WO2024099435A1 - Tead inhibitor - Google Patents

Tead inhibitor Download PDF

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WO2024099435A1
WO2024099435A1 PCT/CN2023/131008 CN2023131008W WO2024099435A1 WO 2024099435 A1 WO2024099435 A1 WO 2024099435A1 CN 2023131008 W CN2023131008 W CN 2023131008W WO 2024099435 A1 WO2024099435 A1 WO 2024099435A1
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ring
membered
methyl
compound
formula
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PCT/CN2023/131008
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French (fr)
Chinese (zh)
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张学军
臧杨
杨辉
李超
李金平
李莉娥
杨俊�
朱圣姬
李禹琼
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武汉人福创新药物研发中心有限公司
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Publication of WO2024099435A1 publication Critical patent/WO2024099435A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically, the present invention relates to a 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.
  • Invenva Pharma’s patents show that inhibiting the interaction between YAP/TAZ and TEADs can significantly inhibit the proliferation of tumor cells (WO 2017064277).
  • 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 compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; the compound can significantly inhibit the activity of TEAD transcription as a TEAD inhibitor, and can be used to prevent and/or treat diseases related to increased TEAD expression.
  • Ring A is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;
  • Ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;
  • X 1 , X 2 , and X 3 are each independently N or CR a ;
  • W is O, NH
  • L is absent or is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
  • R 1 , R 2 , and Ra are each independently hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl are optionally substituted with 1, 2, or 3 identical or different substituents selected from the following: halogen, hydroxyl, amino, -SF 5 , and C 1 -C 6 alkyl;
  • R 1 When R 1 is multiple, the R 1 are the same or different;
  • R 2 When R 2 is multiple, the R 2 are the same or different;
  • Ra When Ra is multiple, the Ra are the same or different;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • -WL- is -NH-CH 2 - or -O-CH 2 -.
  • ring A is a 6-12 membered bicyclic saturated carbocyclic ring; preferably, ring A is
  • ring B is a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring, wherein the 6-12 membered bicyclic ring or the 8-15 membered tricyclic ring is a 5-membered N-containing heteroaromatic ring and a saturated heterocyclic ring; preferably, the 6-12 membered bicyclic ring or the 8-15 membered tricyclic ring is an imidazolyl saturated heterocyclic ring.
  • ring B when ring B is a 6-12 membered bicyclic ring, ring B is Wherein, ring B' is a 5-membered heteroaromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, and when there are multiple heteroatoms, the heteroatoms are the same or different; ring B" is a 5-membered or 6-membered saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, and when there are multiple heteroatoms, the heteroatoms are the same or different.
  • Ring B when ring B is a 6-12 membered bicyclic ring, ring B is Wherein, Ring B" is a 5-membered or 6-membered saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different.
  • ring B is a 6-12 membered bicyclic ring, -LW- is not -O- or Not a benzene ring or pyridine.
  • -WL- is -NH-CH 2 -, -O-CH 2 -, -NH-, or -O-; preferably, -LW- is -NH-CH 2 - or -O-CH 2 -.
  • ring B when ring B is an 8-15 membered tricyclic ring, ring B is Wherein ring B'' is a 6-10 membered cyclic ring; preferably, ring B'' is a 6-10 membered saturated cyclic ring, the cyclic ring optionally contains 1, 2 or 3 heteroatoms; preferably, the ring B is
  • R 2 , R 3 , and R 4 are each independently hydrogen or a C 1 -C 6 alkyl group; more preferably, R 2 , R 3 , and R 4 are each independently hydrogen or a methyl group.
  • the compound represented by formula I has the structure:
  • Ring A is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, or a 6-12 membered bicyclic ring;
  • Ring B is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, or a 6-12 membered bicyclic ring;
  • X 1 , X 2 , and X 3 are each independently N or CRa;
  • W is O, NH
  • L is absent or is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
  • R 1 , R 2 , and Ra are each independently hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl are optionally substituted with 1, 2, or 3 identical or different substituents selected from the following: halogen, hydroxyl, amino, -SF 5 , and C 1 -C 6 alkyl;
  • R 1 When R 1 is multiple, the R 1 are the same or different;
  • R 2 When R 2 is multiple, the R 2 are the same or different;
  • Ra When Ra is multiple, the Ra are the same or different;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the compound represented by formula I satisfies one or more of the following conditions:
  • R 1 is -SF 5 ;
  • Ring A is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;
  • Ring B is a 6-12 membered bicyclic ring, and -L-W- is not -O-;
  • the ring A is a saturated carbocyclic ring; preferably, the ring A is a bis-cyclic ring or a spirocyclic ring.
  • Ring B is Wherein, ring B' is an aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O, and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
  • Ring B is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 (preferably 1 or 2) heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms may be the same or different.
  • the compound of formula I has the structure of formula II
  • R 21 and R 22 are each independently selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; or,
  • R 21 , R 22 and the imidazole to which they are commonly connected together form a ring B";
  • the ring B" is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
  • the ring B" is optionally substituted by 1, 2 or 3 identical or different R2 ; the R2 is selected from halogen, C1 - C6 alkyl, C1 - C6 haloalkyl.
  • the compound represented by formula II satisfies one or more of the following conditions:
  • R 1 is -SF 5 ;
  • Ring A is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;
  • R 2 , R 3 and the group to which they are commonly attached together form a ring B′′, and -LW- is not -O-;
  • R 1 is fluoromethyl, fluoroethyl, or fluoropropyl; preferably, the fluoromethyl is -CF 3 , CH 2 F, or CHF 2 ;
  • Ring A is a benzene ring
  • R 21 is methyl, R 22 is H;
  • -WL- is -NH-CH 2 -.
  • the ring A is a saturated carbocyclic ring; preferably, the ring A is a bis-cyclic ring or a spirocyclic ring.
  • the ring A is
  • the ring A is
  • R 1 is independently F or methyl.
  • R 1 is F or methyl.
  • X 1 and X 2 are N.
  • X1 is CRa and X2 is N.
  • X 1 and X 2 are CRa.
  • Ra is hydrogen
  • the compound of formula I has the structure shown in formula Ia
  • X 1 and X 2 are N;
  • X1 is CH, X2 is N;
  • X 1 and X 2 are CH.
  • the compound of formula I has the structure shown in formula Ib
  • X 1 and X 2 are N;
  • X1 is CH, X2 is N;
  • X 1 and X 2 are CH.
  • the compound of formula I has a structure shown in formula Ic
  • X 1 and X 2 are N.
  • X1 is CH and X2 is N.
  • X 1 and X 2 are CH.
  • R 2 is methyl, ethyl, propyl, halomethyl, haloethyl, or halopropyl.
  • R2 is methyl
  • the compound of formula I has a structure shown in formula Ic-1, formula Ic-2 or formula Ic-3
  • R 1 is F or -CH 3 .
  • Ring B" is a 5- or 6-membered saturated heterocyclic ring, wherein the heteroatom is selected from N or O.
  • the compound of formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has structure Id
  • X1 is N
  • X2 is CH
  • R2 is methyl, ethyl or propyl
  • W is O or NH
  • R 2 is methyl
  • L is -CH 2 -;
  • the compound of formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has structure
  • R 1 , R 2 , W, and L are as defined above;
  • R 1 is fluoromethyl, fluoroethyl, fluoropropyl; preferably, the fluoromethyl is -CF 3 , CFH 2 , CF 2 H;
  • ring A is a benzene ring
  • R 21 is methyl, and R 22 is H;
  • -WL- is -NH-CH 2 -;
  • W is O or -NH-
  • L is absent or is -CH 2 .
  • W is O and L is absent.
  • W is O and L is -CH 2 -.
  • W is -NH- and L is absent.
  • W is -NH- and L is -CH 2 -.
  • the compound of formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has structure Ie
  • the compound represented by Formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:
  • the "group covalently bound to an amino acid residue” refers to an amino acid residue (e.g., cysteine, lysine, histidine or other residues that can be covalently modified) that can covalently bind to the binding pocket of the target protein (e.g., TEAD), thereby irreversibly inhibiting the protein.
  • it refers to a group that can covalently bind to Cys359 of hTEAD1, Cys405 of hTEAD1, Cys380 of hTEAD2, Cys368 of hTEAD3, and/or Cys367 of hTEAD4.
  • it refers to a group that can covalently bind to Ser356 of hTEAD1, Ser345 and/or Ser377 of hTEAD2, Ser365 of hTEAD3, and/or Ser364 of hTEAD4. In some embodiments, it refers to a group that can covalently bind to Lys336 of hTEAD1, Lys357 of hTEAD2, Lys345 of hTEAD3, and/or Lys344 of hTEAD4.
  • the "group covalently bound to the amino acid residue” contains a “leaving group”, which is a group that undergoes nucleophilic displacement, including but not limited to groups containing halogen, alkenyl, alkynyl, nitro, and oxo. Suitable leaving groups are well known in the art, for example, see “Advanced Organic Chemistry", Jerry March, 5th Ed., pp.351-357, John Wiley and Sons, NY.
  • Such leaving groups include but are not limited to halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl and diazo moieties.
  • Typical non-"leaving groups are alkyl groups, such as methyl. It does not belong to the category of “groups covalently bonded to amino acid residues”.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as described in any one of the first aspects, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides a use of the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition as described in the second aspect, comprising:
  • the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.
  • the disease is a cell proliferative disorder.
  • the cell proliferative disorder is cancer.
  • the cancer is selected from the group consisting of mesothelioma, ovarian cancer, bile duct cancer, blood cancer, lymphoma, myeloma, leukemia, nervous system cancer, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer and vascular 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 represented by formula (I), 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 cancer is selected from the group consisting of mesothelioma, ovarian cancer, bile duct cancer, blood cancer, lymphoma, myeloma, leukemia, nervous system cancer, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer and vascular cancer.
  • the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
  • the patient is a mammal, preferably a human.
  • the inventors unexpectedly developed a new TEAD inhibitor, in particular a TEAD inhibitor that does not contain a group covalently bound to an amino acid residue; the TEAD inhibitor can significantly inhibit the activity of TEAD transcription and can be used to prevent and/or treat diseases associated with increased TEAD expression; the TEAD inhibitor has excellent pharmacokinetic properties, good drugability, and has a significant effect of inhibiting the growth of NCI-H226 mesothelioma.
