WO2022161480A1 - Substituted bicyclo-aromatic heterocyclic amine inhibitor, preparation method therefor, and use thereof - Google Patents

Substituted bicyclo-aromatic heterocyclic amine inhibitor, preparation method therefor, and use thereof Download PDF

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WO2022161480A1
WO2022161480A1 PCT/CN2022/074828 CN2022074828W WO2022161480A1 WO 2022161480 A1 WO2022161480 A1 WO 2022161480A1 CN 2022074828 W CN2022074828 W CN 2022074828W WO 2022161480 A1 WO2022161480 A1 WO 2022161480A1
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substituted
group
alkyl
unsubstituted
alkoxy
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PCT/CN2022/074828
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Chinese (zh)
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吕彬华
崔大为
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Publication of WO2022161480A1 publication Critical patent/WO2022161480A1/en

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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • 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
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, in particular to a substituted bicyclic aromatic heterocyclic amine inhibitor and a preparation method and application thereof.
  • Lung cancer is one of the important causes of human cancer death.
  • Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) according to cell type, and NSCLC accounts for 85% of all lung cancer patients.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the global NSCLC market in 2016 was about US$20.9 billion, of which the US market accounted for half, followed by Japan, Germany and China.
  • the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
  • chemotherapy drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, resulting in relatively strong side effects.
  • molecularly targeted drugs have gradually become a research hotspot due to their obvious advantages such as high selectivity, relatively small toxic and side effects, and the ability to achieve precise treatment.
  • NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocartetinib, etc.) Ni et al), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimert
  • KRAS mutations occur in 20-40% of lung adenocarcinomas, and this prevalence is higher in Western (vs Asian) populations (26% vs 11%) and in smokers (vs non-smokers) ( 30% vs 10%).
  • the most common mutations occurred in codons 12 and 13, and the most common mutations included G12C, G12V, and G12D. So far, there are still no approved drugs targeting KRAS mutations on the market.
  • the KRAS protein transitions between inactive and activated states.
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • activated state and can activate downstream signaling pathways.
  • GEF guanine nucleotide exchange factor
  • GAP GTPase activating protein
  • SOS proteins are mainly found to be involved in tumors.
  • the SOS protein is widely expressed in vivo and contains two isoforms, SOS1 and SOS2.
  • SOS 1 plays a key role in mutant KRAS activation and oncogenic signaling. Decreased levels of SOS1 resulted in decreased proliferation and survival in KRAS-mutated tumor cells, but not in KRAS wild-type cell lines. The effect of SOS1 deletion could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role for SOS1 GEF activity in KRAS mutant cancer cells (see WO2019122129A1).
  • SOS1 target proteins are pathologically associated with a variety of diseases, there is a need for novel SOS1 inhibitors for clinical treatment.
  • Highly selective and highly active SOS1 inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
  • each independently is a single bond or a double bond
  • X, Y, U and V are each independently selected from: C, CR x or N, wherein R x is selected from: H, D, CN or halogen;
  • Ring A is selected from the group consisting of substituted or unsubstituted groups: phenyl, 5-6 membered heteroaryl, C4 - C6 cycloalkyl and 4-6 membered heterocyclyl;
  • Ring B is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl or 5-14 membered heteroaryl;
  • R 1 , R 2 are the same or different, and are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 3 -C 20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocycloalkyl, substituted or unsubstituted C 1 -C 18 alkylene C 3 -C 20 cycloalkylene, substituted or unsubstituted C 1 -C 18 alkylene 4-20 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 , -(CH 2 ) h COR 6
  • 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 and 5-14 membered heteroaryl;
  • 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 and 4-6 membered heterocyclyl;
  • substitution in the above-mentioned ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the following group : hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl hydroxyl, C 3 -C 20 ring Alkyl, 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, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide and urea;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, 4 or 5;
  • h 0, 1, 2, 3, 4, 5 or 6;
  • p 0, 1, 2, 3, 4, 5, or 6;
  • q 1 or 2.
  • Parts are substituted or unsubstituted cyclic, bridged or spiro structures.
  • R 4 and R 5 are each independently selected from: halogen, C 1 -C 3 alkyl, preferably, R 4 and R 5 are methyl.
  • W is selected from: N or CR y ;
  • R y is selected from the following group: hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
  • 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;
  • Ring B is defined as above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (II) Structure shown:
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (III) Structure shown:
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
  • the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have formula (IV) Structure shown:
  • R 1 , R 2 , R 3 , ring A, ring B, m, and n are as defined above.
  • Ring C is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl;
  • X 1 and X 2 are each independently selected from: O, CR 9 R 10 , NR 11 ;
  • X 3 is selected from: N or CR 9 ;
  • R 9 and R 10 are each independently selected from substituted or unsubstituted groups from the following group : hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 10 ring Alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-10-membered heterocyclic group, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide or urea group; R 11 is
  • substitution in ring C, R 9 , R 10 , R 11 refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C10 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group or urea group;
  • n1 is 1, 2 or 3;
  • n2 is 0, 1 or 2;
  • n3 is 1, 2, 3 or 4.
  • ring C is selected from the group consisting of substituted or unsubstituted groups: C 5 -C 6 cycloalkyl, 5-6-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, wherein , the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-10-membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide group
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (V) Structure shown:
  • W is selected from: N or CR y ;
  • R y is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
  • 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;
  • R 1 , R 2 , R 3 , ring B, m and n are as defined above.
  • the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (VI) Structure shown:
  • R 1 , R 2 , R 3 , ring B, m, n and R y are as defined above.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 4 alkenyl , substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl , substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 13 cycloalkylene, substituted or unsubstituted C 1 -C 6 alkylene 4-12 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 , -(CH 2 )
  • h 0, 1, 2, 3, 4, 5 or 6;
  • substitution in R 1 , R 2 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C6 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group and urea group.
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl and 5-6-membered heteroaryl, wherein the substitution refers to the group selected from the group One or more groups substituted: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 - C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, oxo, cyano , ester group, amine group, amide group, sulfonamide group or urea group.
  • Ring B is selected from Substituted or unsubstituted groups of the following group: C 3 -C 10 cycloalkyl, 4-16 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, oxo, cyano group, ester group, amine group,
  • * represents R or S configuration.
  • R 3 is selected from:
  • X, Y, U, V, R 1 , R 2 , R 3 , R 4 , R 5 , ring A, ring B, m, n, W and R y are the specific compounds in the examples the corresponding group.
  • the compound is preferably the compound prepared in the examples.
  • the second aspect of the present invention provides a method for preparing a compound of formula (III), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein, the method includes the steps:
  • LG is selected from: halogens, OTs, OMs or OTf;
  • LG-X is selected from: SOCl 2 , SO 2 Cl 2 , POCl 3 , MsCl, TsCl, TfOH, TMSOTf, Tf 2 O or Ms 2 O, etc.;
  • R 1 , R 2 , R 3 , X, ring B, m and n are as defined above.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) one or more of the compounds described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable compounds a 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 as described in the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Or the use of the pharmaceutical composition in the third aspect for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of SOS1.
  • the disease is cancer.
  • the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophagus cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain cancer tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • a fifth aspect of the present invention provides a non-diagnostic, non-therapeutic method for inhibiting SOS1, comprising the steps of: administering to a patient in need an effective amount of the compound, its stereoisomers, and tautomers as described above form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administer a pharmaceutical composition as described above.
  • the present inventors unexpectedly discovered a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
  • alkyl refers to a straight or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms.
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl groups, including from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl n-butyl, tert-butyl, isobutyl (such as ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • alkylene refers to a group formed by removing one hydrogen atom from “alkyl”, such as methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as )Wait.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group comprising 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaromatic ring), fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclic or fused aryl ring, the above cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted. Any two or more atoms on the ring can be further cyclolinked with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • cycloalkylene refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as: Wait.
  • alkylenecycloalkylene refers to the above-mentioned cycloalkylalkyl or alkylcycloalkyl group formed by removing two hydrogen atoms, wherein "C1-C18 alkylene C3-C20 alkylene”"Cycloalkyl” or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning, preferably, C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to: Wait.
  • heterocyclyl refers to fully saturated or partially unsaturated cyclic groups (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 a ring having at least one carbon atom.
  • Each heterocyclic ring containing a heteroatom may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur may be oxidized or the nitrogen may Quaternized.
  • a heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepanyl gene, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms on the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further cyclically connected; the heterocyclic group can be substituted or unsubstituted, and when substituted,
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate, where
  • heterocyclylene refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclyl, including but not limited to:
  • heterocycloalkylene alkylene refers to a group formed by removing two hydrogen atoms from a cycloalkylalkyl group or an alkylcycloalkyl group, wherein "4-20 membered heterocycloalkylene C1-C18 "Alkylene” or "C1-C18 alkylene 4-20 membered heterocycloalkylene” have the same meaning, preferably 4-12 membered heterocycloalkylene C1-6 alkylene, including but not limited to: Wait.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclyl or fused ring aryl, the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • C1-C18 alkoxy refers to a straight or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropyl oxy and butoxy, etc. Preferably it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group.
  • C1-C18 alkyleneoxy refers to a group obtained by removing one hydrogen atom from "C1-C18 alkoxy”.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo refers to substitution with halogen.
  • deuterated refers to substitution with deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2.
  • cyano refers to a group with the structure CN.
  • 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 substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.
  • the compound of formula (I) has the following structure:
  • X, Y, U, V, Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined above.
  • the compound of formula I has the structure shown in formula (II):
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined above.
  • the compound of formula I has the structure shown in formula (III):
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
  • the compound of formula I has the structure shown in formula (IV):
  • R 1 , R 2 , R 3 , ring A, ring B, m, and n are as defined above.
  • the compound of formula I has the structure shown in formula (V):
  • W is selected from: N or CR y ;
  • R y is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
  • 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;
  • R 1 , R 2 , R 3 , ring B, m and n are as defined above.
  • the compound of formula I has the structure shown in formula (VI):
  • R 1 , R 2 , R 3 , ring B, m, n and R y are as defined above.
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted Substituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted Substituted C 1 -C 6 alkylene C 3 -C 13 cycloalkylene, substituted or unsubstituted C 1 -C 6 alkylene 4-12 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 ,
  • h 0, 1, 2, 3, 4, 5 or 6;
  • R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl and 5-6-membered heteroaryl, wherein the substitution in R 3 refers to being substituted by one or more groups selected from the group of: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxy, C 3 -C 6 cycloalkyl, C 1 - C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amido , sulfonamide or ureido; preferably, R is selected from:
  • Ring B is selected from the group consisting of substituted or unsubstituted C3 - C10 cycloalkyl, 4-15 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the substitution described in Ring B means substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, Hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide or urea groups.
  • substitution in R 1 , R 2 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C6 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group and urea group.
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to 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, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compounds of the present invention are prepared by the following methods
  • LG is selected from: halogens, OTs, OMs or OTf;
  • LG-X is selected from: SOCl 2 , SO 2 Cl 2 , POCl 3 , MsCl, TsCl, TfOH, TMSOTf, Tf 2 O, or Ms 2 O, etc.
  • R 1 , R 2 , R 3 , X, ring B, m and n are as defined above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nanometer preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical 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 people) in need of treatment, and the dose is a pharmaceutically considered effective dose when administered, and for a person with a body weight of 60kg, 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 the general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting SOS1.
  • the present invention has the following main advantages:
  • the compound has a good selective inhibitory effect on SOS1;
  • the compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • the first step preparation of 2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile
  • N-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide (200 mg, 0.9 mmol) was added to ethanol (2 mL) followed by Hydrogen peroxide (2 mL) and sodium hydroxide (44 mg, 1.1 mmol). The resulting reaction solution was stirred at reflux overnight, then cooled and concentrated. The residue was adjusted to pH 2 with 2N hydrochloric acid and filtered. The solid was collected and dried to obtain the desired product (150 mg, yield: 75%). It was used directly in the next reaction without further purification.
  • Step 5 (R)-N-(1-(3-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8-dihydro-[1 Preparation of ,4]dioxin[2,3-g]quinazolin-4-amine
  • the obtained reaction solution was stirred at 80 degrees overnight, then cooled down, poured into 50 mL of water, and extracted three times with 20 mL of ethyl acetate. The combined organic phases were dried and filtered, the filtrate was concentrated, and the obtained residue was separated by preparative high performance liquid chromatography to obtain the target product (43 mg, yield: 15%).
  • Example 2 Four isomers were obtained by chiral separation
  • Table 1 shows the inhibitory activity of the example compounds of the present invention on the binding of KRAS G12C enzyme and SOS1.
  • the compounds of the examples of the present invention showed good inhibitory activity on the binding of KRAS G12C and SOS1.
