[go: up one dir, main page]

WO2025113627A1 - Inhibiteur de tead contenant un cycle hétérocyclique - Google Patents

Inhibiteur de tead contenant un cycle hétérocyclique Download PDF

Info

Publication number
WO2025113627A1
WO2025113627A1 PCT/CN2024/135617 CN2024135617W WO2025113627A1 WO 2025113627 A1 WO2025113627 A1 WO 2025113627A1 CN 2024135617 W CN2024135617 W CN 2024135617W WO 2025113627 A1 WO2025113627 A1 WO 2025113627A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cancer
optionally substituted
alkynyl
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/135617
Other languages
English (en)
Chinese (zh)
Inventor
张学军
臧杨
杨辉
宋泽金
赵细军
孙正军
江文
吴浩淼
李莉娥
杨俊�
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Original Assignee
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co filed Critical Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Publication of WO2025113627A1 publication Critical patent/WO2025113627A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D471/20—Spiro-condensed 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines 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
    • A61K31/495—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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • 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
    • C07D471/10—Spiro-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
    • C07D487/10—Spiro-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
    • C07D487/12—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 three hetero rings
    • C07D487/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention belongs to the field of medicine, and in particular, the present invention relates to a heterocyclic TEAD inhibitor and uses thereof.
  • the Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades, which is involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development.
  • NF2 neurofibromatosis type 2
  • MST1/2 Mesmalian sterile 20-like kinase 1/2
  • LAST1/2 large tumor suppressor kinase 1/2
  • the activated LATS1/2 phosphorylates YAP (Yes Associated Protein)/TAZ (Transcriptional coactivator with PDZ-binding motif).
  • Phosphorylated YAP/TAZ are localized in the cytoplasm and degraded in a ubiquitin-dependent manner, while unphosphorylated YAP/TAZ are translocated to the nucleus and bind to several nuclear transcription factors including TEADs to form a transcription complex, inducing the expression of several downstream target genes including CTGF (Connective tissue growth factor), Cyr61 (Mysteine rich angiogenic inducer 61) and AXL (AXL receptor tyrosine kinase), thereby promoting the body's physiological and pathological processes.
  • CTGF Connective tissue growth factor
  • Cyr61 Mysteine rich angiogenic inducer 61
  • AXL AXL receptor tyrosine kinase
  • TEADs/TEAD Transcriptional Enhanced Associated Domains
  • TEAD1 TEAD2, TEAD3 and TEAD4.
  • All TEADs subtypes have a DNA-binding TEA domain at the N-terminus and a YAP/TAZ-binding domain at the C-terminus.
  • the DNA-binding domain and the YAP/TAZ-binding domain are highly conserved in mammals, but they are very different in the linker connecting the TEA domain and the transactivation domain.
  • the overall homology of the four TEADs subtypes ranges from 61% to 73%.
  • the function of TEADs is mediated by its interaction with nuclear co-activators, and YAP is the main nuclear co-activator that interacts with TEADs.
  • YAP/TAZ-TEADs activation promotes tumor development, and inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors.
  • the YAP/TAZ-TEADs complex is often overactivated or overexpressed, leading to cancer progression. This overactivation is usually caused by changes in genes upstream of the Hippo signaling pathway.
  • 40%-50% of tumors have NF2 mutations or deletions, ⁇ 25% of tumors have MST1 or LAST1/2 mutations or deletions, and 70% of YAP is highly expressed.
  • Overactivation of the YAP/TAZ-TEADs complex helps promote tumor cell proliferation, metastasis, epithelial to mesenchymal transition (EMT), and maintenance of tumor stem cells.
  • EMT epithelial to mesenchymal transition
  • the interaction between YAP and TEADs is essential for initiating transcriptional programs to drive tumorigenesis and proliferation.
  • TEADs with defects in the DNA binding domain can block tumor formation mediated by mutations in genes upstream of the Hippo signaling pathway, indicating that inhibiting the interaction between YAP/TAZ and TEADs has an anti-tumor effect. Inhibiting the interaction between YAP/TAZ and TEADs can significantly inhibit the proliferation of tumor cells.
  • YAP/TAZ and TEADs interaction inhibitors (VT-01, IK-930) have entered the clinical stage. Inhibition of YAP/TAZ and TEADs interaction may be a promising new anti-tumor chemotherapy.
  • the present invention provides a TEAD inhibitor containing a heterocycle, wherein the TEAD inhibitor is a compound of formula I' or formula I described in the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; the compound can significantly inhibit the activity of TEAD transcription, and can be used to prevent and/or treat diseases or conditions associated with increased TEAD expression.
