WO2021115286A1 - Dérivé cyclique aromatique à cinq et six chaînons contenant des hétéroatomes d'azote qui peuvent être utilisés comme inhibiteur de shp2 - Google Patents

Dérivé cyclique aromatique à cinq et six chaînons contenant des hétéroatomes d'azote qui peuvent être utilisés comme inhibiteur de shp2 Download PDF

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WO2021115286A1
WO2021115286A1 PCT/CN2020/134658 CN2020134658W WO2021115286A1 WO 2021115286 A1 WO2021115286 A1 WO 2021115286A1 CN 2020134658 W CN2020134658 W CN 2020134658W WO 2021115286 A1 WO2021115286 A1 WO 2021115286A1
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group
independently selected
tritium
deuterium
cyano
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Chinese (zh)
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阳安乐
易韬
王志
张德伟
沈欢
胡凯
王浩
何权鸿
余攀
杨旭东
胡晓
王燕
杨奇
苏忠海
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成都倍特药业股份有限公司
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Priority to CN202080069976.8A priority Critical patent/CN114829362A/zh
Publication of WO2021115286A1 publication Critical patent/WO2021115286A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to a six-membered five-membered aromatic ring heterocyclic derivative compound containing a nitrogen heteroatom, their synthesis and their use in the treatment of SHP2-mediated diseases, and belongs to the field of medicinal chemistry.
  • SHP2 The Src Homolgy-2 phosphate is an important member of protein tyrosine phosphatase (PTP), and it is a type of widely expressed non-receptor protein tyrosine Acid phosphatase.
  • SHP2 encoded by the PTPN11 gene and its homologous family member SHP1 have a similar structure, with two SH2 domains (N-SH2 and C-SH2) and a PTP catalytic domain.
  • the N-terminal SH2 domain binds to the PTP structure to form intramolecular interactions, preventing the catalytically active site from approaching the substrate, so SHP2 is in a state of self-inhibition; when the N-terminal SH2 domain of SHP2 directly interacts with other
  • the protein's phosphorylated tyrosine residues ligands containing phosphorylated tyrosine residues
  • bind, or indirectly through growth factor receptor bound protein 2 (growth factor receptor bound protein 2, GRB2), related binding protein 1 (Grb2- Associated binder 1, GAB1) or GAB2 combination can cause its configuration to change, exposing the catalytic active site of the PTP domain, releasing the self-inhibition state, and participating in the signal transduction level initiated by tyrosine phosphorylation. Joint reaction.
  • SHP2 can be used as a key component in a variety of tumor signaling pathways (key signaling factors downstream of tyrosine kinases), and its excessive activation will activate Ras-ERK, PI3K-AKT, JAK/STAT, MET, FGFR, EGFR and NF- Tumor signaling pathways such as kB play an important role in the proliferation, differentiation, cell cycle maintenance and migration of tumor cells.
  • SHP2 is also involved in the regulation of the PD-1/PD-L1 immune signaling pathway, and promotes the immune escape of tumor cells. As a downstream molecule of PD-1 signal transduction, SHP2 not only inhibits the activation of T cells but also promotes the disability of T cells.
  • SHP2 can promote the occurrence and development of a variety of tumor diseases, and its germline mutations can lead to the occurrence of Noonan syndrome and leopard skin syndrome. Its somatic mutations mainly occur in a variety of hematological malignancies, such as Myelocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia/lymphoma, and acute myeloid leukemia.
  • One of the objectives of the present invention is to provide a compound represented by general formula I, tautomers, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Ring B is selected from the group consisting of 5 to 8 membered monocyclic rings, 6 to 12 membered bicyclic rings, 10 to 18 membered tricyclic rings, and 14 to 20 membered tetracyclic rings.
  • the single heterocyclic ring independently contains 1 to 4 heteroatoms, the heteroatoms are independently selected from N, O, S, and at least one of the heteroatoms is N;
  • the diheterocycle independently includes 1 to 5 heteroatoms, the heteroatoms are independently selected from N, O, S, and at least one of the heteroatoms is N;
  • the triheterocycle independently includes 1 to 8 heteroatoms, the heteroatoms are independently selected from N, O, S, and at least one of the heteroatoms is N;
  • the tetraheterocycle independently includes 1-10 heteroatoms, the heteroatoms are independently selected from N, O, S, and at least one of the heteroatoms is N;
  • X 1 , X 2 , and X 3 are each independently selected from C and N;
  • X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from CR 1 , N, and NR 2 , wherein each R 1 , R 2 is independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, amide;
  • L is selected from covalent bond, S, CR 3 R 4 , NR 0 , S(O) 2 , S(O), O, wherein said R 0 , R 3 , R 4 are each independently selected from hydrogen, deuterium, Tritium, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, amide;
  • the R a and R b are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, cyano, hydroxyl, mercapto, ester, and carboxy;
  • R c , R d and R e are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, Sulfhydryl group, ester group, carboxyl group, amide group;
  • the C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group, C 3 ⁇ C 6 cycloalkyl group described in the present invention are optionally selected by one or more independently selected from deuterium, tritium, halogen, nitro Group, hydroxyl, cyano, mercapto, amino, ester, carboxy, and amide substitution;
  • the L is selected from covalent bonds
  • S, O, NH, CR 3 R 4 , and R 3 and R 4 are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, amide;
  • X 6 and X 8 in the present invention are each independently selected from CR 1 and N.