  • 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.
  • cycloalkyl or “carbocyclyl” refers to a cyclic alkyl group.
  • mn-membered cycloalkyl or “C m -C n cycloalkyl” should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms.
  • 3-10-membered cycloalkyl or “C 3 -C 10 cycloalkyl” refers to a cyclic alkyl group containing 3 to 10 carbon atoms, which may contain 1 to 3 rings.
  • the cyclic alkyl group includes a monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring.
  • unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • the cycloalkyl group may be substituted by one or more substituents.
  • the cycloalkyl group may be a cycloalkyl group fused to an aryl or heteroaryl group.
  • heterocycloalkyl when alone or as part of another substituent refers to a cycloalkyl in which one or more (in some embodiments 1, 2 or 3) carbon atoms are replaced by heteroatoms, such as but not limited to N, O, S and P.
  • m-n membered heterocycloalkyl is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms.
  • the term “5-10 membered heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having 5 to 10 atoms.
  • the heterocycloalkyl can be a heterocycloalkyl fused to an aryl or heteroaryl group.
  • heteroatoms 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.
  • 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.
  • bicyclic or "bicyclic ring” refers to two rings that share one or more atoms, including spiro or fused rings.
  • spiro refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system. According to the number of spiro atoms shared between the rings, spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl, preferably monospiroalkyl.
  • spiroalkyl groups include:
  • Non-limiting examples include:
  • the term "paracyclic” refers to two monocyclic rings sharing two or more atoms (called spiro atoms), which may contain one or more double bonds.
  • the monocyclic ring may be a saturated, unsaturated or partially unsaturated ring.
  • the monocyclic ring may be a carbocyclic group, a heterocyclic alkyl group or a heteroaryl group.
  • 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 amido 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” refer 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” refer 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 its salt 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 at one or more of the atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • a radioactive isotope such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • the total isotopic composition of the compounds of the present invention is Any transformation, whether radioactive or not, is 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.
  • Step 1 Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) and (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2b)
  • Methyl cyclopent-3-ene-1-carboxylate (10.0 g, 79.3 mmol) was dissolved in tetrahydrofuran (100 mL), sodium iodide (6 g, 40.0 mmol) was added, and (trifluoromethyl)trimethylsilane (28.2 g, 198.3 mmol) was added, and the mixture was refluxed for reaction overnight. After the reaction, the reaction solution was concentrated, and the residue was dissolved in dichloromethane (100 mL), washed with sodium thiosulfate solution (0.1 M, 50 mL) and dried over anhydrous sodium sulfate.
  • A2-2a 1 H NMR (600 MHz, CDCl3) ⁇ 3.68 (s, 3H), 2.88–2.79 (m, 1H), 2.31–2.19 (m, 4H), 2.03–1.98 (m, 2H).
  • A2-2b 1 H NMR (600 MHz, CDCl3) ⁇ 3.66 (s, 3H), 3.17–3.10 (m, 1H), 2.40–2.26 (m, 4H), 2.05–1.97 (m, 2H).
  • Step 4 Synthesis of ((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methylamine (A2-4)
  • Step 5 Synthesis of 5-bromo-6-((((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A2)
  • the synthetic route is as follows:
  • Step 1 Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (A4-1)
  • reaction solution was concentrated under reduced pressure, water (5 mL) was added to the residue, and then the pH of the solution was adjusted to 6 with dilute hydrochloric acid (2 mol/L), followed by extraction with ethyl acetate (20 mL ⁇ 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound (1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (A4-1) (0.8 g, yield 87.0%).
  • Step 2 Synthesis of tert-butyl ((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)carbamate (A4-2)
  • Step 3 Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-amine hydrochloride (A4-3)
  • Step 4 Synthesis of 5-bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A4)
  • reaction solution was diluted with 100 mL of dichloromethane, and the organic phase was washed with aqueous hydrochloric acid solution (0.5 M, 150 mL). The organic phase was collected, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
  • the crude product was slurried with petroleum ether/methyl tert-butyl ether (10/1, v/v) (100 mL) to obtain 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A6-2) (12 g, yield 70.6%).
  • Step 2 Synthesis of 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A6-3)
  • Step 1 Synthesis of (R)-5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (A6-5)
  • the organic phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product.
  • Step 3 Synthesis of (R)-4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)benzenesulfonamide (A6)
  • the synthetic route is as follows:
  • Benzyl mercaptan (13.8 g, 111 mmol) was dissolved in tetrahydrofuran (200 mL), sodium hydride (6.67 g, 166 mmol) was added in batches at 0°C, and the mixture was stirred at 0°C for 2 hours.
  • 2,5-dichloropyrazine (18.2 g, 122 mmol) was added in batches to the reaction solution, and the reaction solution was continued to react at 0°C for 2 hours.
  • Saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL ⁇ 2).
  • the synthetic route is as follows:
  • Step 1 Synthesis of N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A8-1)
  • N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide 300 mg, 866 ⁇ mol was dissolved in acetonitrile (8 mL), and N-bromosuccinamide (154 mg, 866 ⁇ mol) and carbon tetrachloride (2 mL) were added, and the mixture was stirred at 0°C for 2 hours.
  • the synthetic route is as follows:
  • Step 1 Synthesis of N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A9-1)
  • N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (121.3 mg, 0.35 mmol) in N,N-dimethylformamide (10 mL), add N-bromosuccinimide (90.8 mg, 0.51 mmol), and react at room temperature overnight. After the reaction is completed, add water (20 mL) and then add ethyl acetate. The residue was extracted with ethyl acetate (20 mL ⁇ 3), and the organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate.
  • the synthetic route is as follows:
  • Step 2 Synthesis of methyl 2-(2-oxo-3-azabicyclo[3.1.0]hex-3-yl)acetate (A10-3)
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Step 1 Synthesis of 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[4-(pentafluoro- ⁇ 6 -mercapto)phenyl]methylamino]pyridine-3-sulfonamide (B1-2)
  • Step 2 Synthesis of N-[(4-methoxyphenyl)methyl]-N-methyl-5-(1-methylimidazol-4-yl)-6-[[3-(pentafluoro- ⁇ 6 -mercapto)phenyl]methoxy]pyridine-3-sulfonamide (B1-3)
  • Step 3 Synthesis of N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-1)
  • reaction solution was cooled to room temperature, added to water (50.0 mL), and the pH value of the solution was adjusted to about 7 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (50 mL ⁇ 2), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • the synthetic route is as follows:
  • Step 1 Synthesis of 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-2)
  • Step 2 Synthesis of N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-3)
  • Step 3 Synthesis of N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-(pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-2)
  • N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- ⁇ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-3) (150 mg, 248 ⁇ mol) was dissolved in trifluoroacetic acid (5.00 mL) and stirred at 60°C for 2 hours.
  • reaction solution was added to water (50 mL), the pH of the solution was adjusted to about 7 with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (50 mL ⁇ 2), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • the synthetic route is as follows:
  • Step 1 Synthesis of (R)-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl))benzyl)amino)benzenesulfonamide (B5-2)
  • Step 2 Synthesis of (R)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (I-5)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-2)
  • Step 2 Synthesis of (R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-3)
  • Step 3 (R)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (I-6)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[3-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (B7-2)
  • reaction solution was extracted with ethyl acetate (50.0 mL), the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to obtain a brown oily compound 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[3-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (B7-2) (800 mg, yield 99.3%).
  • Step 2 Synthesis of (R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B7-3)
  • Step 3 Synthesis of (R)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (I-7)
  • reaction solution was added to water (50 mL), the pH was adjusted to 7 with saturated potassium carbonate aqueous solution, and then extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (80 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • the synthetic route is as follows:
  • Step 1 Synthesis of methyl 2-(3-oxomorpholino)acetate (B11-2)
  • Morpholine-3-one (B11-1) (10.0 g, 98.9 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (4.35 g, 109 mmol) was added in batches, the reaction solution was stirred at 25°C for 1 hour, and then methyl bromoacetate (16.6 g, 109 mmol) was added to the reaction solution, and stirred at 25°C for 9 hours.
  • Step 4 Synthesis of 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B11-5)
  • Step 5 Synthesis of 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-(4-methoxybenzyl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (168-6)
  • reaction solution was added dropwise to 1M hydrochloric acid (100 mL), neutralized with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product.
  • Step 6 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (I-11)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B14-2)
  • reaction solution was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, washed with water (20 mL) in turn, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Synthesis of 6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-14)
  • reaction solution was concentrated under reduced pressure, and dichloromethane (30 mL) was added to dissolve it, and the aqueous phase was washed with saturated sodium bicarbonate solution until the pH of the aqueous phase was 7-8.
  • intermediate A2 was replaced with intermediate A3 to obtain compound 6-((((1R, 3r, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-15).
  • the synthetic route is as follows:
  • Step 1 Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B16-2)
  • Step 2 Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-16)
  • intermediate A4 was replaced with intermediate A5 to obtain compound 6-(((1R, 3r, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-17).
  • the synthetic route is as follows:
  • Step 1 Synthesis of (1R,5S,6r)-3,3-difluorocyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B24-2)
  • Step 3 Synthesis of ((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B24-4)
  • reaction solution was cooled to room temperature, quenched with water (1 mL) at 0°C, stirred for 15 minutes, and then 15% sodium hydroxide solution (0.5 mL) was added, stirred at room temperature for 15 minutes, filtered, and the filter cake was washed with ethyl acetate (50 mL), and the filtrate was washed with water (10 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound ((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B24-4) (0.57 g, yield 75.0%).