  • the TEAD inhibitor is a compound of formula I' or formula I described in the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof; the compound can significantly inhibit the activity of TEAD transcription, and can be used to prevent and/or treat diseases or conditions associated with increased TEAD expression.
  • the present invention provides a compound represented by formula I', its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • ring A is a benzene ring or a 5-6-membered heteroaromatic ring
  • the ring A is optionally substituted by one or more Ra; when Ra is multiple, the Ra are the same or different;
  • Ring B is a 4-7 membered cycloalkyl group or a 4-7 membered heterocycloalkyl group;
  • the ring B is optionally substituted by 1-3 identical or different R 4 ;
  • R 1 and R 4 are each independently hydrogen, halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , oxo ( ⁇ O), The C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , Each independently is optionally substituted by one or more R 10 ; when R 10 is multiple, the R 10 are the same or different;
  • R 11 and R 12 are each independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 11 , R 12 and the P to which they are connected together form a 4-7 membered ring;
  • V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
  • the V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different;
  • G 1 and G 2 are each independently -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , -NRg-C(O)R 2 , -NRg-S(O) 2 R 2 , -NRg-S(O)R 2 , -C(O)-NRg-R 2 , -S(O) 2 -NRg-R 2 , -S(O)-NRg-R 2 , R 3 , and only one of G 1 and G 2 is R 3 ;
  • Each Rg is independently H, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 2 is selected from -NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ; said R 2 is optionally substituted by one or more R 21 ; when R 21 is multiple, said R 21 are the same or different;
  • R 3 is a benzene ring or a 5-12 membered heteroaromatic ring; said R 3 is optionally substituted by one or more R 31 ; when there are multiple R 31 , said R 31 are the same or different;
  • R 10 , R 21 , R 31 , Ra, and Rv are each independently selected from: halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and oxo ( ⁇ O); said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 are optionally substituted by a substituent selected from the following:
  • the present invention also provides a compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
  • ring A is a benzene ring or a 5-6-membered heteroaromatic ring
  • the ring A is optionally substituted by one or more Ra; when Ra is multiple, the Ra are the same or different;
  • R 1 is hydrogen, halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , oxo ( ⁇ O), The C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , Each independently is optionally substituted by one or more R 10 ; when R 10 is multiple, the R 10 are the same or different;
  • R 11 and R 12 are each independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or R 11 , R 12 and the P to which they are connected together form a 4-7 membered ring;
  • V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
  • the V is optionally substituted by one or more Rv; when Rv is multiple, the Rv are the same or different;
  • n are each independently 1, 2 or 3;
  • G 1 and G 2 are each independently -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , or R 3 , and only one of G 1 and G 2 is R 3 ;
  • R 2 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 ; said R 2 is optionally substituted by one or more R 21 ; when R 21 is multiple, said R 21 are the same or different;
  • R 3 is a benzene ring or a 5-12 membered heteroaromatic ring; said R 3 is optionally substituted by one or more R 31 ; when there are multiple R 31 , said R 31 are the same or different;
  • R 10 , R 21 , R 31 , Ra, and Rv are each independently selected from: halogen, -OH, -NH 2 , -NO 2 , -CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -SF 5 , -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , and oxo ( ⁇ O); said C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 are optionally substituted by a substituent selected from the following:
  • the ring A is a benzene ring, pyridine, pyridazine, pyrimidine or pyrazine.
  • n and n are each independently 1 or 2; preferably, m is 1 and n is 2.
  • the compound has a structure shown in Formula II:
  • n and n are each independently 1 or 2;
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N;
  • V, R 1 , G 1 , and G 2 are as defined above;
  • V is -CH 2 - or -C(O)-.
  • the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has a structure shown in Formula III or Formula IV:
  • E is N or CRe
  • Re is selected from H, halogen, -OH, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
  • p and q are each independently 1 or 2;
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N;
  • V, R 1 , R 4 , G 1 and G 2 have the same meanings as described above.
  • V is -CH 2 - or -C(O)-;
  • E is N or CH.
  • the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has a structure shown in Formula Ic, Formula Id, or Formula Ie:
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N;
  • R 1 , R 4 , V, G 1 and G 2 have the same meanings as described above.
  • V is -CH 2 - or -C(O)-.
  • the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in Formula Id':
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N;
  • R 1 , R 4 , V, G 1 and G 2 have the same meanings as described above.