  • R 1a , R 1b , R 1c , and R 2 are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, amino, cyano, Halogen, nitro, hydroxyl, mercapto, ester, carboxy, amide, the C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group are optionally one or more independently selected from deuterium, tritium , Halogen, nitro, hydroxyl, cyano, mercapto, amino, ester, carboxy, and amide substitution.
  • the R 1a , R 1b , R 1c , and R 2 are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, amino , Cyano, halogen, nitro, hydroxy, mercapto, the C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group are optionally one or more independently selected from deuterium, tritium, halogen, nitro Groups, hydroxyl groups, cyano groups, mercapto groups, amino groups, ester groups, carboxyl groups, and amide groups are substituted.
  • the R 1a , R 1b , R 1c , and R 2 are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkoxy, amino , Cyano, halogen, hydroxyl, mercapto, the C 1 ⁇ C 3 alkyl group, C 1 ⁇ C 3 alkoxy group is optionally one or more independently selected from deuterium, tritium, halogen, hydroxyl, mercapto, Amino group, ester group, carboxyl group, amide group substitution;
  • the R 1a , R 1b , R 1c , and R 2 are each independently selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, methoxy, ethoxy, Hydroxymethyl, hydroxyethyl, chloromethyl, chloroethyl, aminomethyl, aminoethyl, amino, cyano, halogen, hydroxyl, sulfhydryl.
  • the R 1a , R 1b , R 1c , and R 2 are each independently selected from hydrogen, deuterium, tritium, methyl, ethyl, methoxy, hydroxymethyl, chloromethyl, Aminomethyl, amino, cyano, fluorine, chlorine, hydroxyl.
  • the present invention provides a compound represented by structural formula II:
  • X 4 and X 7 are each independently selected from N and CR 1c , and X 4 and X 7 are not CR 1c at the same time;
  • R 1a , R 1b , L, ring A, and ring B are consistent with those described in the present invention.
  • the L is selected from covalent bond
  • S, CR 3 R 4 , and R 3 and R 4 are each independent
  • the ground is selected from hydrogen, deuterium, tritium, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, and amide.
  • X 7 in the present invention is N, and X 4 is CR 1c .
  • X 7 and X 4 in the present invention are both N.
  • X 7 in the present invention is CR 1c
  • X 4 is N.
  • the present invention provides a compound represented by structural formula III:
  • R 1a , R 1b , R 1c , L, ring A, and ring B are consistent with those described in the present invention.
  • the L is selected from covalent bond
  • S, CR 3 R 4 , and R 3 , R 4 are each independently selected from hydrogen, deuterium, tritium, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, Amide group.
  • the present invention provides a compound represented by structural formula IV:
  • R 1b , R 1c , L, ring A, and ring B are consistent with the foregoing.
  • the L is selected from covalent bond
  • S, CR 3 R 4 , and R 3 and R 4 are each independently It is selected from hydrogen, deuterium, tritium, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, and amide.
  • the present invention provides a compound represented by structural formula V:
  • R 1a , R 1b , R 2 , L, ring A, and ring B are the same as those described above.
  • the L is selected from the group consisting of covalent bond, S, CR 3 R 4 , and R 3 , R 4 Each is independently selected from hydrogen, deuterium, tritium, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, and amide.
  • the present invention provides a compound represented by structural formula VI-I or VI-II:
  • R 1a , R 1b , R 1c , L, ring A, and ring B are the same as those described above.
  • the L is selected from the group consisting of covalent bond, S, CR 3 R 4 , and R 3 , R 4 Each is independently selected from hydrogen, deuterium, tritium, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, cyano, halogen, nitro, hydroxyl, mercapto, ester, carboxy, and amide.
  • the ring A of the present invention is selected from
  • n is selected from 1, 2, 3, 4, 5, 6, preferably 1, 2, 3;
  • p is selected from 1, 2, 3, q is selected from 1, 2, 3, o is selected from 0, 1, 2 and o+p+q ⁇ 6; r and s are each independently selected from 0, 1, 2, 3 , 4, and r+s ⁇ 6;
  • Y 1 , Y 2 , and Y 3 are each independently selected from O, S, CH, CH 2 , N, and NH;
  • Y 4 , Y 5 , Y 6 , and Y 7 are each independently selected from O, S, CH, N, and NH, and at least one of Y 4 , Y 5 , Y 6 , and Y 7 is selected from CH; said Y 4 , Y 5 , Y 6 , and Y 7 are preferably selected from CH, N, and NH; preferably selected from CH, N, and NH;
  • Y 8 is independently selected from C and N;
  • the C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group, C 3 ⁇ C 6 cycloalkyl group of the present invention are optionally selected from deuterium, tritium, halogen, Nitro, hydroxyl, cyano, mercapto, amino, ester, carboxy, and amide substitution.
  • the ring A is selected from Preferred from More preferably from More preferably from
  • the ring A described in the present invention is selected from Preferred from More preferably from
  • the present invention provides a compound represented by structural formula VI-1:
  • R 1a , R 1b , R 5a , R 5b , R 5c , L, X 4 , X 7 , and ring B are consistent with those described in the present invention.
  • the present invention provides a compound represented by structural formula VI-2:
  • R 1a , R 1b , R 5a , R 5b , R 5c , L, X 4 , X 7 , and ring B are consistent with those described in the present invention.
  • the present invention provides a compound represented by structural formula VI-3:
  • R 1a , R 1b , R 5a , R 5b , R 5c , L, X 4 , X 7 , and ring B are consistent with those described in the present invention.
  • the present invention provides a compound represented by structural formula VII:
  • R 1a , R 1b , R 5a , R 5b , R 5c , L, X 4 , X 7 , and ring B are consistent with those described in the present invention.