  • Step 4 Synthesis of 5-bromo-6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B24-5)
  • reaction solution was cooled to room temperature, water (10 mL) was added, and ethyl acetate (20 mL ⁇ 3) was used for extraction. The organic phases were combined, washed with water (20 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Synthesis of 6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B24-6)
  • Step 6 Synthesis of 6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-24)
  • Step 1 Synthesis of 5-bromo-6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B25-1)
  • Step 5 Synthesis of 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B25-2)
  • Step 6 Synthesis of 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-25)
  • the synthetic route is as follows:
  • Step 1 Synthesis of ((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methanol (B28-2)
  • Step 2 Synthesis of 5-bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B28-3)
  • Step 3 Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B28-4)
  • Step 4 Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-28)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (30-2)
  • Step 2 Synthesis of 6-bromo-5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (B30-2)
  • Step 3 Synthesis of 5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-30)
  • the synthetic route is as follows:
  • Step 1 Synthesis of N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (B36-2)
  • reaction solution was added to water (200 mL), and then extracted with ethyl acetate (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonyl (B36-2) (200 mg, yield 59.9%).
  • Step 2 6-Bromo-N-methyl-5-((3-(trifluoromethyl)benzyl)amino]pyrazine-2-sulfonamide (B36-3)
  • N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (B36-2, 200 mg, 577 ⁇ mol) and diisopropylethylamine (224 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinamide (102 mg, 577 ⁇ mol) was added, and the mixture was stirred at 25°C for 2 hours.
  • the synthetic route is as follows:
  • 6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide 80.0 mg, 154 ⁇ mol was dissolved in toluene (20 mL), tetrakis(triphenylphosphine)palladium (17.8 mg, 15.4 ⁇ mol) and tributyl-[(2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl]stannane (116 mg, 169 ⁇ mol) were added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 6 hours.
  • the synthetic route is as follows:
  • 6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide 100.0 mg, 235 ⁇ mol was dissolved in N,N-dimethylformamide (1.0 mL), tetrakis(triphenylphosphine)palladium (27.2 mg, 23.5 ⁇ mol) and N-methyl-4-(tributyltin)imidazole (104.7 mg, 282.2 ⁇ mol) were added, and the argon atmosphere was replaced three times. The reaction solution was reacted at 110°C for 16 hours.
  • reaction solution was cooled to room temperature, and saturated potassium fluoride aqueous solution (5 mL) and ethyl acetate (5 mL) were added thereto. The mixture was stirred for 30 minutes and then filtered. The filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and layered.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Step 3 Synthesis of 5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-4)
  • Step 4 Synthesis of 6-bromo-5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-5)
  • Step 5 Synthesis of 5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-57)
  • the synthetic route is as follows:
  • Step 3 Synthesis of 5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-4)
  • Step 4 Synthesis of 6-bromo-5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-5)
  • Step 5 Synthesis of 5-((3-(difluoromethyl)benzyl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-58)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)benzenesulfonamide (B59-1)
  • Step 2 Synthesis of N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-(4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (B59-2)
  • Step 3 Synthesis of N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (I-59)
  • the synthetic route is as follows:
  • Step 1 Synthesis of 2,4-difluoro-N-((4-methoxyphenyl)methyl)-N-methyl-benzenesulfonamide (B60-2)
  • 2,4-difluorobenzenesulfonyl chloride (B60-1) (10.0 g, 47.0 mmol) was dissolved in dichloromethane (100 mL), triethylamine (14.2 g, 141 mmol) and 1-(4-methoxyphenyl)-N-methyl-methylamine (7.47 g, 49.3 mmol) were added, and the reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, 1M hydrochloric acid (100 mL) was added to the reaction solution, and it was extracted with dichloromethane (200 mL).
  • Step 2 Synthesis of 2,4-difluoro-3-iodo-N-((4-methoxyphenyl)methyl)-N-methyl-benzenesulfonamide (B60-3)
  • reaction solution was poured into saturated ammonium chloride (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, filtered and concentrated to give a crude compound 2,4-difluoro-3-iodo-N(-((4-methoxyphenyl)methyl))-N-methyl-benzenesulfonamide (B60-3) (4.00 g, yield 96.3%).
  • reaction solution was added to a sodium carbonate solution (200 mL), and then extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine (200 mL), and then dried with sodium sulfate, filtered and concentrated to obtain a crude compound 2,4-difluoro-3-iodo-N-methyl-benzenesulfonamide (B60-4) (2.00 g, yield 90.7%).
  • Step 4 Synthesis of 2-fluoro-3-iodo-N-methyl-4-((-((4-(trifluoromethyl)phenyl))methylamino))benzenesulfonamide (B60-5)
  • Step 5 Synthesis of 2-fluoro-N-methyl-3(-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl))-4((-((4-(trifluoromethyl)phenyl))methylamino))benzenesulfonamide (I-60)
  • the synthetic route is as follows:
  • Step 2 Synthesis of 5-bromo-2-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B61-3)
  • reaction solution was added to sodium carbonate solution (200 mL), then extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, filtered and concentrated to obtain a crude compound 5-bromo-2-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B61-3) (1.00 g, yield 21.6%).
  • Step 3 Synthesis of 2-fluoro-N-methyl-5-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-61)
  • the synthetic route is as follows:
  • Part 1 Add cuprous chloride (142 mg, 1.44 mmol) to water (10.0 mL), control the temperature between -5°C and 5°C, add thionyl chloride (8.58 g, 72.1 mmol) dropwise, and react for 1 hour.
  • Part 2 Add 3-bromo-4,5-difluoroaniline (B62-1) (3.00 g, 14.4 mmol) to concentrated hydrochloric acid (40.0 mL, 12 M) in batches, dissolve sodium nitrite (1.09 g, 15.8 mmol) in hydrochloric acid (6.0 mL, 12 M) and add dropwise to the above reaction solution, control the temperature between -5°C and 5°C during the addition process, and continue stirring for 0.5 hours.
  • reaction solution of the second part was added to the reaction solution of the first part, control the temperature between -5°C and 5°C during the reaction process, and continue stirring the reaction solution for 1 hour.
  • the reaction solution was poured into water (30.0 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 3-bromo-4,5-difluoro-benzenesulfonyl chloride (B62-2) (4.00 g, yield 95.1%).
  • Step 3 Synthesis of 3-bromo-5-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B62-4)
  • reaction solution was added to hydrochloric acid (1 mol/L, 100 mL), then extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude compound 3-bromo-5-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B62-4) (1.50 g, yield 81.0%).
  • Step 5 Synthesis of 3-fluoro-N-methyl-5-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-62)
  • the synthetic route is as follows:
  • Methylamine hydrochloride (821 mg, 12.1 mmol) and triethylamine (2.46 g, 24.3 mmol) were added to dichloromethane (20.0 mL), and then 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4) (3.10 g, 8.11 mmol) was added, and the reaction solution was stirred at 25°C for 4 hours.
  • Step 5 6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (B63-6)
  • 6-Bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5) (1.50 g, 3.98 mmol) and 4-(trifluoromethyl)benzylamine (836 mg, 4.77 mmol) were added to a toluene solution (30.0 mL), and tris(biphenylmethyleneacetone)dipalladium (3.10 g, 8.11 mmol), (1,1'-binaphthyl)-2,2'-di(diphenylphosphine) (99.1 mg, 159 ⁇ mol) and potassium tert-butoxide (669 mg, 5.97 mmol) were added in sequence.
  • reaction solution was stirred at 80 ° C for 8 hours under nitrogen protection.
  • Step 6 (R)-N-methyl-6-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (I-63)
  • 6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (20.0 mg, 47.1 ⁇ mol) was dissolved in toluene (20.0 mL), tetrakis(triphenylphosphine)palladium (544 ⁇ g, 0.471 ⁇ mol), cuprous iodide (897 ⁇ g, 4.71 ⁇ mol) and tributyl-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)stannane (23.3 mg, 56.5 ⁇ mol) were added, and the reaction solution was stirred at 100°C for 6 hours under nitrogen protection.
  • the synthetic route is as follows:
  • Step 1 Synthesis of (1R,5S,6R)-2-oxybicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-2)
  • Step 2 Synthesis of (1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-3)
  • Step 4 Synthesis of ((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B64-5)
  • Step 5 Synthesis of 5-bromo-6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methylpyridine-3-sulfonamide (B64-7)
  • Step 6 Synthesis of 6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-64)
  • 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+200ug/ml Hygromycin as complete medium. Cells in the logarithmic phase were seeded in 384-well plates, 2500 cells/well/35ul, incubated overnight at 37°C, 5% CO 2. On the second day, 5uL of diluted compound was added to each well (the final concentration of DMSO was 0.1%). At the same time, a positive control group with only DMSO added was set up, and the signal value of 2 ⁇ M Okacid acid was used as the signal of the negative control group. Then, it was incubated at 37°C, 5% CO 2 for 48h.
  • luciferase assay system Promega, E2550
  • fluorescence signal value was measured 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, IC50 was calculated using Graphpad 7.0.
  • Inhibition% (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100
  • Table 1 TEADs transcriptional inhibition activity of test compounds in HEK293T-TEAD-LUC reporter cell line cells
  • 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).
  • mice For the pharmacokinetic test in mice, three male ICR mice, 20-25 g, fasted overnight, were administered orally by gavage (10 mg/kg). Blood was collected before and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. The blood samples were centrifuged at 6800g, 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. The plasma at each time point was taken, mixed with 3-5 times the amount of acetonitrile solution containing the internal standard, vortexed for 1 minute, centrifuged at 13,000 rpm and 4°C for 10 minutes, the supernatant was taken, mixed with 3 times the amount of water, and an appropriate amount of the mixed solution was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
  • mice pharmacokinetic test showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drugability.
  • Test Example 4 NCI-H226 mesothelioma mouse tumor efficacy test
  • NCI-H226 cells in the logarithmic phase were resuspended in PBS, and 5 ⁇ 10 6 NCI-H226 cells were inoculated subcutaneously at the right posterior part of the mice at 100 ⁇ L/mouse.
  • the tumor growth was observed regularly.
  • the mice were randomly divided into a model group and a treatment group according to the tumor size and mouse weight. The tumor volume and animal weight were measured and recorded before and during the treatment.
  • the model group was used as the control group, and the tumor growth inhibition effect of the treatment group was statistically analyzed to calculate the TGI.

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Abstract

The present invention provides a compound represented by formula I, and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. As a TEAD inhibitor, the compound can significantly inhibit the activity of TEAD transcription, and can be used for preventing and/or treating diseases related to increased TEAD expression.