  • mice 100 uL of 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right hind flank of nude mice. Mice health were monitored daily, starting when tumors grew to palpable size.
  • the tumor volume calculation formula adopts: 0.5 ⁇ L ⁇ W 2 , where L and W represent the length and width of the tumor, respectively.
  • Tumors grew to -150 mm3 and mice were randomized. Mice were given the corresponding doses (15, 50 mg/Kg) of compound in CMC-Na suspension by gavage every day, and their general status was monitored at the same time. Tumors were measured 3 times a week and body weights were measured twice a week.
  • the compound of the present invention has a good anti-tumor effect.

Abstract

The present invention relates to a substituted bicyclo-aromatic heterocyclic amine inhibitor, a preparation method therefor, and the use thereof. Specifically, a compound of the present invention has a structure as represented by formula (I). Further disclosed are a method for preparing the compound, and the use thereof as an SOS1 inhibitor. The compound of the present invention has a good selective inhibitory effect on SOS1, better pharmacodynamic and pharmacokinetic properties, and lower toxic side effects.

Description

取代双环并芳杂环胺类抑制剂及其制备方法和应用Substituted bicyclic aromatic heterocyclic amine inhibitor and preparation method and application thereof 技术领域technical field
本发明属于药物领域，具体涉及一种取代双环并芳杂环胺类抑制剂及其制备方法和应用。The invention belongs to the field of medicine, in particular to a substituted bicyclic aromatic heterocyclic amine inhibitor and a preparation method and application thereof.
背景技术Background technique
肺癌是人类癌症致死的重要原因之一。按照细胞类型肺癌可以分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)，其中NSCLC占所有肺癌患者的85％。据统计2016年全球NSCLC的市场约为209亿美元，其中美国市场占据一半，其次是日本、德国和中国。从现有趋势来看，非小细胞肺癌市场保持着持续增长，预计2023年全球市场将达到540亿美元(Nature，2018；553(7689):446-454)。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. According to statistics, 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. Judging from the existing trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018;553(7689):446-454).
目前NSCLC的主要治疗用药分为化疗药物、分子靶向药物以及肿瘤免疫疗法等。其中化疗药物主要包括吉西他滨、紫杉醇以及铂类药物等，但是这类药物普遍具有选择性差、毒性大从而导致比较强烈的毒副作用。近年来，分子靶向药物因其选择性较高、毒副作用相对较小，能够实现精准治疗等明显优势从而逐渐成为研究热点。现有的NSCLC分子靶向药物包括EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Pyrotinib、Rociletinib、Osimertinib等)，ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼等)，以及VEGFR抑制剂(Sorafenib、Regorafenib、Cabozantinib、Sunitinib、多纳非尼等)(Current Medicinal Chemistry,2019,26,1-39)。At present, the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted drugs and tumor immunotherapy. Among them, 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. In recent years, 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. Existing NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocartetinib, etc.) Ni et al), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).
KRAS突变发生在20-40％的肺腺癌中，这一患病率在西方(vs亚洲)人群中更高(26％vs 11％)，在吸烟者(vs非吸烟者)中更高(30％vs 10％)。最常见的突变发生在密码子12和13中，最常见的突变包括G12C、G12V和G12D。到目前为止，市场上仍然没有针对KRAS突变的药物被批准上市。KRAS mutations occur in 20-40% of lung adenocarcinomas, and this prevalence is higher in Western (vs Asian) populations (26% vs 11%) and in smokers (vs non-smokers) ( 30% vs 10%). The most common mutations occurred in codons 12 and 13, and the most common mutations included G12C, G12V, and G12D. So far, there are still no approved drugs targeting KRAS mutations on the market.
在细胞内，KRAS蛋白在失活和激活状态之间转变，当KRAS与鸟苷二磷酸(GDP)结合时，它处于失活状态，当它与鸟苷三磷酸(GTP)结合时，它处于激活状态，并且可以激活下游信号通路。KRAS在失活与激活状态之间的转换受到两类因子的调节。一类是鸟嘌呤核苷酸交换因子(GEF)，这类蛋白催化KRAS与GTP的结合，从而促进KRAS的激活，其中包括SOS1蛋白。另一类是GTP酶激活蛋白(GAP)，这类蛋白能够促进与KRAS结合的GTP水解成为GDP，从而抑制KRAS的活性。Inside the cell, the KRAS protein transitions between inactive and activated states. When KRAS is bound to guanosine diphosphate (GDP), it is in an inactive state, and when it is bound to guanosine triphosphate (GTP), it is in an inactive state. activated state and can activate downstream signaling pathways. The transition of KRAS between inactive and active states is regulated by two types of factors. One is the guanine nucleotide exchange factor (GEF), which catalyzes the binding of KRAS to GTP to promote KRAS activation, including the SOS1 protein. Another type is GTPase activating protein (GAP), which can promote the hydrolysis of KRAS-bound GTP into GDP, thereby inhibiting the activity of KRAS.
到目前为止，已经确定了三大类特定于RAS的GEF，在肿瘤中主要发现SOS蛋白参与。SOS蛋白在体内广泛表达，含有两个亚型SOS1和SOS2。已发表的数据表明，在突变KRAS激活和致癌信号中，SOS 1起着关键作用。SOS1水平的降低导致了携带KRAS突变的肿瘤细胞的增殖率和存活率的降低，而KRAS野生型细胞系则未见影响。 SOS1缺失的效果不能通过引入一个在催化位点发生突变的SOS1来挽救，这说明SOS1GEF活性在KRAS突变癌细胞中的重要作用(参见WO2019122129A1)。So far, three major classes of RAS-specific GEFs have been identified, and 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. Published data suggest that SOS 1 plays a key role in mutant KRAS activation and oncogenic signaling. Decreased levels of SOS1 resulted in decreased proliferation and survival in KRAS-mutated tumor cells, but not in KRAS wild-type cell lines. The effect of SOS1 deletion could not be rescued by introducing a SOS1 mutated at the catalytic site, suggesting an important role for SOS1 GEF activity in KRAS mutant cancer cells (see WO2019122129A1).
由于不管是突变的还是野生型的KRAS结合GTP都依赖于SOS1，所以选择性的抑制SOS1之后，不管KRAS突变与否，都能阻止SOS1与KRAS的相互作用从而最终抑制KRAS激活。Since both mutant and wild-type KRAS are dependent on SOS1 for binding to GTP, selective inhibition of SOS1, regardless of KRAS mutation, can prevent the interaction of SOS1 with KRAS and ultimately inhibit KRAS activation.
由于SOS1靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的SOS1抑制剂用于临床治疗。高选择性高活性的SOS1抑制剂可以对KRAS突变导致的癌症等疾病更有效治疗，以及减少脱靶效应的潜力，因而具有更迫切的临床需求。Since SOS1 target proteins are pathologically associated with a variety of diseases, there is a need for novel SOS1 inhibitors for clinical treatment. Highly selective and highly active SOS1 inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一类新型的对SOS1有选择性抑制作用和/或更好药效学性能的化合物及其用途。The purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties and uses thereof.
本发明第一方面，提供一种式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：The first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
Figure PCTCN2022074828-appb-000001
Figure PCTCN2022074828-appb-000001
式中：where:
Figure PCTCN2022074828-appb-000002
相同或不同，各自独立地为单键或者双键；
Figure PCTCN2022074828-appb-000002
The same or different, each independently is a single bond or a double bond;
X、Y、U和V各自独立地选自：C、CR x或N，其中，R x选自：H、D、CN或卤素； X, Y, U and V are each independently selected from: C, CR x or N, wherein R x is selected from: H, D, CN or halogen;
环A选自取代或未取代的下组基团：苯基、5-6元杂芳基、C 4-C 6环烷基和4-6元杂环基； Ring A is selected from the group consisting of substituted or unsubstituted groups: phenyl, 5-6 membered heteroaryl, C4 - C6 cycloalkyl and 4-6 membered heterocyclyl;
环B选自取代或未取代的下组基团：C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基或5-14元杂芳基； Ring B is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl or 5-14 membered heteroaryl;
R 1、R 2相同或不同，各自独立地选自下组：氢、氘、卤素、氰基、氧代基、取代或未取代C 2-C 18烯基、取代或未取代C 2-C 18炔基、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环烷基、取代或未取代C 1-C 18亚烷基C 3-C 20亚环烷基、取代或未取代C 1-C 18亚烷基4-20元亚杂环烷基、-(CH 2) hO(CH 2) pR 6、-(CH 2) hSR 6、-(CH 2) hCOR 6、-(CH 2) hC(O)OR 6、-(CH 2) hS(O) qR 6、-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hS(O) qNR 6R 7、-(CH 2) hNR 6S(O) qR 7、-(CH 2) hNR 6S(O) qNR 7R 8；其中，CH 2中的H可以任选地被取代；R 6、R 7和R 8各自独立地选自下组：氢、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环基、取代或未取代C 6-C 14芳基和取代或未取代5-14元杂芳基；或者在-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hS(O) qNR 6R 7中，R 6和R 7与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hNR 6S(O) qR 7、 -(CH 2) hNR 6S(O) qNR 7R 8中，R 7和R 8与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 6和R 7与其相邻的原子环合形成取代或未取代的4-8元杂环基； R 1 , R 2 are the same or different, and are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 3 -C 20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocycloalkyl, substituted or unsubstituted C 1 -C 18 alkylene C 3 -C 20 cycloalkylene, substituted or unsubstituted C 1 -C 18 alkylene 4-20 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 , -(CH 2 ) h COR 6 , -(CH 2 ) h C(O)OR 6 , -(CH 2 ) h S(O) q R 6 , -(CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h S(O) q NR 6 R 7 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 ; wherein, H in CH 2 can be optionally substituted; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 18 alkyl, substituted or Unsubstituted C3 - C20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocyclyl, substituted or unsubstituted C6 - C14 aryl and substituted or unsubstituted 5-14 membered heteroaryl; or in- (CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h S(O) q NR 6 R 7 , R 6 and R 7 are adjacent to it cyclization of the N atom of the substituted or unsubstituted 4-8 membered heterocyclic group; or in -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 , R 7 and R 8 and their adjacent N atom rings form a substituted or unsubstituted 4-8-membered heterocyclic group, or R 6 and R 7 are cyclized with their adjacent atoms to form a substituted or unsubstituted 4-8-membered heterocyclic group;
R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基和5-14元杂芳基； 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 and 5-14 membered heteroaryl;
R 4、R 5独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基和4-6元杂环基； 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 and 4-6 membered heterocyclyl;
其中，上述环A、环B、R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8中的取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基； Wherein, the substitution in the above-mentioned ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the following group : hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl hydroxyl, C 3 -C 20 ring Alkyl, 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, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide and urea;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n为0、1、2、3、4或5；n is 0, 1, 2, 3, 4 or 5;
h为0、1、2、3、4、5或6；h is 0, 1, 2, 3, 4, 5 or 6;
p为0、1、2、3、4、5或6；p is 0, 1, 2, 3, 4, 5, or 6;
q为1或2。q is 1 or 2.
在另一优选例中，
Figure PCTCN2022074828-appb-000003
部分为取代或者未取代的并环、桥环或者螺环结构。 In another preferred embodiment,
Figure PCTCN2022074828-appb-000003
Parts are substituted or unsubstituted cyclic, bridged or spiro structures.
在另一优选例中，式I中，
Figure PCTCN2022074828-appb-000004
部分选自：
Figure PCTCN2022074828-appb-000005
Figure PCTCN2022074828-appb-000006
In another preferred embodiment, in formula I,
Figure PCTCN2022074828-appb-000004
Partially selected from:
Figure PCTCN2022074828-appb-000005
Figure PCTCN2022074828-appb-000006
在另一优选例中，式I中，R 4和R 5各自独立地选自：卤素、C 1-C 3烷基，优选地，R 4和R 5为甲基。 In another preferred embodiment, in formula I, R 4 and R 5 are each independently selected from: halogen, C 1 -C 3 alkyl, preferably, R 4 and R 5 are methyl.
在另一优选例中，式I中，
Figure PCTCN2022074828-appb-000007
部分为
Figure PCTCN2022074828-appb-000008
其中，环A和环B的定义如上所述。 In another preferred embodiment, in formula I,
Figure PCTCN2022074828-appb-000007
part of
Figure PCTCN2022074828-appb-000008
Wherein, the definitions of ring A and ring B are as described above.
