8Hz,1H),7.89(s,1H),7.69(s,1H),7.62–7.48(m,1H),7.19(d,J＝8.6Hz,1H),7.05–6.95(m,2H),6.86(d,J＝9.6Hz,2H),6.77–6.63(m,2H),5.55(m,3H),5.02(dd,J＝12.8,5.4Hz,1H),4.16(d,J＝11.9Hz,2H),3.85(s,3H),3.33(m,4H),2.97–2.80(m,1H),2.59(m,2H),2.34(m,3H),2.03(m,1H),1.54(d,J＝7.0Hz,3H),1.17(s,2H),0.87(s,2H).
按照实施例12的方法以不同的起始原料合成了以下化合物：
实施例13 1-(((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)氧基)甲基)-N-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)丙基)环丙烷-1-甲酰胺
Figure PCTCN2022080000-appb-000144
LC-MS:m/z 803(M+H) +。 1H NMR(400MHz,DMSO)δ11.08(s,1H),8.16(s,1H),7.96(d,J＝7.8Hz,1H),7.74(dd,J＝15.6,10.1Hz,2H),7.57–7.40(m,1H),7.01(dd,J＝17.5,8.9Hz,3H),6.86(d,J＝9.1Hz,2H),6.80–6.61(m,2H),5.56(dd,J＝14.5,7.1Hz,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.30–4.14(m,2H),3.83(s,4H),3.37–3.28(m,8H),3.19(d,J＝5.9Hz,4H),2.89(dd,J＝22.7,8.5Hz,2H),2.70–2.55(m,2H),2.36(s,4H),2.03(dd,J＝15.8,10.6Hz,1H),1.76–1.64(m,2H),1.54(d,J＝7.0Hz,3H),1.17(s,2H),0.88(s,2H).
实施例14 1-(((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)氧基)甲基)-N-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)丁基)环丙烷-1-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000145
LC-MS:m/z 817(M+H) +。 1H NMR(400MHz,DMSO)δ11.11(s,1H),8.16(s,1H),7.94(d,J＝7.9Hz,1H),7.66(dd,J＝13.1,7.7Hz,2H),7.59–7.44(m,1H),7.10–6.94(m,3H),6.86(d,J＝9.2Hz,2H),6.70(s,1H),6.51(t,J＝5.5Hz,1H),5.55(m,3H),5.04(dd,J＝12.7,5.4Hz,1H),4.25–4.12(m,2H),3.85(s,3H),3.29(m,2H),3.20–3.10(m,2H),2.94–2.77(m,1H),2.70–2.55(m,2H),2.39–2.31(m,3H),2.04(m,1H),1.53(m,7H),1.15(s,2H),0.86(s,2H).
实施例15 1-(((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)氧基)甲基)-N-(5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)戊基)环丙烷-1-甲酰胺
Figure PCTCN2022080000-appb-000146
LC-MS:m/z 831(M+H) +。 1H NMR(400MHz,DMSO)δ11.08(s,1H),7.94(d,J＝8.0Hz,1H),7.71(s,1H),7.59(t,J＝5.4Hz,1H),7.55–7.47(m,1H),7.07–6.93(m,3H),6.86(d,J＝8.5Hz,2H),6.70(s,1H),6.49(t,J＝5.7Hz,1H),5.55(m,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.29–4.10(m,2H),3.88(s,3H),3.28–3.18(m,2H),3.16–3.05(m,2H),2.89(m,1H),2.70–2.55(m,2H),2.35(s,3H),2.12–1.92(m,1H),1.56(t,J＝10.1Hz,5H),1.45(m,2H),1.35–1.19(m,2H),1.14(s,2H),0.85(s,2H).
实施例16 1-(((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)氧基)甲基)-N-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)己基)环丙烷-1-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000147
LC-MS:m/z 845(M+H) +。 1H NMR(400MHz,DMSO)δ11.10(s,1H),8.17(s,1H),7.93(d,J＝8.0Hz,1H),7.70(s,1H),7.65–7.44(m,2H),7.13–6.93(m,3H),6.86(d,J＝8.0Hz,2H),6.70(s,1H),6.49(t,J＝5.6Hz,1H),5.55(m,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.28–4.11(m,2H),3.87(s,3H),3.25(m,2H),3.10(m,2H),2.96–2.80(m,1H),2.71–2.56(m,2H),2.33(m,3H),2.04(m,1H),1.58(m,5H),1.50–1.21(m,6H),1.14(s,2H),0.85(s,2H).
实施例17 1-(((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)氧基)甲基)-N-(7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)庚基)环丙烷-1-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000148
LC-MS:m/z 859(M+H) +。 1H NMR(400MHz,DMSO)δ11.10(s,1H),8.16(s,1H),7.93(d,J＝7.9Hz,1H),7.71(s,1H),7.55(t,J＝7.8Hz,2H),7.02(m,3H),6.86(d,J＝8.0Hz,2H),6.70(s,1H),6.48(t,J＝5.7Hz,1H),5.55(m,3H),5.04(dd,J＝12.8,5.3Hz,1H),4.25–4.12(m,2H),3.88(s,3H),3.24(m,2H),3.10(m,2H),2.95–2.80(m,1H),2.60(m,2H),2.33(s,3H),2.12–1.94(m,1H),1.54(m,5H),1.45–1.37(m,2H),1.26(m,6H),1.14(d,J＝2.4Hz,2H),0.85(s,2H).
实施例18 1-(((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)氧基)甲基)-N-(8-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)辛基)环丙烷-1-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000149
LC-MS:m/z 873(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.14(s,1H),8.01(d,J＝7.0Hz,1H),7.72(s,1H),7.56(m,2H),7.11–6.93(m,3H),6.86(d,J＝7.8Hz,2H),6.70(s,1H),6.49(t,J＝5.6Hz,1H),5.56(m,3H),5.05(dd,J＝12.8,5.3Hz,1H),4.26–4.14(m,2H),3.88(s,3H),3.24(m,2H),3.09(m,2H),2.96–2.81(m,1H),2.70–2.56(m,2H),2.36(s,3H),2.04(m,1H),1.54(m,5H),1.40(m,2H),1.24(m,8H),1.14(s,2H),0.85(s,2H).
实施例19 1-(((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)氧基)甲基)-N-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-2-氧乙氧基)乙氧)丙烷-1-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000150
LC-MS:m/z 847(M+H) +。 1H NMR(400MHz,DMSO)δ11.20(m,1H),10.21(m,1H),8.53(m,1H),8.14(s,1H),7.88(d,J＝5.4Hz,1H),7.67(m,2H),7.55(m,1H),7.39(d,J＝7.3Hz,1H),6.82(m,3H),6.68(s,1H),5.64–5.35(m,3H),5.18(m,1H),4.37–4.22(m,1H),4.16(m,2H),4.03–3.88(m,1H),3.85(s,3H),3.72(m,2H),3.59(m,2H),2.99–2.85(m,1H),2.70–2.54(m,2H),2.36(t,J＝8.2Hz,3H),2.1(m,1H),1.52(m,3H),1.21(m,2H),0.88(m,2H).
实施例20 1-(((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)氧基)甲基)-N-(2-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-2-氧乙氧基)乙氧基)乙基)环丙烷-1-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000151
LC-MS:m/z 891(M+H) +。 1H NMR(400MHz,DMSO)δ11.15(s,1H),10.27(s,1H),8.66(d,J＝8.4Hz,1H),8.14(s,1H),7.90(d,J＝7.9Hz,1H),7.79(t,J＝7.9Hz,1H),7.68(d,J＝13.0Hz,1H),7.63(dd,J＝16.3,10.9Hz,1H),7.57(d,J＝7.3Hz,1H),7.01(s,1H),6.86(d,J＝8.7Hz,2H),6.70(s,1H),5.62–5.44(m,3H),5.16(dd,J＝12.9,5.3Hz,1H),4.22–4.09(m,4H),3.89(s,3H),3.66(m,4H),3.47(m,2H),2.98–2.82(m,1H),2.69–2.56(m,2H),2.34(s,3H),2.16–1.94(m,1H),1.54(d,J＝7.0Hz,3H),1.14(m,2H),0.92–0.78(m,2H).
实施例21(2S,4R)-1-((S)-2-(4-(1-(((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)氧基)甲基)环丙烷-1-甲酰胺基)丁酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯啉-2-甲酰胺甲酸盐
Figure PCTCN2022080000-appb-000152
LC-MS:m/z 988(M+H) +。 1H NMR(400MHz,DMSO)δ8.98(s,1H),8.61(t,J＝5.9Hz,1H),8.18(s,1H),7.92(dd,J＝29.4,8.6Hz,2H),7.70(s,1H),7.65(t,J＝5.3Hz,1H),7.40(q,J＝8.2Hz,4H),7.04(s,1H),6.86(d,J＝8.6Hz,2H),6.70(s,1H),5.61–5.46(m,3H),4.52(d,J＝9.3Hz,1H),4.49–4.38(m,2H),4.35(s,1H),4.27–4.14(m,3H),3.87(s,3H),3.63(m,2H),3.10(m,2H),2.44(s,3H),2.35(s,3H),2.30–2.10(m,2H),2.08–1.83(m,2H),1.69–1.59(m,2H),1.54(d,J＝7.0Hz,3H),1.16(s,2H),0.93(s,9H),0.86(s,2H).
实施例22 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基丙酰胺甲酸盐的制备
Figure PCTCN2022080000-appb-000153
第一步：(R)-1-(((4-((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)氧基)甲基)-N-甲基环丙烷-1-甲酰胺的制备
在圆底烧瓶中依次加入化合物(R)-1-(((4-((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)氧基)甲基)环丙烷-1-甲酸(1g，2mmol)、甲胺盐酸盐(688mg，10mmol)、N,N-二异丙基乙基胺(1.3g，10mmol)和N,N-二甲基甲酰胺(15mL)，搅拌 溶解，随后分批加入HATU(1.5g，4mmol)。加完后反应液在室温搅拌反应16小时，然后加入水和乙酸乙酯分层萃取。有机相用饱和食盐水洗涤，然后用无水硫酸镁干燥后过滤。滤液减压浓缩，残余物用硅胶柱层析分离得到目标化合物(1.2g)。
LC-MS:m/z 504(M+H) +。
第二步：(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((1-((甲基氨基)甲基)环丙基)甲氧基)喹唑啉-4-胺的制备
在圆底烧瓶中依次加入化合物(R)-1-(((4-((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)氧基)甲基)-N-甲基环丙烷-1-甲酰胺(1.2g，2.38mmol)和四氢呋喃(25mL)，搅拌溶解，随后分批加入锂铝氢(181mg，4.77mmol)。加完后反应液加热回流反应2小时。降至室温，依次加入水(0.2mL)、氢氧化钠溶液(15％wt，0.2mL)、及水(0.3mL)，然后过滤。滤液减压浓缩得目标化合物(1.1g)，无需纯化直接用于下一步反应。
LC-MS:m/z 490(M+H) +。
第三步：N-((1-(((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)氧基)甲基)环丙基)甲基)-3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基丙酰胺甲酸盐的制备
在圆底烧瓶中依次加入化合物(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-((1-((甲基氨基)甲基)环丙基)甲氧基)喹唑啉-4-胺(40mg，0.08mmol)、3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)丙酸(26mg，0.08mmol)、吡啶(19mg，0.24mmol)和N,N-二甲基甲酰胺(1mL)，搅拌溶解，随后分批加入EDCI(31mg，0.16mmol)。加完后反应液在室温反应1小时，然后用制备液相分离得到目标化合物(24mg，36.8％收率)。
LC-MS:m/z 817(M+H) +。 1H NMR(400MHz,DMSO)δ11.07(s,1H),8.22(s,1H),7.83(m,1H),7.50-7.25(m,2H),6.97(d,J＝7.1Hz,1H),6.92–6.74(m,4H),6.71–6.40(m,2H),5.52(m,3H),5.00(dd,J＝12.7,5.2Hz,1H),4.00–3.70(m,5H),3.55(m,2H),2.92(m,5H),2.74–2.55(m,4H),2.32(d,J＝8.1Hz,3H),2.00(m,1H),1.53(d,J＝6.6Hz,3H),0.65(m,4H).
按照实施例22的方法以不同的起始原料合成了以下化合物：
实施例23 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基丁酰胺甲酸盐
Figure PCTCN2022080000-appb-000154
LC-MS:m/z 831(M+H) +。 1H NMR(400MHz,DMSO)δ11.08(s,1H),8.27(s,1H),7.91–7.76(m,1H),7.65–7.45(m,1H),7.28(m,1H),7.01(m,1H),6.88(m,3H),6.81–6.59(m,2H),6.43(d,J＝5.9Hz,1H),5.51(m,3H),5.08–4.92(m,1H),3.98–3.70(m,5H),3.48(m,2H),2.99–2.78(m,4H),2.70–2.58(m,2H),2.33(m,5H),2.09–1.98(m,1H),1.61(m,2H),1.53(m,3H),0.65(m,4H).
实施例24 N-((1-(((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)氧基)甲基)环丙基)甲基)-5-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基戊酰胺甲酸盐
Figure PCTCN2022080000-appb-000155
LC-MS:m/z 845(M+H) +。 1H NMR(400MHz,DMSO)δ11.08(s,1H),8.19(s,1H),7.94–7.78(m,1H),7.62–7.40(m,2H),7.11–6.76(m,5H),6.69(s,1H),6.40(m,1H),5.56(m,3H),5.04(dd,J＝12.5,5.0Hz,1H),3.98–3.74(m,5H),3.51(m,2H),3.08(m,1H),2.86(m,3H),2.62(m,2H),2.45–2.20(m,5H),2.10–1.97(m,1H),1.51(m,3H),1.49–1.17(m,4H),0.64(m,4H).
实施例25 N-((1-(((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)氧基)甲基)环丙基)甲基)-6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基己酰胺甲酸盐
Figure PCTCN2022080000-appb-000156
LC-MS:m/z 859(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.30(s,1H),7.91(m,1H),7.64–7.40(m,3H),7.12–6.97(m,2H),6.83(m,2H),6.68(s,1H),6.37(m,1H),5.63–5.41(m,3H),5.04(dd,J＝13.1,4.4Hz,1H),3.96–3.73(m,5H),3.47(m,2H),2.93(m,3H),2.71–2.54(m,2H),2.38–2.15(m,5H),2.10–1.91(m,1H),1.56(m,3H),1.48–1.08(m,6H),0.67(m,4H).
实施例26 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺甲酸盐
Figure PCTCN2022080000-appb-000157
LC-MS:m/z 873(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.21(s,1H),7.87(m,1H),7.56(m,2H),7.14–6.95(m,3H),6.94–6.80(m,2H),6.69(s,1H),6.41(m,1H),5.56(m,3H),5.04(dd,J＝12.9,5.3Hz,1H),3.98–3.79(m,5H),3.51(m,2H),3.04(m,1H),2.95–2.79(m,3H),2.69–2.55(m,2H),2.38–2.13(m,5H),2.10–1.90(m,1H),1.56(m,3H),1.41–0.78(m,8H),0.67(m,4H).
实施例27 N-((1-(((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)氧基)甲基)环丙基)甲基)-10-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基奎酰胺甲酸盐
Figure PCTCN2022080000-appb-000158
LC-MS:m/z 915(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.23(s,1H),7.87 (m,1H),7.65–7.49(m,2H),7.11–6.94(m,3H),6.85(s,2H),6.69(s,1H),6.48(s,1H),5.56(m,3H),5.05(dd,J＝12.8,5.3Hz,1H),3.84(m,5H),3.44(m,2H),3.28–3.20(m,1H),2.96–2.79(m,3H),2.62(m,2H),2.38–2.22(m,4H),2.17(t,J＝7.1Hz,1H),2.01(m,1H),1.66–1.41(m,5H),1.37–0.78(m,12H),0.67(m,4H).
实施例28 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙氧基)-N-甲基乙酰胺甲酸盐
Figure PCTCN2022080000-appb-000159
LC-MS:m/z 847(M+H) +。 1H NMR(400MHz,DMSO)δ11.10(d,J＝9.4Hz,1H),8.15(s,1H),7.88(d,J＝7.8Hz,1H),7.63–7.46(m,2H),7.10–6.89(m,3H),6.85(d,J＝8.1Hz,2H),6.69(s,1H),6.56(d,J＝5.5Hz,1H),5.64–5.42(m,3H),5.05(dd,J＝12.4,5.2Hz,1H),4.25(m,1H),4.13(m,1H),3.90(m,4H),3.77(m,1H),3.44(m,5H),2.99(s,2H),2.94–2.78(m,3H),2.69–2.55(m,2H),2.34(s,3H),2.08–1.94(m,1H),1.53(d,J＝7.0Hz,3H),0.66(m,4H).
实施例29 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙氧基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000160
LC-MS:m/z 861(M+H) +。 1H NMR(400MHz,DMSO)δ11.13(d,J＝12.9Hz,1H),7.87(t,J＝7.7Hz,1H),7.68–7.40(m,2H),7.07–6.80(m,5H),6.68(s,1H),6.61–6.39(m,1H),5.52(m,3H),5.05(dd,J＝12.8,5.2Hz,1H),3.94–3.72(m,5H),3.56–3.39(m,6H),3.16(m,3H),2.89(m,3H),2.65(m,2H),2.33(d,J＝1.8Hz,3H),2.13–2.05(m,1H),1.53(m,3H),0.66(m,4H).