Description

TEAD抑制剂TEAD inhibitors
本申请要求享有：This application requires:
于2022年11月10日向中国国家知识产权局提交的，专利申请号为2022114083146，名称为“TEAD抑制剂”的在先申请的优先权；Priority to the prior application for patent application number 2022114083146, entitled “TEAD Inhibitors,” filed with the State Intellectual Property Office of China on November 10, 2022;
于2023年3月10日向中国国家知识产权局提交的，专利申请号为2023102475409，名称为“TEAD抑制剂”的在先申请的优先权；Priority to the prior application for patent application number 2023102475409, entitled “TEAD Inhibitors,” filed with the State Intellectual Property Office of China on March 10, 2023;
该在先申请的全文通过引用的方式结合于本申请中。The entire content of this prior application is incorporated into this application by reference.
技术领域Technical Field
本发明属于医药领域，具体地，本发明涉及到一种TEAD抑制剂及其用途。The present invention belongs to the field of medicine, and specifically, the present invention relates to a TEAD inhibitor and uses thereof.
背景技术Background technique
Hippo信号通路是由一系列激酶级联组成的高度保守的信号通路，参与调节细胞增殖、细胞分化、细胞干性、细胞外间质沉积、损伤修复、器官发育等生理过程。Hippo信号通路被上游的GPCR、机械应力等信号激活后，导致NF2(neurofibromatosis type 2，神经纤维蛋白2)激活MST1/2(Mammalian sterile 20-like kinase 1/2)，MST1/2激活LAST1/2(large tumor suppressor kinase 1/2)，激活的LATS1/2磷酸化YAP(Yes Associated Protein，Yes相关蛋白)/TAZ(Transcriptional coactivator with PDZ-binding motif，带有PDZ结合基序的转录辅助激活因子)，磷酸化的YAP/TAZ定位于细胞质并以泛素依赖的方式降解，而未磷酸化的YAP/TAZ转移到细胞核并与包括TEADs在内的几个核转录因子结合，形成转录复合物，诱导包括CTGF(Connective tissue growth factor，结缔组织生长因子)、Cyr61(Mysteine rich angiogenic inducer 61，富含半胱氨酸的血管生成诱导剂61)和AXL(AXL receptor tyrosine kinase，受体酪氨酸激酶AXL)在内的几个下游靶基因的表达，进而促进了机体的生理病理过程。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. After the Hippo signaling pathway is activated by upstream GPCR, mechanical stress and other signals, NF2 (neurofibromatosis type 2) activates MST1/2 (Mammalian sterile 20-like kinase 1/2), MST1/2 activates LAST1/2 (large tumor suppressor kinase 1/2), and 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.
TEADs/TEAD(Transcriptional Enhanced Associate Domains，转录增强相关结构域)是Hippo信号通路的最终效应器，有四个家族成员，分别为TEAD1、TEAD2、TEAD3和TEAD4，所有TEADs亚型N端都有一个与DNA结合的TEA结构域，在C末端都有一个与YAP/TAZ结合的结构域，DNA结合域和YAP/TAZ结合域在哺乳动物中高度保守，但在连接TEA结构域和反式激活结构域的连接子上有很大的不同，四个TEADs亚型的总体同源性介于61％至73％之间。TEADs的功能由其与核辅助激活因子的相互作用介导，YAP是与TEADs相互作用的主要核辅助激活因子。TEADs/TEAD (Transcriptional Enhanced Associated Domains) are the final effectors of the Hippo signaling pathway. There are four family members, namely 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激活促进肿瘤发展，抑制YAP/TAZ与TEADs的相互作用具有治疗肿瘤的潜力。在一些癌症中，如恶性间皮瘤、卵巢癌和胆管癌，YAP/TAZ-TEADs复合物经常过度激活或过度表达，导致癌症进展。这种过度激活通常是由Hippo信号通路上游基因的改变引起的，尤其在恶性间皮瘤患者中，40％-50％的肿瘤NF2突变或缺失，<25％的肿瘤MST1或LAST1/2突变或缺失，70％的YAP高表达，YAP/TAZ-TEADs复合物的过度激活有助于促进肿瘤细胞的增殖、转移、上皮向间充质转化(EMT)和肿瘤干细胞的维持。YAP和TEADs的相互作用对于启动转录程序以驱动肿瘤发生和增殖至关重要，DNA结合域缺陷的TEADs能够阻断Hippo信号通路上游基因突变介导的肿瘤形成，这表明抑制YAP/TAZ与TEADs的相互作用具有抗肿瘤作用。Invenva Pharma公开的专利表明，抑制YAP/TAZ与TEADs的相互作用后能明显抑制肿瘤细胞的增殖(WO 2017064277)。其他的研究还表明YAP/TAZ-TEADs的下游蛋白CTGF和CYR61能够诱导肿瘤细胞对紫杉醇等化疗药物产生耐药性，YAP/TAZ-TEADs已成为耐药癌细胞的替代生存途径。这些都表明抑制YAP/TAZ与TEADs的相互作用具有治疗肿瘤的潜力，特别是Hippo信号通路上游过度激活或突变的肿瘤。YAP/TAZ-TEADs activation promotes tumor development, and inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, 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. Especially in patients with malignant mesothelioma, 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. 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. Invenva Pharma’s patents show that inhibiting the interaction between YAP/TAZ and TEADs can significantly inhibit the proliferation of tumor cells (WO 2017064277). Other studies have also shown that the downstream proteins CTGF and CYR61 of YAP/TAZ-TEADs can induce tumor cells to develop resistance to chemotherapy drugs such as paclitaxel, and YAP/TAZ-TEADs have become an alternative survival pathway for drug-resistant cancer cells. All of this indicates that inhibiting the interaction between YAP/TAZ and TEADs has the potential to treat tumors, especially tumors with overactivation or mutations in the upstream of the Hippo signaling pathway.
目前一些YAP/TAZ与TEADs相互作用抑制剂(VT-01、IK-930)已进入临床阶段，YAP/TAZ与TEADs相互作用抑制可能是有希望的新型抗肿瘤化疗法。Currently, some 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.
发明内容Summary of the invention
本发明提供了一种式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药；所述化合物作为TEAD抑制剂能明显抑制TEAD转录的活性，可以用于预防和/或治疗与TEAD表达增加相关的疾病。The present invention provides a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; the compound can significantly inhibit the activity of TEAD transcription as a TEAD inhibitor, and can be used to prevent and/or treat diseases related to increased TEAD expression.
在本发明第一方面，提供了一种式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药 学上可接受的盐或前药：In the first aspect of the present invention, there is provided a compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutical compositions, Pharmaceutically acceptable salts or prodrugs:
其中， in,
环A为6-10元芳环、5-10元杂芳环、6-12元双环或8-15元三环；Ring A is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;
环B为6-10元芳环、5-10元杂芳环、6-12元双环或8-15元三环；Ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;
X1、X2、X3各自独立地为N或CRa；X 1 , X 2 , and X 3 are each independently N or CR a ;
W为O、NH；W is O, NH;
L不存在或为-CH2-、-CH2CH2-、-CH2CH2CH2-；L is absent or is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
R1、R2、Ra各自独立地为氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、-SF5、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基；所述C1-C6烷基、C1-C6烷氧基、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基任选地被1、2或3个相同或不同的选自下列的取代基取代：卤素、羟基、氨基、-SF5、C1-C6烷基；R 1 , R 2 , and Ra are each independently hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl are optionally substituted with 1, 2, or 3 identical or different substituents selected from the following: halogen, hydroxyl, amino, -SF 5 , and C 1 -C 6 alkyl;
当R1为多个时，所述R1相同或不同；When R 1 is multiple, the R 1 are the same or different;
当R2为多个时，所述R2相同或不同；When R 2 is multiple, the R 2 are the same or different;
当Ra为多个时，所述Ra相同或不同；When Ra is multiple, the Ra are the same or different;
R3、R4各自独立地选自：氢、C1-C6烷基、C1-C6卤代烷基；R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0、1、2或3。n is 0, 1, 2 or 3.
在一优选实施方式中，为-W-L-为-NH-CH2-或-O-CH2-。In a preferred embodiment, for -WL- is -NH-CH 2 - or -O-CH 2 -.
在一优选实施方式中，环A为6-12元双环饱和碳环；较佳地，环A为 In a preferred embodiment, ring A is a 6-12 membered bicyclic saturated carbocyclic ring; preferably, ring A is
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，环B为6-12元双环或8-15元三环，所述6-12元双环或8-15元三环为5元含N杂芳环并饱和杂环；较佳地，所述6-12元双环或8-15元三环为咪唑并饱和杂环。In a preferred embodiment, ring B is a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring, wherein the 6-12 membered bicyclic ring or the 8-15 membered tricyclic ring is a 5-membered N-containing heteroaromatic ring and a saturated heterocyclic ring; preferably, the 6-12 membered bicyclic ring or the 8-15 membered tricyclic ring is an imidazolyl saturated heterocyclic ring.
在一优选实施方式中，当环B为6-12元双环时，环B为其中，环B’为具有1、2、3或4个选自N、O、S的杂原子的5元杂芳环，当杂原子为多个时，所述杂原子相同或不同；环B”为具有1、2、3或4个选自N、O、S的杂原子的5元或6元饱和杂环，当杂原子为多个时，所述杂原子相同或不同。 In a preferred embodiment, when ring B is a 6-12 membered bicyclic ring, ring B is Wherein, ring B' is a 5-membered heteroaromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, and when there are multiple heteroatoms, the heteroatoms are the same or different; ring B" is a 5-membered or 6-membered saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, and when there are multiple heteroatoms, the heteroatoms are the same or different.
在一优选实施方式中，当环B为6-12元双环时，环B为其中，环B”为具有1、2、3或4个选自N、O、S的杂原子的5元或6元饱和杂环，当杂原子为多个时，所述杂原子相同或不同。In a preferred embodiment, when ring B is a 6-12 membered bicyclic ring, ring B is Wherein, Ring B" is a 5-membered or 6-membered saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different.