  • R 5a , R 5b , and R 5c described in the present invention are each independently preferably selected from hydrogen, deuterium, tritium, -NR a R b , hydroxyl, amide, C 3 ⁇ C 6 cycloalkyl, fluoro, chloro, cyano, -C (O) CR c R d R e, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group, said R a, R b are each independently Selected from hydrogen, deuterium, tritium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the R c , R d , and R e are each independently Selected from hydrogen, deuterium, tritium, methyl, ethyl, methoxy, ethoxy, amino, halogen,
  • R 5a , R 5b , and R 5c described in the present invention are each independently selected from hydrogen, deuterium, tritium, -NR a R b , hydroxyl, C 3 ⁇ C 6 cycloalkyl , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -NHCOH, -NHCOCH 3 , -N(CH 3 )COCH 3 , fluorine, chlorine, cyano, -C(O)CR c R d R e , C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkoxy, the C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkoxy, C 3 ⁇ C 6 cycloalkyl are optionally one or more groups independently selected from deuterium, tritium, a halogen, a nitro group, a hydroxyl group, a cyano group, a mercapto group
  • R 5a , R 5b , and R 5c in the present invention are each independently selected from hydrogen, deuterium, tritium, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 ,- NHC 2 H 5 , -N(C 2 H 5 ) 2 , -NCH 3 C 2 H 5 , Hydroxyl, cyclopropyl, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , fluorine, chlorine, cyano, -C(O)CH 3 , -C(O)CF 3 , -C(O) CH 2 NH 2 , -C(O)CH(CH 3 ) 2 , methyl, ethyl, n-propyl, methoxy, ethoxy, hydroxymethyl, aminomethyl, chloromethyl, trifluoromethyl base;
  • R 5a , R 5b , and R 5c in the present invention are each independently selected from hydrogen, deuterium, tritium, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 ,- NHC 2 H 5 , -N(C 2 H 5 ) 2 , -NCH 3 C 2 H 5 , Hydroxyl, cyclopropyl, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , fluorine, chlorine, cyano, -C(O)CH 3 , -C(O)CF 3 , -C(O) CH 2 NH 2 , methyl, ethyl, n-propyl, methoxy, ethoxy, hydroxymethyl, aminomethyl, chloromethyl, trifluoromethyl.
  • the ring A is selected from
  • the ring B of the present invention is selected from
  • Z 1 , Z 4 , Z 5 , and Z 6 are each independently selected from O, S, NH, CH 2 , CH, and N;
  • Z 2 and Z 3 are each independently selected from C, N, and CH;
  • G is not present, O, S or NH;
  • a is 1;
  • b is 0 or 1;
  • G is absent, O, S.
  • Cy is selected from 6-membered aryl, 5- to 10-membered heteroaryl, 3- to 8-membered alicyclic group, and 3- to 8-membered alicyclic group; each of the heteroaryl and heterocyclic groups independently optionally includes 1 Or 2 heteroatoms selected from N, O or S;
  • the C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkoxy group are optionally one or more independently selected from deuterium, tritium, halogen, nitro, hydroxyl, cyano, mercapto, amino, ester group , Carboxyl, amide substitution.
  • Cy is preferably selected from
  • the ring B of the present invention is selected from Preferred from More preferably from More preferably from More preferably from More preferably from
  • said ring B is optionally substituted with 0-6 R 6
  • said R 6 is each independently selected from deuterium, tritium, nitro, hydroxyl, -NH 2 , mercapto, halogen, cyano, ester, carboxyl
  • the ring B is selected from Preferred from More preferably from
  • R 6c , R 6d , R 6e , and R 6f are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, -NH 2 , mercapto, halogen, cyano, ester, carboxy, amide, C 1 to C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 6 ⁇ C 10 aryl, C 5 ⁇ C 10 heteroaryl;
  • the C 1 ⁇ C 6 alkyl group and C 1 ⁇ C 6 alkoxy group described in the present invention are optionally one or more independently selected from deuterium, tritium, halogen, nitro, hydroxyl, cyano, mercapto, Amino group, ester group, carboxyl group, amide group substitution;
  • R 6c , R 6d , R 6e , R 6f are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, -NH 2 , mercapto, halogen, cyano, ester, carboxy, amide, C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkoxy, C 6 ⁇ C 8 aryl, C 5 ⁇ C 6 heteroaryl;
  • the C 1 ⁇ C 3 alkyl group and C 1 ⁇ C 3 alkoxy group described in the present invention are optionally one or more independently selected from deuterium, tritium, halogen, nitro, hydroxyl, cyano, mercapto, Amino group, ester group, carboxyl group, amide group substitution;
  • the R 6c , R 6d , R 6e , R 6f are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, -NH 2 ,
  • the ring B of the present invention is selected from
  • the present invention provides compounds as shown below, tautomers, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the aforementioned compounds, tautomers, enantiomers, diastereomers or mixtures thereof, and pharmacologically An acceptable salt, and at least one pharmaceutically acceptable excipient.
  • Another object of the present invention is to provide the aforementioned compound or its tautomers, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, for use in the preparation of The use of the drug;
  • the disease or disorder mediated by SHP2 is cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis or visual disorder;
  • the disease or disorder mediated by SHP2 is selected from Noonan syndrome, Leopard syndrome, myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous Leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer or a combination thereof;
  • the disease or disorder mediated by SHP2 is selected from Noonan syndrome, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer , Gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer or a combination thereof.
  • Alkyl refers to a saturated aliphatic hydrocarbon group.