实施例30 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙氧基)乙氧基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000161
LC-MS:m/z 905(M+H) +。 1H NMR(400MHz,DMSO)δ11.11(d,J＝14.1Hz,1H),7.89(d,J＝7.9Hz,1H),7.57(dd,J＝14.1,5.8Hz,2H),7.06(dt,J＝11.4,6.0Hz,3H),6.85(d,J＝7.8Hz,2H),6.69(s,1H),6.56(d,J＝7.2Hz,1H),5.53(m,3H),5.05(dd,J＝12.3,4.8Hz,1H),3.89(t,J＝9.9Hz,4H),3.82–3.72(m,1H),3.58–3.38(m,10H),3.04(m,3H),2.95–2.79(m,3H),2.59(m,3H),2.46(m,1H),2.34(d,J＝2.2Hz,3H),2.07(t,J＝7.5Hz,1H),1.53(d,J＝7.0Hz,3H),0.66(m,4H).
实施例31 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙酰胺基)-N-甲基乙酰胺甲酸盐
Figure PCTCN2022080000-appb-000162
LC-MS:m/z 860(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.15(s,1H),8.01(t,J＝4.7Hz,1H),7.86(d,J＝7.5Hz,1H),7.66–7.46(m,2H),7.09–6.98(m,2H),6.93(s,1H),6.83(m,3H),6.69(s,1H),5.64–5.44(m,3H),5.06(dd,J＝12.8,5.0Hz,1H),4.19–3.73(m,9H),3.06(s,3H),2.95–2.80(m,3H),2.60(m,2H),2.34(s,3H),2.10–1.92(m,1H),1.54(d,J＝7.0Hz,3H),0.66(m,4H).
实施例32 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙酰胺基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000163
LC-MS:m/z 874(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.04–7.76(m,2H),7.63–7.41(m,2H),7.13–6.93(m,2H),6.86(t,J＝8.3Hz,3H),6.70(dm,2H),5.53(m,3H),5.07(dd,J＝12.7,4.6Hz,1H),3.97–3.61(m,7H),3.47(m,2H),3.27–2.98(m,3H),2.90(m,3H),2.61(m,3H),2.42(m,1H),2.30(m,3H),2.08(d,J＝4.8Hz,1H),1.53(d,J＝7.0Hz,3H),0.66(m,4H).
实施例33 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙酰胺基)-N-甲基丁酰胺甲酸盐
Figure PCTCN2022080000-appb-000164
LC-MS:m/z 888(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),8.15(s,1H),7.98(dd,J＝27.2,22.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.65–7.47(m,2H),7.03(dd,J＝14.8,6.0Hz,2H),6.97–6.77(m,4H),6.69(s,1H),5.63–5.44(m,3H),5.07(dd,J＝12.8,5.3Hz,1H),4.00–3.74(m,5H),3.09–2.77(m,7H),2.60(m,2H),2.35(m,4H),2.22(m,1H),2.04(m,1H),1.58–1.39(m,5H),0.66(m,4H).
实施例34 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)乙酰胺基)-N-甲基乙酰胺甲酸盐
Figure PCTCN2022080000-appb-000165
LC-MS:m/z 861(M+H) +。 1H NMR(400MHz,DMSO)δ11.12(s,1H),8.16(s,1H),7.95(d,J＝7.6Hz,1H),7.87(d,J＝7.4Hz,1H),7.75(dt,J＝13.1,8.1Hz,1H),7.59(d,J＝29.9Hz,1H),7.46(t,J＝7.9Hz,1H),7.35(dd,J＝13.5,7.8Hz,1H),7.00(d,J＝2.0Hz,1H),6.85(d,J＝9.4Hz,2H),6.68(s,1H),5.54(m,3H),5.17–4.96(m,1H),4.78(s,2H),4.20(m,1H),4.03(m,1H),3.95–3.75(m,5H),3.07(s,3H),2.97–2.79(m,3H),2.70–2.55(m,2H),2.34(s,3H),2.11–1.91(m,1H),1.51(t,J＝16.1Hz,3H),0.80–0.52(m,4H).
实施例35 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)乙酰胺基)-N-甲基丙酰胺甲酸盐
Figure PCTCN2022080000-appb-000166
LC-MS:m/z 875(M+H) +。 1H NMR(400MHz,DMSO)δ11.28–11.02(m,1H),8.21(s,1H),7.85(s,1H),7.73(dt,J＝23.4,8.1Hz,1H),7.48(dd,J＝14.2,9.9Hz,2H),7.36–7.23(m,1H),7.01–6.90(m,2H),6.88–6.52(m,3H),5.63–5.30(m,3H),5.16(dd,J＝27.0,8.6Hz,1H),4.80–4.31(m,2H),3.90(m,5H),3.65(m,2H),3.04(s,3H),2.99–2.82(m,3H),2.61(m,2H),2.40–2.21(m,3H),2.20–1.93(m,1H),1.62–1.35(m,3H),0.78–0.48(m,4H).
实施例36 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)乙酰胺基)-N-甲基丁酰胺甲酸盐
Figure PCTCN2022080000-appb-000167
LC-MS:m/z 889(M+H) +。 1H NMR(400MHz,DMSO)δ11.13(s,1H),8.15(s,1H),7.97–7.83(m,2H),7.77(dd,J＝11.4,4.4Hz,1H),7.56(d,J＝15.1Hz,1H),7.47(dd,J＝7.2,2.2Hz,1H),7.34(dd,J＝11.2,8.8Hz,1H),7.01(d,J＝3.3Hz,1H),6.85(d,J＝9.1Hz,2H),6.69(s,1H),5.53(m,3H),5.11(dd,J＝12.9,5.2Hz,1H),4.73(t,J＝12.8Hz,2H),3.88(t,J＝10.1Hz,4H),3.77(m,1H),3.13–2.78(m,8H),2.61(m,2H),2.42–2.18(m,5H),2.02(m,1H),1.61–1.41(m,5H),0.66(m,4H).
实施例37 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氨基)乙酰胺基)-N-甲基乙酰胺甲酸盐
Figure PCTCN2022080000-appb-000168
LC-MS:m/z 860(M+H) +。 1H NMR(400MHz,DMSO)δ11.05(d,J＝4.0Hz,1H),8.20(s,1H),7.91(dd,J＝13.3,8.5Hz,1H),7.86(d,J＝7.8Hz,1H),7.67–7.50(m,2H),7.34(d,J＝6.0Hz,1H),7.01(t,J＝7.7Hz,1H),6.93(s,1H),6.84(t,J＝9.1Hz,3H),6.69(s,1H),5.63–5.42(m,3H),5.03(dd,J＝12.2,4.2Hz,1H),4.18–3.76(m,9H),3.05(s,3H),2.97–2.78(m,3H),2.70–2.55(m,2H),2.35(s,3H),2.00(d,J＝8.9Hz,1H),1.54(d,J＝7.0Hz,3H),0.75–0.49(m,4H).
实施例38 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氨基)乙酰胺基)-N-甲基丙酰胺甲酸盐
Figure PCTCN2022080000-appb-000169
LC-MS:m/z 874(M+H) +。 1H NMR(400MHz,DMSO)δ11.06(s,1H),8.17(s,1H),7.97–7.77(m,2H),7.64–7.48(m,2H),7.27(d,J＝23.3Hz,1H),7.02(t,J＝8.7Hz,1H),6.94–6.71(m,4H),6.69(s,1H),5.52(m,3H),5.04(dd,J＝12.9,5.3Hz,1H),4.01–3.65(m,7H),3.15(m,2H),3.01(s,3H),2.93–2.78(m,3H),2.63(m,2H),2.42–2.26(m,5H),2.04–1.95(m,1H),1.53(d,J＝7.0Hz,3H),0.65(m,4H).
实施例39 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氨基)乙酰胺基)-N-甲基丁酰胺甲酸盐
Figure PCTCN2022080000-appb-000170
LC-MS:m/z 888(M+H) +。 1H NMR(400MHz,DMSO)δ11.06(s,1H),8.17(s,1H),8.05–7.93(m,1H),7.88(d,J＝5.5Hz,1H),7.62–7.47(m,2H),7.32(d,J＝5.6Hz,1H),7.01(d,J＝5.2Hz,1H),6.93(s,1H),6.85(d,J＝9.0Hz,3H),6.69(s,1H),5.53(m,3H),5.03(dd,J＝12.7,4.9Hz,1H),3.94–3.84(m,4H),3.77(m,3H),3.44(m,2H),3.01(m,3H),2.96–2.77(m,4H),2.62–2.53(m,2H),2.34(m,4H),2.20(t,J＝7.1Hz,1H),2.00(d,J＝5.8Hz,1H),1.53(d,J＝7.0Hz,3H),1.46(d,J＝5.8Hz,2H),0.65(m,4H).
实施例40 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氧基)乙酰胺基)-N-甲基乙酰胺甲酸盐
Figure PCTCN2022080000-appb-000171
LC-MS:m/z 861(M+H) +。 1H NMR(400MHz,DMSO)δ11.11(s,1H),8.17(s,1H),8.06(d,J＝37.0Hz,1H),7.91–7.74(m,2H),7.59(d,J＝31.7Hz,1H),7.38(dd,J＝17.6,6.0Hz, 1H),7.33–7.20(m,1H),6.99(s,1H),6.85(d,J＝8.8Hz,2H),6.68(s,1H),5.52(m,3H),5.12(dd,J＝12.9,5.3Hz,1H),4.70(m,2H),4.17(m,1H),4.02–3.74(m,6H),3.07(s,3H),2.95–2.80(m,3H),2.61(m,2H),2.32(m,3H),2.12–1.91(m,1H),1.54(d,J＝7.0Hz,3H),0.68(m,4H).
实施例41 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氧基)乙酰胺基)-N-甲基丙酰胺甲酸盐
Figure PCTCN2022080000-appb-000172
LC-MS:m/z 875(M+H) +。 1H NMR(400MHz,DMSO)δ11.12(s,1H),8.16(s,1H),7.99(dd,J＝24.4,18.5Hz,1H),7.80(t,J＝10.8Hz,2H),7.54(d,J＝21.8Hz,1H),7.32(d,J＝2.5Hz,1H),7.28–7.17(m,1H),6.98(s,1H),6.83(d,J＝7.8Hz,2H),6.68(s,1H),5.61–5.37(m,3H),5.13(dd,J＝12.9,5.1Hz,1H),4.63–4.40(m,2H),4.03–3.69(m,5H),3.64–3.52(m,2H),3.05(s,3H),2.97–2.81(m,3H),2.61(m,3H),2.46(m,1H),2.39–2.21(m,3H),2.13–1.94(m,1H),1.52(d,J＝7.0Hz,3H),0.66(m,4H).
实施例42 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氧基)乙酰胺基)-N-甲基丁酰胺甲酸盐
Figure PCTCN2022080000-appb-000173
LC-MS:m/z 889(M+H) +。 1H NMR(400MHz,DMSO)δ11.11(s,1H),8.21–8.09(m,2H),7.90–7.81(m,2H),7.56(d,J＝19.2Hz,1H),7.42(dd,J＝6.2,1.9Hz,1H),7.35(td,J＝8.6,2.1Hz,1H),7.01(d,J＝7.4Hz,1H),6.85(d,J＝8.5Hz,2H),6.69(s,1H),5.53(s,3H),5.12(dd,J＝12.9,5.3Hz,1H),4.65(d,J＝10.0Hz,2H),3.97–3.81(m,4H),3.77(m,1H),3.48–3.43(m,2H),3.12–2.80(m,6H),2.68–2.54(m,2H),2.41–2.30(m,4H),2.23(t,J＝7.2Hz,1H),2.11–1.93(m,1H),1.52(t,J＝9.6Hz,5H),0.66(t,J＝18.4Hz,4H).
实施例43 5-(4-((S)-3-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)胺基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)四氢吡咯-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000174
LC-MS:m/z 801(M+H) +。
实施例44 3-(5-(4-((S)-3-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)胺基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)四氢吡咯-1-基)哌啶-1-基)哌啶-1-基)-1-氧异喹啉-2-基)哌啶-2,6-二酮
Figure PCTCN2022080000-appb-000175
LC-MS:m/z 787(M+H) +。
实施例45 5-(4-((S)-3-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)胺基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)四氢吡咯-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000176
LC-MS:m/z 819(M+H) +。
实施例46 3-(5-(4-(((S)-3-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)胺基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)四氢吡咯-1-基)甲基)哌啶-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮
Figure PCTCN2022080000-appb-000177
LC-MS:m/z 801(M+H) +。
实施例47 3-(5-(4-((S)-3-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)胺基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)四氢吡咯-1-甲酰基)哌啶-1-基)-1-氧异吲哚-2-基)哌啶-2,6-二酮
Figure PCTCN2022080000-appb-000178
LC-MS:m/z 815(M+H) +。
实施例48 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)氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)戊酰胺
Figure PCTCN2022080000-appb-000179
LC-MS:m/z 748(M+H) +。 1H NMR(400MHz,DMSO)δ11.10(s,1H),10.59(s,1H),8.26(s,1H),7.97–7.83(m,3H),7.70(s,1H),7.02(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.64–5.46(m,3H),5.12(dd,J＝12.9,5.4Hz,1H),4.17–4.07(m,2H),3.86(s,3H),2.99–2.78(m,1H),2.68–2.45(m,4H),2.34(s,3H),2.09–1.97(m,1H),1.94–1.79(m,4H),1.55(d,J＝7.1Hz,3H).
实施例49 3-(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 唑啉-6-基)氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)丙酰胺
Figure PCTCN2022080000-appb-000180
LC-MS:m/z 764(M+H) +。 1H NMR(400MHz,DMSO)δ11.10(s,1H),10.63(s,1H),8.24(s,1H),7.93–7.81(m,3H),7.69(s,1H),7.00(s,1H),6.86(s,1H),6.84(s,1H),6.68(s,1H),5.60–5.47(m,3H),5.12(dd,J＝12.8,5.4Hz,1H),4.26–4.16(m,2H),3.89–3.79(m,7H),2.97–2.83(m,1H),2.70(t,J＝6.1Hz,2H),2.64–2.49(m,2H),2.34(s,3H),2.09–1.97(m,1H),1.53(d,J＝7.1Hz,3H).
实施例50 3-(2-(2-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)丙酰胺
Figure PCTCN2022080000-appb-000181
LC-MS:m/z 808(M+H) +。 1H NMR(400MHz，DMSO)δ1H NMR(400MHz,DMSO)δ11.08(s,1H),10.59(s,1H),8.23(s,1H),7.95–7.81(m,3H),7.69(s,1H),7.01(s,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.61–5.46(m,3H),5.10(dd,J＝12.7,5.3Hz,1H),4.24–4.15(m,2H),3.88–3.79(m,5H),3.76(t,J＝6.1Hz,2H),3.66–3.56(m,4H),2.93–2.82(m,1H),2.70–2.46(m,4H),2.35(s,3H),2.09–2.00(m,1H),1.54(d,J＝7.0Hz,3H).
实施例51 4-(4-((S)-3-((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)氧基)吡咯烷-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000182
LC-MS:m/z 801(M+H) +。 1H NMR(400MHz,DMSO)δ11.07(s,1H),7.95(d,J＝8.0Hz,1H),7.72–7.62(m,2H),7.34(dd,J＝7.8,4.8Hz,2H),7.04(s,1H),6.89(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.47(m,3H),5.13–5.04(m,2H),3.87(s,3H),3.74–3.63(m,2H),3.21–3.14(m,1H),3.00–2.90(m,2H),2.89–2.64(m,4H),2.64–2.53(m,1H),2.46–2.28(m,5H),2.08–1.92(m,4H),1.88–1.75(m,1H),1.72–1.58(m,2H),1.55(d,J＝7.0Hz,3H).
实施例52 4-(4-(((S)-3-((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)氧基)吡咯烷-1-基)甲基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000183
LC-MS:m/z 815(M+H) +。 1H NMR(400MHz,DMSO)δ11.07(s,1H),7.95(d,J＝8.1Hz,1H),7.67(dd,J＝8.5,7.1Hz,1H),7.62(s,1H),7.36–7.28(m,2H),7.03(s,1H),6.89(s,1H),6.85(s,1H),6.69(s,1H),5.62–5.47(m,3H),5.13–5.04(m,2H),3.87(s,3H),3.74–3.64(m,2H),3.12–3.05(m,1H),2.95–2.81(m,3H),2.72–2.65(m,1H),2.65–2.53(m,4H),2.45–2.29(m,5H),2.07–1.96(m,2H),1.92–1.76(m,3H),1.76–1.62(m,1H),1.55(d,J＝7.0Hz,3H),1.42–1.27(m,2H).
实施例53(2S,4R)-1-((S)-2-(1-(((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)氧基)甲基)环丙烷-1-甲酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺
Figure PCTCN2022080000-appb-000184
LC-MS:m/z 904(M+H) +。 1H NMR(400MHz,DMSO)δ8.94(s,1H),8.52(t,J＝6.1Hz,1H),7.81(s,1H),7.40–7.30(m,5H),7.06(s,1H),6.88(s,1H),6.86(s,1H),6.70(s,1H),5.64–5.46(m,3H),5.14(d,J＝3.5Hz,1H),4.61(d,J＝9.2Hz,1H),4.46–4.30(m,4H),4.28–4.18(m,1H),4.06(d,J＝10.9Hz,1H),3.90(s,3H),3.71–3.58(m,2H),2.43–2.35(m,6H),2.09–1.86(m,2H),1.55(d,J＝7.0Hz,3H),1.30–1.14(m,4H),0.92(s,9H).