在一优选实施方式中，环B为6-12元双环，-L-W-不为-O-或者不为苯环或吡啶。In a preferred embodiment, ring B is a 6-12 membered bicyclic ring, -LW- is not -O- or Not a benzene ring or pyridine.
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，-W-L-为-NH-CH2-、-O-CH2-、-NH-、-O-；较佳地，-L-W-为-NH-CH2-或-O-CH2-。In a preferred embodiment, -WL- is -NH-CH 2 -, -O-CH 2 -, -NH-, or -O-; preferably, -LW- is -NH-CH 2 - or -O-CH 2 -.
在一优选实施方式中，当环B为8-15元三环时，环B为其中环B”’为6-10元并环；较佳地，环B”’为6-10元饱和并环，所述并环任选地含有1、2或3杂原子；较佳地，所述环B为 In a preferred embodiment, when ring B is an 8-15 membered tricyclic ring, ring B is Wherein ring B'' is a 6-10 membered cyclic ring; preferably, ring B'' is a 6-10 membered saturated cyclic ring, the cyclic ring optionally contains 1, 2 or 3 heteroatoms; preferably, the ring B is
在一优选实施方式中，中不含有与氨基酸残基共价结合的基团；较佳地，其中，R2、R3、R4各自独立地为氢或C1-C6烷基；更佳地，R2、R3、R4各自独立地为氢或甲基。In a preferred embodiment, It does not contain a group covalently bonded to an amino acid residue; preferably, R 2 , R 3 , and R 4 are each independently hydrogen or a C 1 -C 6 alkyl group; more preferably, R 2 , R 3 , and R 4 are each independently hydrogen or a methyl group.
在一优选实施方式中，式I所示化合物具有结构：In a preferred embodiment, the compound represented by formula I has the structure:
其中， in,
环A为6-10元芳环、6-10元杂芳环、6-12元双环；Ring A is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, or a 6-12 membered bicyclic ring;
环B为6-10元芳环、6-10元杂芳环、6-12元双环；Ring B is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, or a 6-12 membered bicyclic ring;
X1、X2、X3各自独立地为N或CRa；X 1 , X 2 , and X 3 are each independently N or CRa;
W为O、NH；W is O, NH;
L不存在或为-CH2-、-CH2CH2-、-CH2CH2CH2-；L is absent or is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
R1、R2、Ra各自独立地为氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、-SF5、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基；所述C1-C6烷基、C1-C6烷氧基、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基任选地被1、2或3个相同或不同的选自下列的取代基取代：卤素、羟基、氨基、-SF5、C1-C6烷基；R 1 , R 2 , and Ra are each independently hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl are optionally substituted with 1, 2, or 3 identical or different substituents selected from the following: halogen, hydroxyl, amino, -SF 5 , and C 1 -C 6 alkyl;
当R1为多个时，所述R1相同或不同；When R 1 is multiple, the R 1 are the same or different;
当R2为多个时，所述R2相同或不同；When R 2 is multiple, the R 2 are the same or different;
当Ra为多个时，所述Ra相同或不同；When Ra is multiple, the Ra are the same or different;
R3、R4各自独立地选自：氢、C1-C6烷基、C1-C6卤代烷基；R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0、1、2或3。 n is 0, 1, 2 or 3.
在一优选实施方式中，所述式I所示化合物满足以下一个或多个条件：In a preferred embodiment, the compound represented by formula I satisfies one or more of the following conditions:
i)R1为-SF5；i) R 1 is -SF 5 ;
ii)X1、X2为N；ii) X 1 and X 2 are N;
iii)环A为6-12元(较佳地为6或7元)双环；iii) Ring A is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;
iv)环B为6-12元双环，且-L-W-不为-O-；iv) Ring B is a 6-12 membered bicyclic ring, and -L-W- is not -O-;
在一优选实施方式中，所述环A为饱和碳环；较佳地，所述环A为并环或螺环。In a preferred embodiment, the ring A is a saturated carbocyclic ring; preferably, the ring A is a bis-cyclic ring or a spirocyclic ring.
在一优选实施方式中，环B为其中，环B’为具有1、2、3或4个选自N、O、S的杂原子的芳环，当杂原子为多个时，所述杂原子相同或不同；In a preferred embodiment, Ring B is Wherein, ring B' is an aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O, and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
环B”为具有1、2、3或4个(较佳地为1或2个)选自N、O、S的杂原子的饱和、不饱和或部分不饱和的杂环，当杂原子为多个时，所述杂原子相同或不同。Ring B" is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 (preferably 1 or 2) heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms may be the same or different.
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有式II所示结构
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure of formula II
其中，R21、R22各自独立地选自：氢、C1-C6烷基、C1-C6卤代烷基；或者，Wherein, R 21 and R 22 are each independently selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; or,
R21、R22与它们共同连接的咪唑一起形成环B”；环B”为具有1、2、3或4个选自N、O、S的杂原子的饱和、不饱和或部分不饱和的杂环，当杂原子为多个时，所述杂原子相同或不同；R 21 , R 22 and the imidazole to which they are commonly connected together form a ring B"; the ring B" is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
所述环B”任选地被1、2或3个相同或不同的R2取代；所述R2选自卤素、C1-C6烷基、C1-C6卤代烷基。The ring B" is optionally substituted by 1, 2 or 3 identical or different R2 ; the R2 is selected from halogen, C1 - C6 alkyl, C1 - C6 haloalkyl.
在一优选实施方式中，式II所示化合物满足以下一个或多个条件：In a preferred embodiment, the compound represented by formula II satisfies one or more of the following conditions:
i)R1为-SF5；i) R 1 is -SF 5 ;
ii)X1、X2为N；ii) X 1 and X 2 are N;
iii)环A为6-12元(较佳地为6或7元)双环；iii) Ring A is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;
iv)R2、R3与它们共同连接的基团一起形成环B”，且-L-W-不为-O-；iv) R 2 , R 3 and the group to which they are commonly attached together form a ring B″, and -LW- is not -O-;
v)R1为氟代甲基、氟代乙基、氟代丙基；较佳地，所述氟代甲基为-CF3、CH2F、CHF2；v) R 1 is fluoromethyl, fluoroethyl, or fluoropropyl; preferably, the fluoromethyl is -CF 3 , CH 2 F, or CHF 2 ;
vi)环A为苯环；vi) Ring A is a benzene ring;
vii)R21为甲基，R22为H；vii) R 21 is methyl, R 22 is H;
viii)-W-L-为-NH-CH2-。viii) -WL- is -NH-CH 2 -.
在一优选实施方式中，所述环A为饱和碳环；较佳地，所述环A为并环或螺环。In a preferred embodiment, the ring A is a saturated carbocyclic ring; preferably, the ring A is a bis-cyclic ring or a spirocyclic ring.
在一优选实施方式中，基团为 In a preferred embodiment, the group for
在一优选实施方式中，所述环A为 In a preferred embodiment, the ring A is
在一优选实施方式中，所述环A为 In a preferred embodiment, the ring A is
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
较佳地，R1各自独立地为F或甲基。Preferably, R 1 is independently F or methyl.
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，R1为F或甲基。In a preferred embodiment, R 1 is F or methyl.
在一优选实施方式中，X1、X2为N。In a preferred embodiment, X 1 and X 2 are N.
在一优选实施方式中，X1为CRa，X2为N。In a preferred embodiment, X1 is CRa and X2 is N.
在一优选实施方式中，X1、X2为CRa。In a preferred embodiment, X 1 and X 2 are CRa.
在一优选实施方式中，Ra为氢。In a preferred embodiment, Ra is hydrogen.
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有式Ia所示结构
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in formula Ia
较佳地，X1、X2为N；Preferably, X 1 and X 2 are N;
较佳地，X1为CH，X2为N；Preferably, X1 is CH, X2 is N;
较佳地，X1、X2为CH。Preferably, X 1 and X 2 are CH.
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有式Ib所示结构
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has the structure shown in formula Ib
较佳地，X1、X2为N；Preferably, X 1 and X 2 are N;
较佳地，X1为CH，X2为N；Preferably, X1 is CH, X2 is N;
较佳地，X1、X2为CH。Preferably, X 1 and X 2 are CH.
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有式Ic所示结构
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has a structure shown in formula Ic
在一优选实施方式中，X1、X2为N。In a preferred embodiment, X 1 and X 2 are N.
在一优选实施方式中，X1为CH，X2为N。In a preferred embodiment, X1 is CH and X2 is N.
在一优选实施方式中，X1、X2为CH。In a preferred embodiment, X 1 and X 2 are CH.
在一优选实施方式中，R2为甲基、乙基、丙基、卤代甲基、卤代乙基、卤代丙基。In a preferred embodiment, R 2 is methyl, ethyl, propyl, halomethyl, haloethyl, or halopropyl.
在一优选实施方式中，R2为甲基。In a preferred embodiment, R2 is methyl.
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有式Ic-1、式Ic-2或式Ic-3所示结构

In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has a structure shown in formula Ic-1, formula Ic-2 or formula Ic-3

在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，R1为F或-CH3。In a preferred embodiment, R 1 is F or -CH 3 .
在一优选实施方式中，环B”为5或6元饱和杂环，所述杂原子选自N或O。In a preferred embodiment, Ring B" is a 5- or 6-membered saturated heterocyclic ring, wherein the heteroatom is selected from N or O.
在一优选实施方式中，基团选自 In a preferred embodiment, the group Selected from
较佳地，为 Preferably, for
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有结构Id
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has structure Id
较佳地，X1为N，X2为CH，R2为甲基、乙基或丙基，W为O、NH；Preferably, X1 is N, X2 is CH, R2 is methyl, ethyl or propyl, and W is O or NH;
较佳地，R2为甲基；Preferably, R 2 is methyl;
较佳地，L为-CH2-；Preferably, L is -CH 2 -;
较佳地，为 Preferably, for
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有结构If
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has structure If
其中，R1、R2、W、L的定义如上所述；Wherein, R 1 , R 2 , W, and L are as defined above;
较佳地，R1为氟代甲基、氟代乙基、氟代丙基；较佳地，所述氟代甲基为-CF3、CFH2、CF2H；Preferably, R 1 is fluoromethyl, fluoroethyl, fluoropropyl; preferably, the fluoromethyl is -CF 3 , CFH 2 , CF 2 H;
较佳地，环A为苯环；Preferably, ring A is a benzene ring;
较佳地，R21为甲基，R22为H；Preferably, R 21 is methyl, and R 22 is H;
较佳地，-W-L-为-NH-CH2-；Preferably, -WL- is -NH-CH 2 -;
较佳地，为 Preferably, for
在一优选实施方式中，W为O或-NH-，L不存在或为-CH2。In a preferred embodiment, W is O or -NH-, and L is absent or is -CH 2 .