  • the alkyl moiety may be linear alkyl group, branched alkyl group also may be; used in the present invention, C 1 -C 6 alkyl refers to a straight-chain alkyl group or branched alkyl group containing 1 to 6 carbon atoms, a C -C 3 alkyl group means a linear alkyl or branched alkyl group containing 1 to 3 carbon atoms.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
  • Alkoxy refers to -O-alkyl
  • C 1 -C 6 alkoxy used in the present invention refers to straight or branched alkoxy containing 1 to 6 carbons
  • the 3- alkyl group refers to a straight-chain alkoxy group or a branched-chain alkoxy group containing 1 to 3 carbons.
  • Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • Ring refers to any cyclic covalent closed structure, including, for example, carbocyclic ring (for example, aromatic ring or alicyclic ring) and heterocyclic ring (for example, aromatic heterocyclic ring or aliphatic heterocyclic ring).
  • a carbocyclic ring refers to a ring composed only of carbon atoms
  • a heterocyclic ring refers to a ring composed of heteroatoms covalently bonded to carbon atoms and heteroatoms to form a closed structure.
  • the ring can be a single ring, a bicyclic ring, a tricyclic ring or a polycyclic ring; the bicyclic ring can be a parallel ring, a bridged ring or a spiro ring; the tricyclic ring can be a spiro ring and a single ring.
  • Cycloalkyl refers to a saturated aliphatic carbocyclic group.
  • the C 3 -C 6 cycloalkyl group used in the present invention refers to a cyclic alkyl group containing 3 to 6 carbons.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Heteroatom refers to any atom other than a carbon atom that can be covalently bonded to a carbon atom. Common heteroatoms include but are not limited to O, S, and N.
  • Metal means the number of skeletal atoms constituting the ring.
  • Typical 5-membered rings can include but are not limited to cyclopentane, pyrrole, imidazole, thiazole, furan, and thiophene;
  • typical 6-membered rings include but are not limited to cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyran, etc. Oxazine, pyrimidine, benzene, etc.
  • Single heterocyclic ring refers to a single ring containing heteroatoms; the single heterocyclic ring used in the present invention contains one heteroatom or multiple heteroatoms.
  • Typical single heterocyclic rings include but are not limited to:
  • Bi-heterocyclic ring refers to two rings containing heteroatoms; the bi-heterocyclic ring used in the present invention can be a fused ring, a spiro ring or a bridged ring, and the bi-heterocyclic ring can contain one heteroatom or multiple heteroatoms.
  • Typical bicyclic heterocycles include but are not limited to:
  • Tri-heterocyclic ring refers to three rings containing heteroatoms; the tri-heterocyclic ring used in the present invention may be a spirocyclic and monocyclic ring, or a spiro tricyclic ring, and it may also be an optional option that can be easily conceived by those skilled in the art. In other forms of tricyclic rings, the triheterocyclic ring may contain one heteroatom or multiple heteroatoms. Typical tricyclic heterocyclic rings include but are not limited to:
  • Tetraheterocyclic ring refers to four rings containing heteroatoms; the tetraheterocyclic ring used in the present invention may be a spirocyclic fused bicyclic ring, or a spirocyclic tetracyclic ring, or any that those skilled in the art can easily think of. In other forms of tetracyclic rings, the tetraheterocyclic ring may contain one heteroatom or multiple heteroatoms. Typical tetraheterocyclic rings include but are not limited to:
  • Aromatic ring refers to a fully unsaturated ring, including aromatic rings and aromatic heterocycles.
  • Non-aromatic ring refers to a fully saturated or partially unsaturated ring, including alicyclic and heterocyclic aliphatic rings.
  • Aromatic ring or “aryl” refers to a fully unsaturated carbocyclic ring whose planar ring has a delocalized ⁇ electron system and contains 4n+2 ⁇ electrons, where n is an integer.
  • the aromatic ring can be composed of six, eight, ten, or more than ten carbon atoms, and the aromatic ring can be monocyclic or polycyclic. Common aromatic rings include but are not limited to benzene ring, naphthalene ring, phenanthrene ring, anthracene ring, fluorene ring and indene ring.
  • the C 6 -C 10 aryl group used in the present invention refers to an aromatic ring group composed of 6 to 10 skeleton atoms.
  • Aromatic heterocycle or “heteroaryl” refers to an aromatic ring containing heteroatoms. Typical aromatic heterocycles or heteroaryl groups include but are not limited to:
  • the C 5 to C 10 heteroaryl group used in the present invention refers to an aromatic heterocyclic group composed of 5 to 10 skeleton atoms.
  • Alicyclic or alicyclic refers to a saturated or partially unsaturated carbocyclic ring.
  • the alicyclic ring can be composed of 3-10 atoms, and can be monocyclic or polycyclic.
  • Typical alicyclic structures include but are not limited to:
  • Aliphatic heterocyclic ring or “aliphatic heterocyclic group” refers to an alicyclic ring containing heteroatoms. Typical aliphatic heterocyclic rings include but are not limited to:
  • the "6-membered heteroaromatic monocyclic and 6-membered alicyclic monocyclic ring" in the present invention refers to a bicyclic structure formed by the fusion of a 6-membered aromatic heterocyclic ring and a 6-membered aliphatic heterocyclic ring.
  • Heterocyclic monocyclic ring includes but is not limited to
  • Halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl means that at least one hydrogen in an alkyl group is replaced by a halogen atom.