  • the compound has a structure shown in Formula Ia or Ib
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N;
  • R 1 , V, G 1 , and G 2 are as defined above;
  • V is -CH 2 - or -C(O)-.
  • the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has a structure shown in Formula IIIa or IIIb:
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N;
  • V, R 1 , R 4 , G 1 , and G 2 are as defined above;
  • V is -CH 2 - or -C(O)-.
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N, and the number of N is 0, 1, 2 or 3 (preferably 0, 1 or 2).
  • X 1 , X 2 , X 3 , and X 4 are each independently CH or N, and 0, 1, 2, or 3 of X 1 , X 2 , X 3 , and X 4 are N.
  • X1 , X2 , X3 , and X4 are CH; and/or X1 is N, and X2 , X3 , and X4 are CH; and/or X4 is N, and X1 , X2 , and X3 are CH; and/or X1 , X4 are N, and X2, and X3 are CH .
  • the compound has a structure selected from the following:
  • R 1 , G 1 , G 2 , and V are as defined above;
  • the G 2 is a benzene ring or a 5-6 membered heteroaromatic ring; the benzene ring or the 5-6 membered heteroaromatic ring is substituted by 1, 2 or 3 identical or different R 31 ;
  • the 5-6 membered heteroaromatic ring is selected from benzene ring, pyridine, pyridazine, pyrimidine, pyrazine;
  • R 31 is 1 or 2.
  • the G2 is
  • R 31 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , -S(C 1 -C 6 alkyl); the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -S(C 1 -C 6 alkyl) are optionally substituted with substituents selected from the following: halogen, -NH 2 , -NO 2 , -CN, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -SF 5 .
  • R 31 is selected from C 1 -C 3 haloalkyl and C 1 -C 3 haloalkoxy.
  • R 31 is selected from -CF 3 and -OCF 3 .
  • G 1 is -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , -NRg-C(O)R 2 , -NRg-S(O) 2 R 2 ; said R 2 is optionally substituted by one or more R 21 ; preferably, Rg is selected from H, C 1 -C 3 alkyl.
  • G 1 is -C(O)R 2 , -S(O) 2 R 2 , -S(O)R 2 , -NH-C(O)R 2 , -NH-S(O) 2 R 2 ; said R 2 is optionally substituted by one or more R 21 .
  • R 2 is selected from NH 2 , C 1 -C 3 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; said R 2 is optionally substituted by one or more R 21 .
  • R 2 is selected from NH 2 , methyl, ethyl, propyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl; said R 2 is optionally substituted by one or more R 21 .
  • R 21 is selected from NH 2 , OH, F, Cl, methyl, ethyl, —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 .
  • G1 is selected from:
  • R 4 is hydrogen, methyl, -CHF 2 , or -CH 2 OH.
  • G 1 is -C(O)R 2 ;
  • R 2 is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; and the C 2 -C 6 alkenyl or C 2 -C 6 alkynyl is optionally substituted by R 21 .
  • the R 21 is halogen; the halogen is preferably F or Cl.
  • R 1 is H, halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy,
  • the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy group is optionally substituted by one or more R 10 ; when there are multiple R 10s , the R 10s are the same or different.
  • the R 10 is F, Cl, or -OH.
  • R 1 is H, F, Cl, CN, C 1 -C 3 alkyl, The C 1 -C 3 alkyl group is optionally substituted with one or more -OH groups.
  • R 1 is H, F, Cl, CN, -CH(OH)-CH 2 (OH),
  • the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:
  • the present invention also provides a pharmaceutical composition, comprising any compound as described above, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.
  • the present invention also provides a use of the compound as described above, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition as described in the second aspect, wherein the use is selected from at least one of the following:
  • the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.
  • the disease is a cell proliferative disorder.
  • the cell proliferative disorder is cancer.
  • the disease is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, myeloblast, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic leukemia), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, soft tissue sarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, Blood disease, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal carcinoma, end
  • the disease is selected from the group consisting of: mesothelioma, soft tissue sarcoma, meningioma, glioma, lung cancer.
  • the present invention also provides a method for treating a disease, comprising administering to a patient a therapeutically effective amount of at least one of the compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs or pharmaceutical compositions.
  • the disease is a disease associated with increased TEAD expression.
  • the TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4.
  • the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
  • the disease is the disease described in the third aspect.
  • the patient is a mammal, preferably a human.
  • the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH 2 O is equivalent to OCH 2 .
  • halogen by itself or as part of another substituent refers to fluorine, chlorine, bromine, iodine.
  • alkyl means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond, when alone or as part of other substituents.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.
  • Alkyl groups may be unsubstituted or substituted with one or more suitable substituents.