在一优选实施方式中，W为O，L不存在。In a preferred embodiment, W is O and L is absent.
在一优选实施方式中，W为O，L为-CH2-。In a preferred embodiment, W is O and L is -CH 2 -.
在一优选实施方式中，W为-NH-，L不存在。In a preferred embodiment, W is -NH- and L is absent.
在一优选实施方式中，W为-NH-，L为-CH2-。In a preferred embodiment, W is -NH- and L is -CH 2 -.
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有结构Ie
In a preferred embodiment, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has structure Ie
其中，为8-15元三环。in, It is a 8-15 membered tricyclic ring.
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，为 In a preferred embodiment, for
在一优选实施方式中，，选自： 较佳地，为 In a preferred embodiment, Selected from: Preferably, for
在一优选实施方式中，所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，选自：




In a preferred embodiment, the compound represented by Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from:




在一优选实施方式中，所述“与氨基酸残基共价结合的基团”是指能够共价结合存在于靶蛋白(例如TEAD)结合口袋中的氨基酸残基(例如半胱氨酸、赖氨酸、组氨酸或其他能够被共价修饰的残基)，从而不可逆地抑制蛋白质。在一些实施方案中，是指能够共价结合hTEAD1的Cys359、hTEAD1的Cys405、hTEAD2的Cys380、hTEAD3的Cys368和/或hTEAD4的Cys367的基团。在一些实施例中，是指能够共价结合hTEAD1的Ser356、hTEAD2的Ser345和/或Ser377、hTEAD3的Ser365和/或hTEAD4的Ser364的基团。在一些实施方案中，是指能够共价结合hTEAD1的Lys336、hTEAD2的Lys357、hTEAD3的Lys345和/或hTEAD4的Lys344的基团。In a preferred embodiment, the "group covalently bound to an amino acid residue" refers to an amino acid residue (e.g., cysteine, lysine, histidine or other residues that can be covalently modified) that can covalently bind to the binding pocket of the target protein (e.g., TEAD), thereby irreversibly inhibiting the protein. In some embodiments, it refers to a group that can covalently bind to Cys359 of hTEAD1, Cys405 of hTEAD1, Cys380 of hTEAD2, Cys368 of hTEAD3, and/or Cys367 of hTEAD4. In some embodiments, it refers to a group that can covalently bind to Ser356 of hTEAD1, Ser345 and/or Ser377 of hTEAD2, Ser365 of hTEAD3, and/or Ser364 of hTEAD4. In some embodiments, it refers to a group that can covalently bind to Lys336 of hTEAD1, Lys357 of hTEAD2, Lys345 of hTEAD3, and/or Lys344 of hTEAD4.
在一优选实施方式中，所述“与氨基酸残基共价结合的基团”含有“离去基团”，所述离去基团为经历亲核置换的基团，包括但不限于含有卤素、烯基、炔基、硝基、氧代的基团。合适的离去基团在本领域中是众所周知的,例如,参见“Advanced Organic Chemistry”,Jerry March,5th Ed.,pp.351-357,John Wiley and Sons,N.Y.。这样的离去基团包括但不限于卤素、烷氧基、磺酰氧基、任选取代的烷基磺酰氧基、任选取代的烯基磺酰氧基、任选取代的芳基磺酰氧基、酰基和重氮部分。合适的离去基团的实例包括但不限于氯、碘、溴、氟、乙酰氧基、甲磺酰氧基(甲磺酰氧基)、甲苯磺酰氧基、三甲磺酰氧基、硝基-苯基磺酰氧基(nosyloxy)和溴-苯基磺酰氧基(brosyloxy)、氧代、NO2、CN、-NHC(O)CH＝CH2、-C(O)CH＝CH2、-CH2CH＝CH2、-C(O)OCH2Cl、-C(O)OCH2F、-C(O)OCH2CN、-C(O)CH2Cl、-C(O)CH2F、-C(O)CH2CN、-CH2C(O)CH3、-S(O)2-F、-O-吡啶基、-O-嘧啶基、-O-CF3、取代的(例如)。In a preferred embodiment, the "group covalently bound to the amino acid residue" contains a "leaving group", which is a group that undergoes nucleophilic displacement, including but not limited to groups containing halogen, alkenyl, alkynyl, nitro, and oxo. Suitable leaving groups are well known in the art, for example, see "Advanced Organic Chemistry", Jerry March, 5th Ed., pp.351-357, John Wiley and Sons, NY. Such leaving groups include but are not limited to halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl and diazo moieties. Examples of suitable leaving groups include, but are not limited to, chloro, iodo, bromo, fluoro, acetoxy, methanesulfonyloxy (mesyloxy), toluenesulfonyloxy, trismethylsulfonyloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy), oxo, NO2 , CN, -NHC(O)CH= CH2 , -C(O)CH= CH2 , -CH2CH=CH2, -C(O) OCH2Cl , -C (O) OCH2F , -C(O)OCH2CN, -C(O ) CH2Cl, -C(O) CH2F , -C(O) CH2CN , -CH2C (O) CH3 , -S(O) 2 -F, -O-pyridyl, -O-pyrimidinyl, -O- CF3 , substituted (For example ).
典型的非“离去基团”为烷基，如甲基。例如 不属于“与氨基酸残基共价结合的基团”。Typical non-"leaving groups" are alkyl groups, such as methyl. It does not belong to the category of “groups covalently bonded to amino acid residues”.
本发明第二方面，提供了一种药物组合物，包括如第一方面任一所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，和药学上可接受的载体。In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I as described in any one of the first aspects, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier.
本发明第三方面，提供了一种如第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或如第二方面所述的药物组合物的用途，包括：The third aspect of the present invention provides a use of the compound of formula I as described in the first aspect, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the use of the pharmaceutical composition as described in the second aspect, comprising:
制备用于预防和/或治疗与TEAD表达增加相关的疾病的药物、药物组合物或制剂；和/或，Preparation of a medicament, pharmaceutical composition or formulation for preventing and/or treating a disease associated with increased TEAD expression; and/or,
制备用于降低/抑制TEAD表达、TEAD活性增加的药物、药物组合物或制剂；和/或，Preparing a drug, pharmaceutical composition or formulation for reducing/inhibiting TEAD expression or increasing TEAD activity; and/or,
制备用于降低/抑制Hippo信号通路的药物、药物组合物或制剂；Preparing a drug, pharmaceutical composition or preparation for reducing/inhibiting the Hippo signaling pathway;
在一优选实施方式中，所述TEAD包括：TEAD1、TEAD2、TEAD3和TEAD4。 In a preferred embodiment, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4.
在一优选实施方式中，所述疾病是细胞增殖性病症。In a preferred embodiment, the disease is a cell proliferative disorder.
在一优选实施方式中，所述细胞增殖性病症为癌症。In a preferred embodiment, the cell proliferative disorder is cancer.
在一优选实施方式中，所述癌症选自：间皮瘤、卵巢癌、胆管癌、血液癌、淋巴瘤、骨髓瘤、白血病、神经系统癌症、皮肤癌、乳腺癌、前列腺癌、结直肠癌、肺癌、头颈癌、胃肠道癌、肝癌、胰腺癌、泌尿生殖系统癌、骨癌、肾癌和血管癌。In a preferred embodiment, the cancer is selected from the group consisting of mesothelioma, ovarian cancer, bile duct cancer, blood cancer, lymphoma, myeloma, leukemia, nervous system cancer, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer and vascular cancer.
本发明还提供一种治疗疾病的方法，包括给与患者治疗有效量的式(I)所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐、前药或所述药物组合物中的至少一种。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 represented by formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs or pharmaceutical compositions.
在本发明一优选实施方式中，所述疾病为与TEAD表达增加相关的疾病。所述TEAD包括：TEAD1、TEAD2、TEAD3和TEAD4。In a preferred embodiment of the present invention, the disease is a disease associated with increased TEAD expression. The TEAD includes: TEAD1, TEAD2, TEAD3 and TEAD4.
在一优选实施方式中，所述癌症选自：间皮瘤、卵巢癌、胆管癌、血液癌、淋巴瘤、骨髓瘤、白血病、神经系统癌症、皮肤癌、乳腺癌、前列腺癌、结直肠癌、肺癌、头颈癌、胃肠道癌、肝癌、胰腺癌、泌尿生殖系统癌、骨癌、肾癌和血管癌。In a preferred embodiment, the cancer is selected from the group consisting of mesothelioma, ovarian cancer, bile duct cancer, blood cancer, lymphoma, myeloma, leukemia, nervous system cancer, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer and vascular cancer.
在本发明一优选实施方式中，所述疾病是细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。In a preferred embodiment of the present invention, the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
在一些实施方案中，所述患者哺乳动物，优选是人。In some embodiments, the patient is a mammal, preferably a human.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.
有益效果Beneficial Effects
本发明人经过广泛而深入地研究，意外地开发了一种新的TEAD抑制剂，特别是一种不含有与氨基酸残基共价结合的基团的TEAD抑制剂；所述TEAD抑制剂能明显抑制TEAD转录的活性，可以用于预防和/或治疗与TEAD表达增加相关的疾病；所述TEAD抑制剂具有优良的药代动力学性质，成药性良好，具有显著的抑制NCI-H226间皮瘤生长的作用。After extensive and in-depth research, the inventors unexpectedly developed a new TEAD inhibitor, in particular a TEAD inhibitor that does not contain a group covalently bound to an amino acid residue; the TEAD inhibitor can significantly inhibit the activity of TEAD transcription and can be used to prevent and/or treat diseases associated with increased TEAD expression; the TEAD inhibitor has excellent pharmacokinetic properties, good drugability, and has a significant effect of inhibiting the growth of NCI-H226 mesothelioma.