  • Amide or “amide group” refers to a chemical structure with -C(O)NR X R Y or -NR X C(O)R Y , wherein R X and R Y are each independently selected from hydrogen, deuterium, and tritium , Alkyl, common amide groups include but are not limited to -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -NHCOH, -NHCOCH 3 , -N(CH 3 )COCH 3 .
  • Ester refers to a 'chemical structure, wherein R' is selected from alkyl having a formula -COOR, an alicyclic group, an aliphatic heterocyclic group, an aromatic ring group, a heteroaryl group.
  • substitution refers to one or more hydrogen atoms in the group, preferably at most 5, more preferably 1 to 3 hydrogen atoms independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • Inhibitor refers to a substance that reduces the activity of an enzyme.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically usable” refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity , Irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned.
  • Tautomers or “tautomeric forms” refer to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is the imidazole moiety, in which protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • Non-limiting examples of tautomers include, but are not limited to,
  • Enantiomers refer to compounds with the same molecular formula and functional groups that are isomerized due to the different arrangement of atoms in space. At the same time, the compounds form stereoisomers that are mirror images of each other and cannot be superimposed.
  • Diastereoisomers refer to compounds with the same molecular formula and functional groups, which are caused by the different arrangement of atoms in space, and the stereoisomerism between the compounds does not show the relationship between the physical objects and the mirror images. body.
  • the present invention also provides a synthesis method of the above compound.
  • the synthesis method of the present invention is mainly based on preparation methods reported in chemical literature or using commercially available chemical reagents as starting materials for related synthesis.
  • ring A, ring B, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are consistent with the foregoing of the present invention.
  • compound 1 is first substituted by iodination reagent to obtain compound 2; compound 2 is coupled with borated ring A to obtain compound 3; compound 3 is subjected to nucleophilic substitution reaction with ring B to obtain compound 4.
  • the aforementioned borated ring A may be a commercially available product, or it may be prepared by a person skilled in the art through a preparation method disclosed in the prior art.
  • ring A, ring B, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are consistent with the foregoing of the present invention.
  • compound 5 is firstly substituted with ring B to obtain compound 6; compound 6 is coupled with borated ring A to obtain compound 7.
  • the method of obtaining borated ring A is the same as described above.
  • ring A, ring B, L, X 3 , X 4 , X 5 , X 6 and X 8 are consistent with the foregoing of the present invention.
  • compound 8 is firstly subjected to amide condensation reaction with carboxylated ring A-L to obtain compound 9; compound 9 is subjected to ring-closure reaction to obtain compound 10; compound 10 is then subjected to nucleophilic substitution reaction with ring B to obtain compound 11.
  • carboxylated ring A-L can be a commercially available product, or can be prepared by a person skilled in the art through a preparation method disclosed in the prior art.
  • ring A, ring B, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are consistent with the foregoing of the present invention.
  • the brominated ring A is reacted with the sulfhydryl reagent to obtain intermediate compound 12, and then deprotected to obtain the sulfhydryl ring A, which is compound 13; compound 13 is then condensed with compound 2 to obtain compound 14; compound 14 A nucleophilic substitution reaction occurs with ring B to obtain compound 15.
  • the aforementioned brominated ring A may be a commercially available product, or it may be prepared by a person skilled in the art through a preparation method disclosed in the prior art.
  • ring A, ring B, L, X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are consistent with the foregoing of the present invention.
  • the brominated ring A-L and compound 5 undergo nucleophilic substitution reaction to obtain compound 16; compound 16 then undergoes nucleophilic substitution reaction with ring B to obtain compound 17.
  • the aforementioned brominated ring A-L can be a commercially available product, or can be prepared by a person skilled in the art through a preparation method disclosed in the prior art.
  • reaction solution was slowly added dropwise to saturated sodium carbonate solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 2.4 g of the title compound.
  • the preparation method is similar to the preparation method adopted in the aforementioned preparation example 1.
  • the preparation method is similar to the preparation method adopted in the aforementioned preparation example 1.
  • the preparation method is similar to the preparation method adopted in the aforementioned preparation example 1.
  • the preparation method is similar to the preparation method adopted in the aforementioned preparation example 1.
  • methyl 3-chloro-2-methylisonicotinate 140mg was dissolved in methanol (2mL), tetrahydrofuran (2mL) and water (2mL), and lithium hydroxide monohydrate (128mg) was added to the system. The temperature was raised to 50°C and reacted for 1 hour. TLC showed that the reaction was complete. Add ethyl acetate and water to the system, adjust the pH to about 4-5 with 1N dilute hydrochloric acid, separate and extract, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain 130 mg of crude product.
  • the preparation method is similar to the preparation method used in Preparation Example 7 above.
  • methyl 2-chloro-3-cyanobenzoate (0.24mg) was dissolved in methanol (2mL), tetrahydrofuran (2mL) and water (2mL), and lithium hydroxide monohydrate (103mg) was added to the system. The temperature was raised to 50°C and reacted for 1 hour. TLC showed that the reaction was complete. Add ethyl acetate and water to the system, adjust the pH to about 4 to 5 with 1N dilute hydrochloric acid, separate and extract, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain 220 mg of crude product.
  • Step 1 Preparation of tert-butyl (3-chloropyridin-2-yl)carbamate
  • Step 1 Preparation of 8-chloro-3-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazine-1-carbaldehyde
  • Step 3 Preparation of 8-chloro-3-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine
  • 2,3-Dichloro-N'-(3-chloropyrazin-2-yl)benzohydrazine (40 mg) was dissolved in phosphorus oxychloride (1 mL), replaced with nitrogen, and the temperature was raised to 100° C. to react for 4 hours. After TLC showed that the reaction was complete, the system was concentrated, saturated sodium carbonate solution was adjusted to pH weakly alkaline, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated to obtain 35 mg of crude product. Purified and used directly in the next step.