在另一优选例中，式I中，
Figure PCTCN2022074828-appb-000009
部分为
Figure PCTCN2022074828-appb-000010
其中，W选自：N或CR y；R y选自下组：氢、氘、卤素、氰基、取代或未取代C 1-C 3烷基、取代或未取代3-6元环烷基和取代或未取代4-6元杂环烷基； In another preferred embodiment, in formula I,
Figure PCTCN2022074828-appb-000009
part of
Figure PCTCN2022074828-appb-000010
Wherein, W is selected from: N or CR y ; R y is selected from the following group: hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝 基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Wherein, the above-mentioned 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;
环B的定义如上所述。Ring B is defined as above.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(II)所示结构：In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (II) Structure shown:
Figure PCTCN2022074828-appb-000011
Figure PCTCN2022074828-appb-000011
式中，环A、环B、R 1、R 2、R 3、R 4、R 5、m和n的定义如上所述。 In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined above.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(III)所示结构：In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (III) Structure shown:
Figure PCTCN2022074828-appb-000012
Figure PCTCN2022074828-appb-000012
式中，环A、环B、R 1、R 2、R 3、R 4、m和n的定义如上所述。 In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(IV)所示结构：In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs have formula (IV) Structure shown:
Figure PCTCN2022074828-appb-000013
Figure PCTCN2022074828-appb-000013
式中：R 1、R 2、R 3、环A、环B、m、和n的定义如上所述。 wherein: R 1 , R 2 , R 3 , ring A, ring B, m, and n are as defined above.
在另一优选例中，式II-IV中，
Figure PCTCN2022074828-appb-000014
部分为
Figure PCTCN2022074828-appb-000015
其中，W和环B的定义如上所述。 In another preferred embodiment, in formula II-IV,
Figure PCTCN2022074828-appb-000014
part of
Figure PCTCN2022074828-appb-000015
where W and ring B are as defined above.
在另一优选例中，式I中，
Figure PCTCN2022074828-appb-000016
部分选自：
Figure PCTCN2022074828-appb-000017
Figure PCTCN2022074828-appb-000018
In another preferred embodiment, in formula I,
Figure PCTCN2022074828-appb-000016
Partially selected from:
Figure PCTCN2022074828-appb-000017
Figure PCTCN2022074828-appb-000018
环C选自取代或未取代的下组基团：C 3-C 8环烷基、4-8元杂环基、C 6-C 10芳基、5-10元杂芳基； Ring C is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl;
X 1、X 2各自独立地选自：O、CR 9R 10、NR 11；X 3选自：N或CR 9；R 9、R 10各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤 代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；R 11选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基； X 1 and X 2 are each independently selected from: O, CR 9 R 10 , NR 11 ; X 3 is selected from: N or CR 9 ; R 9 and R 10 are each independently selected from substituted or unsubstituted groups from the following group : hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 10 ring Alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-10-membered heterocyclic group, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide or urea group; R 11 is selected from substituted or unsubstituted lower groups Group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl , 4-10 membered heterocyclic group;
其中，环C、R 9、R 10、R 11中所述取代是指被1、2、3或4个选自下组的基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Wherein, the substitution in ring C, R 9 , R 10 , R 11 refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C10 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group or urea group;
n1为1、2或3；n1 is 1, 2 or 3;
n2为0、1或2；n2 is 0, 1 or 2;
n3为1、2、3或4。n3 is 1, 2, 3 or 4.
在另一优选例中，环C选自取代或未取代的下组基团：C 5-C 6环烷基、5-6元杂环基、苯基、5-6元杂芳基，其中，所述取代是指被1、2、3或4个选自下组的基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred example, ring C is selected from the group consisting of substituted or unsubstituted groups: C 5 -C 6 cycloalkyl, 5-6-membered heterocyclyl, phenyl, 5-6-membered heteroaryl, wherein , the substitution refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkylhydroxy, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14-membered heteroaryl, 4-10-membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide group, sulfonamide group or urea group.
在另一优选例中，式II-IV中，
Figure PCTCN2022074828-appb-000019
部分选自：
Figure PCTCN2022074828-appb-000020
Figure PCTCN2022074828-appb-000021
Figure PCTCN2022074828-appb-000022
其中，环C、X 1、X 2、X 3、n1、n2、n3的定义如上所述。 In another preferred embodiment, in formula II-IV,
Figure PCTCN2022074828-appb-000019
Partially selected from:
Figure PCTCN2022074828-appb-000020
Figure PCTCN2022074828-appb-000021
Figure PCTCN2022074828-appb-000022
The definitions of ring C, X 1 , X 2 , X 3 , n1 , n2 and n3 are as described above.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(V)所示结构：In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (V) Structure shown:
Figure PCTCN2022074828-appb-000023
Figure PCTCN2022074828-appb-000023
式中：where:
W选自：N或CR y；R y选自下组：氢、氘、卤素、氰基、取代或未取代C 1-C 3烷基、取 代或未取代3-6元环烷基和取代或未取代4-6元杂环烷基； W is selected from: N or CR y ; R y is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Wherein, the above-mentioned 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;
R 1、R 2、R 3、环B、m和n的定义如上所述。 R 1 , R 2 , R 3 , ring B, m and n are as defined above.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其具有式(VI)所示结构：In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof has formula (VI) Structure shown:
Figure PCTCN2022074828-appb-000024
Figure PCTCN2022074828-appb-000024
式中，In the formula,
R 1、R 2、R 3、环B、m、n和R y的定义如上所述。 R 1 , R 2 , R 3 , ring B, m, n and R y are as defined above.
在另一优选例中，式I-VI中，R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、氧代基、取代或未取代C 2-C 4烯基、取代或未取代C 2-C 4炔基、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基、取代或未取代4-6元杂环烷基、取代或未取代C 1-C 6亚烷基C 3-C 13亚环烷基、取代或未取代C 1-C 6亚烷基4-12元亚杂环烷基、-(CH 2) hO(CH 2) pR 6、-(CH 2) hSR 6、-(CH 2) hCOR 6、-(CH 2) hC(O)OR 6、-(CH 2) hS(O) qR 6、-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hS(O) qNR 6R 7、-(CH 2) hNR 6S(O) qR 7、-(CH 2) hNR 6S(O) qNR 7R 8；R 6、R 7和R 8各自独立地选自下组：氢、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基、取代或未取代4-6元杂环基、取代或未取代C 6-C 14芳基和取代或未取代5-14元杂芳基；或者在-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hS(O) qNR 6R 7中，R 6和R 7与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hNR 6S(O) qR 7、-(CH 2) hNR 6S(O) qNR 7R 8中，R 7和R 8与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 6和R 7与其相邻的原子环合形成取代或未取代的4-8元杂环基； In another preferred example, in formulas I-VI, R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 4 alkenyl , substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl , substituted or unsubstituted C 1 -C 6 alkylene C 3 -C 13 cycloalkylene, substituted or unsubstituted C 1 -C 6 alkylene 4-12 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 , -(CH 2 ) h COR 6 , -(CH 2 ) h C(O)OR 6 , -(CH 2 ) h S(O ) q R 6 , -(CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h S(O) q NR 6 R 7 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 ; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclyl, substituted or unsubstituted C 6 -C 14 aryl and substituted or unsubstituted 5-14 membered heteroaryl; or at -(CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h S(O) q NR 6 R 7 , R 6 and R 7 are cyclized with their adjacent N atoms Form a substituted or unsubstituted 4-8 membered heterocyclyl; or at -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -( CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 , R 7 and R 8 are cyclized with their adjacent N atoms to form substituted or unsubstituted A substituted 4-8 membered heterocyclyl, or R6 and R7 are cyclized with their adjacent atoms to form a substituted or unsubstituted 4-8 membered heterocyclyl;
h为0、1、2、3、4、5或6；h is 0, 1, 2, 3, 4, 5 or 6;
其中，R 1、R 2、R 6、R 7和R 8中的取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。 Wherein, substitution in R 1 , R 2 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C6 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group and urea group.
在另一优选例中，式I-VI中，R 3选自取代或未取代的下组基团：苯基和5-6元杂芳基，其中所述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred embodiment, in formulas I-VI, R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl and 5-6-membered heteroaryl, wherein the substitution refers to the group selected from the group One or more groups substituted: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 - C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, oxo, cyano , ester group, amine group, amide group, sulfonamide group or urea group.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其中，环B选自取代或未取代的下组基团：C 3-C 10环烷基、4-16元杂环基、苯基和5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein Ring B is selected from Substituted or unsubstituted groups of the following group: C 3 -C 10 cycloalkyl, 4-16 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the substitution refers to being selected from the group Substituted with one or more groups of: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, oxo, cyano group, ester group, amine group, amide group, sulfonamide group or urea group.
在另一优选例中，
Figure PCTCN2022074828-appb-000025
选自：
Figure PCTCN2022074828-appb-000026
Figure PCTCN2022074828-appb-000027
In another preferred embodiment,
Figure PCTCN2022074828-appb-000025
Selected from:
Figure PCTCN2022074828-appb-000026
Figure PCTCN2022074828-appb-000027
在另一优选例中，
Figure PCTCN2022074828-appb-000028
为
Figure PCTCN2022074828-appb-000029
其中，*表示R或S构型。 In another preferred embodiment,
Figure PCTCN2022074828-appb-000028
for
Figure PCTCN2022074828-appb-000029
Wherein, * represents R or S configuration.
在另一优选例中，R 3选自： In another preferred embodiment, R 3 is selected from:
Figure PCTCN2022074828-appb-000030
Figure PCTCN2022074828-appb-000030
在另一优选例中，X、Y、U、V、R 1、R 2、R 3、R 4、R 5、环A、环B、m、n、W和R y为实施例中具体化合物所对应基团。 In another preferred example, X, Y, U, V, R 1 , R 2 , R 3 , R 4 , R 5 , ring A, ring B, m, n, W and R y are the specific compounds in the examples the corresponding group.
在另一优选例中，所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其中，所述化合物选自下组：In another preferred embodiment, the compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein the compound is selected from From the next group:
Figure PCTCN2022074828-appb-000031
Figure PCTCN2022074828-appb-000031
Figure PCTCN2022074828-appb-000032
Figure PCTCN2022074828-appb-000032
Figure PCTCN2022074828-appb-000033
Figure PCTCN2022074828-appb-000033
Figure PCTCN2022074828-appb-000034
Figure PCTCN2022074828-appb-000034
Figure PCTCN2022074828-appb-000035
Figure PCTCN2022074828-appb-000035
Figure PCTCN2022074828-appb-000036
Figure PCTCN2022074828-appb-000036
Figure PCTCN2022074828-appb-000037
Figure PCTCN2022074828-appb-000037
Figure PCTCN2022074828-appb-000038
Figure PCTCN2022074828-appb-000038
Figure PCTCN2022074828-appb-000039
Figure PCTCN2022074828-appb-000039
Figure PCTCN2022074828-appb-000040
Figure PCTCN2022074828-appb-000040
Figure PCTCN2022074828-appb-000041
Figure PCTCN2022074828-appb-000041
Figure PCTCN2022074828-appb-000042
Figure PCTCN2022074828-appb-000042
Figure PCTCN2022074828-appb-000043
Figure PCTCN2022074828-appb-000043
Figure PCTCN2022074828-appb-000044
Figure PCTCN2022074828-appb-000044
在另一优选例中，所述化合物优选为实施例中所制备的化合物。In another preferred embodiment, the compound is preferably the compound prepared in the examples.