  • Alkyl groups may also be isotopic isomers of natural abundance alkyl groups rich in isotopes of carbon and/or hydrogen (i.e., deuterium or tritium).
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,
  • C 1 -C 3 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms.
  • said radical has 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
  • C2 - C6 alkenyl when used alone or as part of another substituent is understood to mean a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example, 2 or 3 carbon atoms (i.e., C2 - C3 alkenyl). It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (
  • C 2 -C 6 alkynyl is understood to mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, for example 2 or 3 carbon atoms ("C 2 -C 3 alkynyl").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4
  • the alkynyl group is ethynyl, prop-1-ynyl or prop
  • C 1 -C 6 alkoxy is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or is represented by C 1 -C 6 alkyl-O-.
  • the definition of C 1 -C 6 alkyl is as described in the present specification, and the oxygen atom can be connected to any carbon atom of the linear or branched chain of the C 1 -C 6 alkyl group.
  • ring When alone or as part of other substituents, the term “ring” includes carbocyclic rings, heterocyclic rings, and the rings can be saturated, unsaturated or partially unsaturated rings.
  • the rings include heterocycloalkyl, cycloalkyl, aryl, heteroaryl, etc.
  • 4-7 membered ring refers to the above rings composed of 4, 5, 6 or 7 atoms.
  • heteroaryl or “heteroaromatic ring” or “heteroaromatic ring group” when used alone or as part of other substituents refers to a monocyclic or polycyclic aromatic ring system, in certain embodiments, 1 to 3 atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to N, O, S or P.
  • heteroatoms i.e., elements other than carbon, including but not limited to N, O, S or P.
  • heteroaromatic ring refers to an aromatic ring system containing 5 or 6 atoms containing heteroatoms.
  • heteroaromatic rings include, but are not limited to, furanyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolyl and isoquinolyl.
  • the heteroaromatic ring group may be optionally fused to a benzene ring, and may also include a monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring.
  • Halo can be used interchangeably with the term “halogen-substituted” when used alone or as part of other substituents.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as but not limited to carboxyl, hydroxyl and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as protecting groups).
  • Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amine protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc.
  • Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salts” refers to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule.
  • the prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule.
  • the keto form predominates; while in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.
  • solvate means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules.
  • the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds.
  • radioactive isotope labeled compounds may be used, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of the type of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature of each step can be appropriately selected according to the solvent, starting material, reagent, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc.
  • the target compound can be separated and purified from the reaction system according to the common method, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and the like. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • the reaction of each step of the present invention is preferably carried out in an inert solvent
  • the inert solvent includes but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.
  • heterocyclic TEAD inhibitor which is a compound of formula I' or formula I described in the present invention.
  • the compound can significantly inhibit the activity of TEAD transcription and can be used to prevent and/or treat diseases associated with increased TEAD expression.
  • the synthetic route is as follows:
  • Step 1 Synthesis of 2-oxo-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-1'-carboxylic acid-2-methylpropan-2-yl ester (1-2)
  • reaction solution is filtered through diatomaceous earth, the filter cake is washed with dichloromethane (40 mL), the filtrates are combined, washed with water (15 mL), and then dried over anhydrous sodium sulfate.
  • Step 2 Synthesis of 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one hydrochloride (1-3)
  • Step 3 Synthesis of 1'-(2-fluoro-1-oxoprop-2-enyl)-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one (I-1)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 1'-(1-oxoprop-2-enyl)-1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole]-2-one (I-2)
  • the synthetic route is as follows:
  • 3-Bromopyridin-2-amine (3-1) (3.0 g, 17.4 mmol) was placed in a reaction bottle, anhydrous acetonitrile (20 mL) was added under argon protection, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), 1-Boc-pyrrolidine-3-carboxylic acid (6.2 g, 28.8 mmol) and methylimidazole (3.6 g, 45 mmol) were added at room temperature, and the reaction solution was stirred at 45 ° C for 16 h.