实施例54 1-(((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)氧基)甲基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)环丙烷-1-甲酰胺
Figure PCTCN2022080000-appb-000185
LC-MS:m/z 746(M+H) +。 1H NMR(400MHz,DMSO)δ11.03(d,J＝5.6Hz,1H),10.12(s,1H),8.66(d,J＝8.5Hz,1H),7.98–7.92(m,1H),7.85(t,J＝7.9Hz,1H),7.79(s,1H),7.60(d,J＝7.3Hz,1H),7.01(s,1H),6.89(s,1H),6.87(s,1H),6.70(s,1H),5.61–5.46(m,3H),5.01–4.93(m,1H),4.44–4.30(m,2H),3.76(d,J＝3.4Hz,3H),2.87–2.73(m,1H),2.57–2.45(m,1H),2.43–2.28(m,4H),2.03–1.89(m,1H),1.55(dd,J＝7.1,3.3Hz,3H),1.45–1.34(m,2H),1.19–1.10(m,2H).
实施例55 1-(((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)氧基)甲基)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)环丙烷-1-甲酰胺
Figure PCTCN2022080000-appb-000186
LC-MS:m/z 746(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),9.90(s,1H),8.23(s,1H),8.04(dd,J＝8.2,1.9Hz,1H),7.99–7.92(m,1H),7.89(d,J＝8.2Hz,1H),7.77(s,1H),7.07(s,1H),6.88(s,1H),6.86(s,1H),6.71(s,1H),5.63–5.47(m,3H),5.12(dd,J＝12.9,5.4Hz,1H),4.45–4.32(m,2H),3.87(s,3H),2.95–2.83(m,1H),2.68–2.48(m,2H),2.37(s,3H),2.09–1.95(m,1H),1.56(d,J＝7.0Hz,3H),1.47–1.37(m,2H),1.13–1.04(m,2H).
实施例56 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌啶-4-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000187
LC-MS:m/z 872(M+H) +。 1H NMR(400MHz,DMSO)δ11.07(s,1H),7.87(dd,J＝12.3,7.9Hz,1H),7.61–7.51(m,2H),7.27(t,J＝6.4Hz,1H),7.06–6.93(m,2H),6.87(s,1H),6.85(s,1H),6.68(d,J＝9.4Hz,1H),5.59–5.44(m,3H),5.12–5.02(m,1H),3.94–3.84(m,4H),3.84–3.73(m,1H),3.66–3.33(m,4H),3.13–2.82(m,4H),2.75–2.50(m,4H),2.36– 2.24(m,4H),2.24–2.17(m,1H),2.09–1.93(m,1H),1.84–1.64(m,1H),1.64–1.48(m,5H),1.23–0.81(m,2H),0.77–0.61(m,4H).
实施例57 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000188
LC-MS:m/z 857(M+H) +。 1H NMR(400MHz,DMSO)δ11.09–10.97(m,1H),7.92–7.84(m,1H),7.70–7.52(m,2H),7.35–7.11(m,2H),7.02(d,J＝10.1Hz,1H),6.89–6.81(m,2H),6.69(s,1H),5.59–5.45(m,3H),5.09–5.00(m,1H),3.95–3.77(m,5H),3.69–3.38(m,4H),3.21–2.74(m,5H),2.63–2.43(m,2H),2.34(s,3H),2.13–2.06(m,1H),2.05–1.95(m,1H),1.74–1.30(m,8H),0.80–0.57(m,4H).
实施例58 4-(4-((S)-3-((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)氧基)吡咯烷-1-羰基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000189
LC-MS:m/z 829(M+H)+。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.96(d,J＝7.9Hz,1H),7.81(d,J＝26.7Hz,1H),7.73–7.63(m,1H),7.39–7.29(m,2H),7.07(d,J＝5.0Hz,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.46(m,3H),5.27–5.02(m,2H),3.96–3.85(m,4H),3.83–3.64(m,4H),3.63–3.53(m,1H),3.04–2.80(m,3H),2.78–2.51(m,3H),2.36(s,3H),2.31–1.94(m,3H),1.89–1.70(m,4H),1.60–1.53(m,3H).
实施例59 4-(4-(2-((S)-3-((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)氧基)吡咯烷-1-基)-2-氧乙基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000190
LC-MS:m/z 843(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.96(d,J＝8.0Hz,1H),7.79(d,J＝19.0Hz,1H),7.72–7.61(m,1H),7.38–7.24(m,2H),7.09–7.03(m,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.44(m,3H),5.27–5.02(m,2H),3.93–3.80(m,4H),3.74–3.54(m,5H),3.52–3.40(m,1H),2.96–2.76(m,3H),2.69–2.52(m,2H),2.40–2.20(m,6H),2.17–1.87(m,3H),1.87–1.71(m,2H),1.56(dd,J＝6.8,3.4Hz,3H),1.51–1.30(m,2H).
实施例60 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氮杂环丁烷-3-基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000191
LC-MS:m/z 912(M+H) +。1H NMR(400MHz,DMSO)δ11.05(s,1H),7.87(dd,J＝8.2,3.5Hz,1H),7.59–7.51(m,2H),7.11(d,J＝7.0Hz,1H),7.08–6.81(m,3H),6.75(d,J＝8.6Hz,1H),6.69(s,1H),5.62–5.45(m,3H),5.03(dd,J＝12.8,5.5Hz,1H),4.27–4.10(m,2H),3.99–3.70(m,7H),3.52–3.41(m,2H),3.18–2.81(m,5H),2.76–2.47(m,4H),2.34(s,3H),2.05–1.75(m,2H),1.53(d,J＝7.0Hz,3H),1.49–1.35(m,4H),1.34–1.21(m,2H),0.79–0.58(m,4H).
实施例61 4-((2-(5-(1-(((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)氧基)甲基)环丙烷-1-羰基)六氢吡咯基[3,4-c]吡咯-2(1H)-基)-2-氧代乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000192
LC-MS:m/z 899(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.86(d,J＝7.9Hz,1H),7.69–7.49(m,5H),7.05(s,1H),7.04(s,1H),6.97(s,1H),6.86(s,1H),6.84(s,1H),6.69(s,1H),5.62–5.44(m,3H),5.06(dd,J＝12.9,5.5Hz,1H),4.42–3.98(m,5H),3.98–3.80(m,4H),3.79–3.51(m,2H),3.50–3.32(m,2H),3.07–2.81(m,3H),2.69–2.49(m,2H),2.34(s,3H),2.09–1.95(m,1H),1.53(dd,J＝7.2,3.7Hz,3H),0.98–0.89(m,4H).
实施例62 4-((2-(2-(1-(((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)氧基)甲基)环丙烷-1-羰基)-2,7-二氨代螺[3.5]壬烷-7-基)-2-氧代乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000193
LC-MS:m/z 913(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.89(d,J＝8.0Hz,1H),7.65(s,1H),7.60(dd,J＝8.5,7.1Hz,1H),7.15–7.04(m,4H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.44(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.32–4.02(m,6H),3.91(s,3H),3.72–3.56(m,2H),3.54–3.35(m,4H),2.96–2.82(m,1H),2.66–2.52(m,2H),2.36(s,3H),2.10–1.97(m,1H),1.80–1.70(m,2H),1.70–1.62(m,2H),1.55(d,J＝7.0Hz,3H),1.12–1.03(m,2H),0.94–0.84(m,2H).
实施例63 4-((2-(2-(1-(((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)氧基)甲基)环丙烷-1-羰基)-2,8-二氨代螺[4.5]癸烷-8-基)-2-氧代乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000194
LC-MS:m/z 926(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(d,J＝8.0Hz,1H),7.66(s,1H),7.63–7.56(m,1H),7.17–6.99(m,4H),6.87(s,1H),6.86(s,1H),6.70(s,1H),5.65–5.45(m,3H),5.07(dd,J＝12.8,5.4Hz,1H),4.32–3.96(m,5H),3.94–3.80(m,3H),3.80–3.39(m,6H),3.27–3.15(m,1H),2.98–2.83(m,1H),2.66–2.52(m,2H),2.35(s,3H),2.10–2.01(m,1H),1.91–1.68(m,2H),1.64–1.39(m,7H),1.13–0.87(m,4H).
实施例64 4-(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)氧基)戊-1-炔-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000195
LC-MS:m/z 715(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),8.01–7.92(m,1H),7.90–7.77(m,3H),7.74(s,1H),7.03(s,1H),6.87(s,1H),6.84(s,1H),6.68(s,1H),5.61–5.44(m,3H),5.15–5.06(m,1H),4.29–4.22(m,2H),3.88(s,3H),2.96–2.86(m,1H),2.76(t,J＝7.1Hz,2H),2.63–2.45(m,2H),2.35(s,3H),2.21–2.10(m,2H),2.04–1.96(m,1H),1.54(d,J＝7.0Hz,3H).
实施例65 N-((1-(((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)氧基)甲基)环丙基)甲基)-N-甲基-7-((2-(1-甲基-2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)庚酰胺
Figure PCTCN2022080000-appb-000196
LC-MS:m/z 887(M+H) +。1H NMR(400MHz,DMSO)δ7.93–7.87(m,1H),7.62–7.51(m,2H),7.07–6.90(m,3H),6.88–6.83(m,2H),6.70(s,1H),6.40(dt,J＝20.5,5.9Hz,1H),5.60–5.45(m,3H),5.11(dd,J＝13.0,5.4Hz,1H),3.96–3.75(m,5H),3.56–3.35(m,2H),3.17–3.08(m,1H),3.08–2.86(m,8H),2.80–2.71(m,1H),2.60–2.52(m,1H),2.32(d,J＝8.1Hz,3H),2.23(dt,J＝34.8,7.5Hz,2H),2.09–2.00(m,1H),1.53(d,J＝7.0Hz,3H),1.41–1.25(m,4H),1.20–0.89(m,4H),0.76–0.58(m,4H).
实施例66 N-((1-(((4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000197
LC-MS:m/z 858(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),8.03–7.95(m,1H),7.69–7.50(m,2H),7.50–7.43(m,1H),7.39–7.18(m,2H),7.13–6.85(m,3H),6.39(dt,J＝24.4,5.9Hz,1H),5.82–5.73(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.99–3.75(m,5H),3.56–3.42(m,2H),3.16–2.81(m,6H),2.65–2.55(m,2H),2.35–2.15(m,5H),2.07–1.97(m,1H),1.58(d,J＝7.1Hz,3H),1.36–1.22(m,4H),1.19–0.84(m,4H),0.75–0.63(m,4H).
实施例67 N-((1-(((4-(((R)-1-(3-氨基-5-(二氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000198
LC-MS:m/z 855(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.90–7.82(m,1H),7.65–7.52(m,2H),7.11–6.95(m,3H),6.94–6.64(m,3H),6.58(s,1H),6.42(dt,J＝18.0,5.9Hz,1H),5.59–5.50(m,1H),5.32(s,2H),5.05(dd,J＝12.9,5.4Hz,1H),3.99–3.72(m,5H),3.54–3.37(m,2H),3.19–3.09(m,1H),3.10–2.82(m,5H),2.63–2.52(m,2H),2.33(d,J＝6.0Hz,3H),2.23(dt,J＝36.0,7.4Hz,2H),2.10–1.99(m,1H),1.52(d,J＝7.0Hz,3H),1.43–1.22(m,4H),1.21–0.91(m,4H),0.76–0.58(m,4H).
实施例68 N-((1-(((4-(((R)-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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000199
LC-MS:m/z 917(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),8.01–7.93(m,1H),7.67–7.49(m,3H),7.33–7.25(m,1H),7.23–7.14(m,1H),7.08–6.87(m,3H),6.40(dt,J＝21.4,5.9Hz,1H),5.82–5.73(m,1H),5.30(s,1H),5.04(dd,J＝12.8,5.4Hz,1H),4.02–3.77(m,5H),3.59–3.38(m,2H),3.17–2.98(m,3H),2.95–2.82(m,3H),2.63–2.51(m,2H),2.32–2.16(m,5H),2.09–1.99(m,1H),1.56(d,J＝7.0Hz,3H),1.42–1.25(m,4H),1.25–1.18(m,6H),1.17–0.90(m,4H),0.79–0.59(m,4H).
实施例69(3-(4-((7-(((1-(((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)氧基)甲基)环丙基)甲基)(甲基)氨基)-7-氧代庚基)氨基)-1,3-二氧异吲哚-2-基)-2,6-二氧哌啶-1-基)甲基特戊酸酯
Figure PCTCN2022080000-appb-000200
LC-MS:m/z 988(M+H) +。1H NMR(400MHz,DMSO)δ7.93–7.85(m,1H),7.63–7.53(m,2H),7.07–6.91(m,3H),6.90–6.85(m,2H),6.70(s,1H),6.46–6.34(m,1H),5.66(s,2H),5.60–5.47(m,3H),5.24(dd,J＝12.9,5.4Hz,1H),3.97–3.75(m,5H),3.55–3.35(m,2H),3.18–3.10(m,1H),3.10–2.99(m,2H),2.93–2.80(m,3H),2.63–2.54(m,2H),2.33(d,J＝7.2Hz,3H),2.24(dt,J＝34.5,7.4Hz,2H),2.14–2.05(m,1H),1.54(d,J＝7.0Hz,3H),1.41–1.22(m,4H),1.20–0.85(m,13H),0.76–0.59(m,4H).
实施例70(1-(((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)氧基)甲基)环丙基)甲基7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)庚酸酯
Figure PCTCN2022080000-appb-000201
LC-MS:m/z 860(M+H) +。 1H NMR(400MHz,DMSO)δ11.09(s,1H),7.94(d,J＝8.0Hz,1H),7.66(s,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.04–6.94(m,3H),6.87(s,1H),6.85(s,1H),6.69(s,1H),6.43(t,J＝6.0Hz,1H),5.61–5.46(m,3H),5.04(dd,J＝12.8,5.4Hz,1H),4.13–4.05(m,2H),4.03–3.92(m,2H),3.87(s,3H),3.19–3.10(m,2H),2.94–2.81(m,1H),2.64–2.52(m,2H),2.34(s,3H),2.29(t,J＝7.3Hz,2H),2.06–1.99(m,1H),1.54(d,J＝7.1Hz,3H),1.51–1.39(m,4H),1.33–1.17(m,4H),0.76–0.65(m,4H).
实施例71 N-((1-(((4-(((R)-1-(3-氰基-2-甲基苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000202
LC-MS:m/z 829(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),8.12–8.03(m,1H),7.77(dd,J＝8.0,3.8Hz,1H),7.64–7.48(m,3H),7.38–7.29(m,1H),7.09–6.81(m,3H),6.44–6.27(m,1H),5.65–5.53(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.01–3.75(m,5H),3.58–3.44(m,2H),3.12–3.01(m,2H),2.99–2.81(m,4H),2.70(s,3H),2.64–2.53(m,2H),2.35–2.15(m,5H),2.11–2.00(m,1H),1.52(d,J＝7.0Hz,3H),1.40–1.17(m,4H),1.17–0.81(m,4H),0.79–0.60(m,4H).
实施例72 N-((1-(((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)氧基)甲基)环丙基)甲基)-1'-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-N-甲基-[1,4'-联哌啶]-4-甲酰胺
Figure PCTCN2022080000-appb-000203
LC-MS:m/z 941(M+H) +。1H NMR(400MHz,DMSO)δ10.92(s,1H),7.74(d,J＝7.9Hz,1H),7.64(t,J＝7.8Hz,1H),7.55(s,1H),7.32–7.25(m,2H),7.03(s,1H),6.86(s,2H),6.70(s,1H),5.58–5.50(m,1H),5.36(s,2H),5.05(dd,J＝12.6,5.5Hz,1H),3.98–3.76(m,5H),3.71(d,J＝12.0Hz,2H),3.49–3.41(m,2H),2.95–2.79(m,6H),2.69–2.52(m,4H),2.39–2.26(m,4H),2.22–2.09(m,1H),2.10–1.99(m,1H),1.89–1.64(m,3H),1.62–1.50(m,5H),1.50–1.23(m,5H),0.79–0.54(m,4H).
实施例73 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000204
LC-MS:m/z 886(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.94–7.85(m,1H),7.68–7.54(m,2H),7.33(dd,J＝7.2,4.9Hz,1H),7.22–6.97(m,2H),6.87(s,1H),6.85 (s,1H),6.68(s,1H),5.58–5.49(m,3H),5.09(dd,J＝13.1,5.4Hz,1H),4.01–3.76(m,5H),3.57–3.41(m,4H),3.22–2.96(m,5H),2.96–2.81(m,3H),2.65–2.55(m,2H),2.49–2.43(m,4H),2.39–2.26(m,5H),2.08–1.96(m,1H),1.54(d,J＝7.1Hz,3H),0.79–0.59(m,4H).
实施例74 N-((1-(((4-(((R)-1-(3-氨基-5-(1,1-二氟-2-羟基-2-甲基丙基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000205
LC-MS:m/z 914(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.85(dd,J＝8.0,5.0Hz,1H),7.62–7.51(m,2H),7.06–6.93(m,3H),6.71(s,1H),6.69(s,1H),6.56(s,1H),6.48–6.38(m,1H),5.58–5.46(m,1H),5.16(s,2H),5.11–5.01(m,2H),3.98–3.69(m,5H),3.56–3.45(m,2H),3.20–3.02(m,3H),2.95–2.82(m,3H),2.64–2.52(m,2H),2.32(d,J＝4.3Hz,3H),2.30–2.16(m,2H),2.07–2.00(m,1H),1.52(d,J＝7.0Hz,3H),1.45–1.23(m,4H),1.20–0.92(m,4H),0.76–0.57(m,4H).