本发明第二方面，提供一种制备式(III)化合物、其立体异构体、互变异构体、晶型、 药学上可接受的盐、水合物、溶剂合物或前药的方法，其中，所述方法包括步骤：The second aspect of the present invention provides a method for preparing a compound of formula (III), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Wherein, the method includes the steps:
Figure PCTCN2022074828-appb-000045
Figure PCTCN2022074828-appb-000045
方法一method one
(i)惰性溶剂中，式(X-1)化合物与醋酸酐反应，得到式(X-2)化合物；(i) in an inert solvent, the compound of formula (X-1) reacts with acetic anhydride to obtain the compound of formula (X-2);
(ii)在氧化剂(如H 2O 2等)和碱(如氢氧化钠等)存在下，式(X-2)化合物分子内关环得到式(X-3)化合物； (ii) in the presence of an oxidizing agent (such as H2O2, etc.) and a base (such as sodium hydroxide, etc.), the compound of formula (X- 2 ) is intramolecularly closed to obtain a compound of formula (X-3);
(iii)在碱(如TEA、DIPEA、Py、DMAP、或DBU等)及缩合剂(如BOP、或PyBOP等)存在下，式(X-3)化合物与胺(式X-4)反应，得到式(III)化合物；(iii) in the presence of a base (such as TEA, DIPEA, Py, DMAP, or DBU, etc.) and a condensing agent (such as BOP, or PyBOP, etc.), the compound of formula (X-3) is reacted with amine (formula X-4), to obtain the compound of formula (III);
方法二Method Two
(i)惰性溶剂中，式(X-1)化合物与醋酸酐反应，得到式(X-2)化合物；(i) in an inert solvent, the compound of formula (X-1) reacts with acetic anhydride to obtain the compound of formula (X-2);
(ii)在氧化剂(如H 2O 2等)和碱(如氢氧化钠等)存在下，式(X-2)化合物分子内关环得到式(X-3)化合物； (ii) in the presence of an oxidizing agent (such as H2O2, etc.) and a base (such as sodium hydroxide, etc.), the compound of formula (X- 2 ) is intramolecularly closed to obtain a compound of formula (X-3);
(iv)在碱(如TEA、DIPEA、Py、或DMAP等)存在下，式(X-3)与化合物LG-X反应，得到式(X-5)化合物(iv) In the presence of a base (such as TEA, DIPEA, Py, or DMAP, etc.), formula (X-3) reacts with compound LG-X to obtain a compound of formula (X-5)
(v)在碱(如TEA、DIPEA、Py、或DMAP等)存在下，式(X-5)与化合物与胺(式X-4)反应，得到式(III)化合物；(v) in the presence of a base (such as TEA, DIPEA, Py, or DMAP, etc.), the compound of formula (X-5) is reacted with an amine (formula X-4) to obtain a compound of formula (III);
式中，In the formula,
LG选自：卤素、OTs、OMs或OTf；LG is selected from: halogens, OTs, OMs or OTf;
LG-X选自：SOCl 2、SO 2Cl 2、POCl 3、MsCl、TsCl、TfOH、TMSOTf、Tf 2O或Ms 2O等； LG-X is selected from: SOCl 2 , SO 2 Cl 2 , POCl 3 , MsCl, TsCl, TfOH, TMSOTf, Tf 2 O or Ms 2 O, etc.;
R 1、R 2、R 3、X、环B、m和n定义如上所述。 R 1 , R 2 , R 3 , X, ring B, m and n are as defined above.
本发明第三方面，提供一种药物组合物，其包含i)一种或多种第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药；和ii)药学上可接受的载体。A third aspect of the present invention provides a pharmaceutical composition comprising i) one or more of the compounds described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable compounds a salt, hydrate, solvate or prodrug; and ii) a pharmaceutically acceptable carrier.
在另一优选例中，所述药物组合物还包括选自下组的一种或多种治疗剂：PD-1抑制剂(如nivolumab,pembrolizumab,pidilizumab,cemiplimab，JS-001，SHR-120，BGB-A317，IBI-308，GLS-010，GB-226，STW204，HX008,HLX10,BAT 1306,AK105,LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab,atezolizumab, avelumab，CS1001，KN035,HLX20,SHR-1316，BGB-A333，JS003,CS1003,KL-A167,F 520,GR1405,MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab,obinutuzumab,ofatumumab,veltuzumab,tositumomab,131I-tositumomab,ibritumomab,90Y-ibritumomab,90In-ibritumomab,ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4，CC-90002，TTI-621，TTI-622,OSE-172，SRF-231，ALX-148，NI-1701，SHR-1603，IBI188，IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。In another preferred embodiment, 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, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231 , ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, ocaltinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozant inib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib , Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 Inhibitors (eg, RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.
本发明第四方面，提供一种如第一方面所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或第三方面所述的药物组合物的用途，用于制备预防和/或治疗与SOS1活性或表达量相关的疾病的药物组合物。The fourth aspect of the present invention provides a compound as described in the first aspect, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, Or the use of the pharmaceutical composition in the third aspect for preparing a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of SOS1.
在另一优选例中，所述疾病为癌症。In another preferred embodiment, the disease is cancer.
在另一优选例中，所述癌症选自：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophagus cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer, brain cancer tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
本发明第五方面，提供一种非诊断性、非治疗性地抑制SOS1的方法，其包括步骤：向所需患者施用有效量的如上所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或施用如上所述的药物组合物。A fifth aspect of the present invention provides a non-diagnostic, non-therapeutic method for inhibiting SOS1, comprising the steps of: administering to a patient in need an effective amount of the compound, its stereoisomers, and tautomers as described above form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administer a pharmaceutical composition as described above.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.
附图说明Description of drawings
无none
具体实施方式Detailed ways
本发明人经过长期而深入的研究，意外地发现了一类新型的SOS1有选择性抑制作用和/或更好药效学性能的化合物。在此基础上，发明人完成了本发明。After long-term and in-depth research, the present inventors unexpectedly discovered a new class of compounds with selective inhibitory effect on SOS1 and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
术语the term
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.
术语“烷基”是指直链或支链或环状烷烃基，包含1-20个碳原子，如1-18个碳原子，尤其指1-18个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、
Figure PCTCN2022074828-appb-000046
戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等等。 The term "alkyl" refers to a straight or branched chain or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms. Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl,
Figure PCTCN2022074828-appb-000046
Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
术语“C1-C18烷基”指的是直链或支链或环状烷基，包括从1-18个碳原子，如甲基、乙基、丙基、异丙基
Figure PCTCN2022074828-appb-000047
正丁基、叔丁基、异丁基(如
Figure PCTCN2022074828-appb-000048
)、正戊基、异戊基、正己基、异己基、正庚基、异庚基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。 The term "C1-C18 alkyl" refers to straight or branched chain or cyclic alkyl groups, including from 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl
Figure PCTCN2022074828-appb-000047
n-butyl, tert-butyl, isobutyl (such as
Figure PCTCN2022074828-appb-000048
), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ), nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 Re , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O) R a , OC(=O) NR b R c , NR b C(=O) OR e , NR d C (=O) NRbRc , NRdS (=O) 2NRbRc , NRdP ( =O ) 2NRbRc , NRbC ( =O ) Ra , or NRbP ( =O) 2 R e , wherein R a appearing here may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with N atom can form a heterocycle; R e can independently represent hydrogen, alkyl, cycloalkane alkenyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring may be optionally substituted.
术语“亚烷基”是指“烷基”再脱掉一个氢原子所形成的基团，如亚甲基、亚乙基、亚丙基、亚异丙基(如
Figure PCTCN2022074828-appb-000049
)、亚丁基(如
Figure PCTCN2022074828-appb-000050
)、亚戊基(如
Figure PCTCN2022074828-appb-000051
)、亚己基(如
Figure PCTCN2022074828-appb-000052
)、亚庚基(如
Figure PCTCN2022074828-appb-000053
)等。 The term "alkylene" refers to a group formed by removing one hydrogen atom from "alkyl", such as methylene, ethylene, propylene, isopropylidene (such as
Figure PCTCN2022074828-appb-000049
), butylene (such as
Figure PCTCN2022074828-appb-000050
), pentylene (such as
Figure PCTCN2022074828-appb-000051
), ahexyl (such as
Figure PCTCN2022074828-appb-000052
), heptidene (such as
Figure PCTCN2022074828-appb-000053
)Wait.
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基， 可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选被取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。 The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group comprising 1-4 rings, each ring containing 3-8 carbon atoms. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, a monohalogen substituent or a polyhalogen substituent such as trifluoromethyl or an alkyl group containing Cl ), nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 Re , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O) R a , OC(=O) NR b R c , NR b C(=O) OR e , NR d C (=O) NRbRc , NRdS (=O) 2NRbRc , NRdP ( =O ) 2NRbRc , NRbC ( =O ) Ra , or NRbP ( =O) 2 R e , wherein R a appearing here may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c together with N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned 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.
术语“亚环烷基”是指环烷基脱掉两个氢原子所形成的基团，如：
Figure PCTCN2022074828-appb-000054
Figure PCTCN2022074828-appb-000055
Figure PCTCN2022074828-appb-000056
等。 The term "cycloalkylene" refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as:
Figure PCTCN2022074828-appb-000054
Figure PCTCN2022074828-appb-000055
Figure PCTCN2022074828-appb-000056
Wait.
术语“亚烷基亚环烷基”是指上述的环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“C1-C18亚烷基C3-C20亚环烷基”或“C3-C20亚环烷基C1-C18亚烷基”具有相同含义，优选地，C1-C6亚烷基C3-C12亚环烷基，包括但不限于：
Figure PCTCN2022074828-appb-000057
Figure PCTCN2022074828-appb-000058
Figure PCTCN2022074828-appb-000059
Figure PCTCN2022074828-appb-000060
等。 The term "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:
Figure PCTCN2022074828-appb-000057
Figure PCTCN2022074828-appb-000058
Figure PCTCN2022074828-appb-000059
Figure PCTCN2022074828-appb-000060
Wait.
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环，6-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1、2、3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基，其中，环上的任意两个或两个以上的原子可以与其他环烷基、杂环基、芳基和杂芳基进一步并环连接，如5-12元杂环基并苯基、5-12元杂环基并5-6元杂芳基、5-15元杂环基并苯基、5-15元杂环基并5-6元杂芳基。The term "heterocyclyl" refers to fully saturated or partially unsaturated cyclic groups (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 a ring having at least one carbon atom. Each heterocyclic ring containing a heteroatom may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur may be oxidized or the nitrogen may Quaternized. A heterocyclic group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepanyl gene, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms on the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further cyclically connected; the heterocyclic group can be substituted or unsubstituted, and when substituted, The substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate, wherein the ring Any two or more atoms can be further attached to other cycloalkyl, heterocyclyl, aryl and heteroaryl groups, such as 5-12-membered heterocyclyl-acyl, 5-12-membered heterocyclyl 5-6 membered heteroaryl, 5-15 membered heterocyclylacyl, 5-15 membered heterocyclyl and 5-6 membered heteroaryl.
术语“亚杂环基”是指上述杂环基脱掉两个氢原子所形成的基团，包括但不限于：The term "heterocyclylene" refers to a group formed by removing two hydrogen atoms from the above-mentioned heterocyclyl, including but not limited to:
Figure PCTCN2022074828-appb-000061
Figure PCTCN2022074828-appb-000062
等。
Figure PCTCN2022074828-appb-000061
Figure PCTCN2022074828-appb-000062
Wait.
术语“亚杂环烷基亚烷基”是指环烷基烷基或烷基环烷基脱掉两个氢原子所形成的基团，其中，“4-20元亚杂环烷基C1-C18亚烷基”或“C1-C18亚烷基4-20元亚杂环烷基”具有相 同含义，优选地为4-12元亚杂环烷基C1-6亚烷基，包括但不限于：
Figure PCTCN2022074828-appb-000063
Figure PCTCN2022074828-appb-000064
等。 The term "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:
Figure PCTCN2022074828-appb-000063
Figure PCTCN2022074828-appb-000064
Wait.
术语“芳基”是指芳香环状烃类化合物基团，具有1-5个环，尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。 The term "aryl" refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ), nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 Re , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 Re , NR b P(=O) 2 Re , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O) R a , OC(=O) NR b R c , NR b C(=O) OR e , NR d C (=O) NRbRc , NRdS (=O) 2NRbRc , NRdP ( =O ) 2NRbRc , NRbC ( =O ) Ra , or NRbP ( =O) 2 R e , wherein R a appearing here may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c together with N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclyl or fused ring aryl, the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷 氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
术语“C1-C18烷氧基”是指具有1至18个碳原子的直链或支链或环状烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C8烷氧基，更优选C1-C6烷氧基。The term "C1-C18 alkoxy" refers to a straight or branched chain or cyclic alkoxy group having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropyl oxy and butoxy, etc. Preferably it is a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group.
术语“C1-C18亚烷氧基”是指“C1-C18烷氧基”脱掉一个氢原子所得基团。The term "C1-C18 alkyleneoxy" refers to a group obtained by removing one hydrogen atom from "C1-C18 alkoxy".
术语“卤素”或“卤”是指氯、溴、氟、碘。The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
术语“卤代”是指被卤素取代。The term "halo" refers to substitution with halogen.
术语“氘代”是指被氘取代。The term "deuterated" refers to substitution with deuterium.
术语“羟基”是指带有结构OH的基团。The term "hydroxyl" refers to a group with the structure OH.
术语“硝基”是指带有结构NO 2的基团。 The term "nitro" refers to a group with the structure NO2.
术语“氰基”是指带有结构CN的基团。The term "cyano" refers to a group with the structure CN.
术语“酯基”是指带有结构-COOR的基团，其中R代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环。The term "ester" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
术语“胺基”是指带有结构-NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。The term "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.
术语“酰胺基”是指带有结构-CONRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。The term "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.
术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。 The term "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.
术语“脲基”是指带有结构-NRCONR'R"的基团，其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。The term "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.
术语"烷基胺基烷基"是指带有结构-RNHR'的基团，其中R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'可以相同或不同。The term "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.
术语"二烷基胺基烷基"是指带有结构-RNHR'R"的基团，其中R、R'和R"可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。The term "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.
术语"杂环基烷基"是指带有结构-RR'的基团，其中R可以独立的代表烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基；R'代表杂环或取代的杂环。The term "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.
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido and so on.
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom that is not in a valence state has enough hydrogen atoms to replenish its valence state.