  • Step 2 Synthesis of 2-methylpropane-2-yl 3-[[(3-bromopyridin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylate (3-3)
  • Step 3 Synthesis of 2-methylpropan-2-yl 1'-[(4-methoxyphenyl)methyl]-2'-oxyde-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-1-carboxylate (3-4)
  • Step 4 Synthesis of 1-(1-oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (3-5)
  • the above crude product was added dropwise to a saturated sodium carbonate solution (5 mL), and then sodium bicarbonate (200 mg) and acetonitrile (5 mL) were added, followed by acryloyl chloride (64 mg, 0.6 mmol) at 0°C, and the reaction solution was stirred at 0°C for 15 min. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove acetonitrile, and then extracted with ethyl acetate (50 mL). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Synthesis of 1-(1-oxoprop-2-enyl)-1'-[4-(trifluoromethyl)phenyl]-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[2,3-b]pyridine]-2'-one (I-3)
  • reaction solution was extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (50 mL ⁇ 3), then dried over anhydrous sodium sulfate, filtered and concentrated.
  • the synthetic route is as follows:
  • Step 1 Synthesis of 2-methylpropane-2-yl 3-[[(2-bromopyridin-3-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylate (4-2)
  • 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction bottle, anhydrous acetonitrile (20 mL) was added under argon protection, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), 1-Boc-pyrrolidine-3-carboxylic acid (6.2 g, 28.8 mmol) and methylimidazole (3.6 g, 45 mmol) were added at room temperature, and stirred at 45 ° C for 16 h. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of 2-methylpropan-2-yl 3-[[(2-bromopyridin-3-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylate (4-3)
  • Step 3 Synthesis of 2-methylpropan-2-yl 1'-[(4-methoxyphenyl)methyl]-2'-oxo-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-1-carboxylate (4-4)
  • reaction solution was cooled to room temperature, ethyl acetate (500 mL) was added, and then washed with saturated aqueous sodium chloride solution (500 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 Synthesis of 1-(1-oxoprop-2-enyl)-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (4-5)
  • Step 5 Synthesis of 1-(1-oxoprop-2-enyl)-1'-[4-(trifluoromethyl)phenyl]-1,1',2,2',4,5-hexahydrospiro[pyrrole-3,3'-pyrrolo[3,2-b]pyridine]-2'-one (I-4)
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (200 mL) and diluted, and washed with saturated sodium chloride aqueous solution (200 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • the synthetic route is as follows:
  • Step 1 Synthesis of compound 1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indole-3,3'-pyrrole](5-2)
  • Step 2 Synthesis of compound 1-[1-[4-(trifluoromethyl)phenyl]-1,1',2,2',4',5'-hexahydrospiro[indol-3,3'-pyrrole]-1'-yl]prop-2-en-1-one (I-5)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 2-methylpropane-2-yl 3-[[(3-bromopyrazin-2-yl)amino]carbonyl]tetrahydropyrrole-1-carboxylate (6-2)
  • 3-Bromopyrazin-2-amine (6-1) (3.0 g, 17.2 mmol) was placed in a reaction bottle, and anhydrous acetonitrile (20 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), 1-Boc-pyrrolidine-3-carboxylic acid (6.2 g, 28.8 mmol) and methylimidazole (3.6 g, 45 mmol) were added under argon protection, and the reaction solution was stirred at 45 ° C for 16 h.
  • Step 2 Synthesis of 2-methylpropane-2-yl 3-[[(3-bromopyrazin-2-yl)[(4-methoxyphenyl)methyl]amino]carbonyl]tetrahydropyrrole-1-carboxylate (6-3)
  • Step 3 Synthesis of 2-methylpropan-2-yl 5'-[(4-methoxyphenyl)methyl]-6'-oxo-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[3,2-b]pyrazine]-1-carboxylate (6-4)
  • Step 4 Synthesis of 1-(1-oxoprop-2-enyl)-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (6-5)
  • Step 5 Synthesis of 1-(1-oxoprop-2-enyl)-5'-[4-(trifluoromethyl)phenyl]-1,2,4,5,5',6'-hexahydrospiro[pyrrole-3,7'-pyrrolo[2,3-b]pyrazine]-6'-one (I-6)
  • the synthetic route is as follows:
  • Step 1 Synthesis of compound 4-((2-bromopyridin-3-yl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (7-1)
  • 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction bottle, anhydrous acetonitrile (20 mL) was added, and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), methylimidazole (3.6 g, 45 mmol), and 1-Boc-4-piperidinic acid (4.78 g, 20.88 mmol) were added at room temperature. The reaction solution was stirred at 45 ° C for 16 h under nitrogen protection.
  • Step 2 Synthesis of compound 4-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (7-2)
  • Step 3 Synthesis of compound 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-3)
  • Step 4 Synthesis of compound 2'-oxo-1',2'-dihydrospiro[piperidin-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-4)
  • reaction solution was added dropwise to a saturated sodium carbonate solution (5 mL), the pH was adjusted to 7, and sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by di-tert-butyl dicarbonate (425 mg, 4.0 mmol) at 0°C, and the reaction solution was stirred at 0°C for 15 min.
  • Step 5 Synthesis of compound 2-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro-[piperidine-4,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (7-5)