  • the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, and the saturated sodium chloride solution was backwashed once, anhydrous sulfuric acid After drying with sodium and concentrating, the resulting crude product was purified by column chromatography to obtain 800 mg of the title compound.
  • Step 1 1-(tert-butyl)-4-ethyl 4((2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1, Preparation of 4-dicarboxylate
  • Step 3 Preparation of tert-butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate
  • Step 4 Preparation of (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester
  • Step 5 Preparation of (S)-3-methyl-4-oxo-2-oxa-8-azaspiro[-4]decane-8-carboxylic acid tert-butyl ester
  • Step 6 (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8- Preparation of tert-butyl carboxylate
  • Step 2 Preparation of tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate
  • Step 1 Preparation of tert-butyl 4-((((benzyloxy)carbonyl)amino)methyl)-4-fluoropiperidine-1-carboxylate
  • Step 2 Preparation of benzyl ((4-fluoropiperidin-4-yl)methyl) carbamate
  • Step 1 Preparation of tert-butyl 4-(aminomethyl)-4-methylpiperidine-1-carboxylate
  • Step 2 Preparation of 4-(benzyloxy)carbonyl)amino)methyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester
  • Step 3 Preparation of benzyl ((4-methylpiperidin-4-yl)methyl) carbamate
  • Step 1 Preparation of 1-(tert-butyl)4-ethyl 4-benzylpiperidine-1,4-dicarboxylate
  • Step 3 Preparation of 1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 4 (R,E)-1-((tert-butylsulfinyl)imino)tert-butyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxy Preparation of acid salt
  • Step 5 (S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert Preparation of butyl ester
  • Step 2 Preparation of tert-butyl 4-(2-(2-fluorophenyl)-1,3-dithio-2-yl)-4-hydroxypiperidine-1-carboxylate
  • Step 3 Preparation of tert-butyl 4-(2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate
  • Step 4 Preparation of 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 5 (R,Z)-3-((tert-butylsulfinyl)imino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester preparation
  • Step 7 Preparation of (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide
  • Step 4 Preparation of tert-butyl 4-(2-bromo-3-methoxybenzyl)-4-cyanopiperidine-1-carboxylate
  • Step 5 Preparation of 7-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • the system was cooled to room temperature, ethyl acetate was added, filtered by adding diatomaceous earth, water was added to the filtrate, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, and the saturated sodium chloride solution was backwashed twice, anhydrous sodium sulfate Dry and concentrate.
  • the obtained crude product was purified by column chromatography to obtain 0.64 g of the title compound.
  • Step 6 Preparation of (Z)-1-(hydroxyimino)-7-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • the system was concentrated under reduced pressure to remove methanol, quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, backwashed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 150 mg of crude product.
  • Step 7 Preparation of 1-amino-7-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • the system was concentrated under reduced pressure to remove most of the acetic acid, ethyl acetate and water were added, the ethyl acetate layer was discarded, the aqueous phase was adjusted to pH 9-10 with aqueous sodium carbonate, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and saturated The sodium chloride solution was backwashed twice, dried over anhydrous sodium sulfate, and concentrated to obtain 90 mg of crude product.
  • Step 8 Preparation of 7-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine hydrochloride
  • Step 2 Preparation of tert-butyl 4-((2-bromopyridin-3-yl)methyl)-4-cyanopiperidine-1-carboxylate
  • Step 3 Preparation of 7-oxo-5,7-dihydrospiro[cyclopentan[b]pyridine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • the system was cooled to room temperature, ethyl acetate was added, filtered by adding diatomaceous earth, water was added to the filtrate, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, and the saturated sodium chloride solution was backwashed twice, anhydrous sodium sulfate Dry and concentrate.
  • the obtained crude product was purified by column chromatography to obtain 0.42 g of the title compound.
  • reaction solution was quenched with hydrochloric acid (6M, 10 mL), then the pH was adjusted to about 7, the solvent was removed by concentration under reduced pressure, water was added to the system, and ethyl acetate was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product Purified by column chromatography to obtain 2.3 g of the title compound.
  • 5-Amino-2-chloroisonicotinic acid (10.0g) was dissolved in methanol (100mL), thionyl chloride (17mL) was added dropwise under an ice-water bath, and then the system was heated to 70°C for overnight reaction. The system was cooled to room temperature, concentrated to remove the solvent, water, ethyl acetate, and sodium bicarbonate powder were slowly added to adjust the pH of the system to around 8.
  • the organic phase was collected, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, and saturated chlorinated
  • the sodium solution was backwashed once, dried with anhydrous sodium sulfate, concentrated to about 30mL ethyl acetate remaining, moved to an ice-water bath and stirred, petroleum ether (50mL) was added dropwise, stirring was continued at this temperature for 30 minutes, filtered with suction, and the filter cake was petroleum-based After washing with ether and drying the filter cake, 6.4 g of the title compound was obtained.