实施例75 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-4-基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000206
LC-MS:m/z 859(M+H) +。1H NMR(400MHz,DMSO)δ11.01(s,1H),7.93–7.85(m,1H),7.58(d,J＝20.3Hz,1H),7.27(t,J＝7.7Hz,1H),7.03(d,J＝11.0Hz,1H),6.92(d,J＝7.4Hz,1H),6.89–6.83(m,2H),6.70(s,1H),6.68–6.60(m,1H),5.61–5.49(m,3H),5.43(dt,J＝19.6,5.5Hz,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.28–4.08(m,2H),3.97–3.74(m,5H),3.56–3.39(m,2H),3.11–2.84(m,6H),2.66–2.58(m,1H),2.39–2.16(m,6H),2.10–2.00(m,1H),1.54(d,J＝7.0Hz,3H),1.42–1.18(m,5H),1.18–0.92(m,3H),0.77–0.58(m,4H).
实施例76 顺式-N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)-N-甲基环己烷-1-甲酰胺和反式N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)-N-甲基环己烷-1-甲酰胺
Figure PCTCN2022080000-appb-000207
异构体1：LC-MS:m/z 941(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),8.03–7.86(m,1H),7.70(t,J＝7.8Hz,1H),7.66–7.45(m,1H),7.38–7.28(m,2H),7.10–7.00(m,1H),6.90–6.82(m,2H),6.70(s,1H),5.65–5.47(m,3H),5.13–5.05(m,1H),4.01–3.81(m,5H),3.79–3.70(m,1H),3.55–3.41(m,1H),3.29–3.20(m,4H),3.16–3.11(m,1H),2.95– 2.81(m,4H),2.73–2.54(m,4H),2.40–2.23(m,4H),2.10–1.99(m,1H),1.96–1.73(m,1H),1.64–1.39(m,8H),1.36–1.15(m,4H),0.92–0.57(m,4H).
异构体2：LC-MS:m/z 941(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.99–7.87(m,1H),7.69(t,J＝7.7Hz,1H),7.56(d,J＝20.2Hz,1H),7.37–7.27(m,2H),7.10–6.99(m,1H),6.87–6.83(m,2H),6.68(d,J＝11.7Hz,1H),5.63–5.47(m,3H),5.12–5.05(m,1H),3.97–3.71(m,6H),3.29–3.19(m,3H),3.15–3.10(m,1H),3.04–2.78(m,6H),2.72–2.54(m,4H),2.42–2.23(m,6H),2.10–1.99(m,3H),1.95–1.86(m,1H),1.81–1.43(m,6H),1.16–0.99(m,2H),0.80–0.58(m,4H).
实施例77 N-((1-(((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)氧基)甲基)环丙基)甲基)-5-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)-N-甲基戊酰胺
Figure PCTCN2022080000-appb-000208
LC-MS:m/z 915(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),8.00–7.88(m,1H),7.72–7.54(m,2H),7.34(dd,J＝7.1,3.2Hz,1H),7.24–7.01(m,2H),6.89–6.83(m,2H),6.67(s,1H),5.64–5.45(m,3H),5.09(dd,J＝12.8,5.5Hz,1H),4.00–3.74(m,5H),3.51–3.43(m,4H),3.19–2.97(m,5H),2.96–2.81(m,3H),2.64–2.52(m,2H),2.42–2.32(m,3H),2.29(d,J＝11.9Hz,3H),2.26–2.14(m,3H),2.11–1.98(m,1H),1.54(d,J＝7.0Hz,3H),1.40–1.19(m,3H),1.14–1.05(m,1H),0.79–0.57(m,4H).
实施例78 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000209
LC-MS:m/z 900(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.92(d,J＝7.9Hz,1H),7.74–7.54(m,2H),7.34(t,J＝6.5Hz,1H),7.19(dd,J＝34.5,8.5Hz,1H),7.04(d,J＝9.5Hz,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.61–5.46(m,3H),5.09(dd,J＝12.9,5.4Hz,1H),4.00–3.77(m,5H),3.54–3.44(m,2H),3.21–3.05(m,5H),2.97–2.80(m,3H),2.64–2.53(m,2H),2.42–2.27(m,8H),2.26–2.12(m,2H),2.08–1.96(m,2H),1.63–1.43(m,5H),0.80–0.57(m,4H).
实施例79 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-((1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌啶-4-基)氧基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000210
LC-MS:m/z 901(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(d,J＝7.9Hz,1H),7.71–7.54(m,2H),7.32(dd,J＝7.2,4.1Hz,1H),7.17(dd,J＝53.5,8.5Hz,1H),7.03(s,1H),6.88(s,1H),6.86(s,1H),6.69(s,1H),5.63–5.45(m,3H),5.09(dd,J＝12.9,5.4Hz,1H),4.01–3.74(m,5H),3.56–3.41(m,5H),3.30–3.04(m,3H),3.00–2.72(m,5H),2.65–2.53(m,4H),2.32(d,J＝8.7Hz,3H),2.10–1.97(m,1H),1.87–1.65(m,2H),1.62– 1.35(m,5H),0.79–0.57(m,4H).
实施例80 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(5-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000211
LC-MS:m/z 898(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.88(d,J＝7.9Hz,1H),7.65–7.52(m,2H),7.27–7.19(m,1H),7.13–6.97(m,2H),6.90–6.82(m,2H),6.69(s,1H),5.61–5.46(m,3H),5.13–5.05(m,1H),3.98–3.72(m,5H),3.58–3.37(m,6H),3.28–3.03(m,3H),2.96–2.82(m,3H),2.82–2.54(m,6H),2.35(d,J＝5.2Hz,3H),2.33–2.22(m,2H),2.08–1.98(m,1H),1.53(d,J＝7.1Hz,3H),0.75–0.56(m,4H).
实施例81 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(9-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-3,9-二氮杂螺[5.5]十一烷-3-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000212
LC-MS:m/z 941(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.97–7.86(m,1H),7.74–7.53(m,2H),7.31(t,J＝7.8Hz,1H),7.26–7.08(m,1H),7.04(d,J＝16.5Hz,1H),6.88(s,1H),6.86(s,1H),6.71–6.63(m,1H),5.59–5.48(m,3H),5.12–5.03(m,1H),4.00–3.70(m,5H),3.68–3.37(m,2H),3.17–2.80(m,10H),2.64–2.53(m,2H),2.33–2.23(m,3H),2.23–2.10(m,4H),2.08–1.95(m,1H),1.54(d,J＝5.5Hz,3H),1.47–1.15(m,8H),0.80–0.58(m,4H).
实施例82 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)丁氧基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000213
LC-MS:m/z 875(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.86(dd,J＝8.1,4.2Hz,1H),7.64–7.50(m,2H),7.07–6.97(m,3H),6.86(s,1H),6.85(s,1H),6.69(s,1H),6.47(t,J＝6.1Hz,1H),5.59–5.47(m,3H),5.05(dd,J＝12.9,5.4Hz,1H),4.22–3.74(m,7H),3.56–3.35(m,2H),3.24–3.12(m,4H),3.05–2.82(m,4H),2.64–2.53(m,2H),2.33(s,3H),2.09–1.97(m,1H),1.53(d,J＝7.0Hz,3H),1.49–1.36(m,4H),0.78–0.57(m,4H).
实施例83 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氧基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000214
LC-MS:m/z 874(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.88(t,J＝7.6Hz,1H),7.83–7.74(m,1H),7.57(d,J＝20.7Hz,1H),7.48–7.30(m,2H),7.03(d,J＝11.2Hz,1H),6.87(s,1H),6.86(s,1H),6.69(s,1H),5.62–5.44(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.09–3.75(m,7H),3.53–3.42(m,2H),3.06(s,1H),2.97–2.81(m,3H),2.64–2.53(m,2H),2.39–2.17(m,5H),2.09–1.96(m,1H),1.62–1.43(m,5H),1.39–1.23(m,3H),1.21–1.10(m,2H),1.08–0.94(m,1H),0.78–0.59(m,4H).
实施例84 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000215
LC-MS:m/z 873(M+H) +。1H NMR(400MHz,DMSO)δ11.04(s,1H),7.88(t,J＝7.6Hz,1H),7.58(d,J＝14.3Hz,1H),7.55(d,J＝2.7Hz,1H),7.03(d,J＝11.1Hz,1H),7.00–6.89(m,2H),6.87(s,1H),6.85(s,1H),6.83–6.72(m,1H),6.70(s,1H),5.62–5.44(m,3H),5.03(dd,J＝12.8,5.4Hz,1H),3.98–3.74(m,5H),3.56–3.40(m,2H),3.10–2.81(m,6H),2.63–2.52(m,2H),2.33(d,J＝7.6Hz,3H),2.24(dt,J＝33.7,7.4Hz,2H),2.04–1.96(m,1H),1.54(d,J＝7.1Hz,3H),1.42–1.23(m,4H),1.22–1.04(m,3H),1.02–0.91(m,1H),0.78–0.57(m,4H).
实施例85 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氧基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000216
LC-MS:m/z 874(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.89(t,J＝8.2Hz,1H),7.81(dd,J＝8.3,3.0Hz,1H),7.58(d,J＝23.2Hz,1H),7.35(dd,J＝11.0,2.3Hz,1H),7.32–7.20(m,1H),7.03(d,J＝13.4Hz,1H),6.88–6.83(m,2H),6.68(s,1H),5.61–5.45(m,3H),5.12(dd,J＝13.0,5.3Hz,1H),4.03–3.74(m,7H),3.54–3.42(m,2H),3.07(s,1H),2.96–2.83(m,3H),2.65–2.53(m,2H),2.38–2.16(m,5H),2.10–2.02(m,1H),1.54(d,J＝7.0Hz,3H),1.50–1.38(m,2H),1.38–1.04(m,4H),1.03–0.85(m,2H),0.77–0.58(m,4H).
实施例86 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-5-氟-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000217
LC-MS:m/z 891(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.94(s,1H),7.58(d,J＝16.2Hz,1H),7.48–7.36(m,1H),7.07(dd,J＝7.9,3.4Hz,1H),7.03(d,J＝9.4Hz, 1H),6.87–6.83(m,2H),6.70(s,1H),6.44–6.32(m,1H),5.66–5.43(m,3H),5.07(dd,J＝12.7,5.3Hz,1H),3.97–3.72(m,5H),3.57–3.35(m,4H),3.05(s,1H),2.96–2.82(m,3H),2.65–2.53(m,2H),2.34(d,J＝5.8Hz,3H),2.23(dt,J＝37.1,7.5Hz,2H),2.10–1.97(m,1H),1.54(d,J＝7.0Hz,3H),1.43–1.22(m,4H),1.22–1.02(m,3H),1.02–0.90(m,1H),0.77–0.57(m,4H).
实施例87 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-4-氟-1,3-二氧异吲哚-5-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000218
LC-MS:m/z 891(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(t,J＝8.4Hz,1H),7.57(d,J＝21.7Hz,1H),7.50(dd,J＝8.2,1.3Hz,1H),7.03(d,J＝12.2Hz,1H),6.95–6.74(m,4H),6.70(s,1H),5.65–5.44(m,3H),5.05(dd,J＝12.7,5.4Hz,1H),3.99–3.74(m,5H),3.57–3.37(m,2H),3.12–2.81(m,6H),2.66–2.53(m,2H),2.33(d,J＝7.9Hz,3H),2.23(dt,J＝34.8,7.3Hz,2H),2.09–1.97(m,1H),1.54(d,J＝7.0Hz,3H),1.39–1.22(m,4H),1.20–0.90(m,4H),0.77–0.57(m,4H).
实施例88 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-7-氟-1,3-二氧异吲哚-4-基)氨基)-N-甲基庚酰
Figure PCTCN2022080000-appb-000219
LC-MS:m/z 891(M+H) +。1H NMR(400MHz,DMSO)δ11.13(s,1H),7.91(t,J＝7.6Hz,1H),7.58(d,J＝22.9Hz,1H),7.49–7.38(m,1H),7.09–6.94(m,2H),6.90–6.83(m,2H),6.69(s,1H),6.38(dt,J＝22.0,5.9Hz,1H),5.66–5.43(m,3H),5.06(dd,J＝12.8,5.4Hz,1H),3.97–3.84(m,4H),3.84–3.73(m,1H),3.57–3.41(m,2H),3.14–3.08(m,1H),3.06(s,1H),3.04–2.95(m,1H),2.95–2.82(m,3H),2.64–2.54(m,2H),2.32(d,J＝8.8Hz,3H),2.30–2.15(m,2H),2.10–1.99(m,1H),1.53(d,J＝7.0Hz,3H),1.39–1.20(m,4H),1.20–0.82(m,4H),0.77–0.58(m,4H).
实施例89 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(8-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-2,8-二氮杂螺[4.5]癸烷-2-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000220
LC-MS:m/z 926(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.88(dd,J＝14.3,7.9Hz,1H),7.68–7.54(m,2H),7.31(d,J＝7.1Hz,1H),7.13(dd,J＝8.5,5.3Hz,1H),7.04(d,J＝16.8Hz,1H),6.87–6.82(m,2H),6.68(s,1H),5.58–5.42(m,3H),5.09(dd,J＝12.9,5.4Hz,1H),4.00–3.73(m,5H),3.49(dd,J＝39.5,14.1Hz,2H),3.33–3.17(m,3H),3.17–3.00(m,4H),2.99–2.74(m,5H),2.64–2.53(m,2H),2.49–2.38(m,1H),2.30(d,J＝8.2Hz,3H),2.25–2.09(m,1H),2.08–1.96(m,1H),1.62–1.38(m,9H),0.78–0.57(m,4H).
实施例90 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)丙氧基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000221
LC-MS:m/z 875(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.87(d,J＝7.9Hz,1H),7.63–7.49(m,2H),7.06–6.92(m,3H),6.87(s,1H),6.85(s,1H),6.70(s,1H),6.60(dt,J＝34.5,5.9Hz,1H),5.62–5.46(m,3H),5.04(dd,J＝12.9,5.4Hz,1H),3.98–3.75(m,5H),3.54–3.37(m,5H),3.30–3.23(m,2H),3.21–3.13(m,1H),3.07(s,1H),2.96–2.80(m,3H),2.69–2.51(m,4H),2.34(d,J＝6.6Hz,3H),2.09–1.97(m,1H),1.77–1.58(m,2H),1.54(d,J＝7.1Hz,3H),0.75–0.56(m,4H).
实施例91 N-((1-(((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)氧基)甲基)环丙基)甲基)-8-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-N-甲基辛-7-炔酰胺
Figure PCTCN2022080000-appb-000222
LC-MS:m/z 868(M+H) +。1H NMR(400MHz,DMSO)δ11.19–11.12(m,1H),8.00–7.89(m,1H),7.87–7.72(m,3H),7.58(d,J＝15.5Hz,1H),7.02(d,J＝3.2Hz,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.45(m,3H),5.14(dd,J＝12.9,5.4Hz,1H),3.99–3.73(m,5H),3.55–3.44(m,2H),3.06(s,1H),2.98–2.82(m,3H),2.65–2.54(m,2H),2.41–2.19(m,7H),2.10–1.98(m,1H),1.54(d,J＝7.0Hz,3H),1.51–1.43(m,1H),1.43–1.29(m,4H),1.29–1.14(m,1H),0.78–0.56(m,4H).
实施例92 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-((4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)丁-3-炔-1-基)氧基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000223
LC-MS:m/z 870(M+H) +。1H NMR(400MHz,DMSO)δ11.20–11.12(m,1H),7.91–7.73(m,4H),7.58(d,J＝19.2Hz,1H),7.02(s,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.62–5.46(m,3H),5.14(dd,J＝12.9,5.4Hz,1H),3.97–3.73(m,5H),3.57–3.41(m,6H),3.07(s,1H),2.96–2.81(m,3H),2.70–2.52(m,6H),2.33(d,J＝5.4Hz,3H),2.10–1.98(m,1H),1.54(d,J＝7.1Hz,3H),0.75–0.56(m,4H).
实施例93 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000224
LC-MS:m/z 874(M+H) +。1H NMR(400MHz,DMSO)δ11.13(s,1H),8.56(d,J＝4.8Hz,1H),7.89(d,J＝7.4Hz,1H),7.57(d,J＝17.4Hz,1H),7.03(d,J＝10.7Hz,1H),6.98–6.88(m,2H),6.88–6.81(m,2H),6.69(s,1H),5.62–5.45(m,3H),5.09(dd,J＝12.8,5.4Hz,1H),3.99–3.72(m,5H),3.60–3.42(m,4H),3.05(s,1H),2.97–2.81(m,3H),2.65–2.52(m,2H),2.33(d,J＝3.5Hz,3H),2.31–2.15(m,2H),2.10–1.98(m,1H),1.53(d,J＝7.0Hz,3H),1.47–1.21(m,4H),1.21–0.91(m,4H),0.78–0.56(m,4H).
实施例94 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000225
LC-MS:m/z 900(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.90(d,J＝7.7Hz,1H),7.60–7.52(m,2H),7.08–6.98(m,3H),6.89–6.82(m,2H),6.71–6.67(m,2H),5.62–5.45(m,3H),5.07(dd,J＝13.0,5.4Hz,1H),3.99–3.72(m,5H),3.61–3.38(m,3H),3.29–3.21(m,2H),3.14(s,1H),2.97–2.77(m,4H),2.72–2.52(m,5H),2.44–2.38(m,1H),2.34(s,3H),2.06–1.92(m,2H),1.66–1.38(m,6H),1.35–1.23(m,1H),0.78–0.59(m,4H).
实施例95 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)甘氨酰基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000226
LC-MS:m/z 914(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.90(t,J＝9.5Hz,1H),7.63–7.52(m,2H),7.10–7.01(m,4H),6.90–6.83(m,2H),6.70(s,1H),5.62–5.47(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.35–4.01(m,3H),3.98–3.88(m,3H),3.88–3.68(m,2H),3.67–3.56(m,1H),3.48–3.38(m,1H),3.19(s,1H),3.09–2.79(m,5H),2.77–2.65(m,1H),2.65–2.53(m,2H),2.36(s,3H),2.33–2.13(m,1H),2.09–1.96(m,1H),1.55(dd,J＝7.2,2.1Hz,3H),1.52–1.37(m,2H),1.37–1.22(m,2H),0.82–0.57(m,4H).