  • Step 5 Synthesis of compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[piperidin-4,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-7)
  • reaction solution was added dropwise to a saturated sodium carbonate solution (3 mL), the pH of the reaction solution was adjusted to 7, sodium bicarbonate (300 mg) and acetonitrile (3 mL) were added, and then acryloyl chloride (180 mg, 2.0 mmol) was added at 0°C, and the reaction solution was stirred at 0°C for 15 min.
  • the synthetic route is as follows:
  • Step 1 Synthesis of compound 3-((2-bromopyridin-3-yl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-1)
  • 2-Bromopyridin-3-amine (4-1) (3.0 g, 17.4 mmol) was placed in a reaction bottle, and dry acetonitrile (20 mL) was added.
  • N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (7.35 g, 26.2 mmol), methylimidazole (3.6 g, 45 mmol), and 1-N-Boc-3-azetidinecarboxylic acid (4.19 g, 20.88 mmol) were added at room temperature.
  • the reaction solution was stirred at 45 ° C for 16 h under nitrogen protection.
  • Step 2 Synthesis of compound 3-((2-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylic acid tert-butyl ester (8-2)
  • Step 3 Synthesis of compound 1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-3)
  • Step 4 Synthesis of compound 2'-oxo-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-4)
  • reaction solution was added dropwise to a saturated sodium carbonate solution (5 mL), and after neutralization, sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by di-tert-butyl dicarbonate (425 mg, 4.0 mmol) at 0°C, and the reaction solution was stirred at 0°C for 15 min.
  • Step 5 Synthesis of compound 2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-1-carboxylic acid tert-butyl ester (8-5)
  • Step 6 Synthesis of compound 1-acryloyl-1'-(4-(trifluoromethyl)phenyl)spiro[azetidine-3,3'-pyrrolo[3,2-b]pyridinyl]-2'(1'H)-one (I-8)
  • reaction solution was added dropwise to a saturated sodium carbonate solution (3 mL), the pH of the reaction solution was adjusted to 7, and then sodium bicarbonate (300 mg) and acetonitrile (3 mL) were added, followed by acryloyl chloride (180 mg, 2.0 mmol) at 0°C, and the reaction solution was allowed to react at 0°C for 15 min.
  • the synthetic route is as follows:
  • reaction solution was added dropwise to a saturated sodium carbonate solution (5 mL), the pH of the reaction solution was adjusted to 7, and then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by 2-fluoroacryloyl chloride (501 mg, 4.0 mmol) at 0°C, and the reaction solution was reacted at 0°C for 15 min.
  • the synthetic route is as follows:
  • Step 1 Synthesis of compound 1-(2-fluoroacryloyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (10-1)
  • reaction solution was added dropwise to a saturated sodium carbonate solution (5 mL), the pH of the reaction solution was adjusted to 7, and then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by 2-fluoroacryloyl chloride (501 mg, 4.0 mmol) at 0°C, and the reaction solution was reacted at 0°C for 15 minutes.
  • Step 2 Synthesis of compound 1-(2-fluoroacryloyl)-1'-(4-(trifluoromethyl)phenyl)spiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one (I-10)
  • the synthetic route is as follows:
  • reaction solution was added dropwise to a saturated sodium carbonate solution (5 mL), the reaction solution was adjusted to 7, and then sodium bicarbonate (400 mg) and acetonitrile (5 mL) were added, followed by methanesulfonyl chloride (164 mg, 1.44 mmol) at 0°C, and the reaction solution was reacted at 0°C for 15 min.
  • the synthetic route is as follows:
  • Step 1 Synthesis of tert-butyl (3-((2-bromopyridin-3-yl)carbamoyl)cyclobutyl)carbamate
  • reaction solution was then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (200 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 Synthesis of tert-butyl (3-((2-bromopyridin-3-yl)((4-methoxyphenyl)methyl)carbamoyl)cyclobutyl)carbamate
  • Step 3 Synthesis of tert-butyl ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A1) and tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2)
  • Step 4 Synthesis of (1s,3s)-3-aminospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-1)
  • Step 5 Synthesis of tert-butyl (1s,3s)-(2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-2)
  • Step 6 Synthesis of tert-butyl ((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-3)
  • tert-butyl (1s,3s)-(2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (13-2) (150.5 mg, 0.52 mmol) in acetonitrile (5 mL), add 4-iodotrifluorotoluene (106.1 mg, 0.39 mmol), cuprous iodide (119 mg, 0.62 mmol), potassium carbonate (216.0 mg, 1.56 mmol), and then add N,N'-dimethylethylenediamine (59.6 mg, 0.68 mmol), and react in a microwave at 100 ° C for 1 hour under nitrogen protection.
  • Step 7 Synthesis of (1s,3s)-3-amino-1'-(4-(trifluoromethyl)phenyl)spiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-2'(1'H)-one (13-4)
  • Step 8 Synthesis of N-((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)prop-2-enamide (I-13A)
  • Compound I-13B was synthesized by referring to the synthesis method of compound I-13A, except that raw material A1 was replaced with tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2).
  • Compound I-14B was synthesized by referring to the synthesis method of compound I-14A, except that raw material A1 was replaced with tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2).