  • Step 5 Preparation of methyl (5-bromo-2-methylpyridin-4-yl)methanesulfonate
  • Step 1 Preparation of tert-butyl 4-(2-bromo-3-(trifluoromethyl)benzyl)-4-cyanopiperidine-1-carboxylate
  • Step 2 Preparation of 1-oxo-7-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 3 Preparation of 1-hydroxy-7-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 4 1-((Methylsulfonyl)oxy)-7-(trifluoromethyl)-1,3-tert-hydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert Preparation of butyl ester
  • Step 5 Preparation of 1-azido-7-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 6 Preparation of 1-amino-7-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • Step 1 Preparation of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate
  • Step 2 Preparation of tert-butyl 4-((3-chloropyridin-4-yl)(hydroxy)methyl)-4-methylpiperidine-1-carboxylate
  • Step 3 Preparation of tert-butyl 4-(3-chloroisonicotinyl)-4-methylpiperidine-1-carboxylate
  • Step 4 Preparation of 5-oxo-5,7-dihydrospiro[cyclopentan[c]pyridine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester
  • reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was collected, concentrated, dissolved in toluene, petroleum ether was added until no new solids were produced, filtered, the filtrate was collected, and concentrated to obtain 1.12 g of the title compound.
  • the crude product was dissolved in ethyl acetate, washed with 5% citric acid and saturated sodium chloride aqueous solution twice, and the organic phases were combined, dried, and concentrated.
  • the crude product obtained was purified by column chromatography to obtain the title Compound 11.50g.
  • Step 2 Preparation of 3-((tert-butoxycarbonyl)amino)-5-fluoropyridine-2-carboxylic acid methyl ester
  • methyl 3-bromo-5-fluoropyridine-2-carboxylate (3.76 g) was dissolved in methanol, sodium borohydride (1.82 g) was added in portions, and the reaction was carried out for 1 hour. TLC monitored the completion of the reaction. The system was concentrated to remove the solvent, the crude product was dissolved in ethyl acetate, washed twice with saturated sodium chloride solution, the organic phases were combined, dried, and concentrated to obtain 1.35 g of the title compound.
  • the raw materials and reagents were obtained from commercial or prior art reports, and the product demethylation preparation method of Preparation Example 24 was used for synthesis.
  • Step 1 tert-Butyl (1-(3-(2,3-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-4 -Methylpiperidin-4-yl) carbamate preparation
  • Step 3 Preparation of 7-chloro-3-(2,3-dichlorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-c]pyridine
  • Step 5 tert-Butyl (1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)-4-methylpiperidine-4 -Base) carbamate preparation
  • Step 1 Preparation of tert-butyl (1-(3-bromoimidazo[1,2-a]pyrazin-8-yl)-4-methylpiperidin-4-yl)carbamate
  • the reaction system was added to saturated ammonium chloride solution for quenching, extracted with ethyl acetate 3 times, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated.
  • reaction system was quenched by adding water (50 mL), extracted with ethyl acetate 3 times, the organic phase was backwashed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain 830 mg of crude product.
  • Step 1 Preparation of tert-butyl (4-methyl-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)carbamate
  • the tert-butyl (1-(3-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazin-8-yl)-4-methylpiperidin-4-yl)carbamate The ester (110 mg) was dissolved in a hydrochloric acid-ethyl acetate solution (5 mL) and reacted at room temperature for 1 hour. The system was concentrated, saturated sodium carbonate solution was added to adjust the pH to 8, and the crude product was obtained by concentration. The obtained crude product was purified by preparative HPLC to obtain 50 mg of the title compound.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 3.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 6.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 6.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 6.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 6.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 6.
  • the preparation method is similar to the preparation method adopted in the foregoing Example 6.

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Abstract

L'invention concerne le composé ayant une activité d'inhibition de SHP2 représentée par la formule (I), un procédé de préparation de celui-ci, une composition contenant ledit composé, et une application de celui-ci en tant qu'inhibiteur de SHP2 et une utilisation pharmaceutique de celui-ci. Dans la formule (I), le cycle A est sélectionné parmi un cycle alicyclique de 3 à 10 chaînons, un cycle aromatique à 6-10 chaînons, un cycle hétérocyclique alicyclique de 5 à 10 chaînons, et un cycle hétérocyclique aromatique de 5 à 10 chaînons ; le cycle B est sélectionné dans le groupe constitué par un cycle hétérocyclique monocyclique de 5 à 8 chaînons, un cycle hétérocyclique bicyclique de 6 à 12 chaînons, un cycle hétérocyclique tricyclique de 10 à 18 chaînons, et un cycle hétérocyclique tétracyclique de 14 à 20 chaînons ; chacun de X1, X2, et X3 est indépendamment sélectionné parmi C et N ; chacun de X4, X5, X6, X7, et X8 est indépendamment sélectionné parmi CR1, N, and NR2 ; L est sélectionné parmi une liaison covalente, S, CR3R4, NR0, S(O)2, S(O), et O.
PCT/CN2020/134658 2019-12-10 2020-12-08 Dérivé cyclique aromatique à cinq et six chaînons contenant des hétéroatomes d'azote qui peuvent être utilisés comme inhibiteur de shp2 WO2021115286A1 (fr)

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WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
CN114920759A (zh) * 2022-05-18 2022-08-19 江南大学 杂环-三氮唑并噻二唑杂环串联化合物、合成方法、药物组合物及用途
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
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WO2023282702A1 (fr) 2021-07-09 2023-01-12 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et son utilisation
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024175081A1 (fr) * 2023-02-24 2024-08-29 深圳真实生物医药科技有限公司 Composé inhibiteur de shp2 et son utilisation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2662163A1 (fr) * 1990-05-16 1991-11-22 Lipha Nouvelles 8-amino-1,2,4-triazolo(4,3-a) pyrazines, procedes de preparation et medicaments les contenant.