术语定义与说明Definition and explanation of terms
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combinations and combinations shall fall within the scope of the description of this application.
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular form used in this specification and claims includes the plural form of the referred thing. It should also be noted that unless otherwise stated, the "or" and "or" used mean "and/or". In addition, the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。Definitions of standard chemical terms can be found in the references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are used. Unless specific definitions are provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, 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. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。如本文所用，表示基团的连接位点。如本文所用，“R1”、“R1”和“R1”的含义相同，可相互替换。对于R2等其它其他符号，类似定义的含义相同。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 . As used herein, Indicates the attachment site of a group. As used herein, "R 1 ", "R1" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R 2 , similar definitions have the same meaning.
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。 The section headings used herein are only for the purpose of organizing the article and should not be interpreted as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference in their entirety.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～5的整数”应当理解为记载了0、1、2、3、4和5的每一个整数。When the numerical range described in the specification and claims of this application is understood as an "integer", it should be understood that the two endpoints of the range and each integer in the range are recorded. For example, "an integer from 0 to 5" should be understood as recording each integer of 0, 1, 2, 3, 4 and 5.
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘。As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, iodine.
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。如本文所用，术语“烯基”表示无支链或支链的单价烃链，其含有一个或多个碳-碳双键。如本文所用，术语“炔基”是指无支链或支链的一价烃链，其含有一个或多个碳-碳三键。As used herein, the term "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. Examples of 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). As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
在单独或作为其他取代基一部分时，术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。术语“C1-C3烷基”应理解为表示具有1、2或3个碳原子的直链或支链饱和一价烃基。特别地，所述基团具有1、2或3个碳原子(“C1-C3烷基”)，例如甲基、乙基、正丙基或异丙基。The term "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, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof. The term "C 1 -C 3 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2 or 3 carbon atoms. In particular, said radical has 1, 2 or 3 carbon atoms ("C 1 -C 3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.
在单独或作为其他取代基一部分时，术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“Cm-Cn环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-10元环烷基”或者“C3-C10环烷基”是指含有3至10个碳原子的环状烷基，它可能包含1至3个环。所述环状烷基包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中，环烷基可以是与芳基或杂芳基稠合的环烷基。When alone or as part of other substituents, the term "cycloalkyl" or "carbocyclyl" refers to a cyclic alkyl group. The term "mn-membered cycloalkyl" or "C m -C n cycloalkyl" should be understood to mean a saturated, unsaturated or partially saturated carbocyclic ring having m to n atoms. For example, "3-10-membered cycloalkyl" or "C 3 -C 10 cycloalkyl" refers to a cyclic alkyl group containing 3 to 10 carbon atoms, which may contain 1 to 3 rings. The cyclic alkyl group includes a monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring. The cycloalkyl group may be substituted by one or more substituents. In some embodiments, the cycloalkyl group may be a cycloalkyl group fused to an aryl or heteroaryl group.
在单独或作为其他取代基一部分时，术语“杂环烷基”、“杂环”或“杂环基”是指其中一个或多个(在一些实施方案中为1、2或3个)碳原子被杂原子取代的环烷基，所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的环。例如，术语“5-10元杂环烷基”应理解为表示具有5至10个原子的饱和、不饱和或部分饱和的环。在一些实施方案中，杂环烷基可以是与芳基或杂芳基稠合的杂环烷基。The term "heterocycloalkyl", "heterocycle" or "heterocyclyl" when alone or as part of another substituent refers to a cycloalkyl in which one or more (in some embodiments 1, 2 or 3) carbon atoms are replaced by heteroatoms, such as but not limited to N, O, S and P. The term "m-n membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms. For example, the term "5-10 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 5 to 10 atoms. In some embodiments, the heterocycloalkyl can be a heterocycloalkyl fused to an aryl or heteroaryl group.
在单独或作为其他取代基一部分时，术语“杂芳环基”或“杂芳环”是指单环或多环芳环系统，在某些实施方案中，环系统中1至3个原子是杂原子，即除碳以外的元素，包括但不限于N，O、S或P。例如呋喃基，咪唑基，二氢吲哚基，吡咯烷基，嘧啶基，四唑基，噻吩基，吡啶基，吡咯基，N-甲基吡咯基，喹啉基和异喹啉基。杂芳环基可任选与苯环稠合，也可以是包括单环、二环、三环、螺环或桥环。The term "heteroaromatic ring group" or "heteroaromatic ring" 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. For example, furanyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, 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.
在单独或作为其他取代基一部分时，术语“卤代”可与术语“卤素取代”互换使用。“卤代烷基”或“卤素取代的烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。The term "halo" can be used interchangeably with the term "halogen-substituted" when used alone or as part of other substituents. "Haloalkyl" or "halogen-substituted alkyl" refers to saturated aliphatic hydrocarbon groups including branched and straight chains having a specific number of carbon atoms, substituted with one or more halogens (such as -CvFw, where v = 1 to 3, w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
术语“双环”或“二环”是指共用一个或多个原子的两个环，包括螺环或并环。The term "bicyclic" or "bicyclic ring" refers to two rings that share one or more atoms, including spiro or fused rings.
在单独或作为其他取代基一部分时，术语“螺环”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基。螺环烷基的非限制性实例包括：
When alone or as part of other substituents, the term "spiro" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. According to the number of spiro atoms shared between the rings, spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl, preferably monospiroalkyl. Non-limiting examples of spiroalkyl groups include:
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:
术语“并环”指两个单环之间共用2个或2个以上原子(称螺原子)，其可以含有一个或多个双键。所述单环可以是饱和、不饱和或部分不饱和的环。所述单环可以是碳环基、杂环烷基或杂芳基。The term "paracyclic" refers to two monocyclic rings sharing two or more atoms (called spiro atoms), which may contain one or more double bonds. The monocyclic ring may be a saturated, unsaturated or partially unsaturated ring. The monocyclic ring may be a carbocyclic group, a heterocyclic alkyl group or a heteroaryl group.
本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。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 amido 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.
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "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.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。"Pharmaceutically acceptable acid addition salts" refer 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" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, 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.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。Depending on the choice of starting materials and methods, 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. When describing optically active compounds, 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.
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985,62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "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. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In this application, "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.
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "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.
在本申请中，术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。In the present application, the term "solvate" means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.
在本申请中，术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。In the present application, the term "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. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成 的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as deuterium ( 2H ), tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). The total isotopic composition of the compounds of the present invention is Any transformation, whether radioactive or not, is included within the scope of the present invention.
在本申请中，术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。In this application, the term "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.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, i.e. arresting its development;
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or
(iv)减轻该疾病或病症所造成的症状。(iv) alleviating the symptoms caused by the disease or condition.
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。本发明各步反应优选地在惰性溶剂中进行，所述惰性溶剂包括但不限于：甲苯、苯、水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。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. After the reaction of each step is completed, 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, and 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.
具体实施方式Detailed ways
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。The present invention is further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. On the basis of a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solution of the present invention, and such changes should be deemed to be included in the scope of protection of the present invention.
中间体A1的制备
Preparation of intermediate A1
将5-溴-6-氯吡啶-3-磺酰氯(10.0g,34.4mmol)溶于二氯甲烷(50mL)，加入N,N-二异丙基乙胺(8.89g,68.8mmol)，氮气保护，0℃加入1-(4-甲氧基苯基)-N-甲基甲胺(5.20g,34.4mmol)，再室温搅拌2小时。反应液用水(20mL×2)洗涤，收集有机相并浓缩，得到粗品用石油醚/乙酸乙酯(120mL,V：V＝10:1)打浆，过滤收集滤饼，真空干燥后得到化合物5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A1)(11.86g，产率：85.0％)。5-Bromo-6-chloropyridine-3-sulfonyl chloride (10.0 g, 34.4 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (8.89 g, 68.8 mmol) was added. Under nitrogen protection, 1-(4-methoxyphenyl)-N-methylmethylamine (5.20 g, 34.4 mmol) was added at 0°C, and then stirred at room temperature for 2 hours. The reaction solution was washed with water (20 mL × 2), and the organic phase was collected and concentrated to obtain a crude product. It was slurried with petroleum ether/ethyl acetate (120 mL, V: V = 10: 1), and the filter cake was collected by filtration. After vacuum drying, the compound 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A1) (11.86 g, yield: 85.0%) was obtained.
LC-MS,M/Z(ESI):405.1[M+H]+。LC-MS, M/Z (ESI): 405.1 [M+H] + .
中间体A2的制备
Preparation of intermediate A2
第一步：(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)和(1R,3r,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2b)合成
Step 1: Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) and (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2b)
将环戊-3-烯-1-甲酸甲酯(10.0g,79.3mmol)溶解在四氢呋喃(100mL)中，加入碘化钠(6g,40.0mmol)，再加入(三氟甲基)三甲基硅烷(28.2g,198.3mmol)，回流反应过夜。反应结束后，反应液浓缩，残留物溶于二氯甲烷(100mL)，依次用硫代硫酸钠溶液(0.1M,50mL)洗涤、无水硫酸钠干燥，有机相浓缩,粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯(V/V)＝49:1)，分别得到(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)(9.06g，收率64.9％)和(1R,3r,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2b)(2.46g，收率17.6％)。Methyl cyclopent-3-ene-1-carboxylate (10.0 g, 79.3 mmol) was dissolved in tetrahydrofuran (100 mL), sodium iodide (6 g, 40.0 mmol) was added, and (trifluoromethyl)trimethylsilane (28.2 g, 198.3 mmol) was added, and the mixture was refluxed for reaction overnight. After the reaction, the reaction solution was concentrated, and the residue was dissolved in dichloromethane (100 mL), washed with sodium thiosulfate solution (0.1 M, 50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 49:1) to obtain (1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) (9.06 g, yield 64.9%) and (1R, 3r, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2b) (2.46 g, yield 17.6%), respectively.