当取代基为非末端取代基时，其为相应基团的亚基，例如烷基对应于亚烷基、环烷基对应亚环烷基、杂环基对亚杂环基、烷氧基对应亚烷氧基等。When 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.
活性成分Active ingredient
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。As used herein, "compounds of the present invention" refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.
本发明中，式(I)化合物具有如下结构：In the present invention, the compound of formula (I) has the following structure:
Figure PCTCN2022074828-appb-000065
Figure PCTCN2022074828-appb-000065
式中，X、Y、U、V、环A、环B、R 1、R 2、R 3、R 4、R 5、m和n的定义如上所述。 In the formula, X, Y, U, V, Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined above.
优选地，式I中，
Figure PCTCN2022074828-appb-000066
部分选自：
Figure PCTCN2022074828-appb-000067
Figure PCTCN2022074828-appb-000068
Preferably, in formula I,
Figure PCTCN2022074828-appb-000066
Partially selected from:
Figure PCTCN2022074828-appb-000067
Figure PCTCN2022074828-appb-000068
优选地，所述的式I化合物具有式(II)所示结构：Preferably, the compound of formula I has the structure shown in formula (II):
Figure PCTCN2022074828-appb-000069
Figure PCTCN2022074828-appb-000069
式中，环A、环B、R 1、R 2、R 3、R 4、R 5、m和n的定义如上所述。 In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined above.
优选地，所述的式I化合物具有式(III)所示结构：Preferably, the compound of formula I has the structure shown in formula (III):
Figure PCTCN2022074828-appb-000070
Figure PCTCN2022074828-appb-000070
式中，环A、环B、R 1、R 2、R 3、R 4、m和n的定义如上所述。 In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
优选地，所述的式I化合物具有式(IV)所示结构：Preferably, the compound of formula I has the structure shown in formula (IV):
Figure PCTCN2022074828-appb-000071
Figure PCTCN2022074828-appb-000071
式中：R 1、R 2、R 3、环A、环B、m、和n的定义如上所述。 wherein: R 1 , R 2 , R 3 , ring A, ring B, m, and n are as defined above.
优选地，所述的式I化合物具有式(V)所示结构：Preferably, the compound of formula I has the structure shown in formula (V):
Figure PCTCN2022074828-appb-000072
Figure PCTCN2022074828-appb-000072
式中：where:
W选自：N或CR y；R y选自下组：氢、氘、卤素、氰基、取代或未取代C 1-C 3烷基、取代或未取代3-6元环烷基和取代或未取代4-6元杂环烷基； W is selected from: N or CR y ; R y is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Wherein, the above-mentioned 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;
R 1、R 2、R 3、环B、m和n的定义如上所述。 R 1 , R 2 , R 3 , ring B, m and n are as defined above.
优选地，所述的式I化合物具有式(VI)所示结构：Preferably, the compound of formula I has the structure shown in formula (VI):
Figure PCTCN2022074828-appb-000073
Figure PCTCN2022074828-appb-000073
式中，In the formula,
R 1、R 2、R 3、环B、m、n和R y的定义如上所述。 R 1 , R 2 , R 3 , ring B, m, n and R y are as defined above.
优选地，式I-VI中，R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、氧代基、取代或未取代C 2-C 4烯基、取代或未取代C 2-C 4炔基、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基、取代或未取代4-6元杂环烷基、取代或未取代C 1-C 6亚烷基C 3-C 13亚环烷基、取代或未取代C 1-C 6亚烷基4-12元亚杂环烷基、-(CH 2) hO(CH 2) pR 6、-(CH 2) hSR 6、-(CH 2) hCOR 6、-(CH 2) hC(O)OR 6、-(CH 2) hS(O) qR 6、-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hS(O) qNR 6R 7、-(CH 2) hNR 6S(O) qR 7、 -(CH 2) hNR 6S(O) qNR 7R 8；R 6、R 7和R 8各自独立地选自下组：氢、取代或未取代C 1-C 6烷基、取代或未取代C 3-C 6环烷基、取代或未取代4-6元杂环基、取代或未取代C 6-C 14芳基和取代或未取代5-14元杂芳基；或者在-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hS(O) qNR 6R 7中，R 6和R 7与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hNR 6S(O) qR 7、-(CH 2) hNR 6S(O) qNR 7R 8中，R 7和R 8与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 6和R 7与其相邻的原子环合形成取代或未取代的4-8元杂环基；优选地，R 1、R 2各自独立地选自下组：氢、氘、卤素、氰基、氧代基、取代或未取代C 1-C 6烷基、CH 2OCH 3、CH 2CH 2OCH 3、CH 2CH 2OCH 2CH 3； Preferably, in formulae I-VI, R 1 and R 2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted Substituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted Substituted C 1 -C 6 alkylene C 3 -C 13 cycloalkylene, substituted or unsubstituted C 1 -C 6 alkylene 4-12 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 , -(CH 2 ) h COR 6 , -(CH 2 ) h C(O)OR 6 , -(CH 2 ) h S(O) q R 6 , -(CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h S(O) q NR 6 R 7 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S (O) q NR 7 R 8 ; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkane group, substituted or unsubstituted 4-6 membered heterocyclyl, substituted or unsubstituted C 6 -C 14 aryl and substituted or unsubstituted 5-14 membered heteroaryl; or in -(CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h S(O) q NR 6 R 7 , R 6 and R 7 are cyclized with their adjacent N atoms to form substituted or unsubstituted Substituted 4-8 membered heterocyclyl; or at -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 , R 7 and R 8 are cyclized with their adjacent N atoms to form a substituted or unsubstituted 4- 8-membered heterocyclic group, or R 6 and R 7 are cyclized with their adjacent atoms to form a substituted or unsubstituted 4-8-membered heterocyclic group; preferably, R 1 and R 2 are each independently selected from the following group: hydrogen , deuterium, halogen, cyano, oxo, substituted or unsubstituted C 1 -C 6 alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 3 ;
h为0、1、2、3、4、5或6；h is 0, 1, 2, 3, 4, 5 or 6;
R 3选自取代或未取代的下组基团：苯基和5-6元杂芳基，其中，R 3中所述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；优选地，R 3选自： R 3 is selected from the group consisting of substituted or unsubstituted groups: phenyl and 5-6-membered heteroaryl, wherein the substitution in R 3 refers to being substituted by one or more groups selected from the group of: C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxy, C 3 -C 6 cycloalkyl, C 1 - C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amido , sulfonamide or ureido; preferably, R is selected from:
Figure PCTCN2022074828-appb-000074
Figure PCTCN2022074828-appb-000074
环B选自取代或未取代的下组基团：C 3-C 10环烷基、4-15元杂环基、苯基和5-6元杂芳基，其中，环B中所述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 Ring B is selected from the group consisting of substituted or unsubstituted C3 - C10 cycloalkyl, 4-15 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the substitution described in Ring B means substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, Hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide or urea groups.
其中，R 1、R 2、R 6、R 7和R 8中的取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-6元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基。 Wherein, substitution in R 1 , R 2 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C6 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-6 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group and urea group.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱 式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。The 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. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when 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". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) 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, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等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, mesylate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salts, pectates, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonates, dodecanoates, etc.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。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.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。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.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。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.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单 个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, 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.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。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.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。 Specific functional groups and chemical term definitions are detailed below. For the purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. 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.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。 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. Examples of 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. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the aforementioned compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioisotopes of3H and14C , are also among them and are useful in drug and substrate tissue distribution experiments. Tritium, ie 3 H and carbon-14, ie 14 C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie, 2 H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. 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.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If a synthesis of a particular enantiomer of a compound of the present invention is desired, it 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. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, 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.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. Generally, whether the term "substituted" appears before or after the term "optional", 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. When multiples of a particular structure are substituted at positions with multiple specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence. Furthermore, 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. As used herein, the term "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.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.
制备方法Preparation
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。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.
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。Typically, 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.
优选地，本发明化合物采用如下方法制备Preferably, the compounds of the present invention are prepared by the following methods
Figure PCTCN2022074828-appb-000075
Figure PCTCN2022074828-appb-000075
方法一method one
(i)式(X-1)化合物与醋酸酐反应得到式(X-2)化合物；(i) the compound of formula (X-1) reacts with acetic anhydride to obtain the compound of formula (X-2);
(ii)在氧化剂(如H 2O 2等)和碱(如氢氧化钠等)存在下，式(X-2)化合物分子内关环得到式(X-3)化合物； (ii) in the presence of an oxidizing agent (such as H2O2, etc.) and a base (such as sodium hydroxide, etc.), the compound of formula (X- 2 ) is intramolecularly closed to obtain a compound of formula (X-3);
(iii)在碱(如TEA、DIPEA、Py、DMAP、或DBU等)及缩合剂(如BOP、或PyBOP等)存在下，式(X-3)化合物与胺(式X-4)反应，得到式(III)化合物；(iii) in the presence of a base (such as TEA, DIPEA, Py, DMAP, or DBU, etc.) and a condensing agent (such as BOP, or PyBOP, etc.), the compound of formula (X-3) is reacted with amine (formula X-4), to obtain the compound of formula (III);
方法二Method Two
(i)式(X-1)化合物与醋酸酐反应得到式(X-2)化合物；(i) the compound of formula (X-1) reacts with acetic anhydride to obtain the compound of formula (X-2);
(ii)在氧化剂(如H 2O 2等)和碱(如氢氧化钠等)存在下，式(X-2)化合物分子内关环得到式(X-3)化合物； (ii) in the presence of an oxidizing agent (such as H2O2, etc.) and a base (such as sodium hydroxide, etc.), the compound of formula (X- 2 ) is intramolecularly closed to obtain a compound of formula (X-3);
(iv)在碱(如TEA、DIPEA、Py、或DMAP等)存在下，式(X-3)与化合物LG-X反应，得到式(X-5)化合物；(iv) in the presence of a base (such as TEA, DIPEA, Py, or DMAP, etc.), formula (X-3) reacts with compound LG-X to obtain a compound of formula (X-5);
(v)在碱(如TEA、DIPEA、Py、或DMAP等)存在下，式(X-5)与化合物与胺(式X-4)反应，得到式(III)化合物；(v) in the presence of a base (such as TEA, DIPEA, Py, or DMAP, etc.), the compound of formula (X-5) is reacted with an amine (formula X-4) to obtain a compound of formula (III);
式中，In the formula,
LG选自：卤素、OTs、OMs或OTf；LG is selected from: halogens, OTs, OMs or OTf;
LG-X选自：SOCl 2、SO 2Cl 2、POCl 3、MsCl、TsCl、TfOH、TMSOTf、Tf 2O、或Ms 2O等 LG-X is selected from: SOCl 2 , SO 2 Cl 2 , POCl 3 , MsCl, TsCl, TfOH, TMSOTf, Tf 2 O, or Ms 2 O, etc.
R 1、R 2、R 3、X、环B、m和n定义如上所述。 R 1 , R 2 , R 3 , X, ring B, m and n are as defined above.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
本发明所述的药物组合物用于预防和/或治疗以下疾病：炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。The pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与 其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。The compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When co-administered, the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently. When the compound of formula I is administered concomitantly with one or more other drugs, 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. When a compound of formula I is administered in pharmaceutical combination with one or more other drugs, 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.
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如nivolumab、pembrolizumab、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT 1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如durvalumab、atezolizumab、avelumab、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003,KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如rituximab、obinutuzumab、ofatumumab、veltuzumab、tositumomab、131I-tositumomab、ibritumomab、90Y-ibritumomab、90In-ibritumomab、ibritumomab tiuxetan等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622,OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如Ceritinib、Alectinib、Brigatinib、Lorlatinib、奥卡替尼)、PI3K抑制剂(如Idelalisib、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如Ibrutinib、Tirabrutinib、Acalabrutinib、Zanubrutinib、Vecabrutinib等)、EGFR抑制剂(如Afatinib、Gefitinib、Erlotinib、Lapatinib、Dacomitinib、Icotinib、Canertinib、Sapitinib、Naquotinib、Pyrotinib、Rociletinib、Osimertinib等)、VEGFR抑制剂(如Sorafenib、Pazopanib、Regorafenib、Sitravatinib、Ningetinib、Cabozantinib、Sunitinib、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、Vorinostat、Fimepinostat、Droxinostat、Entinostat、Dacinostat、Quisinostat、Tacedinaline等)、CDK抑制剂(如Palbociclib、Ribociclib、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如Selumetinib(AZD6244)、Trametinib(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)或其组合。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, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibody (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX -148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocaltinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Caboza ntinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib , Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 Inhibitors (eg, RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.
本发明所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。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.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。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. Usually, 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. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基 纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022074828-appb-000076
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as
Figure PCTCN2022074828-appb-000076
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。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 .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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 monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。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.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能 需要的推进剂一起混合。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.