  • the synthetic route is as follows:
  • Step 1 Synthesis of tert-butyl ((1s,3s)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)(methyl)carbamate
  • Step 2 tert-butyl (methyl)((1s,3s)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (15-2)
  • Step 3 tert-butyl methyl((1s,3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1',2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-3-yl)carbamate
  • Step 4 N-methyl-N-((1s, 3s)-2'-oxo-1'-(4-(trifluoromethyl)phenyl)-1', 2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)acrylamide (I-15A)
  • Compound I-15B was synthesized by referring to the synthesis method of compound I-15A, except that raw material A1 was replaced with tert-butyl ((1r,3r)-1'-(4-methoxybenzyl)-2'-oxo-1',2'-dihydrospiro(cyclobutane-1,3'-pyrrolo[3,2-b]pyridine)-3-yl)carbamate (A2).
  • the synthetic route is as follows:
  • Step 1 Synthesis of tert-butyl 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-1)
  • Step 2 Synthesis of tert-butyl 5-bromo-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro[indole-3,3'-pyrrolidine]-1'-carboxylate (16-2)
  • the compound 5-bromo-2-oxospiro(indole-3,3'-pyrrolidine)-1'-carboxylic acid tert-butyl ester (16-1) (1.0 g, 2.73 mmol) was placed in a reaction bottle, and 4-iodotrifluorotoluene (0.90 g, 3.28 mmol), cuprous iodide (0.52 g, 2.73 mmol), potassium carbonate (1.2 g, 8.2 mmol), N,N-dimethylethylenediamine (0.3 g, 3.28 mmol) were added, followed by acetonitrile (10 mL), and the reaction solution was stirred at 60 ° C for 2 h under nitrogen protection.
  • Step 3 Synthesis of tert-butyl 2-oxo-1-(4-(trifluoromethyl)phenyl)-5-vinylspiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-3)
  • Step 4 Synthesis of tert-butyl 5-(1,2-dihydroxyethyl)-2-oxo-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-1'-carboxylate (16-4)
  • Step 5 Synthesis of 1'-acryloyl-5-(1,2-dihydroxyethyl)-1-(4-(trifluoromethyl)phenyl)spiro(indole-3,3'-pyrrolidine)-2-one (I-16)
  • Test Example 1 TEADs-mediated transcription inhibition IC 50 evaluation test
  • HEK293T-TEAD Reporter Assay was used to detect the inhibitory effect of small molecule compounds on TEADs-mediated transcription.
  • HEK293T-TEAD-LUC reporter cell line was cultured in DMEM+10% FBS+1% PS+200 ⁇ g/mL Hygromycin as complete medium. Cells in the logarithmic phase were seeded in 384-well plates, 2500 cells/well/35 ⁇ L, incubated overnight at 37°C, 5% CO 2 , and 5 ⁇ L of diluted compound was added to each well the next day (DMSO final concentration was 0.1%). A positive control group with only DMSO was set up, and the 2 ⁇ M Okacid acid signal value was used as the negative control group signal. Then, the plates were incubated at 37°C, 5% CO 2 for 48h. After incubation, the plates were used.
  • luciferase assay system Promega, E2550 was used to measure the fluorescence signal value on Envision 2104 Multilabel Reader according to the instructions provided by the supplier.
  • the inhibition rate was calculated by the following formula, and then a curve was drawn with the Log value of the inhibitor concentration as the X-axis and the inhibition rate as the Y-axis, and the IC 50 was calculated using Graphpad 7.0.
  • Inhibition% (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100
  • HEK293T-TEAD Reporter Assay showed that the compounds of the present invention can significantly inhibit the transcriptional activity of TEADs in HEK293T-TEAD-LUC reporter cell line cells.
  • Test Example 2 Inhibition of malignant mesothelioma cell proliferation test
  • the NF2 mutant NCI-H226 cell proliferation assay was used to detect the inhibitory effect of small molecule compounds on the proliferation of malignant mesothelioma cells.
  • NCI-H226 (ATCC, cat#CRL5826) was cultured in RPMI1640+10% FBS+1% PS as complete medium. Cells in the logarithmic phase were inoculated in 96-well plates, 800 cells/well/195 ⁇ L, incubated overnight at 37°C, 5% CO 2 , and 5 ⁇ L of diluted compound (DMSO final concentration was 0.1%) was added to each well the next day. At the same time, a positive control group with only DMSO added was set up, and the 1 ⁇ M Staurosporine signal value was used as the negative control group signal, and then incubated at 37°C, 5% CO 2 for 6 days.
  • DMSO final concentration was diluted compound
  • Inhibition% (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100
  • NCI-H226 cell proliferation test showed that the compounds of the present invention can significantly inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).
  • PBS phosphate buffered saline
  • thermodynamic solubility test show that the compound of the present invention has good thermodynamic solubility under neutral conditions and good drugability.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de TEAD contenant un cycle hétérocyclique, qui a la structure telle que représentée dans la formule (I'), et est utilisé pour prévenir et/ou traiter des maladies liées à une expression accrue de TEAD.
PCT/CN2024/135617 2023-11-30 2024-11-29 Inhibiteur de tead contenant un cycle hétérocyclique Pending WO2025113627A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202311641928.3 2023-11-30
CN202311641928 2023-11-30
CN202410141328 2024-01-31
CN202410141328.9 2024-01-31
CN202410547186 2024-04-29
CN202410547186.6 2024-04-29