实施例96 顺式-N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环己基)-N-甲基哌啶-4-甲酰胺和反式-N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环己基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000227
异构体1：LC-MS:m/z 954(M+H) +。1H NMR(400MHz,DMSO)δ11.11(s,1H),7.93(d,J＝8.0Hz,1H),7.67–7.50(m,2H),7.16(d,J＝8.7Hz,1H),7.10–7.00(m,2H),6.90–6.82(m,2H),6.70(s,1H),6.14(d,J＝8.2Hz,1H),5.66–5.44(m,3H),5.05(dd,J＝12.7,5.5Hz,1H),4.03–3.79(m,5H),3.73(d,J＝10.3Hz,1H),3.59–3.38(m,4H),3.15(s,1H),2.98–2.80(m,4H),2.72–2.54(m,5H),2.35(s,3H),2.10–1.95(m,4H),1.92(s,1H),1.85–1.63(m,2H),1.55(d,J＝7.0Hz,3H),1.51–1.16(m,6H),0.81–0.58(m,4H).
异构体2：LC-MS:m/z 954(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.93–7.87(m,1H),7.63–7.51(m,2H),7.15(d,J＝8.7Hz,1H),7.09–6.99(m,2H),6.90–6.83(m,2H),6.70(s,1H),6.13(d,J＝8.2Hz,1H),5.68–5.43(m,3H),5.05(dd,J＝12.8,5.4Hz,1H),4.03–3.79(m,5H),3.73(d,J＝10.3Hz,1H),3.59–3.36(m,4H),3.13(s,1H),2.98–2.81(m,4H),2.79–2.66(m,1H),2.65–2.46(m,4H),2.35(s,3H),2.31–2.11(m,2H),2.09–1.94(m,3H),1.88–1.57(m,4H),1.55(d,J＝7.0Hz,3H),1.49–1.17(m,4H),0.82–0.56(m,4H).
实施例97 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(1'-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-[1,3'-二氮杂环丁烷]-3-基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000228
LC-MS:m/z 967(M+H) +。1H NMR(400MHz,DMSO)δ11.06(s,1H),7.88(d,J＝7.9Hz,1H),7.63(d,J＝8.3Hz,1H),7.55(d,J＝16.6Hz,1H),7.03(d,J＝19.8Hz,1H),6.90–6.81(m,2H),6.77(s,1H),6.69(s,1H),6.63(dd,J＝8.4,2.1Hz,1H),5.64–5.44(m,3H),5.05(dd,J＝12.8,5.4Hz,1H),4.00(t,J＝7.9Hz,2H),3.96–3.79(m,5H),3.79–3.69(m,2H),3.61–3.37(m,4H),3.29–3.22(m,2H),3.12(s,1H),2.95–2.86(m,3H),2.86–2.66(m,3H),2.64–2.51(m,4H),2.49–2.36(m,2H),2.34(s,3H),2.08–1.96(m,1H),1.54(d,J＝7.0Hz,3H),1.47–1.20(m,4H),0.81–0.58(m,4H).
实施例98 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(1'-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)-[1,3'-二氮杂环丁烷]-3-基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000229
LC-MS:m/z 967(M+H) +。1H NMR(400MHz,DMSO)δ11.06(s,1H),7.88(d,J＝7.9Hz,1H),7.59–7.51(m,2H),7.10(d,J＝6.9Hz,1H),7.03(d,J＝19.2Hz,1H),6.89–6.81(m,2H),6.76(dd,J＝8.5,2.8Hz,1H),6.69(s,1H),5.61–5.46(m,3H),5.04(dd,J＝12.8,5.4Hz,1H),4.22–4.08(m,2H),3.97–3.85(m,6H),3.85–3.70(m,1H),3.55–3.35(m,4H),3.30–3.22(m,2H),3.12(s,1H),2.95–2.85(m,3H),2.85–2.65(m,3H),2.65–2.52(m,4H),2.48–2.37(m,2H),2.34(s,3H),2.04–1.96(m,1H),1.54(d,J＝7.0Hz,3H),1.47–1.18(m, 4H),0.79–0.57(m,4H).
实施例99 4-((7-((S)-3-((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)氧基)吡咯烷-1-基)-7-氧庚基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000230
LC-MS:m/z 845(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.97(d,J＝8.0Hz,1H),7.78(d,J＝22.1Hz,1H),7.62–7.53(m,1H),7.13–7.04(m,2H),7.02(d,J＝7.6Hz,1H),6.88(s,1H),6.86(s,1H),6.70(s,1H),6.57–6.47(m,1H),5.66–5.47(m,3H),5.23–5.09(m,1H),5.09–5.02(m,1H),3.97–3.75(m,3H),3.72–3.52(m,4H),3.49–3.38(m,1H),3.31–3.21(m,1H),2.95–2.82(m,1H),2.65–2.53(m,2H),2.36(s,3H),2.33–2.27(m,2H),2.26–2.18(m,1H),2.16–2.07(m,1H),2.07–1.96(m,1H),1.68–1.44(m,7H),1.44–1.24(m,4H).
实施例100 4-((6-((S)-3-((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)氧基)吡咯烷-1-基)-6-氧己基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000231
LC-MS:m/z 831(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.99(d,J＝8.0Hz,1H),7.78(d,J＝22.5Hz,1H),7.63–7.53(m,1H),7.13–6.98(m,3H),6.88(s,1H),6.85(s,1H),6.70(s,1H),6.57–6.50(m,1H),5.68–5.46(m,3H),5.25–5.09(m,1H),5.09–5.01(m,1H),3.95–3.77(m,3H),3.73–3.52(m,3H),3.48–3.38(m,1H),2.97–2.82(m,1H),2.81–2.72(m,2H),2.64–2.53(m,2H),2.36(s,3H),2.34–2.19(m,3H),2.16–2.08(m,1H),2.07–1.95(m,1H),1.69–1.48(m,7H),1.45–1.31(m,2H).
实施例101 4-((2-(2-(3-((S)-3-((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)氧基)吡咯烷-1-基)-3-氧丙氧基)乙氧基)乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000232
LC-MS:m/z 877(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.97(dd,J＝8.0,2.4Hz,1H),7.77(d,J＝19.3Hz,1H),7.61–7.51(m,1H),7.12(dd,J＝8.6,6.9Hz,1H),7.09–7.00(m,2H),6.88(s,1H),6.86(s,1H),6.71(s,1H),6.64–6.55(m,1H),5.69–5.46(m,3H),5.23–5.09(m,1H),5.09–5.01(m,1H),3.86(s,3H),3.72–3.39(m,14H),2.95–2.81(m,1H),2.64–2.43(m,4H),2.36(s,3H),2.29–2.17(m,1H),2.15–2.08(m,1H),2.08–1.98(m,1H),1.60–1.53(m,3H).
实施例102 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)丁氧基)-N,2-二甲基丙酰胺
Figure PCTCN2022080000-appb-000233
LC-MS:m/z 903(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.88(d,J＝7.9Hz,1H),7.61–7.50(m,2H),7.08–6.95(m,2H),6.89–6.83(m,2H),6.69(s,1H),6.52–6.43(m,1H),5.62–5.49(m,3H),5.05(dd,J＝12.9,5.4Hz,1H),3.99–3.77(m,5H),3.57–3.44(m,2H),3.28–3.21(m,3H),3.21–3.13(m,2H),2.96–2.82(m,1H),2.65–2.52(m,4H),2.34(s,3H),2.07–2.00(m,1H),1.61–1.44(m,7H),1.25(s,6H),0.66(s,4H).
实施例103 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-((4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环己基)氧基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000234
LC-MS:m/z 929(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.88(t,J＝7.9Hz,1H),7.63–7.52(m,2H),7.15–7.01(m,3H),6.88–6.82(m,2H),6.69(s,1H),6.16–6.08(m,1H),5.62–5.44(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),3.98–3.83(m,4H),3.83–3.73(m,1H),3.62–3.36(m,3H),3.15–3.06(m,2H),3.01–2.82(m,5H),2.64–2.52(m,2H),2.38–2.30(m,4H),2.30–2.20(m,1H),2.07–1.99(m,1H),1.93–1.60(m,4H),1.60–1.44(m,5H),1.22–1.01(m,4H),0.77–0.57(m,4H).
实施例104 N1-((1-(((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)氧基)甲基)环丙基)甲基)-N4-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环己基)-N1,N4-二甲基丁二酰胺
Figure PCTCN2022080000-appb-000235
LC-MS:m/z 956(M+H) +。1H NMR(400MHz,DMSO)δ11.12(s,1H),7.90(t,J＝6.9Hz,1H),7.68–7.53(m,2H),7.21–6.97(m,3H),6.93–6.81(m,2H),6.70(s,1H),6.60–6.08(m,1H),5.72–5.43(m,3H),5.14–5.01(m,1H),4.01–3.74(m,5H),3.66–3.37(m,4H),3.13–3.07(m,1H),2.97–2.81(m,3H),2.68–2.53(m,6H),2.53–2.43(m,1H),2.40–2.23(m,5H),2.11–1.91(m,2H),1.89–1.64(m,2H),1.63–1.42(m,4H),1.41–1.14(m,4H),0.82–0.54(m,4H).
实施例105 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙氧基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000236
LC-MS:m/z 875(M+H) +。 1H NMR(400MHz,DMSO)δ11.11(s,1H),7.91–7.85(m, 1H),7.64–7.51(m,2H),7.10–6.99(m,3H),6.87(s,1H),6.85(s,1H),6.69(s,1H),6.59–6.50(m,1H),5.64–5.46(m,3H),5.10–5.01(m,1H),4.01–3.72(m,5H),3.54–3.34(m,6H),3.19(dt,J＝40.2,6.5Hz,2H),3.03(s,1H),2.96–2.80(m,3H),2.63–2.53(m,2H),2.41–2.31(m,4H),2.31–2.23(m,1H),2.06–1.98(m,1H),1.62–1.49(m,5H),0.75–0.57(m,4H).
实施例106 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000237
LC-MS:m/z 900(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(dd,J＝7.9,4.1Hz,1H),7.70–7.52(m,2H),7.24(dd,J＝17.6,2.3Hz,1H),7.16–7.00(m,2H),6.89(s,1H),6.87(s,1H),6.69(s,1H),5.65–5.42(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),3.98–3.71(m,5H),3.57–3.38(m,2H),3.28–3.20(m,2H),3.20–3.11(m,2H),3.08(s,1H),2.97–2.81(m,3H),2.64–2.53(m,2H),2.38–2.26(m,5H),2.23–2.17(m,2H),2.17–1.99(m,2H),1.98–1.79(m,1H),1.61–1.40(m,5H),0.78–0.58(m,4H).
实施例107 N-((1-(((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)氧基)甲基)环丙基)甲基)-5-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)-N-甲基戊酰胺
Figure PCTCN2022080000-appb-000238
LC-MS:m/z 914(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.92(dd,J＝12.3,7.9Hz,1H),7.70–7.51(m,2H),7.29–7.23(m,1H),7.15–7.01(m,2H),6.89–6.83(m,2H),6.66(s,1H),5.64–5.44(m,3H),5.08(dd,J＝12.8,5.4Hz,1H),3.99–3.84(m,4H),3.83–3.74(m,1H),3.51–3.37(m,2H),3.23–3.18(m,2H),3.15–3.11(m,2H),3.09(s,1H),2.99–2.81(m,3H),2.65–2.52(m,2H),2.38–2.29(m,5H),2.26–2.21(m,2H),2.13–1.98(m,5H),1.54(d,J＝5.5Hz,3H),1.35–1.28(m,2H),1.26–1.18(m,1H),1.09–0.95(m,1H),0.79–0.57(m,4H).
实施例108 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(4-(4-((2,6-二氧哌啶-3-基)氨基)苯基)哌啶-1-基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000239
LC-MS:m/z 831(M+H) +。1H NMR(400MHz,DMSO)δ10.77(s,1H),7.90(dd,J＝8.2,3.3Hz,1H),7.59(d,J＝18.8Hz,1H),7.04(d,J＝6.0Hz,1H),6.97–6.81(m,4H),6.70(s,1H),6.60(s,1H),6.58(s,1H),5.63(d,J＝7.4Hz,1H),5.60–5.51(m,3H),4.33–4.19(m,1H),3.99–3.86(m,4H),3.86–3.76(m,1H),3.56–3.39(m,2H),3.09(s,1H),2.97–2.87(m,2H),2.86–2.77(m,1H),2.77–2.64(m,2H),2.63–2.52(m,2H),2.48–2.37(m,3H),2.35(s,3H),2.24–1.98(m,2H),1.94–1.71(m,3H),1.64–1.44(m,6H),1.43–1.31(m,1H),0.79–0.57(m,4H).
实施例109 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-(1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-基)哌嗪-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000240
LC-MS:m/z 955(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(d,J＝7.9Hz,1H),7.66(dd,J＝8.6,2.0Hz,1H),7.58(d,J＝11.9Hz,1H),7.29(dd,J＝4.0,2.2Hz,1H),7.24–7.17(m,1H),7.03(d,J＝8.0Hz,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.65–5.45(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.03–3.74(m,6H),3.62–3.47(m,2H),3.10(s,1H),3.09–2.97(m,2H),2.97–2.78(m,5H),2.64–2.52(m,3H),2.43–2.31(m,5H),2.31–2.25(m,2H),2.25–2.13(m,4H),2.05–1.98(m,1H),1.76–1.68(m,1H),1.67–1.58(m,1H),1.54(d,J＝7.0Hz,3H),1.41–1.19(m,2H),0.79–0.60(m,4H).
实施例110 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-羰基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000241
LC-MS:m/z 968(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.91(t,J＝7.9Hz,1H),7.65(d,J＝8.5Hz,1H),7.58(d,J＝27.0Hz,1H),7.30(s,1H),7.25–7.15(m,1H),7.05(d,J＝18.8Hz,1H),6.91–6.82(m,2H),6.70(s,1H),5.67–5.44(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.35–4.15(m,1H),4.08–3.95(m,2H),3.92(s,3H),3.89–3.62(m,3H),3.25–3.15(m,2H),3.11–2.73(m,8H),2.63–2.52(m,3H),2.38–2.32(m,3H),2.26–2.09(m,1H),2.06–1.98(m,1H),1.72–1.44(m,8H),1.44–1.33(m,2H),1.32–1.12(m,1H),0.82–0.57(m,4H).
实施例111 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(9-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-3,9-二氮杂螺[5.5]十一烷-3-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000242
LC-MS:m/z 940(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.90(dd,J＝10.9,7.9Hz,1H),7.71–7.53(m,2H),7.28–7.20(m,1H),7.18–7.00(m,2H),6.91–6.82(m,2H),6.67(d,J＝16.8Hz,1H),5.65–5.42(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.01–3.72(m,5H),3.59–3.39(m,2H),3.27–3.16(m,4H),3.15–3.02(m,3H),2.98–2.82(m,3H),2.65–2.54(m,2H),2.31(d,J＝42.7Hz,3H),2.24–2.10(m,4H),2.07–1.96(m,1H),1.53(dd,J＝7.2,2.2Hz,3H),1.40–1.28(m,4H),1.28–1.13(m,4H),0.81–0.58(m,4H).
实施例112 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-(((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氨基)甲基)哌啶-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000243
LC-MS:m/z 900(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.90(dd,J＝8.0,3.4Hz,1H),7.62–7.52(m,2H),7.12–6.99(m,3H),6.86(s,1H),6.84(s,1H),6.70(s,1H),6.59–6.53(m,1H),5.62–5.47(m,3H),5.05(dd,J＝12.9,5.4Hz,1H),3.95–3.83(m,4H),3.82–3.73(m,1H),3.60–3.38(m,2H),3.21–3.00(m,5H),2.97–2.81(m,3H),2.79–2.69(m,2H),2.64–2.52(m,2H),2.34(s,3H),2.07–1.99(m,1H),1.97–1.79(m,2H),1.67–1.39(m,6H),1.28–1.09(m,2H),0.77–0.59(m,4H).
实施例113 N-((1-(((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)氧基)甲基)环丙基)甲基)-7-((1-(2,6-二氧哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)氨基)-N-甲基庚酰胺
Figure PCTCN2022080000-appb-000244
LC-MS:m/z 874(M+H) +。1H NMR(400MHz,DMSO)δ11.06(s,1H),7.90(t,J＝6.8Hz,1H),7.58(d,J＝19.9Hz,1H),7.03(d,J＝11.5Hz,1H),6.90–6.83(m,3H),6.69(s,1H),6.49(d,J＝7.9Hz,1H),6.35(dd,J＝14.5,8.2Hz,1H),5.62–5.46(m,3H),5.28(dd,J＝12.7,5.3Hz,1H),4.88(dt,J＝19.4,5.6Hz,1H),3.96–3.84(m,4H),3.84–3.73(m,1H),3.59(s,3H),3.56–3.37(m,2H),3.06(s,1H),2.96–2.80(m,5H),2.75–2.57(m,2H),2.33(d,J＝3.8Hz,3H),2.25(dt,J＝33.6,7.5Hz,2H),2.05–1.91(m,1H),1.53(dd,J＝7.2,1.9Hz,3H),1.49–1.20(m,5H),1.19–1.07(m,2H),1.03–0.96(m,1H),0.78–0.57(m,4H).