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。The therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as people) in need of treatment, and the dose is a pharmaceutically considered effective dose when administered, and for a person with a body weight of 60kg, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, 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.
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述通式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。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 the general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form the pharmaceutical composition.
本发明还提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明中所述通式(I)化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明所述的药物组合物，用于选择性地抑制SOS1。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.
与现有技术相比，本发明具有以下主要优点：Compared with the prior art, the present invention has the following main advantages:
(1)所述化合物对SOS1具有很好的选择性抑制作用；(1) The compound has a good selective inhibitory effect on SOS1;
(2)所述化合物具有更好的体内外药效学、药代动力学性能和更低的毒副作用。(2) The compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental method of unreceipted specific conditions in the following examples, usually according to routine conditions such as Sambrook et al., molecular cloning: conditions described in laboratory manual (New York:Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer the proposed conditions. Percentages and parts are by weight unless otherwise indicated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。 NMR was detected using a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was determined to include deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc., tetramethylsilane (TMS) was used as the internal standard, and chemical shifts were measured in units of parts per million (ppm).
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。Liquid chromatography-mass spectrometry (LC-MS) was detected using a Waters SQD2 mass spectrometer. The HPLC assay was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0 mm column).
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。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.
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。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.
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。Unless otherwise specified, all the reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.
实施例Example
实施例1(R)-N-(1-(3-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-7,8-二氢-[1,4]二恶英[2,3-g]喹唑啉-4-胺的制备Example 1(R)-N-(1-(3-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8-dihydro-[1, 4] Preparation of dioxin[2,3-g]quinazolin-4-amine
Figure PCTCN2022074828-appb-000077
Figure PCTCN2022074828-appb-000077
第一步：2,3-二氢苯并[b][1,4]二恶英-6-腈的制备The first step: preparation of 2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile
将3,4-二羟基苯腈(5g,37mmol)加入N，N-二甲基甲酰胺(50mL)中，再加入1,2-二溴乙烷(28g,148mmol)和碳酸钾(26g,185mmol)。得到的反应液在80度搅拌过夜，然后降温后倒入500mL水中，再用100毫升乙酸乙酯萃取3次。合并的有机相干燥后过滤，滤液浓缩，得到的残余物用硅胶柱层析(PE:EA＝5:1)分离，得到目标产物(3.5g，收率：58％)。3,4-Dihydroxybenzonitrile (5g, 37mmol) was added to N,N-dimethylformamide (50mL), followed by 1,2-dibromoethane (28g, 148mmol) and potassium carbonate (26g, 185 mmol). The obtained reaction solution was stirred at 80 degrees overnight, then cooled down, poured into 500 mL of water, and extracted three times with 100 mL of ethyl acetate. The combined organic phases were dried and filtered, the filtrate was concentrated, and the obtained residue was separated by silica gel column chromatography (PE:EA=5:1) to obtain the target product (3.5 g, yield: 58%).
LC-MS：m/z 162(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.15-7.13(m,2H),6.92-6.90(m,1H),4.33-4.31(m,2H),4.29-4.27(m,2H). LC-MS: m/z 162 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.15-7.13 (m, 2H), 6.92-6.90 (m, 1H), 4.33-4.31 (m, 2H), 4.29-4.27 (m, 2H).
第二步：7-硝基-2,3-二氢苯并[b][1,4]二恶英-6-腈的制备Step 2: Preparation of 7-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile
将2,3-二氢苯并[b][1,4]二恶英-6-腈(1g,6.2mmol)加入醋酸酐(10mL)中，加入浓硝酸(1mL,15mmol)。得到的反应液在室温搅拌过夜，然后倒入50mL水中，再用50毫升乙酸乙酯萃取。有机相干燥后过滤，滤液浓缩，得到的残余物硅胶柱层析(PE:EA＝10:1)分离，得到目标产物(750mg，收率：58％)。2,3-Dihydrobenzo[b][1,4]dioxin-6-carbonitrile (1 g, 6.2 mmol) was added to acetic anhydride (10 mL), and concentrated nitric acid (1 mL, 15 mmol) was added. The resulting reaction solution was stirred at room temperature overnight, then poured into 50 mL of water, and extracted with 50 mL of ethyl acetate. The organic phase was dried and filtered, the filtrate was concentrated, and the obtained residue was separated by silica gel column chromatography (PE:EA=10:1) to obtain the target product (750 mg, yield: 58%).
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.33(s,1H),4.41(s,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (s, 1H), 7.33 (s, 1H), 4.41 (s, 4H).
第三步:7-氨基-2,3-二氢苯并[b][1,4]二恶英-6-腈的制备Step 3: Preparation of 7-amino-2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile
将7-硝基-2,3-二氢苯并[b][1,4]二恶英-6-腈(500mg)加入甲醇(5mL)中，随后加入钯碳(100mg)。得到的反应液在氢气氛围下在室温搅拌3小时，然后过滤。滤液浓缩，得到目标产物(420mg)。无需进一步纯化，直接用于下一步反应。7-Nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile (500 mg) was added to methanol (5 mL) followed by palladium on carbon (100 mg). The resulting reaction solution was stirred at room temperature for 3 hours under a hydrogen atmosphere, and then filtered. The filtrate was concentrated to obtain the desired product (420 mg). It was used directly in the next reaction without further purification.
LC-MS：m/z 177(M+H) +。 LC-MS: m/z 177 (M+H) + .
第四步:N-(7-氰基-2,3-二氢苯并[b][1,4]二恶英-6-基)乙酰胺的制备Step 4: Preparation of N-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide
将7-氨基-2,3-二氢苯并[b][1,4]二恶英-6-腈(427mg)加入二氯甲烷(5mL)中，随后加入醋酸酐(5mL)。得到的反应液在70度搅拌过夜，然后降温后浓缩，得到目标产物(520mg)。无需进一步纯化，直接用于下一步反应。7-Amino-2,3-dihydrobenzo[b][1,4]dioxin-6-carbonitrile (427 mg) was added to dichloromethane (5 mL) followed by acetic anhydride (5 mL). The obtained reaction solution was stirred at 70 degrees overnight, then cooled and concentrated to obtain the target product (520 mg). It was used directly in the next reaction without further purification.
LC-MS：m/z 219(M+H) +。 LC-MS: m/z 219 (M+H) + .
第五步:2-甲基-7,8-二氢-[1,4]二恶英[2,3-g]喹唑啉-4-醇的制备Step 5: Preparation of 2-methyl-7,8-dihydro-[1,4]dioxin[2,3-g]quinazolin-4-ol
将N-(7-氰基-2,3-二氢苯并[b][1,4]二恶英-6-基)乙酰胺(200mg,0.9mmol)加入乙醇(2mL)中，随后加入双氧水(2mL)和氢氧化钠(44mg,1.1mmol)。得到的反应液回流搅拌过夜，然后降温后浓缩。残余物用2N盐酸调pH到2，然后过滤。固体收集、干燥后得到目标产物(150mg，收率：75％)。无需进一步纯化，直接用于下一步反应。N-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide (200 mg, 0.9 mmol) was added to ethanol (2 mL) followed by Hydrogen peroxide (2 mL) and sodium hydroxide (44 mg, 1.1 mmol). The resulting reaction solution was stirred at reflux overnight, then cooled and concentrated. The residue was adjusted to pH 2 with 2N hydrochloric acid and filtered. The solid was collected and dried to obtain the desired product (150 mg, yield: 75%). It was used directly in the next reaction without further purification.
LC-MS：m/z 219(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.50(s,1H),7.21(s,1H),4.43-4.37(m,4H),2.53(s,3H). LC-MS: m/z 219 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.50(s, 1H), 7.21(s, 1H), 4.43-4.37(m, 4H), 2.53(s, 3H).
第五步:(R)-N-(1-(3-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-7,8-二氢-[1,4]二恶英[2,3-g]喹唑啉-4-胺的制备Step 5: (R)-N-(1-(3-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8-dihydro-[1 Preparation of ,4]dioxin[2,3-g]quinazolin-4-amine
将2-甲基-7,8-二氢-[1,4]二恶英[2,3-g]喹唑啉-4-醇(150mg,0.7mmol)加入N，N-二甲基甲酰胺(2mL)中，随后加入1,8-二氮杂二环十一碳-7-烯(310mg,2.1mmol)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(610mg,1.4mmol)和(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺(180mg,0.9mmol)。得到的反应液在80度搅拌过夜，然后降温后倒入50mL水中，再用20毫升乙酸乙酯萃取3次。合并的有机相干燥后过滤，滤液浓缩，得到的残余物用制备高效液相色谱分离得到目标产物(43mg，收率：15％)。2-Methyl-7,8-dihydro-[1,4]dioxin[2,3-g]quinazolin-4-ol (150 mg, 0.7 mmol) was added to N,N-dimethylmethane amide (2 mL), followed by 1,8-diazabicycloundec-7-ene (310 mg, 2.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphorus Onium hexafluorophosphate (610 mg, 1.4 mmol) and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (180 mg, 0.9 mmol). The obtained reaction solution was stirred at 80 degrees overnight, then cooled down, poured into 50 mL of water, and extracted three times with 20 mL of ethyl acetate. The combined organic phases were dried and filtered, the filtrate was concentrated, and the obtained residue was separated by preparative high performance liquid chromatography to obtain the target product (43 mg, yield: 15%).
LC-MS：m/z 405(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.97(d,J＝8Hz,1H),7.90(s,1H),6.97(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.51(s,3H),4.34(d,J＝3.2Hz,4H),2.32(s,3H),1.51(d,J＝6.8Hz,3H). LC-MS: m/z 405 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.97(d, J=8Hz, 1H), 7.90(s, 1H), 6.97(s, 1H), 6.88(s, 1H), 6.83(s, 1H) ), 6.68(s, 1H), 5.51(s, 3H), 4.34(d, J=3.2Hz, 4H), 2.32(s, 3H), 1.51(d, J=6.8Hz, 3H).
按照实施例1的方法以不同的起始原料合成了以下化合物：The following compounds were synthesized according to the method of Example 1 with different starting materials:
实施例2N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-(甲氧基甲基)-2-甲基-7,8-二氢-[1,4]二氧六环[2,3-g]喹唑啉-4-胺和N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-8-(甲氧基甲基)-2-甲基-7,8-二氢-[1,4]二氧六环[2,3-g]喹唑啉-4-胺混合物的制备Example 2N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(methoxymethyl)-2-methyl-7,8- Dihydro-[1,4]dioxo[2,3-g]quinazolin-4-amine and N-((R)-1-(3-amino-5-(trifluoromethyl)benzene yl)ethyl)-8-(methoxymethyl)-2-methyl-7,8-dihydro-[1,4]dioxo[2,3-g]quinazoline-4- Preparation of Amine Mixtures
Figure PCTCN2022074828-appb-000078
Figure PCTCN2022074828-appb-000078
LC-MS：m/z 449(M+H) +。 1H NMR(400MHz,DMSO-d 6)δ7.98-7.91(m,2H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.52-5.47(m,3H),4.49-4.40(m,2H),4.15-4.09(m,1H),3.64-3.62(m,2H),3.34-3.33(m,3H),2.33(s,3H),1.52-1.50(m,3H). LC-MS: m/z 449 (M+H) + . 1 H NMR (400MHz, DMSO-d 6 )δ7.98-7.91(m, 2H), 6.99(s, 1H), 6.88(s, 1H), 6.83(s, 1H), 6.68(s, 1H), 5.52-5.47(m, 3H), 4.49-4.40(m, 2H), 4.15-4.09(m, 1H), 3.64-3.62(m, 2H), 3.34-3.33(m, 3H), 2.33(s, 3H) ),1.52-1.50(m,3H).
实施例2经手性分离得到四个异构体Example 2 Four isomers were obtained by chiral separation
Figure PCTCN2022074828-appb-000079
Figure PCTCN2022074828-appb-000079
实施例2AExample 2A
LC-MS：m/z 449(M+H) +。 1H NMR(400MHz,DMSO)δ7.96(d,J＝7.4Hz,2H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.63–5.41(m,3H),4.45(t,J＝9.8Hz,2H),4.10(m,1H),3.67–3.53(m,2H),3.34(s,3H),2.33(s,3H),1.50(d,J＝7.0Hz,3H). LC-MS: m/z 449 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.96(d,J=7.4Hz,2H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H), 5.63-5.41(m, 3H), 4.45(t, J=9.8Hz, 2H), 4.10(m, 1H), 3.67-3.53(m, 2H), 3.34(s, 3H), 2.33(s, 3H) ,1.50(d,J=7.0Hz,3H).
