WO2022188819A1 - Modulateur de protéolyse sos1, son procédé de préparation et son application - Google Patents

Modulateur de protéolyse sos1, son procédé de préparation et son application Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
group
amino
alkyl
substituted
methyl
Prior art date
Application number
PCT/CN2022/080000
Other languages
English (en)
Chinese (zh)
Inventor
吕彬华
崔大为
庞旭东
刘连军
Original Assignee
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州泽璟生物制药股份有限公司, 上海泽璟医药技术有限公司 filed Critical 苏州泽璟生物制药股份有限公司
Publication of WO2022188819A1 publication Critical patent/WO2022188819A1/fr

Links

Images

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

La présente invention concerne un modulateur de protéolyse SOS1, son procédé de préparation et son application. En particulier, le composé de la présente invention a une structure représentée par la formule (I). L'invention concerne en outre un procédé de préparation du composé et son utilisation en tant que modulateur de la protéolyse SOS1. Le composé de la présente invention présente un très bon effet de régulation sélective sur l'hydrolyse de SOS1.
PCT/CN2022/080000 2021-03-09 2022-03-09 Modulateur de protéolyse sos1, son procédé de préparation et son application WO2022188819A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202110257396 2021-03-09
CN202110257396.8 2021-03-09
CN202110444241.5 2021-04-23
CN202110444241 2021-04-23
CN202210114053.0 2022-01-30
CN202210114053.0A CN115043817A (zh) 2021-03-09 2022-01-30 Sos1蛋白水解调节剂及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2022188819A1 true WO2022188819A1 (fr) 2022-09-15

Family

ID=83157310

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/080000 WO2022188819A1 (fr) 2021-03-09 2022-03-09 Modulateur de protéolyse sos1, son procédé de préparation et son application

Country Status (2)

Country Link
CN (1) CN115043817A (fr)
WO (1) WO2022188819A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246656A1 (fr) * 2022-06-23 2023-12-28 北京福元医药股份有限公司 Chimère ciblant la protéolyse sos1, composition, préparation et utilisation associées
WO2024067744A1 (fr) * 2022-09-27 2024-04-04 苏州泽璟生物制药股份有限公司 Quinazoline substituée hétérocyclique, son procédé de préparation et son utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115232108A (zh) * 2021-04-23 2022-10-25 上海领泰生物医药科技有限公司 Sos1降解剂及其制备方法和应用

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304572A (zh) * 2012-03-09 2013-09-18 上海医药集团股份有限公司 一类3-氰基喹啉类化合物及其药用组合物和应用
CN104736569A (zh) * 2012-01-12 2015-06-24 耶鲁大学 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
CN108601764A (zh) * 2015-03-18 2018-09-28 阿尔维纳斯股份有限公司 用于靶蛋白的增强降解的化合物和方法
WO2019140380A1 (fr) * 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Agents de dégradation de protéines et utilisations associées
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
CN112218859A (zh) * 2018-04-04 2021-01-12 阿尔维纳斯运营股份有限公司 蛋白水解调节剂及相关使用方法
CN113527260A (zh) * 2020-04-21 2021-10-22 四川海思科制药有限公司 一种具有降解stat3酶的化合物及其制备方法和药学上的应用
WO2022061348A1 (fr) * 2020-09-16 2022-03-24 Biotheryx, Inc. Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104736569A (zh) * 2012-01-12 2015-06-24 耶鲁大学 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法
CN103304572A (zh) * 2012-03-09 2013-09-18 上海医药集团股份有限公司 一类3-氰基喹啉类化合物及其药用组合物和应用
CN108601764A (zh) * 2015-03-18 2018-09-28 阿尔维纳斯股份有限公司 用于靶蛋白的增强降解的化合物和方法
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
WO2019140380A1 (fr) * 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Agents de dégradation de protéines et utilisations associées
CN112218859A (zh) * 2018-04-04 2021-01-12 阿尔维纳斯运营股份有限公司 蛋白水解调节剂及相关使用方法
CN113527260A (zh) * 2020-04-21 2021-10-22 四川海思科制药有限公司 一种具有降解stat3酶的化合物及其制备方法和药学上的应用
WO2022061348A1 (fr) * 2020-09-16 2022-03-24 Biotheryx, Inc. Agents de dégradation de protéine sos1, compositions pharmaceutiques de ceux-ci, et leurs applications thérapeutiques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246656A1 (fr) * 2022-06-23 2023-12-28 北京福元医药股份有限公司 Chimère ciblant la protéolyse sos1, composition, préparation et utilisation associées
WO2024067744A1 (fr) * 2022-09-27 2024-04-04 苏州泽璟生物制药股份有限公司 Quinazoline substituée hétérocyclique, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
CN115043817A (zh) 2022-09-13

Similar Documents

Publication Publication Date Title
WO2022188819A1 (fr) Modulateur de protéolyse sos1, son procédé de préparation et son application
WO2020259432A1 (fr) Inhibiteur de kras-g12c
WO2021078285A1 (fr) Inhibiteurs à base de groupes cycloalkyle et hétéroalkyle, procédé de préparation associé et utilisation associée
JP6395731B2 (ja) ブロモドメイン阻害剤として有用なカルバゾール化合物
KR101828187B1 (ko) 신규 축합 피리미딘 화합물 또는 그 염
WO2021228161A1 (fr) Inhibiteur hétérocyclique substitué par alkyle, son procédé de préparation et son utilisation
WO2020259683A1 (fr) Dérivé de pyrimidine disubstitué en position 2 et 4, son procédé de préparation et ses utilisations
CN112552295A (zh) Kras突变蛋白抑制剂
WO2020200158A1 (fr) Dérivés d'amide n-hétéroaromatiques destinés au traitement du cancer
JP2017531675A (ja) Ｎｉｋ阻害剤としての新規のチエノピリミジン誘導体
CN115043842A (zh) 胺基取代双环类抑制剂及其制备方法和应用
WO2022161480A1 (fr) Inhibiteur amine hétérocyclique bicyclo-aromatique substitué, son procédé de préparation et son utilisation
WO2022166592A1 (fr) Inhibiteur de pyrimidopyridone substitué, son procédé de préparation et son utilisation
WO2022199586A1 (fr) Inhibiteur de pyrimidopyridine, son procédé de préparation et son utilisation
WO2022083657A1 (fr) Inhibiteur d'amine benzo ou pyridopyrimidine substitué, son procédé de préparation et son application
WO2021115457A9 (fr) Composé de pyrazolo[1,5-a]pyridine, son procédé de préparation et son utilisation
CN110914277A (zh) 咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用
WO2021098859A1 (fr) Inhibiteur à cycle aza à sept chaînons, et son procédé de préparation et utilisation associée
CN116082312A (zh) 用作cdk7激酶抑制剂的化合物及其应用
WO2020238776A1 (fr) Dérivé bicyclicque condensé substituté, son procédé de préparation et son application en médecine
WO2023116934A1 (fr) Régulateur d'hydrolyse de protéine krasg12d, son procédé de préparation et son utilisation
CN112513041B (zh) 三环化合物
WO2022111708A1 (fr) Inhibiteur de 2-arylhétérocycle-3-oxo-2,3-dihydropyridazine-4-carboxamide deutéré, son procédé de préparation et son utilisation
CN113527311B (zh) Fgfr4抑制剂、组合物及其在药物制备中的用途
WO2021057867A1 (fr) Classe d'inhibiteur de cdk à base d'arsine organique, son procédé de préparation et application associée

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22766341

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22766341

Country of ref document: EP

Kind code of ref document: A1