实施例114 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-((4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)甲基)哌啶-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000245
LC-MS:m/z 969(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.90(dd,J＝7.9,5.1Hz,1H),7.68(d,J＝8.5Hz,1H),7.58(d,J＝11.6Hz,1H),7.32(s,1H),7.23(dd,J＝8.7,2.3Hz,1H),7.04(d,J＝13.8Hz,1H),6.87(s,1H),6.85(s,1H),6.69(s,1H),5.60–5.51(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),3.92–3.86(m,4H),3.81–3.74(m,1H),3.59–3.47(m,1H),3.43–3.35(m,4H),3.12(s,1H),3.08–2.99(m,2H),2.96–2.82(m,3H),2.74–2.52(m,4H),2.44–2.27(m,7H),2.11–1.97(m,3H),1.92–1.73(m,2H),1.61–1.43(m,5H),1.39–1.22(m,2H),1.12–0.90(m,2H),0.74–0.63(m,4H).
实施例115 顺式-N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)-N-甲基环己烷-1-甲酰胺和反式-N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)-N-甲基环己烷-1-甲酰胺
Figure PCTCN2022080000-appb-000246
异构体1：LC-MS:m/z 940(M+H)+。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.92 (t,J＝9.0Hz,1H),7.68(dd,J＝8.6,4.9Hz,1H),7.57(d,J＝27.8Hz,1H),7.33(dd,J＝8.6,2.1Hz,1H),7.25(dd,J＝8.3,2.5Hz,1H),7.07(d,J＝39.5Hz,1H),6.90–6.81(m,2H),6.70(s,1H),5.63–5.45(m,3H),5.08(dd,J＝12.6,5.1Hz,1H),3.94(d,J＝19.5Hz,3H),3.80(dd,J＝55.3,11.5Hz,2H),3.56–3.44(m,2H),3.44–3.35(m,4H),3.13(s,1H),2.97–2.82(m,3H),2.65–2.53(m,4H),2.47–2.39(m,3H),2.34(d,J＝7.6Hz,3H),2.25–2.09(m,1H),2.06–1.97(m,1H),1.64–1.36(m,7H),1.34–1.13(m,2H),0.83–0.59(m,4H).
异构体2：LC-MS:m/z 940(M+H)+。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.95(s,1H),7.67(dd,J＝8.5,5.1Hz,1H),7.57(d,J＝21.9Hz,1H),7.37–7.18(m,2H),7.04(d,J＝10.0Hz,1H),6.88–6.82(m,2H),6.68(d,J＝14.0Hz,1H),5.63–5.45(m,3H),5.11–5.02(m,1H),4.00–3.61(m,5H),3.49–3.36(m,2H),3.34–3.22(m,2H),3.17–3.01(m,3H),2.97–2.75(m,3H),2.72–2.65(m,1H),2.65–2.53(m,2H),2.48–2.40(m,2H),2.38–2.29(m,3H),2.28–2.13(m,2H),2.12–1.94(m,2H),1.80–1.39(m,7H),1.35–1.16(m,2H),1.15–0.97(m,2H),0.79–0.59(m,4H).
实施例116 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-((4-(2-(2,6-二氧哌啶-3-基)-6-氟-1,3-二氧异吲哚-5-基)哌嗪-1-基)甲基)哌啶-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000247
LC-MS:m/z 987(M+H) +。1H NMR(400MHz,DMSO)δ11.12(s,1H),7.91(dd,J＝8.0,4.5Hz,1H),7.73(d,J＝11.4Hz,1H),7.58(d,J＝12.3Hz,1H),7.43(dd,J＝7.5,3.0Hz,1H),7.04(d,J＝14.4Hz,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.62–5.45(m,3H),5.11(dd,J＝12.8,5.4Hz,1H),3.98–3.73(m,5H),3.61–3.37(m,2H),3.25–3.14(m,4H),3.14–2.99(m,3H),2.97–2.81(m,3H),2.75–2.65(m,2H),2.65–2.54(m,2H),2.45–2.37(m,3H),2.34(d,J＝5.6Hz,3H),2.14–1.95(m,3H),1.95–1.83(m,1H),1.82–1.70(m,1H),1.64–1.42(m,5H),1.40–1.22(m,1H),1.09–0.90(m,2H),0.78–0.60(m,4H).
实施例117 顺式-N-((1-(((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)氧基)甲基)环丙基)甲基)-4-((4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环己基)(甲基)氨基)-N-甲基丁酰胺和反式-N-((1-(((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)氧基)甲基)环丙基)甲基)-4-((4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环己基)(甲基)氨基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000248
异构体1：LC-MS:m/z 942(M+H) +。1H NMR(400MHz,DMSO)δ11.11(s,1H),8.04–7.85(m,1H),7.67–7.51(m,2H),7.18–6.98(m,4H),6.88–6.80(m,1H),6.69(s,1H),6.17–6.06(m,1H),5.68–5.46(m,3H),5.06(dd,J＝13.1,5.4Hz,1H),3.98–3.71(m,5H),3.61–3.48(m,2H),3.12–2.99(m,1H),2.96–2.80(m,3H),2.71–2.55(m,2H),2.40–2.25(m,5H),2.25–2.12(m,3H),2.09–1.82(m,7H),1.76–1.49(m,5H),1.49–1.36(m,4H),1.34– 1.20(m,2H),1.17–1.03(m,2H),0.77–0.57(m,4H).
异构体2：LC-MS:m/z 942(M+H) +。1H NMR(400MHz,DMSO)δ11.13(s,1H),7.89(d,J＝7.8Hz,1H),7.66–7.51(m,2H),7.11–6.99(m,3H),6.91–6.82(m,2H),6.69(s,1H),6.39(t,J＝8.7Hz,1H),5.64–5.43(m,3H),5.13–5.02(m,1H),3.97–3.68(m,5H),3.54–3.39(m,2H),3.12–2.98(m,1H),2.96–2.79(m,3H),2.69–2.54(m,2H),2.38–2.25(m,5H),2.25–2.13(m,3H),2.12–1.87(m,7H),1.74–1.56(m,4H),1.53(d,J＝7.0Hz,3H),1.50–1.36(m,5H),1.35–1.19(m,3H),0.77–0.56(m,4H).
实施例118 N-((1-(((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)氧基)甲基)环丙基)甲基)-1'-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-N-甲基-[1,4'-联哌啶]-4-甲酰胺
Figure PCTCN2022080000-appb-000249
LC-MS:m/z 940(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.90(dd,J＝8.1,3.7Hz,1H),7.66(dd,J＝8.5,3.5Hz,1H),7.55(d,J＝19.8Hz,1H),7.31(s,1H),7.22(dd,J＝8.8,2.4Hz,1H),7.05(d,J＝31.1Hz,1H),6.91–6.80(m,2H),6.69(s,1H),5.63–5.45(m,3H),5.07(dd,J＝13.0,5.3Hz,1H),4.07–3.99(m,2H),3.97–3.70(m,5H),3.53–3.38(m,2H),3.12(s,1H),2.97–2.80(m,5H),2.80–2.67(m,1H),2.66–2.53(m,4H),2.33(d,J＝4.1Hz,3H),2.19–1.95(m,2H),1.79–1.57(m,4H),1.56–1.50(m,3H),1.48–1.18(m,6H),0.81–0.57(m,4H).
实施例119 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-((1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-基)氧基)哌啶-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000250
LC-MS:m/z 970(M+H) +。1H NMR(400MHz,DMSO)δ11.15(s,1H),8.01–7.94(m,1H),7.72(d,J＝8.5Hz,1H),7.64(d,J＝14.2Hz,1H),7.38(d,J＝2.3Hz,1H),7.29(dd,J＝8.7,2.3Hz,1H),7.10(d,J＝14.5Hz,1H),6.92(s,1H),6.90(s,1H),6.75(s,1H),5.68–5.53(m,3H),5.13(dd,J＝12.9,5.4Hz,1H),4.05–3.90(m,4H),3.90–3.74(m,2H),3.69–3.51(m,3H),3.38–3.29(m,2H),3.29–3.19(m,2H),3.18–3.04(m,3H),3.02–2.88(m,3H),2.72–2.57(m,4H),2.40(d,J＝6.1Hz,3H),2.15–1.94(m,3H),1.91–1.66(m,4H),1.60(d,J＝7.0Hz,3H),1.54–1.25(m,4H),0.84–0.65(m,4H).
实施例120 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-(1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)氮杂环丁烷-3-基)哌嗪-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000251
LC-MS:m/z 927(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.91(d,J＝7.9Hz,1H),7.65(d,J＝8.3Hz,1H),7.58(d,J＝15.6Hz,1H),7.04(d,J＝8.8Hz,1H),6.87(s, 1H),6.85(s,1H),6.75(dd,J＝14.9,2.1Hz,1H),6.69(d,J＝5.0Hz,1H),6.65–6.54(m,1H),5.63–5.48(m,3H),5.06(dd,J＝12.9,5.4Hz,1H),4.01(t,J＝7.9Hz,1H),3.95–3.83(m,5H),3.81–3.73(m,2H),3.67–3.49(m,2H),3.46–3.36(m,2H),3.28–3.18(m,1H),3.15–3.00(m,4H),2.96–2.81(m,3H),2.64–2.50(m,4H),2.35(d,J＝15.0Hz,3H),2.32–2.18(m,4H),2.14–1.95(m,1H),1.54(d,J＝7.0Hz,3H),0.78–0.60(m,4H).
实施例121 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-((1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-基)氨基)-N-甲基环己基-1-甲酰胺
Figure PCTCN2022080000-appb-000252
LC-MS:m/z 954(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.91(d,J＝8.1Hz,1H),7.65(d,J＝8.5Hz,1H),7.56(d,J＝20.3Hz,1H),7.31(s,1H),7.22(d,J＝8.4Hz,1H),7.03(d,J＝9.7Hz,1H),6.90–6.82(m,2H),6.70(s,1H),5.66–5.45(m,3H),5.07(dd,J＝12.9,5.5Hz,1H),4.06–3.69(m,7H),3.53–3.43(m,2H),3.14(s,1H),3.07–2.95(m,2H),2.94–2.83(m,3H),2.64–2.51(m,4H),2.34(d,J＝2.7Hz,3H),2.05–1.97(m,1H),1.92–1.75(m,3H),1.70–1.43(m,6H),1.42–1.12(m,7H),0.81–0.48(m,4H).
实施例122 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-(2-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)乙基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000253
LC-MS:m/z 969(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.91(dd,J＝7.9,5.1Hz,1H),7.67(d,J＝8.5Hz,1H),7.56(d,J＝20.0Hz,1H),7.34–7.30(m,1H),7.23(dt,J＝8.7,2.6Hz,1H),7.04(d,J＝23.5Hz,1H),6.90–6.80(m,2H),6.69(d,J＝5.7Hz,1H),5.64–5.46(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),4.01–3.68(m,5H),3.57–3.42(m,2H),3.41–3.30(m,8H),3.13(s,1H),2.96–2.78(m,3H),2.72–2.52(m,4H),2.49–2.38(m,4H),2.38–2.21(m,5H),2.07–1.91(m,2H),1.54(dd,J＝7.1,3.0Hz,3H),1.48–1.17(m,4H),0.80–0.59(m,4H).
实施例123 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-(4-(4-((2,6-二氧哌啶-3-基)氨基)苯基)哌啶-1-基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000254
LC-MS:m/z 845(M+H)+。1H NMR(400MHz,DMSO)δ10.80(s,1H),7.95(s,1H),7.60(d,J＝25.5Hz,1H),7.06(d,J＝17.2Hz,1H),6.97–6.78(m,4H),6.70(s,1H),6.66–6.52(m,2H),5.69(s,1H),5.64–5.42(m,3H),4.34–4.20(m,1H),4.05–3.69(m,5H),3.60–3.41(m,2H),3.08(s,1H),2.96–2.84(m,3H),2.83–2.66(m,2H),2.65–2.52(m,2H),2.34(s,3H),2.27–2.04(m,4H),2.02–1.66(m,4H),1.63–1.35(m,9H),0.81–0.51(m,4H).
实施例124 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(4-((4-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌嗪-1-基)甲基)哌啶-1-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000255
LC-MS:m/z 955(M+H) +。1H NMR(400MHz,DMSO)δ10.95(s,1H),7.95–7.88(m,1H),7.59(d,J＝13.0Hz,1H),7.52(d,J＝8.8Hz,1H),7.08–7.00(m,3H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.47(m,3H),5.05(dd,J＝13.3,5.1Hz,1H),4.27(dd,J＝50.0,17.5Hz,2H),3.95–3.83(m,4H),3.83–3.76(m,1H),3.59–3.51(m,2H),3.45–3.36(m,2H),3.27–3.18(m,4H),3.16–3.01(m,3H),2.97–2.83(m,3H),2.77–2.65(m,2H),2.64–2.54(m,2H),2.44–2.36(m,4H),2.34(d,J＝9.9Hz,3H),2.09–2.01(m,2H),2.00–1.93(m,1H),1.88–1.75(m,1H),1.64–1.41(m,5H),1.10–0.92(m,2H),0.78–0.60(m,4H).
实施例125 N-((1-(((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)氧基)甲基)环丙基)甲基)-3-(4-(((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)甲基)哌啶-1-基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000256
LC-MS:m/z 914(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.89(dd,J＝8.0,4.0Hz,1H),7.62–7.53(m,2H),7.08(dd,J＝8.7,5.3Hz,1H),7.05–6.99(m,2H),6.88–6.83(m,2H),6.69(s,1H),6.58–6.48(m,1H),5.63–5.45(m,3H),5.11–5.01(m,1H),3.94–3.84(m,4H),3.81–3.77(m,1H),3.46(d,J＝9.2Hz,2H),3.18–3.04(m,3H),2.96–2.82(m,3H),2.75–2.68(m,1H),2.65–2.52(m,3H),2.48–2.41(m,1H),2.41–2.25(m,6H),2.11–1.98(m,1H),1.80–1.61(m,2H),1.60–1.38(m,6H),1.21–0.97(m,2H),0.76–0.58(m,4H).
实施例126 N-((1-(((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)氧基)甲基)环丙基)甲基)-4-((1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-基)氧基)-N-甲基环己基-1-甲酰胺
Figure PCTCN2022080000-appb-000257
LC-MS:m/z 955(M+H) +。1H NMR(400MHz,DMSO)δ11.08(s,1H),7.95–7.87(m,1H),7.64(dd,J＝8.5,3.5Hz,1H),7.57(d,J＝20.3Hz,1H),7.29(s,1H),7.25–7.14(m,1H),7.03(d,J＝11.5Hz,1H),6.90–6.82(m,2H),6.69(s,1H),5.63–5.45(m,3H),5.11–5.02(m,1H),3.98–3.80(m,4H),3.79–3.58(m,3H),3.57–3.39(m,4H),3.26–3.06(m,3H),2.98–2.80(m,3H),2.71–2.52(m,2H),2.34(d,J＝8.6Hz,3H),2.05–1.97(m,1H),1.83–1.62(m,3H),1.61–1.46(m,6H),1.46–1.29(m,3H),1.28–1.17(m,1H),1.16–0.85(m,2H),0.78–0.58(m,4H).
实施例127 N-((1-(((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)氧基)甲基)环丙基)甲基)-2-(2-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)乙氧基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000258
LC-MS:m/z 916(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.96–7.89(m,1H),7.71–7.52(m,2H),7.29–7.22(m,1H),7.14–7.02(m,2H),6.89–6.83(m,2H),6.69–6.65(m,1H),5.65–5.45(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),4.14(d,J＝47.0Hz,2H),4.01–3.86(m,4H),3.86–3.76(m,1H),3.59–3.38(m,2H),3.29–3.09(m,6H),3.03(s,1H),2.98–2.80(m,3H),2.67–2.52(m,2H),2.41–2.29(m,5H),2.29–2.18(m,4H),2.06–1.99(m,1H),1.53(d,J＝7.0Hz,3H),0.80–0.60(m,4H).
实施例128(R)-N-((1-(((4-((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)氧基)甲基)环丙基)甲基)-1-(4-(2,4-二氧四氢嘧啶-1(2H)-基)苯基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000259
LC-MS:m/z 789(M+H) +。1H NMR(400MHz,DMSO)δ10.25(s,1H),7.95–7.86(m,1H),7.58(d,J＝25.0Hz,1H),7.14–7.05(m,2H),7.03(d,J＝3.5Hz,1H),6.90–6.75(m,4H),6.70(s,1H),5.64–5.47(m,3H),3.98–3.87(m,2H),3.87–3.75(m,3H),3.74–3.64(m,2H),3.64–3.55(m,1H),3.54–3.39(m,3H),3.18(s,1H),2.92(s,2H),2.89–2.79(m,1H),2.76–2.61(m,3H),2.36(s,3H),2.33–2.21(m,1H),1.62–1.43(m,6H),1.42–1.30(m,1H),0.81–0.58(m,4H).
实施例129(R)-N-((1-(((4-((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)氧基)甲基)环丙基)甲基)-2-(1-(4-(2,4-二氧四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)-N-甲基乙酰胺
Figure PCTCN2022080000-appb-000260
LC-MS:m/z 803(M+H) +。1H NMR(400MHz,DMSO)δ10.26(s,1H),8.06–7.86(m,1H),7.61(d,J＝10.0Hz,1H),7.19–7.01(m,3H),6.90–6.83(m,3H),6.77–6.72(m,1H),6.71–6.66(m,1H),5.66–5.44(m,3H),4.00–3.84(m,4H),3.84–3.77(m,1H),3.75–3.65(m,2H),3.65–3.36(m,2H),3.24–3.16(m,2H),3.15–3.09(m,2H),3.09–3.01(m,2H),2.99–2.83(m,3H),2.75–2.62(m,3H),2.49–2.39(m,4H),2.36(d,J＝3.7Hz,3H),1.53(dd,J＝12.5,7.0Hz,3H),0.81–0.60(m,4H).