实施例2BExample 2B
LC-MS：m/z 449(M+H) +。 1H NMR(400MHz,DMSO)δ8.02–7.87(m,2H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.59–5.42(m,3H),4.43(d,J＝9.7Hz,2H),4.13(m,1H),3.64(t,J＝8.3Hz,2H),3.34(s,3H),2.33(s,3H),1.50(d,J＝7.0Hz,3H). LC-MS: m/z 449 (M+H) + . 1 H NMR(400MHz, DMSO)δ8.02-7.87(m,2H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.59-5.42 (m,3H),4.43(d,J=9.7Hz,2H),4.13(m,1H),3.64(t,J=8.3Hz,2H),3.34(s,3H),2.33(s,3H) ,1.50(d,J=7.0Hz,3H).
实施例2CExample 2C
LC-MS：m/z 449(M+H) +。 1H NMR(400MHz,DMSO)δ7.98(d,J＝8.1Hz,1H),7.91(s,1H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.50(m,3H),4.49(d,J＝4.9Hz,1H),4.41(dd,J＝11.6,2.2Hz,1H),4.10(m,1H),3.63(d,J＝4.8Hz,2H),3.33(s,3H),2.33(s,3H),1.51(d,J＝7.0Hz,3H). LC-MS: m/z 449 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.98(d,J=8.1Hz,1H),7.91(s,1H),6.99(s,1H),6.88(s,1H),6.83(s,1H), 6.68(s, 1H), 5.50(m, 3H), 4.49(d, J=4.9Hz, 1H), 4.41(dd, J=11.6, 2.2Hz, 1H), 4.10(m, 1H), 3.63(d , J=4.8Hz, 2H), 3.33(s, 3H), 2.33(s, 3H), 1.51(d, J=7.0Hz, 3H).
实施例2DExample 2D
LC-MS：m/z 449(M+H) +。 1H NMR(400MHz,DMSO)δ7.98(d,J＝8.1Hz,1H),7.91(s,1H),6.99(s,1H),6.88(s,1H),6.83(s,1H),6.70(d,J＝16.2Hz,1H),5.50(m,3H),4.49(d,J＝4.8Hz,1H),4.41(dd,J＝11.6,2.2Hz,1H),4.11(m,1H),3.63(d,J＝4.8Hz,2H),3.33(s,3H),2.33(s,3H),1.51(d,J＝7.0Hz,3H). LC-MS: m/z 449 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.98(d,J=8.1Hz,1H),7.91(s,1H),6.99(s,1H),6.88(s,1H),6.83(s,1H), 6.70(d,J＝16.2Hz,1H),5.50(m,3H),4.49(d,J＝4.8Hz,1H),4.41(dd,J＝11.6,2.2Hz,1H),4.11(m,1H) ), 3.63(d, J=4.8Hz, 2H), 3.33(s, 3H), 2.33(s, 3H), 1.51(d, J=7.0Hz, 3H).
实施例3(R)-N-(1-(5-氨基-2-氟-3-(三氟甲基)苯基)乙基)-2-甲基-7,8-二氢-[1,4]二氧六环[2,3-g]喹唑啉-4-胺的制备Example 3 (R)-N-(1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8-dihydro-[1 Preparation of ,4]dioxane[2,3-g]quinazolin-4-amine
Figure PCTCN2022074828-appb-000080
Figure PCTCN2022074828-appb-000080
LC-MS：m/z 423(M+H) +。 LC-MS: m/z 423 (M+H) + .
实施例4(R)-N-(1-(2-氟-3-(三氟甲基)苯基)乙基)-2-甲基-7,8-二氢-[1,4]二氧六环Example 4 (R)-N-(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8-dihydro-[1,4]di oxane
[2,3-g]喹唑啉-4-胺的制备Preparation of [2,3-g]quinazolin-4-amine
Figure PCTCN2022074828-appb-000081
Figure PCTCN2022074828-appb-000081
LC-MS：m/z 408(M+H) +。 LC-MS: m/z 408 (M+H) + .
实施例5(R)-1,1-二氟-1-(2-氟-3-(1-((2-甲基-7,8-二氢-[1,4]二氧六环[2,3-g]喹唑啉-4-基)氨基)乙基)苯基)-2-甲基丙烷-2-醇的制备Example 5(R)-1,1-Difluoro-1-(2-fluoro-3-(1-((2-methyl-7,8-dihydro-[1,4]dioxane[ Preparation of 2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol
Figure PCTCN2022074828-appb-000082
Figure PCTCN2022074828-appb-000082
LC-MS：m/z 448(M+H) +。 LC-MS: m/z 448 (M+H) + .
实施例6(R)-2,2二氟-2-(2-氟-3-(1-((2-甲基-7,8-二氢-[1,4]二氧六环[2,3-g]喹唑啉-4-基)氨基)乙基)苯基)乙烷-1-醇的制备Example 6(R)-2,2difluoro-2-(2-fluoro-3-(1-((2-methyl-7,8-dihydro-[1,4]dioxane[2 Preparation of ,3-g]quinazolin-4-yl)amino)ethyl)phenyl)ethane-1-ol
Figure PCTCN2022074828-appb-000083
Figure PCTCN2022074828-appb-000083
LC-MS：m/z 420(M+H) +。 LC-MS: m/z 420 (M+H) + .
实施例7(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-7,8,10,11,13,14-六氢-[1,4,7,10]四氧环十二烷[2,3-g]喹唑啉-4-胺的制备Example 7 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11,13,14-hexa Preparation of Hydro-[1,4,7,10]tetraoxcyclododeca[2,3-g]quinazolin-4-amine
Figure PCTCN2022074828-appb-000084
Figure PCTCN2022074828-appb-000084
LC-MS：m/z 493(M+H) +。 1H NMR(400MHz,CDCl 3)δ7.27(s,1H),7.16(s,1H),7.06(s,1H),6.88(s,1H),6.78(s,1H),5.59(m,2H),4.31–4.16(m,4H),3.96–3.70(m,10H),2.57(s,3H),1.62(d,J＝6.3Hz,3H). LC-MS: m/z 493 (M+H) + . 1 H NMR (400MHz, CDCl 3 ) δ 7.27(s, 1H), 7.16(s, 1H), 7.06(s, 1H), 6.88(s, 1H), 6.78(s, 1H), 5.59(m, 2H), 4.31–4.16 (m, 4H), 3.96–3.70 (m, 10H), 2.57 (s, 3H), 1.62 (d, J=6.3Hz, 3H).
实施例8(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-甲基-[1,3]二氧戊环[4,5-g]喹唑啉-8-胺Example 8 (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methyl-[1,3]dioxolane[4,5 -g]quinazolin-8-amine
Figure PCTCN2022074828-appb-000085
Figure PCTCN2022074828-appb-000085
LC-MS：m/z 391(M+H) +。 LC-MS: m/z 391 (M+H) + .
实施例9(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-甲基-[1,3]二氧戊环[4,5-g]喹唑啉-2,2-d2-8-胺Example 9 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methyl-[1,3]dioxolane[4,5 -g]quinazolin-2,2-d2-8-amine
Figure PCTCN2022074828-appb-000086
Figure PCTCN2022074828-appb-000086
LC-MS：m/z 393(M+H) +。 LC-MS: m/z 393 (M+H) + .
实施例10生物学测试评价Example 10 Biological Test Evaluation
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围。The following biological test examples are further described to illustrate the present invention, but these examples are not meant to limit the scope of the present invention.
化合物对KRAS G12C和SOS1结合的抑制实验。 Inhibition experiments of compounds on KRAS G12C and SOS1 binding.
实验步骤Experimental procedure
(1)待测化合物梯度稀释：将10mM母液(溶解于100％DMSO)加入384孔测试板中，DMSO最终含量为0.25％。(1) Gradient dilution of the compound to be tested: Add 10 mM stock solution (dissolved in 100% DMSO) into a 384-well test plate, and the final content of DMSO is 0.25%.
(2)将5ul Tag1-SOS1溶液加入测试板中，对照组加入5ul稀释缓冲液。(2) 5ul Tag1-SOS1 solution was added to the test plate, and 5ul dilution buffer was added to the control group.
(4)向测试板中加入5ul Tag2-KRAS G12C溶液。 (4) Add 5ul of Tag2-KRAS G12C solution to the test plate.
(4)将10ul Anti-Tag1-Tb3+和Anti-Tag2-XL665检测液加入测试板中。1000rpm离心1分钟，室温孵育2hr。(4) Add 10ul Anti-Tag1-Tb3+ and Anti-Tag2-XL665 detection solution to the test plate. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 2 hr.
(5)读板(5) Board reading
(6)最后应用GraphPad Prism软件计算化合物的IC 50值，并绘出拟合曲线。 (6) Finally, the IC 50 value of the compound was calculated by GraphPad Prism software, and the fitting curve was drawn.
本发明中实施例化合物对KRAS G12C酶和SOS1结合的抑制活性见表1。 Table 1 shows the inhibitory activity of the example compounds of the present invention on the binding of KRAS G12C enzyme and SOS1.
表1本发明中实施例化合物抑制活性Table 1 Inhibitory activity of example compounds in the present invention
IC 50 IC50 (nM)(nM)
实施例1Example 1 3535
实施例2AExample 2A 40.440.4
实施例2BExample 2B 42.342.3
实施例2CExample 2C 23.123.1
实施例2DExample 2D 41.441.4
实施例7Example 7 4.14.1
从表1可以看出：It can be seen from Table 1 that:
本发明实施例化合物对于KRAS G12C和SOS1的结合显示出了很好的抑制活性。 The compounds of the examples of the present invention showed good inhibitory activity on the binding of KRAS G12C and SOS1.
药代动力学测试评价Pharmacokinetic Testing Evaluation
雄性SD大鼠，体重220g左右，禁食过夜后，灌胃给予10mg/kg本发明化合物的溶液[CMC/TW80为载体]。分别在给于本发明化合物后0.5，1.0，2.0，4.0，6.0，8.0，12，和24采血，用LC/MS/MS测定血浆中本发明化合物的浓度。Male SD rats with a body weight of about 220 g were given a solution of 10 mg/kg of the compound of the present invention by gavage [CMC/TW80 as a carrier] after fasting overnight. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, and 24 after administration of the compound of the present invention, respectively, and the concentration of the compound of the present invention in plasma was determined by LC/MS/MS.
由检测结果看出，本发明化合物具有良好的药代动力学特性。It can be seen from the detection results that the compounds of the present invention have good pharmacokinetic properties.
抗肿瘤药效学评价Antitumor Pharmacodynamic Evaluation
将100uL含5x10 6MIA PaCa-2肿瘤细胞悬液皮下接种到裸鼠右后侧腹部。每天监测小鼠健康状况，当肿瘤生长至可触及时开始测量。肿瘤体积计算公式采用:0.5xLxW 2，其中L、W分别代表肿瘤长、宽。肿瘤长至～150mm 3，对小鼠进行随机分组。小鼠每天灌胃给予相应剂量(15、50mg/Kg)化合物的CMC-Na悬液，同时对其一般状态进行监测。肿瘤每周测量3次，体重每周测量两次。 100 uL of 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right hind flank of nude mice. Mice health were monitored daily, starting when tumors grew to palpable size. The tumor volume calculation formula adopts: 0.5×L×W 2 , where L and W represent the length and width of the tumor, respectively. Tumors grew to -150 mm3 and mice were randomized. Mice were given the corresponding doses (15, 50 mg/Kg) of compound in CMC-Na suspension by gavage every day, and their general status was monitored at the same time. Tumors were measured 3 times a week and body weights were measured twice a week.