WO1999040091A1 (fr) * 1998-02-06 1999-08-12 Amgen Inc. Composes et methodes permettant de moduler des conduites alimentaires et des pathologies y afferentes
CN1692115A (zh) * 2002-12-26 2005-11-02 大正制药株式会社 环状氨基取代的吡咯并嘧啶和吡咯并吡啶衍生物
CN103328482A (zh) * 2011-01-03 2013-09-25 韩美药品株式会社 用于调节g蛋白-偶联受体的新双环化合物
WO2015153955A1 (fr) * 2014-04-04 2015-10-08 Duquesne University Of The Holy Spirit Composés de pyrimidine bicycliques substitués par de la tubuline et inhibition de multiples récepteurs
CN106488919A (zh) * 2014-06-25 2017-03-08 武田药品工业株式会社 3‑取代的2‑氨基吲哚衍生物
CN107567452A (zh) * 2015-04-29 2018-01-09 詹森药业有限公司 咪唑并哌嗪和吡唑并嘧啶以及它们作为ampa受体调节剂的用途

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2787714C (fr) * 2010-01-22 2019-04-09 Joaquin Pastor Fernandez Inhibiteurs de la pi3 kinase
ES2682755T3 (es) * 2011-12-21 2018-09-21 Jiangsu Hengrui Medicine Co. Ltd. Derivado del anillo heteroarilo de seis miembros de pirrol, método de preparación del mismo y sus usos medicinales
US11529347B2 (en) * 2016-09-22 2022-12-20 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of use thereof
MX2019008695A (es) * 2017-01-23 2019-09-11 Revolution Medicines Inc Compuestos biciclicos como inhibidores alostericos de shp2.
CN111051305A (zh) * 2017-08-22 2020-04-21 吉利德科学公司 治疗性杂环化合物
TW201940167A (zh) * 2018-03-21 2019-10-16 美商新標利亞治療藥物公司 Shp2抑制劑及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2662163A1 (fr) * 1990-05-16 1991-11-22 Lipha Nouvelles 8-amino-1,2,4-triazolo(4,3-a) pyrazines, procedes de preparation et medicaments les contenant.
WO1999040091A1 (fr) * 1998-02-06 1999-08-12 Amgen Inc. Composes et methodes permettant de moduler des conduites alimentaires et des pathologies y afferentes
CN1692115A (zh) * 2002-12-26 2005-11-02 大正制药株式会社 环状氨基取代的吡咯并嘧啶和吡咯并吡啶衍生物
CN103328482A (zh) * 2011-01-03 2013-09-25 韩美药品株式会社 用于调节g蛋白-偶联受体的新双环化合物
WO2015153955A1 (fr) * 2014-04-04 2015-10-08 Duquesne University Of The Holy Spirit Composés de pyrimidine bicycliques substitués par de la tubuline et inhibition de multiples récepteurs
CN106488919A (zh) * 2014-06-25 2017-03-08 武田药品工业株式会社 3‑取代的2‑氨基吲哚衍生物
CN107567452A (zh) * 2015-04-29 2018-01-09 詹森药业有限公司 咪唑并哌嗪和吡唑并嘧啶以及它们作为ampa受体调节剂的用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KONG JIAO, YAQIU LONG: "Research Advances in the Protein Tyrosine Phosphatase SHP2 and Its Inhibitors", PROGRESS IN PHARMACEUTICAL SCIENCES, CHINA PHARMACEUTICAL UNIVERSITY, CN, vol. 43, no. 7, 1 January 2019 (2019-01-01), CN, pages 517 - 526, XP055819779, ISSN: 1001-5094 *
PAVANA ROHEETH KUMAR; CHOUDHARY SHRUTI; BASTIAN ANJA; IHNAT MICHAEL A.; BAI RUOLI; HAMEL ERNEST; GANGJEE ALEEM: "Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 2, 15 November 2016 (2016-11-15), AMSTERDAM, NL, pages 545 - 556, XP029862894, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2016.11.026 *
SLEPUKHIN P A ET AL: "Simple synthesis of imidazo [1,2-a]pyrazines", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, SPRINGER US, NEW YORK, vol. 38, no. 9, 1 September 2002 (2002-09-01), New York, pages 1142 - 1143, XP002569256, ISSN: 0009-3122, DOI: 10.1023/A:1021282004750 *
SUSVILO INGA, BRUKSTUS ALGIRDAS, TUMKEVICIUS SIGITAS: "A Novel and Efficient Synthesis of 6-Dialkylamino-9-Benzyl-8-Methoxypurines and 6-Dialkylamino-9-Benzylpurin-8-Ones by Reaction of Methyl N-Benzyl-N-(6-Dialkylamino-5-Nitropyrimidin-4-yl)Glycinates with Sodium Alkoxides", SYNLETT, vol. 2006, no. 9, 1 June 2006 (2006-06-01), pages 1422 - 1424, XP009528400, ISSN: 0936-5214, DOI: 10.1055/s-2006-941566 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022060583A1 (fr) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Utilisation d'inhibiteurs de sos1 pour traiter des malignités à mutations de shp2
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235866A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras covalents et leurs utilisations
WO2023282702A1 (fr) 2021-07-09 2023-01-12 주식회사 카나프테라퓨틱스 Inhibiteur de shp2 et son utilisation
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
CN114920759A (zh) * 2022-05-18 2022-08-19 江南大学 杂环-三氮唑并噻二唑杂环串联化合物、合成方法、药物组合物及用途
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024175081A1 (fr) * 2023-02-24 2024-08-29 深圳真实生物医药科技有限公司 Composé inhibiteur de shp2 et son utilisation

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