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WO2022161480A1 - Inhibiteur amine hétérocyclique bicyclo-aromatique substitué, son procédé de préparation et son utilisation - Google Patents

Inhibiteur amine hétérocyclique bicyclo-aromatique substitué, son procédé de préparation et son utilisation Download PDF

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Publication number
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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Chinese (zh)
Inventor
吕彬华
崔大为
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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    • 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
    • C07D491/02—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
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • 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
    • A61K31/535—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D491/02—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
    • 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
    • C07D491/14—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
    • 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
    • C07D491/14—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
    • 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
    • C07D491/22—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.

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Abstract

La présente invention concerne un inhibiteur amine hétérocyclique bicyclo-aromatique substitué, son procédé de préparation et son utilisation. En particulier, un composé de la présente invention a une structure telle que représentée par la formule (I). L'invention concerne en outre un procédé de préparation du composé et son utilisation en tant qu'inhibiteur de SOS1. Le composé de la présente invention présente un bon effet inhibiteur sélectif sur SOS1, de meilleures propriétés pharmacodynamiques et pharmacocinétiques et des effets secondaires toxiques réduits.
PCT/CN2022/074828 2021-02-01 2022-01-28 Inhibiteur amine hétérocyclique bicyclo-aromatique substitué, son procédé de préparation et son utilisation Ceased WO2022161480A1 (fr)

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WO2023109929A1 (fr) * 2021-12-17 2023-06-22 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique ayant une activité antitumorale et son utilisation
WO2023138691A1 (fr) * 2022-01-21 2023-07-27 Shenzhen Ionova Life Science Co., Ltd. Composés hétérocycliques fusionnés utilisés comme modulateurs de la signalisation ras
WO2023230262A1 (fr) * 2022-05-26 2023-11-30 Synnovation Therapeutics, Inc. Composés tricycliques en tant qu'inhibiteurs de pi3kalpha
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
US20240254117A1 (en) * 2020-12-27 2024-08-01 Shanghai Ringene Biopharma Co., Ltd. Pyrimido-heterocyclic compounds, and preparation method therefor and use thereof
WO2024255827A1 (fr) * 2023-06-15 2024-12-19 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un composé antitumoral hétérocyclique

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WO2023165438A1 (fr) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 Dérivé tricyclique, son procédé de préparation et son utilisation
CN119143761A (zh) * 2023-06-15 2024-12-17 石药集团中奇制药技术（石家庄）有限公司 一种杂环类抗肿瘤化合物的晶型、盐型及其用途

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WO2023230262A1 (fr) * 2022-05-26 2023-11-30 Synnovation Therapeutics, Inc. Composés tricycliques en tant qu'inhibiteurs de pi3kalpha
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2024255827A1 (fr) * 2023-06-15 2024-12-19 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un composé antitumoral hétérocyclique

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