实施例130(R)-N-((1-(((4-((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)氧基)甲基)环丙基)甲基)-3-(1-(4-(2,4-二氧四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)-N-甲基丙酰胺
Figure PCTCN2022080000-appb-000261
LC-MS:m/z 818(M+H) +。1H NMR(400MHz,DMSO)δ10.27(s,1H),7.91(t,J＝7.5Hz,1H),7.59(d,J＝23.8Hz,1H),7.15–7.08(m,2H),7.05(d,J＝15.3Hz,1H),6.90–6.81(m,3H),6.77(d,J＝8.9Hz,1H),6.69(s,1H),5.62–5.46(m,3H),4.00–3.86(m,4H),3.86–3.76(m,1H),3.69(t,J＝6.7Hz,2H),3.57–3.47(m,2H),3.47–3.39(m,2H),3.10(s,1H),3.04–2.97(m,2H),2.91(s,2H),2.88–2.80(m,2H),2.73–2.64(m,2H),2.50–2.37(m,5H),2.36(s,3H),2.29–2.17(m,2H),1.54(dd,J＝7.1,4.5Hz,3H),0.81–0.57(m,4H).
实施例131(R)-N-((1-(((4-((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)氧基)甲基)环丙基)甲基)-4-(1-(4-(2,4-二氧四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)-N-甲基丁酰胺
Figure PCTCN2022080000-appb-000262
LC-MS:m/z 831(M+H) +。1H NMR(400MHz,DMSO)δ10.26(s,1H),7.93(d,J＝7.8Hz,1H),7.59(d,J＝21.5Hz,1H),7.17–7.10(m,2H),7.05(d,J＝12.5Hz,1H),6.90–6.79(m,4H),6.70(s,1H),5.64–5.45(m,3H),3.98–3.86(m,4H),3.85–3.76(m,1H),3.70(t,J＝6.6Hz,2H),3.47(d,J＝10.8Hz,2H),3.32–3.25(m,1H),3.08(s,1H),3.03–2.84(m,6H),2.69(t,J＝6.7Hz,2H),2.34(d,J＝7.0Hz,3H),2.32–2.14(m,6H),2.13–2.03(m,1H),2.00–1.84(m,1H),1.54(dd,J＝7.1,1.7Hz,3H),1.52–1.43(m,2H),0.79–0.59(m,4H).
实施例132(R)-N-((1-(((4-((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)氧基)甲基)环丙基)甲基)-5-(1-(4-(2,4-二氧四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)-N-甲基戊酰胺
Figure PCTCN2022080000-appb-000263
LC-MS:m/z 845(M+H) +。1H NMR(400MHz,DMSO)δ10.27(s,1H),7.94(d,J＝7.6Hz,1H),7.58(d,J＝25.2Hz,1H),7.17–7.11(m,2H),7.06(d,J＝18.0Hz,1H),6.89–6.79(m,4H),6.69(s,1H),5.63–5.46(m,3H),3.97–3.85(m,4H),3.85–3.73(m,1H),3.70(t,J＝6.7Hz,2H),3.55(dd,J＝14.3,8.5Hz,1H),3.45–3.36(m,2H),3.08(s,1H),3.01–2.81(m,6H),2.69(t,J＝6.7Hz,2H),2.40–2.27(m,6H),2.27–2.20(m,1H),2.20–1.97(m,4H),1.53(d,J＝7.0Hz,3H),1.40–1.18(m,3H),1.12–0.98(m,1H),0.79–0.57(m,4H).
实施例133(2S,4R)-1-((S)-2-(3-(3-(((1-(((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)环丙基)甲基)(甲基)氨基)-3-氧丙氧基)丙酰胺)-3,3-二甲基丁氧基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯啉-2-甲酰胺
Figure PCTCN2022080000-appb-000264
LC-MS:m/z 1046(M+H) +。1H NMR(400MHz,DMSO)δ8.98(s,1H),8.65(dt,J＝24.0,6.1Hz,1H),7.88(d,J＝7.6Hz,2H),7.57(d,J＝20.1Hz,1H),7.46–7.35(m,4H),7.05(d,J＝8.8Hz,1H),6.87(s,1H),6.85(s,1H),6.70(s,1H),5.62–5.49(m,3H),5.16(dd,J＝6.1, 3.5Hz,1H),4.53(dd,J＝9.3,6.3Hz,1H),4.49–4.40(m,2H),4.38–4.34(m,1H),4.22(dd,J＝15.9,5.4Hz,1H),3.95–3.84(m,4H),3.83–3.72(m,1H),3.71–3.59(m,2H),3.58–3.38(m,6H),2.96(d,J＝73.9Hz,3H),2.68–2.56(m,1H),2.50–2.40(m,4H),2.38–2.25(m,4H),2.09–1.99(m,1H),1.96–1.87(m,1H),1.54(d,J＝7.0Hz,3H),0.93(s,9H),0.75–0.56(m,4H).
实施例134(R)-1-(4-(4-((((1-(((4-((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)氧基)甲基)环丙基)甲基)(甲基)氨基)甲基)哌啶-1-基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
Figure PCTCN2022080000-appb-000265
LC-MS:m/z 775(M+H) +。1H NMR(400MHz,DMSO)δ10.25(s,1H),7.96(d,J＝8.0Hz,1H),7.64(s,1H),7.08–7.00(m,3H),6.92–6.85(m,2H),6.71–6.62(m,3H),5.67–5.47(m,3H),3.98(s,2H),3.86(s,3H),3.67(t,J＝6.7Hz,2H),3.44–3.36(m,2H),2.67(t,J＝6.7Hz,2H),2.38–2.34(m,5H),2.31–2.20(m,5H),2.14(d,J＝7.1Hz,2H),1.68–1.58(m,2H),1.55(d,J＝7.1Hz,3H),1.53–1.44(m,1H),1.08–0.90(m,2H),0.70–0.59(m,2H),0.53–0.44(m,2H).
实施例135 N-((1-(((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)氧基)甲基)环丙基)甲基)-1-((1s,3s)-3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环丁基)-N-甲基哌啶-4-甲酰胺和N-((1-(((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)氧基)甲基)环丙基)甲基)-1-((1r,3r)-3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)环丁基)-N-甲基哌啶-4-甲酰胺
Figure PCTCN2022080000-appb-000266
异构体1：LC-MS:m/z 926(M+H) +。1H NMR(400MHz,DMSO)δ11.12(s,1H),7.90(d,J＝7.9Hz,1H),7.62–7.51(m,2H),7.08(d,J＝7.1Hz,1H),7.03(d,J＝14.3Hz,1H),6.90–6.82(m,3H),6.70(s,1H),6.46(d,J＝5.6Hz,1H),5.64–5.44(m,3H),5.12–5.03(m,1H),4.06–3.85(m,5H),3.85–3.71(m,1H),3.55–3.39(m,2H),3.13(s,1H),2.98–2.83(m,3H),2.82–2.70(m,1H),2.69–2.53(m,4H),2.33(d,J＝11.5Hz,3H),2.30–2.15(m,2H),2.11–1.88(m,3H),1.73–1.59(m,1H),1.54(dd,J＝7.1,2.3Hz,3H),1.50–1.19(m,6H),0.82–0.57(m,4H).
异构体2：LC-MS:m/z 926(M+H) +。1H NMR(400MHz,DMSO)δ11.10(s,1H),7.91(dd,J＝8.0,3.5Hz,1H),7.62–7.51(m,2H),7.09–6.99(m,3H),6.90–6.82(m,2H),6.70(s,1H),6.38–6.32(m,1H),5.65–5.44(m,3H),5.06(dd,J＝12.7,5.4Hz,1H),4.00–3.86(m,4H),3.84–3.70(m,2H),3.54–3.41(m,2H),3.12(s,1H),2.97–2.82(m,3H),2.76–2.65(m,1H),2.65–2.50(m,5H),2.35(s,3H),2.33–2.25(m,1H),2.09–1.96(m,1H),1.79–1.57(m,3H),1.54(d,J＝7.0Hz,3H),1.48–1.16(m,6H),0.81–0.56(m,4H).
实施例136 5-((7-(((1-(((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)氧基)甲基)环丙基)甲基)(甲基)氨基)-7-氧庚烷)氨基)-N-(2,6-二氧哌啶-3-基)-2-氟苯甲酰胺
Figure PCTCN2022080000-appb-000267
LC-MS:m/z 865(M+H) +。1H NMR(400MHz,DMSO)δ10.87(s,1H),8.45–8.34(m, 1H),8.06(s,1H),7.61(d,J＝17.5Hz,1H),7.04(d,J＝12.1Hz,1H),6.99(d,J＝9.7Hz,1H),6.89–6.83(m,2H),6.83–6.76(m,1H),6.70(s,1H),6.66–6.55(m,1H),5.71–5.42(m,4H),4.78–4.71(m,1H),3.98–3.84(m,4H),3.84–3.74(m,1H),3.56–3.38(m,2H),2.97(d,J＝69.1Hz,3H),2.87–2.71(m,3H),2.57–2.52(m,1H),2.35(d,J＝9.8Hz,3H),2.24(dt,J＝34.6,7.5Hz,2H),2.14–1.95(m,2H),1.55(d,J＝7.0Hz,3H),1.39–1.18(m,5H),1.15–1.04(m,2H),1.02–0.90(m,1H),0.79–0.57(m,4H).
实施例137(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-甲氧基乙氧基)-2-甲基-7-(哌啶-4-基氧基)喹唑啉-4-胺
Figure PCTCN2022080000-appb-000268
第一步：(R)-(3-(1-((7-溴-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯
在圆底烧瓶中依次加入化合物7-溴-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-酚(1g，3.2mmol)，(R)-(3-(1-氨基乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(1.3g，3.8mmol)，卡特缩合剂(2.8g，6.4mmol)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(1.5g，9.6mmol)和N,N-二甲基甲酰胺(10mL)。加完后加热至100℃反应20小时，冷却后用制备液相分离得到目标化合物(1.7g)。
LC-MS:m/z 633(M+H) +。
第二步：(R)-(3-(1-((7-羟基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯
在圆底烧瓶中依次加入化合物(R)-(3-(1-((7-溴-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(1.7g，2.7mmol)，氢氧化钾(452mg，8.1mmol)，三(二亚苄基丙酮)二钯(492mg，0.54mmol)，2-二-叔丁膦基-2',4',6'-三异丙基联苯(456mg，1.07mmol)，二氧六环(20mL)和水(4mL)。加完后加热至80℃反应2小时，冷却后用制备液相分离得到目标化合物(1.2g)。
LC-MS:m/z 571(M+H) +。
第三步：(R)-4-((4-((1-(3-(((苄氧基)羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)哌啶-1-甲酸叔丁酯
在圆底烧瓶中依次加入化合物(R)-(3-(1-((7-羟基-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(1.2g，1.9mmol)，4-溴哌啶-1-甲酸叔丁酯(2.2g，8.4mmol)，碳酸钾(870mg，6.3mmol)和N,N-二甲基甲酰胺(15mL)。加完后加热至80℃反应20小时，冷却后用制备液相分离得到目标化合物(900mg)。
LC-MS:m/z 754(M+H) +。
第四步：((R)-(3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(哌啶-4-基氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯
在圆底烧瓶中依次加入化合物(R)-4-((4-((1-(3-(((苄氧基)羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)哌啶-1-甲酸叔丁酯(900mg，1.2mmol)，氯化氢二氧六环溶液(5mL)。加完后室温反应2小时，然后浓缩冻干得目标化合物(800mg)。
LC-MS:m/z 654(M+H) +。
第五步：(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-甲氧基乙氧基)-2-甲基-7-(哌啶-4-基氧基)喹唑啉-4-胺
在圆底烧瓶中依次加入化合物(R)-(3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(哌啶-4-基氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(10mg，0.015mmol)，10％钯碳(5mg，干基)和四氢呋喃(1mL)，接氢气球，氢气置换3次。加完后室温搅拌反应3小时。过滤，浓缩，残余物用制备液相分离得到目标化合物(5mg)。
LC-MS:m/z 520(M+H) +。1H NMR(400MHz,DMSO)δ7.95(d,J＝7.8Hz,1H),7.76(s,1H),7.07(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.62–5.49(m,3H),4.62–4.52(m,1H),4.22(q,J＝4.3Hz,2H),3.75(t,J＝4.7Hz,2H),3.42–3.35(m,5H),3.27–3.12(m,1H),3.02–2.91(m,1H),2.71–2.56(m,1H),2.34(s,3H),2.02–1.85(m,2H),1.64–1.42(m,5H).
按照实施例137同样合成方法，以不同起始原料合成以下化合物.
实施例138(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(2-甲氧基乙氧基)-2-甲基-7-(氮杂环丁烷-3-基氧基)喹唑啉-4-胺
Figure PCTCN2022080000-appb-000269
LC-MS:m/z 492(M+H) +。1H NMR(400MHz,DMSO)δ7.99(d,J＝8.1Hz,1H),7.76(s,1H),6.88(s,1H),6.85(s,1H),6.79–6.64(m,2H),5.67–5.45(m,3H),5.18–4.99(m,1H),4.24(q,J＝4.7Hz,2H),3.97–3.67(m,4H),3.66–3.46(m,2H),3.44–3.38(m,4H),2.35(s,3H),1.55(d,J＝7.1Hz,3H).
实施例139 5-(4-((4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)哌啶-1-基)甲基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000270
第一步：(3-((1R)-1-((7-((1-((1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-基)甲基)哌啶-4-基)氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯
在圆底烧瓶中依次加入化合物1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-甲醛(45mg，0.12mmol)，(R)-(3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(哌啶-4-基氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(80mg，0.12mmol)，三乙酰氧基硼氢化钠(52mg，0.24mmol)和二氯甲烷(2mL)。加完后室温反应20小时。浓缩，残余物用制备液相分离得到目标化合物(50mg)。
LC-MS:m/z 1007(M+H) +。
第二步：5-(4-((4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)哌啶-1-基)甲基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
在圆底烧瓶中依次加入化合物(3-((1R)-1-((7-((1-((1-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌啶-4-基)甲基)哌啶-4-基)氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(50mg，0.05mmol)，10％钯碳(15mg，干基)和四氢呋喃(5mL)，接氢气球，氢气置换3次。加完后室温搅拌反应18小时。过滤，浓缩，残余物用制备液相分离得到目标化合物(13mg)。
LC-MS:m/z 873(M+H) +。1H NMR(400MHz,DMSO)δ11.09(s,1H),7.96(d,J＝8.0Hz,1H),7.76(s,1H),7.65(d,J＝8.5Hz,1H),7.31(d,J＝2.2Hz,1H),7.24(dd,J＝8.8,2.3Hz,1H),7.07(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.62–5.46(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.61–4.51(m,1H),4.28–4.17(m,2H),4.09–4.01(m,2H),3.76(t,J＝4.7Hz,2H),3.39(s,3H),3.02–2.92(m,2H),2.91–2.82(m,1H),2.75–2.64(m,2H),2.63–2.53(m,2H),2.35(s,3H),2.30–2.20(m,2H),2.19–2.12(m,2H),2.06–1.93(m,3H),1.89–1.75(m,3H),1.75–1.63(m,2H),1.54(d,J＝7.0Hz,3H),1.22–1.07(m,2H).
按照实施例139同样合成方法，以不同起始原料合成以下化合物：
实施例140(R)-1-(4-(4-((4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)哌啶-1-基)甲基)哌啶-1-基)苯基)二氢嘧啶-2,4(1H,3H)-二酮
Figure PCTCN2022080000-appb-000271
LC-MS:m/z 805(M+H) +。1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),7.97(d,J＝8.0Hz,1H),7.76(s,1H),7.17–7.10(m,2H),7.07(s,1H),6.96–6.90(m,2H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.63–5.49(m,3H),4.61–4.50(m,1H),4.29–4.16(m,2H),3.76(t,J＝4.7Hz,2H),3.73–3.64(m,4H),3.39(s,3H),2.75–2.60(m,6H),2.35(s,3H),2.30–2.21(m,2H),2.19(d,J＝7.1Hz,2H),2.04–1.93(m,2H),1.85–1.75(m,2H),1.74–1.61(m,3H),1.55(d,J＝7.0Hz,3H),1.26–1.14(m,2H).