Publications (1)

Publication Number Publication Date
WO2025113627A1 true WO2025113627A1 (fr) 2025-06-05

Family

ID=95800925

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/135617 Pending WO2025113627A1 (fr) 2023-11-30 2024-11-29 Inhibiteur de tead contenant un cycle hétérocyclique

Country Status (2)

Country Link
CN (1) CN120058702A (fr)
WO (1) WO2025113627A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025185702A1 (fr) * 2024-03-06 2025-09-12 Zai Lab (Shanghai) Co., Ltd. Composés spirocycliques utilisés en tant qu'inhibiteurs de tead

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006090261A1 (fr) * 2005-02-24 2006-08-31 Pfizer Products Inc. Derives heteroaromatiques bicycliques utilises comme agents anticancereux
CN110305141A (zh) * 2019-07-18 2019-10-08 深圳市三启药物开发有限公司 一种螺(3,3’-异丙基吡咯烷氧化吲哚)类肝x受体调节剂及其制备方法和应用
CN111918654A (zh) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 Mtor的抑制剂化合物
WO2022116995A1 (fr) * 2020-12-02 2022-06-09 上海和誉生物医药科技有限公司 Dérivé de 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine, son procédé de préparation et son utilisation
WO2023122784A2 (fr) * 2021-12-23 2023-06-29 The Katholieke Universiteit Leuven Spiros et analogues associés pour inhiber yap/taz-tead

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006090261A1 (fr) * 2005-02-24 2006-08-31 Pfizer Products Inc. Derives heteroaromatiques bicycliques utilises comme agents anticancereux
CN111918654A (zh) * 2017-12-21 2020-11-10 盖尔德马研究及发展公司 Mtor的抑制剂化合物
CN110305141A (zh) * 2019-07-18 2019-10-08 深圳市三启药物开发有限公司 一种螺(3,3’-异丙基吡咯烷氧化吲哚)类肝x受体调节剂及其制备方法和应用
WO2022116995A1 (fr) * 2020-12-02 2022-06-09 上海和誉生物医药科技有限公司 Dérivé de 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine, son procédé de préparation et son utilisation
WO2023122784A2 (fr) * 2021-12-23 2023-06-29 The Katholieke Universiteit Leuven Spiros et analogues associés pour inhiber yap/taz-tead

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN ZIYANG; CHEN HAO; ZHANG ZIZHEN; DING PENG; YAN XIN; LI YANWEN; ZHANG SONGXUAN; GU QIONG; ZHOU HUIHAO; XU JUN: "Discovery of novel liver X receptor inverse agonists as lipogenesis inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER MASSON, AMSTERDAM, NL, vol. 206, 6 September 2020 (2020-09-06), AMSTERDAM, NL, XP086299096, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2020.112793 *
DATABASE CAS 11 October 2023 (2023-10-11), ANONYMOUS: " Spiro[3H-indole-3,3'-pyrrolidine]-1'-carboxylic acid, 1,2-dihydro-1-[4-(hydroxymethyl)phenyl]-2'-(1-methylethyl)-2-oxo-, 1,1-dimethylethyl ester, (2'R,3R)-rel- (CA INDEX NAME)", XP093319482, Database accession no. 2986869-85-4 *

Also Published As

Publication number Publication date
CN120058702A (zh) 2025-05-30

Similar Documents

Publication Publication Date Title
WO2022017339A1 (fr) Dérivé pyridazinique condensé, son procédé de préparation et son utilisation pharmaceutique
CN108349896B (zh) 作为fgfr抑制剂的杂环化合物
CN115551868A (zh) 大环化合物和其用途
CN115803325B (zh) 一种egfr抑制剂及其制备方法和应用
WO2020063792A1 (fr) Dérivé macrocyclique d'indole, son procédé de préparation et son application en médecine
CN112375077A (zh) 四氢-吡啶并[3,4-b]吲哚雌激素受体调节剂及其用途
AU2013227024A1 (en) Novel piperidine compound or salt thereof
CN114685502A (zh) 作为kras-g12c抑制剂的螺环类化合物
WO2023280254A1 (fr) Inhibiteur de tead
CN102985410B (zh) 在癌症的治疗中使用的考布他汀类似物
JP2020536113A (ja) 上皮成長因子受容体阻害剤
CN117440945A (zh) 嘧啶或吡啶衍生物及其制备方法和在药学上的应用
WO2025113627A1 (fr) Inhibiteur de tead contenant un cycle hétérocyclique
WO2024017384A1 (fr) Composé pour la récupération de la fonction de mutation p53 et son utilisation
WO2023051648A1 (fr) Composé utilisé comme inhibiteur de shp2, son procédé de préparation et son utilisation
WO2024188246A1 (fr) Composé macrocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023116877A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de tead
WO2024148932A1 (fr) Inhibiteur de mutation de l'egfr c797s et son utilisation pharmaceutique
WO2023116763A1 (fr) Composé pyridazine, composition pharmaceutique et leur utilisation
CN117479934A (zh) 用于治疗肾纤维化的噁二唑基二氢吡喃并[2,3-b]吡啶的HIPK2抑制剂
WO2022184049A1 (fr) Inhibiteur de plk4 et son utilisation
WO2025113617A1 (fr) Inhibiteur de tead bicyclique
TWI896726B (zh) 一種ｅｇｆｒ抑制劑及其製備方法和應用
WO2024140933A1 (fr) Dérivé de camptothécine, composition pharmaceutique et procédé de préparation et utilisation associés
WO2024217481A1 (fr) Agent de dégradation d'egfr, composition pharmaceutique et utilisation associées

Legal Events

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

Ref document number: 24896709

Country of ref document: EP

Kind code of ref document: A1