由检测结果看出，本发明化合物具有良好的抗肿瘤效果。It can be seen from the detection results that the compound of the present invention has a good anti-tumor effect.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (13)

  1. 式(I)化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药：Compounds of formula (I), stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:
    Figure PCTCN2022074828-appb-100001
    Figure PCTCN2022074828-appb-100001
    式中：where:
    Figure PCTCN2022074828-appb-100002
    相同或不同，各自独立地为单键或者双键；
    Figure PCTCN2022074828-appb-100002
    The same or different, each independently is a single bond or a double bond;
    X、Y、U和V各自独立地选自：C、CR x或N，其中，R x选自：H、D、CN或卤素； X, Y, U and V are each independently selected from: C, CR x or N, wherein R x is selected from: H, D, CN or halogen;
    环A选自取代或未取代的下组基团：苯基、5-6元杂芳基、C 4-C 6环烷基和4-6元杂环基； Ring A is selected from the group consisting of substituted or unsubstituted groups: phenyl, 5-6 membered heteroaryl, C4 - C6 cycloalkyl and 4-6 membered heterocyclyl;
    环B选自取代或未取代的下组基团：C 3-C 20环烷基、4-20元杂环基、C 6-C 14芳基或5-14元杂芳基； Ring B is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl or 5-14 membered heteroaryl;
    R 1、R 2相同或不同，各自独立地选自下组：氢、氘、卤素、氰基、氧代基、取代或未取代C 2-C 18烯基、取代或未取代C 2-C 18炔基、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环烷基、取代或未取代C 1-C 18亚烷基C 3-C 20亚环烷基、取代或未取代C 1-C 18亚烷基4-20元亚杂环烷基、-(CH 2) hO(CH 2) pR 6、-(CH 2) hSR 6、-(CH 2) hCOR 6、-(CH 2) hC(O)OR 6、-(CH 2) hS(O) qR 6、-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hS(O) qNR 6R 7、-(CH 2) hNR 6S(O) qR 7、-(CH 2) hNR 6S(O) qNR 7R 8；其中，CH 2中的H可以任选地被取代；R 6、R 7和R 8各自独立地选自下组：氢、取代或未取代C 1-C 18烷基、取代或未取代C 3-C 20环烷基、取代或未取代4-20元杂环基、取代或未取代C 6-C 14芳基和取代或未取代5-14元杂芳基；或者在-(CH 2) hNR 6R 7、-(CH 2) hC(O)NR 6R 7、-(CH 2) hS(O) qNR 6R 7中，R 6和R 7与其相邻的N原子环合形成取代或未取代的4-8元杂环基；或者在-(CH 2) hNR 6C(O)R 7、-(CH 2) hNR 6C(O)NR 7R 8、-(CH 2) hNR 6S(O) qR 7、-(CH 2) hNR 6S(O) qNR 7R 8中，R 7和R 8与其相邻的N原子环合形成取代或未取代的4-8元杂环基，或者R 6和R 7与其相邻的原子环合形成取代或未取代的4-8元杂环基； R 1 , R 2 are the same or different, and are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, oxo, substituted or unsubstituted C 2 -C 18 alkenyl, substituted or unsubstituted C 2 -C 18 alkynyl, substituted or unsubstituted C 1 -C 18 alkyl, substituted or unsubstituted C 3 -C 20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocycloalkyl, substituted or unsubstituted C 1 -C 18 alkylene C 3 -C 20 cycloalkylene, substituted or unsubstituted C 1 -C 18 alkylene 4-20 membered heterocycloalkylene, -(CH 2 ) h O(CH 2 ) p R 6 , -(CH 2 ) h SR 6 , -(CH 2 ) h COR 6 , -(CH 2 ) h C(O)OR 6 , -(CH 2 ) h S(O) q R 6 , -(CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h S(O) q NR 6 R 7 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 ; wherein, H in CH 2 may be optionally substituted; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 18 alkyl, substituted or Unsubstituted C3 - C20 cycloalkyl, substituted or unsubstituted 4-20 membered heterocyclyl, substituted or unsubstituted C6 - C14 aryl and substituted or unsubstituted 5-14 membered heteroaryl; or in- (CH 2 ) h NR 6 R 7 , -(CH 2 ) h C(O)NR 6 R 7 , -(CH 2 ) h S(O) q NR 6 R 7 , R 6 and R 7 are adjacent to it cyclization of the N atom of the substituted or unsubstituted 4-8 membered heterocyclic group; or in -(CH 2 ) h NR 6 C(O)R 7 , -(CH 2 ) h NR 6 C(O)NR 7 R 8 , -(CH 2 ) h NR 6 S(O) q R 7 , -(CH 2 ) h NR 6 S(O) q NR 7 R 8 , R 7 and R 8 and their adjacent N atom rings form a substituted or unsubstituted 4-8-membered heterocyclic group, or R 6 and R 7 are cyclized with their adjacent atoms to form a substituted or unsubstituted 4-8-membered heterocyclic group;
    R 3选自取代或未取代的下组基团：C 3-C 18环烷基、4-20元杂环基、C 6-C 14芳基和5-14元杂芳基； 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 and 5-14 membered heteroaryl;
    R 4、R 5独立地选自取代或未取代的下组基团：C 1-C 6烷基、C 3-C 6环烷基和4-6元杂环基； 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 and 4-6 membered heterocyclyl;
    其中，上述环A、环B、R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8中的取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、 C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基和脲基； Wherein, the substitution in the above-mentioned ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 refers to substitution by one or more groups selected from the following group : hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl hydroxyl, C 3 -C 20 ring Alkyl, 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, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide and urea;
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n为0、1、2、3、4或5；n is 0, 1, 2, 3, 4 or 5;
    h为0、1、2、3、4、5或6；h is 0, 1, 2, 3, 4, 5 or 6;
    p为0、1、2、3、4、5或6；p is 0, 1, 2, 3, 4, 5, or 6;
    q为1或2。q is 1 or 2.
  2. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(II)所示结构：The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (II ) shown in the structure:
    Figure PCTCN2022074828-appb-100003
    Figure PCTCN2022074828-appb-100003
    式中，环A、环B、R 1、R 2、R 3、R 4、R 5、m和n的定义如权利要求1所述。 In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined in claim 1 .
  3. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(III)所示结构：The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (III ) shown in the structure:
    Figure PCTCN2022074828-appb-100004
    Figure PCTCN2022074828-appb-100004
    式中，环A、环B、R 1、R 2、R 3、R 4、m和n的定义如权利要求1所述。 In the formula, ring A, ring B, R 1 , R 2 , R 3 , R 4 , m and n are as defined in claim 1 .
  4. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(IV)所示结构：The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (IV ) shown in the structure:
    Figure PCTCN2022074828-appb-100005
    Figure PCTCN2022074828-appb-100005
    式中：R 1、R 2、R 3、环A、环B、m、和n的定义如权利要求1所述。 In the formula: R 1 , R 2 , R 3 , ring A, ring B, m, and n are as defined in claim 1 .
  5. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(V)所示结构：The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that it has the formula (V ) shown in the structure:
    Figure PCTCN2022074828-appb-100006
    Figure PCTCN2022074828-appb-100006
    式中：where:
    W选自：N或CR y；R y选自下组：氢、氘、卤素、氰基、取代或未取代C 1-C 3烷基、取代或未取代3-6元环烷基和取代或未取代4-6元杂环烷基； W is selected from: N or CR y ; R y is selected from the group consisting of hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl and substituted or unsubstituted 4-6 membered heterocycloalkyl;
    其中，上述取代是指被选自下组的一个或多个基团取代：氢、氘、C 1-C 18烷基、氘代C 1-C 18烷基、卤代C 1-C 18烷基、卤代C 1-C 18烷基羟基、C 3-C 20环烷基、C 1-C 18烷氧基、氘代C 1-C 18烷氧基、卤代C 1-C 18烷氧基、C 6-C 14芳基、5-14元杂芳基、4-20元杂环基、卤素、硝基、羟基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Wherein, the above-mentioned 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;
    R 1、R 2、R 3、环B、m和n的定义如权利要求1所述。 R 1 , R 2 , R 3 , ring B, m and n are as defined in claim 1 .
  6. 如权利要求1-5中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，其具有式(VI)所示结构：The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-5, characterized in that , which has the structure shown in formula (VI):
    Figure PCTCN2022074828-appb-100007
    Figure PCTCN2022074828-appb-100007
    式中，In the formula,
    R 1、R 2、R 3、环B、m、和n的定义如权利要求1所述，R y的定义如权利要求5所述。 R 1 , R 2 , R 3 , ring B, m, and n are as defined in claim 1 , and R y is defined as in claim 5 .
  7. 如权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，环B选自取代或未取代的下组基团：C 3-C 10环烷基、4-16元杂环基、苯基和5-6元杂芳基，其中，所述取代是指被选自下组的一个或多个基团取代：C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 6环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基。 The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-6, characterized in that , Ring B is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 10 cycloalkyl, 4-16-membered heterocyclyl, phenyl and 5-6-membered heteroaryl, wherein the substitution refers to Substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, halogen, nitro, hydroxyl, Oxo, cyano, ester, amine, amide, sulfonamide or urea groups.
  8. 如权利要求1所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，
    Figure PCTCN2022074828-appb-100008
    部分选自：
    Figure PCTCN2022074828-appb-100009
    Figure PCTCN2022074828-appb-100010
    The compound of claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein,
    Figure PCTCN2022074828-appb-100008
    Partially selected from:
    Figure PCTCN2022074828-appb-100009
    Figure PCTCN2022074828-appb-100010
    环C选自取代或未取代的下组基团：C 3-C 8环烷基、4-8元杂环基、C 6-C 10芳基、5-10 元杂芳基； Ring C is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl;
    X 1、X 2各自独立地选自：O、CR 9R 10、NR 11；X 3选自：N或CR 9；R 9、R 10各自独立地选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基；R 11选自取代或未取代的下组基团：氢、氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基； X 1 and X 2 are each independently selected from: O, CR 9 R 10 , NR 11 ; X 3 is selected from: N or CR 9 ; R 9 and R 10 are each independently selected from substituted or unsubstituted groups from the following group : hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl hydroxyl, C 3 -C 10 ring Alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-10-membered heterocyclic group, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide or urea group; R 11 is selected from substituted or unsubstituted lower groups Group: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 6 alkyl hydroxyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl , 4-10 membered heterocyclic group;
    其中，环C、R 9、R 10、R 11中所述取代是指被1、2、3或4个选自下组的基团取代：氘、C 1-C 6烷基、氘代C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 6烷基羟基、C 3-C 10环烷基、C 1-C 6烷氧基、氘代C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 6-C 14芳基、5-14元杂芳基、4-10元杂环基、卤素、硝基、羟基、氧代基、氰基、酯基、胺基、酰胺基、磺酰胺基或脲基； Wherein, the substitution in ring C, R 9 , R 10 , R 11 refers to substitution by 1, 2, 3 or 4 groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 - C6 alkyl, halogenated C1 - C6 alkyl, halogenated C1 - C6 alkylhydroxy, C3 - C10 cycloalkyl, C1 - C6 alkoxy, deuterated C1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-10 membered heterocyclyl, halogen, nitro, hydroxyl, oxygen substituted group, cyano group, ester group, amine group, amide group, sulfonamide group or urea group;
    n1为1、2或3；n1 is 1, 2 or 3;
    n2为0、1或2；n2 is 0, 1 or 2;
    n3为1、2、3或4。n3 is 1, 2, 3 or 4.
  9. 如权利要求1-8中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，其特征在于，所述化合物选自下组：The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of any one of claims 1-8, characterized in that , the compound is selected from the group consisting of:
    Figure PCTCN2022074828-appb-100011
    Figure PCTCN2022074828-appb-100011
    Figure PCTCN2022074828-appb-100012
    Figure PCTCN2022074828-appb-100012
    Figure PCTCN2022074828-appb-100013
    Figure PCTCN2022074828-appb-100013
    Figure PCTCN2022074828-appb-100014
    Figure PCTCN2022074828-appb-100014
    Figure PCTCN2022074828-appb-100015
    Figure PCTCN2022074828-appb-100015
    Figure PCTCN2022074828-appb-100016
    Figure PCTCN2022074828-appb-100016
    Figure PCTCN2022074828-appb-100017
    Figure PCTCN2022074828-appb-100017
    Figure PCTCN2022074828-appb-100018
    Figure PCTCN2022074828-appb-100018
    Figure PCTCN2022074828-appb-100019
    Figure PCTCN2022074828-appb-100019
    Figure PCTCN2022074828-appb-100020
    Figure PCTCN2022074828-appb-100020
    Figure PCTCN2022074828-appb-100021
    Figure PCTCN2022074828-appb-100021
    Figure PCTCN2022074828-appb-100022
    Figure PCTCN2022074828-appb-100022
    Figure PCTCN2022074828-appb-100023
    Figure PCTCN2022074828-appb-100023
    Figure PCTCN2022074828-appb-100024
    Figure PCTCN2022074828-appb-100024
  10. 一种药物组合物，其特征在于，包含i)一种或多种权利要求1-9任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药； 和ii)药学上可接受的载体。A pharmaceutical composition is characterized in that, comprising i) one or more compounds described in any one of claim 1-9, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable and ii) a pharmaceutically acceptable carrier.
  11. 一种如权利要求1-9中任一项所述的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药，或权利要求10所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗与SOS1活性或表达量相关的疾病的药物组合物。A compound as claimed in any one of claims 1-9, a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or The use of the pharmaceutical composition according to claim 10, characterized in that it is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of SOS1.
  12. 如权利要求11所述的用途，其特征在于，所述疾病为癌症。The use of claim 11, wherein the disease is cancer.
  13. 如权利要求12所述的用途，其特征在于，所述癌症选自：肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、骨癌、肾癌、胃癌、肝癌、大肠癌、黑色素瘤、淋巴瘤、血癌、脑瘤、骨髓瘤、软组织肉瘤、胰腺癌、皮肤癌。The use of claim 12, wherein 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.
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