实施例141 5-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)-[1,4'-双哌啶]-1'-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000272
第一步：(R)-4-((4-((1-(3-(((苄基氧基)羰基)氨基)-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)-[1,4'-联哌啶]-1'-甲酸叔丁酯
在圆底烧瓶中依次加入化合物(R)-(3-(1-((6-(2-甲氧基乙氧基)-2-甲基-7-(哌啶-4-基氧基)喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(100mg，0.15mmol)，4-氧代哌啶-1-甲酸叔丁酯(61mg，0.31mmol)，三乙酰氧基硼氢化钠(65mg，0.31mmol)和二氯甲烷(1mL)。加完后室温反应20小时。浓缩，残余物用制备液相分离得到目标化合物(150mg)。
LC-MS:m/z 837(M+H) +。
第二步：(R)-(3-(1-((7-([1,4'-联哌啶]-4-基氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯
在圆底烧瓶中依次加入化合物(R)-4-((4-((1-(3-(((苄基氧基)羰基)氨基)-5-(三氟甲基)苯 基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(150mg，0.18mmol)和氯化氢二氧六环溶液(1mL)。加完后室温反应2小时。浓缩冻干得目标化合物(100mg)。
LC-MS:m/z 737(M+H) +。
第三步：(3-((1R)-1-((7-((1'-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-[1,4'-联哌啶]-4-基)氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯
在圆底烧瓶中依次加入化合物(R)-(3-(1-((7-([1,4'-联哌啶]-4-基氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(100mg，0.13mmol)，2-(2,6-二氧哌啶-3-基)-5-氟异吲哚-1,3-二酮(41mg，0.15mmol)，N,N-二异丙基乙基胺(70mg，0.54mmol)和N-甲基吡咯烷酮(1mL)。加完后加热至140℃反应4小时。冷却，残余物用制备液相分离得到目标化合物(50mg)。
LC-MS:m/z 993(M+H) +。
第四步：5-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-7-基)氧基)-[1,4'-联哌啶]-1'-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
在圆底烧瓶中依次加入化合物(3-((1R)-1-((7-((1'-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-[1,4'-联哌啶]-4-基)氧基)-6-(2-甲氧基乙氧基)-2-甲基喹唑啉-4-基)氨基)乙基)-5-(三氟甲基)苯基)氨基甲酸苄酯(50mg，0.05mmol)，10％钯碳(15mg，干基)和四氢呋喃(5mL)，接氢气球，氢气置换3次。加完后室温搅拌反应18小时。过滤，浓缩，残余物用制备液相分离得到目标化合物(3mg)。
LC-MS:m/z 859(M+H) +。1H NMR(400MHz,DMSO)δ11.07(s,1H),7.95(d,J＝7.9Hz,1H),7.75(s,1H),7.66(d,J＝8.5Hz,1H),7.33(s,1H),7.26(d,J＝8.0Hz,1H),7.06(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.63–5.46(m,3H),5.07(dd,J＝12.9,5.4Hz,1H),4.59–4.49(m,1H),4.26–4.17(m,2H),4.14–4.05(m,2H),3.76(t,J＝4.7Hz,2H),3.39(s,3H),3.05–2.92(m,2H),2.91–2.75(m,3H),2.49–2.38(m,2H),2.34(s,3H),2.07–1.92(m,4H),1.90–1.80(m,2H),1.74–1.61(m,2H),1.54(d,J＝7.1Hz,3H),1.53–1.42(m,2H),0.86(t,J＝6.6Hz,2H).
按照实施例141同样合成方法，以不同起始原料合成以下化合物：
实施例142 5-(4-((4-(((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)喹唑啉-7-基)氧基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮
Figure PCTCN2022080000-appb-000273
LC-MS:m/z 788(M+H) +。1H NMR(400MHz,DMSO)δ11.05(s,1H),7.99(d,J＝8.1Hz,1H),7.80(s,1H),7.69(d,J＝8.5Hz,1H),7.39(d,J＝2.3Hz,1H),7.30(dd,J＝8.7,2.3Hz,1H),7.22(s,1H),6.89(s,1H),6.85(s,1H),6.70(s,1H),5.64–5.49(m,3H),5.18–5.12(m,1H),5.08(dd,J＝12.9,5.4Hz,1H),4.94–4.82(m,1H),3.98–3.74(m,6H),3.56–3.47(m,2H),2.96–2.82(m,1H),2.64–2.52(m,2H),2.36(s,3H),2.31–2.17(m,1H),2.14–1.97(m,4H),1.85–1.69(m,2H),1.56(d,J＝7.0Hz,3H).
实施例143 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 (μM)
实施例1 2.6
实施例2 0.391
实施例7 0.681
实施例8 0.18
实施例9 0.1
实施例10 1.0
实施例11 0.141
实施例12 0.073
实施例13 0.183
实施例14 0.176
实施例15 0.452
实施例16 0.515
实施例17 0.813
实施例18 3.0
实施例19 0.266
实施例20 0.335
实施例21 0.036
实施例22 0.149
实施例23 0.253
实施例24 0.145
实施例25 0.164
实施例26 0.455
实施例27 4.56
实施例28 0.109
实施例29 0.104
实施例30 0.04
实施例31 0.02
实施例32 /
实施例33 0.044
实施例34 0.026
实施例35 0.067
实施例36 0.063
实施例37 0.012
实施例38 0.015
实施例39 0.019
实施例40 0.005
实施例41 0.028
实施例42 0.019
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***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 PCTCN2022080000-appb-000274
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 (uM)
实施例9 1.23
实施例10 0.11
实施例11 1.21
实施例12 1.76
实施例21 1.97
实施例22 2.89
实施例24 0.086
实施例25 0.33
实施例26 0.005
实施例28 1.38
实施例29 1.66
实施例30 0.42
实施例31 1.69
实施例32 2.45
实施例33 0.255
实施例37 0.786
实施例38 0.457
实施例39 0.373
实施例40 /
实施例41 1.072
实施例42 1.028
实施例48 0.422
实施例49 0.373
实施例50 1.650
实施例51 0.361
实施例52 0.362
实施例53 0.149
实施例54 0.798
实施例55 0.794
实施例56 0.349
实施例57 1.220
实施例58 0.227
实施例59 0.147
实施例60 0.286
实施例61 /
实施例62 0.514
实施例63 2.891
实施例64 2.324
实施例65 1.375
实施例66 0.216
实施例67 0.016
实施例68 0.357
实施例69 0.018
实施例70 0.032
实施例71 2.048
实施例72 1.178
实施例73 0.709
实施例74 0.219
实施例75 0.047
实施例76异构体1 0.434
实施例76异构体2 1.031
实施例77 1.034
实施例78 0.844
实施例79 0.443
实施例80 0.602
实施例81 0.859
实施例82 0.114
实施例83 0.075
实施例84 0.799
实施例85 0.859
实施例86 0.114
实施例87 0.075
实施例88 0.026
实施例89 0.920
实施例90 0.196
实施例91 0.591
实施例92 1.137
实施例93 0.318
实施例94 0.018
实施例95 1.233
实施例96异构体1 0.051
实施例96异构体2 0.154
实施例97 0.450
实施例98 0.284
实施例99 0.220
实施例100 0.373
实施例101 1.179
实施例102 0.453
实施例103 0.015
实施例104 0.927
实施例105 0.070
实施例106 1.795
实施例107 0.785
实施例108 0.257
实施例109 0.928
实施例110 0.084
实施例111 0.983
实施例112 0.036
实施例113 0.457
实施例114 1.084
实施例115异构体1 1.368
实施例115异构体2 3.468
实施例116 1.967
实施例117异构体1 0.814
实施例117异构体2 1.773
实施例118 0.684
实施例119 0.814
实施例120 1.203
实施例121 0.513
实施例122 0.337
实施例123 0.346
实施例124 1.081
实施例125 0.22
实施例126 0.733
实施例127 0.988
实施例128 0.145
实施例129 0.737
实施例130 0.389
实施例131 0.752
实施例132 0.383
实施例133 2.193
实施例134 0.159
实施例135异构体1 0.203
实施例135异构体2 0.699
实施例139 0.004
实施例142 0.062
化合物对SOS1蛋白水解的调节实验。
实验步骤
(1)接种肿瘤细胞(例如H358，5X105～1X06)在培养皿(2D，P100mm dish)培养2-4 天，至70-80％饱和；
(2)更换10ml新鲜培养液后，继续培养箱内温孵过夜，然后加入相同浓度的本发明的PROTAC候选物以及对照pair的SOSi，轻微摇动混匀。
(3)细胞继续培养1～24小时，做同浓度下(0.1或者1uM)时间曲线(1，2，4，6，8，24)或者6和24小时下剂量曲线(0.0001，0.001，0.01，0.1，1，10uM)。
(4)在所设计的时间或者浓度终点，弃去培养液，把培养皿转移到冰上，用50毫升冰冷PBS清洗3次，尽量吸干剩余液体，然后加入冰冷裂解液(含detergent例如triton,NP40等)以及蛋白水解酶抑制剂。
(5)用细胞刮刀在冰上把细胞刮下，然后转移到1.5毫升离心管内，4度高速离心20分钟，取上清液液，并转移到新的管内。测定蛋白含量后，蛋白上清液用4X上胶液混合，加热(100度，5-10分钟)，冷却后加入10X抗氧剂成最终上胶样品，并于-20度保存。
(6)样品做Western-blot，用SDS-PAGE胶跑电泳，样品可上样10-50微克总蛋白，电转硝酸纤维膜后，切好条带和各自抗体温孵。然后用标记2抗温孵后，做自发光显色，拍照。
(7)最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线。
实验结果表明，本发明的化合物实施例26(图1)具有靶向降解SOS1蛋白的作用。
药代动力学测试评价
雄性SD大鼠，体重220g左右，禁食过夜后，SC或者IP给予本发明化合物的溶液[DMSO/PEG/生理盐水为载体]。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，和24采血，用LC/MS/MS测定血浆中本发明化合物的浓度。
实验结果表明，本发明化合物通过SC或者IP注射给药都具有良好的药代动力学特性，且毒副作用小。
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 (12)

  1. 具有通式(I)结构的化合物、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：
    Figure PCTCN2022080000-appb-100001
    式中：
    ULM代表一个可以和E3连接酶结合的小分子配体部分；
    PTM代表一个可以和SOS1结合的小分子配体部分；
    L可以是键或者是可以连接PTM和ULM的连接基团。
  2. 如权利要求1所述的具有通式(I)结构的化合物、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：
    PTM选自PTM1或PTM2。
  3. 如权利要求1所述的具有通式(I)结构的化合物、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：
    PTM1优选自：
    Figure PCTCN2022080000-appb-100002
    式中：
    虚线表示与L连接；
    在式PTM1-IA和PTM1-IB中，各取代基独立地如下定义：
    X选自下组：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：键、O、NH、CR 7、C＝CR 7、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：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 1-C 18亚烷基、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：键、氢、氘、卤素、氰基、-(CH 2) mR 8、-(CH 2) mO(CH 2) pR 8、-(CH 2) mO(CH 2) pOR 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) mO(CH 2) pR 8-(CH 2) mNR 9R 10、-(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：键、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。
  4. 如权利要求1所述的具有通式(I)结构的化合物、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PTM1选自下组：
    Figure PCTCN2022080000-appb-100003
    Figure PCTCN2022080000-appb-100004
    Figure PCTCN2022080000-appb-100005
    Figure PCTCN2022080000-appb-100006
    Figure PCTCN2022080000-appb-100007
    Figure PCTCN2022080000-appb-100008
    Figure PCTCN2022080000-appb-100009
    Figure PCTCN2022080000-appb-100010
    Figure PCTCN2022080000-appb-100011
    Figure PCTCN2022080000-appb-100012
    Figure PCTCN2022080000-appb-100013
    Figure PCTCN2022080000-appb-100014
    Figure PCTCN2022080000-appb-100015
    Figure PCTCN2022080000-appb-100016
    Figure PCTCN2022080000-appb-100017
    Figure PCTCN2022080000-appb-100018
    Figure PCTCN2022080000-appb-100019
    Figure PCTCN2022080000-appb-100020
    Figure PCTCN2022080000-appb-100021
    Figure PCTCN2022080000-appb-100022
    Figure PCTCN2022080000-appb-100023
    Figure PCTCN2022080000-appb-100024
  5. 如权利要求2所述的具有通式(I)结构的化合物、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，
    PTM2为：
    Figure PCTCN2022080000-appb-100025
    式中：
    虚线表示与L的连接；
    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’选自取代的下组基团：键、C 3-C 20亚环烷基、4-20元亚杂环基；
    R 1’取代或未取代的下组基团：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；
    R 2’相同或不同，各自独立地选自下组：-(CH 2) pR 7’、-(CH 2) mO(CH 2) pR 7’、-(CH 2) mSR 7’、-(CH 2) mCOR 7’、-(CH 2) mC(O)OR 7’、-(CH 2) mS(O) qR 7’、-(CH 2) mNR 7’R 8’、-(CH 2) mC(O)NR 7’R 8’、-(CH 2) mNR 7’C(O)R 8’、-(CH 2) mNR 7’C(O)NR 8’R 9’、-(CH 2) mS(O) qNR 7’R 8’、-(CH 2) mNR 7’S(O) qR 8’、-(CH 2) mNR 7’S(O) qNR 8’R 9’，其中，CH 2中的H可以任选地被取代；R 7’、R 8’和R 9’各自独立地选自下组：氢、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环基和取代或未取代C 1-C 18烷氧基；或者在-(CH 2) mNR 7’R 8’、-(CH 2) mC(O)NR 7’R 8’、-(CH 2) mS(O) qNR 7’R 8’中，R 7’和R 8’与其相连的N原子环合形成取代或未取代4-20元杂环基；或者在-(CH 2) mNR 7’C(O)R 8’、-(CH 2) mNR 7’C(O)NR 8’R 9’、-(CH 2) mNR 7’S(O) qR 8’、-(CH 2) mNR 7’S(O) qNR 8’R 9’中，R 8’和R 9’与其相连的N原子环合形成取代或未取代4-20元杂环基，或者R 7’和R 8’与其相邻的原子环合形成取代或未取代的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；
    R 6’选自：氢、氘、卤素、氨基、氰基、取代或未取代的C 1-C 6烷基和取代或未取代的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基团取代：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’为1、2、3、4或5；
    n’为1、2、3、4或5；
    p’为0、1、2、3、4或5；
    q’为1或2。
  6. 如权利要求2所述的具有通式(I)结构的化合物、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：
    PTM2选自下组：
    Figure PCTCN2022080000-appb-100026
    Figure PCTCN2022080000-appb-100027
    Figure PCTCN2022080000-appb-100028
    Figure PCTCN2022080000-appb-100029
    Figure PCTCN2022080000-appb-100030
  7. 如权利要求1所述的具有通式(I)结构的化合物、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：
    ULM选自可以和VHL(Von Rippel-Lindau)、CRBN(Cereblon)、MDM2(Mouse double-minute homolog2)、或IAP等连接酶结合的小分子VLM、CLM、MLM或ILM配体部分。
  8. 如权利要求1所述的具有通式(I)结构的化合物、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：
    L为：
    Figure PCTCN2022080000-appb-100031
    L任选地通过R L1端或R L6端和PTM或ULM相连接；
    其中，R L1-R L6相同或不同，且独立地优选自取代或未取代的下组基团：键、CH 2、C＝O、O、NH、SO、SO 2、P＝O、NHCO、NHSO 2、OCH 2、OCH 2CH 2、CH 2OCH 2、NHCH 2、NMeCH 2、NHCH 2CH 2、NMeCH 2CH 2、CH 2NHCO、NHCOCH 2、
    Figure PCTCN2022080000-appb-100032
    Figure PCTCN2022080000-appb-100033
    Figure PCTCN2022080000-appb-100034
    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；
    各p L1-p L6独立地选自0、1、2、3、4、5、或6。
  9. 如权利要求1所述的具有通式(I)结构的化合物、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：
    L为取代或未取代的选自下组的基团：
    Figure PCTCN2022080000-appb-100035
    Figure PCTCN2022080000-appb-100036
    Figure PCTCN2022080000-appb-100037
    Figure PCTCN2022080000-appb-100038
    Figure PCTCN2022080000-appb-100039
    Figure PCTCN2022080000-appb-100040
    Figure PCTCN2022080000-appb-100041
    Figure PCTCN2022080000-appb-100042
    Figure PCTCN2022080000-appb-100043
    Figure PCTCN2022080000-appb-100044
    Figure PCTCN2022080000-appb-100045
    Figure PCTCN2022080000-appb-100046
    Figure PCTCN2022080000-appb-100047
    Figure PCTCN2022080000-appb-100048
    Figure PCTCN2022080000-appb-100049
    Figure PCTCN2022080000-appb-100050
    Figure PCTCN2022080000-appb-100051
    Figure PCTCN2022080000-appb-100052
    Figure PCTCN2022080000-appb-100053
    Figure PCTCN2022080000-appb-100054
    Figure PCTCN2022080000-appb-100055
    Figure PCTCN2022080000-appb-100056
    Figure PCTCN2022080000-appb-100057
    Figure PCTCN2022080000-appb-100058
    Figure PCTCN2022080000-appb-100059
    Figure PCTCN2022080000-appb-100060
    Figure PCTCN2022080000-appb-100061
    Figure PCTCN2022080000-appb-100062
    Figure PCTCN2022080000-appb-100063
    Figure PCTCN2022080000-appb-100064
    Figure PCTCN2022080000-appb-100065
    Figure PCTCN2022080000-appb-100066
    Figure PCTCN2022080000-appb-100067
    Figure PCTCN2022080000-appb-100068
    各式中，CH 2、CH可以独立任选地被取代；且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；NH可以独立任选地被氘、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烷基酰基、磺酰基取代；且
    L中，各R L1-R L6基团中相邻的两个基团，可各自独立地通过C、N、O或S原子等彼此连接。
  10. 如权利要求1所述的具有通式(I)结构的化合物、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：
    Figure PCTCN2022080000-appb-100069
    选自取代或未取代的选自下组的基团：
    Figure PCTCN2022080000-appb-100070
    Figure PCTCN2022080000-appb-100071
    Figure PCTCN2022080000-appb-100072
    Figure PCTCN2022080000-appb-100073
    Figure PCTCN2022080000-appb-100074
  11. 如权利要求1所述的具有通式(I)结构的化合物、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：所述化合物选自下组：
    Figure PCTCN2022080000-appb-100075
    Figure PCTCN2022080000-appb-100076
    Figure PCTCN2022080000-appb-100077
    Figure PCTCN2022080000-appb-100078
    Figure PCTCN2022080000-appb-100079
  12. 一种如权利要求1所述的具有通式(I)结构的化合物、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，或包含其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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WO2024067744A1 (zh) * 2022-09-27 2024-04-04 苏州泽璟生物制药股份有限公司 杂环取代喹唑啉及其制备方法和应用

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