A2-2a:1H NMR(600MHz,CDCl3)δ3.68(s,3H),2.88–2.79(m,1H),2.31–2.19(m,4H),2.03–1.98(m,2H).A2-2a: 1 H NMR (600 MHz, CDCl3) δ 3.68 (s, 3H), 2.88–2.79 (m, 1H), 2.31–2.19 (m, 4H), 2.03–1.98 (m, 2H).
A2-2b：1H NMR(600MHz,CDCl3)δ3.66(s,3H),3.17–3.10(m,1H),2.40–2.26(m,4H),2.05–1.97(m,2H).A2-2b: 1 H NMR (600 MHz, CDCl3) δ 3.66 (s, 3H), 3.17–3.10 (m, 1H), 2.40–2.26 (m, 4H), 2.05–1.97 (m, 2H).
第二步：(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酰胺(A2-3)的合成
Step 2: Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxamide (A2-3)
将(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)(1.0g,5.7mmol)溶解在氨甲醇溶液(10mL,7M)中，室温搅拌两天。反应结束后，将反应液浓缩，得白色固体粗品(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酰胺(A2-3)(0.91g，收率99.0％)，直接用于下一步反应。Dissolve (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) (1.0 g, 5.7 mmol) in ammonia methanol solution (10 mL, 7 M) and stir at room temperature for two days. After the reaction, the reaction solution was concentrated to obtain a white solid crude product (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxamide (A2-3) (0.91 g, yield 99.0%), which was directly used in the next step.
第四步：((1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲胺(A2-4)的合成
Step 4: Synthesis of ((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methylamine (A2-4)
将(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酰胺(A2-3)(0.9g,5.6mmol)溶解在无水四氢呋喃(10mL)中，氩气保护，0℃加入四氢铝锂(0.43g,11.2mmol),再回流反应过夜。反应结束后，冷却至室温，0℃加水(1mL)淬灭，搅拌15分钟，再加15％氢氧化钠水溶液(0.5mL)，室温搅拌15分钟，过滤，滤饼用乙酸乙酯(50mL)洗涤，收集滤液，用无水硫酸钠干燥，浓缩，得黄色油状粗品((1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲胺(A2-4)(0.6g，收率73.2％)，直接用于下一步反应。(1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxamide (A2-3) (0.9 g, 5.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (0.43 g, 11.2 mmol) was added at 0°C under argon protection, and the reaction was refluxed overnight. After the reaction was completed, it was cooled to room temperature, quenched with water (1 mL) at 0°C, stirred for 15 minutes, and then 15% sodium hydroxide aqueous solution (0.5 mL) was added, stirred at room temperature for 15 minutes, filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was collected, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily crude product ((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methylamine (A2-4) (0.6 g, yield 73.2%), which was directly used in the next step.
第五步：5-溴-6-((((1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺胺(A2)的合成
Step 5: Synthesis of 5-bromo-6-((((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A2)
将5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A2-4)(182mg,0.45mmol)溶于二甲基亚砜(2mL)中，加入((1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲胺(66mg，0.45mmol)与N,N-二异丙基乙胺(174mg，1.35mmol)，微波120℃反应1小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:2)，得到5-溴-6-((((1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺胺(A2)(100mg，产率43.0％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A2-4) (182 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), ((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methanamine (66 mg, 0.45 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added, and the mixture was reacted at 120 ° C for 1 hour. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:2) to obtain 5-bromo-6-((((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A2) (100 mg, yield 43.0%).
LC-MS,M/Z(ESI):517.1[M+H]+ LC-MS, M/Z(ESI):517.1[M+H] +
中间体A3的制备
Preparation of intermediate A3
参考中间体A2的方法，将(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)替换为(1R,3r,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2b)制备得到中间体A3。Referring to the method of intermediate A2, (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) was replaced with (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2b) to prepare intermediate A3.
中间体A4的制备Preparation of intermediate A4
合成路线如下所示：
The synthetic route is as follows:
第一步：(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸(A4-1)的合成
Step 1: Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (A4-1)
将(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)(1.0g,5.7mmol)溶解于四氢呋喃(5mL)中，加入氢氧化锂(682.6mg,28.5mmol)与水(5mL)，再加入甲醇(5mL)，室温搅拌过夜。反应结束后，反应液减压浓缩，残留物中加入水(5mL)，然后用稀盐酸(2mol/L)调节溶液pH至6，随后用乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，得到化合物(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸(A4-1)(0.8g，产率87.0％)。(1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) (1.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide (682.6 mg, 28.5 mmol) and water (5 mL) were added, and methanol (5 mL) was added, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (5 mL) was added to the residue, and then the pH of the solution was adjusted to 6 with dilute hydrochloric acid (2 mol/L), followed by extraction with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound (1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (A4-1) (0.8 g, yield 87.0%).
1H NMR(400MHz,CDCl3)δ10.46(s,1H),2.94–2.80(m,1H),2.37–2.16(m,4H),2.08–1.96(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.46 (s, 1H), 2.94–2.80 (m, 1H), 2.37–2.16 (m, 4H), 2.08–1.96 (m, 2H).
第二步：((1R,3s,5S)-6,6-二氟双环[3.1.0]己-3-基)氨基甲酸叔丁酯(A4-2)的合成
Step 2: Synthesis of tert-butyl ((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)carbamate (A4-2)
将(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸(A4-1)(0.8g,4.9mmol)与三乙胺(595mg,5.9mmol)加至叔丁醇(20mL)中，加入叠氮磷酸二苯酯(1.48g,5.4mmol)，回流反应过夜。反应结束后，冷却至室温，浓缩，再加乙酸乙酯(50mL)溶解，用碳酸氢钠溶液(1M,60mL)洗涤，无水硫酸钠干燥有机相，有机相浓缩得粗品((1R,3s,5S)-6,6-二氟双环[3.1.0]己-3-基)氨基甲酸叔丁酯(A4-2)，直接用于下一步反应。(1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid (A4-1) (0.8 g, 4.9 mmol) and triethylamine (595 mg, 5.9 mmol) were added to tert-butyl alcohol (20 mL), and diphenylphosphoryl azide (1.48 g, 5.4 mmol) was added, and the mixture was refluxed for overnight reaction. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and dissolved in ethyl acetate (50 mL), washed with sodium bicarbonate solution (1M, 60 mL), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the crude product (tert-butyl ((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)carbamate (A4-2), which was directly used in the next step reaction.
第三步：(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-胺盐酸盐(A4-3)的合成
Step 3: Synthesis of (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-amine hydrochloride (A4-3)
将((1R,3s,5S)-6,6-二氟双环[3.1.0]己-3-基)氨基甲酸叔丁酯(A4-2)(1.15g,4.9mmol)溶解于盐酸二氧六环(20mL,4M)中，室温搅拌2小时。反应结束后，浓缩，浓缩得白色固体粗品(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-胺盐酸盐(A4-3)(0.83g，收率100％)，直接用于下一步反应。Dissolve ((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)carbamic acid tert-butyl ester (A4-2) (1.15 g, 4.9 mmol) in dioxane hydrochloride (20 mL, 4 M) and stir at room temperature for 2 hours. After the reaction is completed, concentrate to obtain a white solid crude product (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-amine hydrochloride (A4-3) (0.83 g, yield 100%), which is directly used in the next step.
第四步：5-溴-6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A4)的合成
Step 4: Synthesis of 5-bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A4)
将5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A4-3)(182mg,0.45mmol)溶于二甲基亚砜(2mL)中，加入粗品(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-胺盐酸盐(84.8mg，0.5mmol)与N,N-二异丙基乙胺(174mg，1.35mmol)，反应液在微波120℃下反应1.5小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝4:1)，得到化合物5-溴-6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A4)(145mg，产率64.2％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A4-3) (182 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and crude (1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-amine hydrochloride (84.8 mg, 0.5 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added, and the reaction solution was reacted at 120 ° C in a microwave for 1.5 hours. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=4:1) to obtain compound 5-bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A4) (145 mg, yield 64.2%).
LC-MS,M/Z(ESI):502.1[M+H]+ LC-MS, M/Z(ESI):502.1[M+H] +
中间体A5的制备
Preparation of intermediate A5
参考中间体A4的方法，将(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)替换为(1R,3r,5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2b)制备得到中间体A5。Referring to the method of intermediate A4, (1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) was replaced with (1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2b) to prepare intermediate A5.
中间体A6的制备

Preparation of intermediate A6

第一步：3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(A6-2)的合成
Step 1: Synthesis of 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A6-2)
在0℃氮气保护下，向1-(4-甲氧基苯基)-N-甲基甲胺(6.63g,43.9mmol)和二异丙基乙胺(9.58mL,54.8mmol)的二氯甲烷(100ml)溶液中滴加3-溴-4-氟苯-1-磺酰氯(A6-1)(10g,36.6mmol)。反应混合物在氮气保护0℃下搅拌0.5小时。然后升温到25℃氮气保护下搅拌2小时。反应结束后，反应液用100mL二氯甲烷稀释，有机相用盐酸水溶液洗(0.5M,150mL)，收集有机相，用无水Na2SO4干燥，过滤，浓缩得到粗品，粗品用石油醚/甲基叔丁基醚(10/1,v/v)(100mL)打浆得到3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(A6-2)(12g,收率70.6％)。Under nitrogen protection at 0°C, 3-bromo-4-fluorobenzene-1-sulfonyl chloride (A6-1) (10 g, 36.6 mmol) was added dropwise to a solution of 1-(4-methoxyphenyl)-N-methylmethylamine (6.63 g, 43.9 mmol) and diisopropylethylamine (9.58 mL, 54.8 mmol) in dichloromethane (100 ml). The reaction mixture was stirred at 0°C under nitrogen protection for 0.5 hours. Then the temperature was raised to 25°C and stirred for 2 hours under nitrogen protection. After the reaction, the reaction solution was diluted with 100 mL of dichloromethane, and the organic phase was washed with aqueous hydrochloric acid solution (0.5 M, 150 mL). The organic phase was collected, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product. The crude product was slurried with petroleum ether/methyl tert-butyl ether (10/1, v/v) (100 mL) to obtain 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A6-2) (12 g, yield 70.6%).
第二步：4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯磺酰胺(A6-3)的合成
Step 2: Synthesis of 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A6-3)
在25℃氮气保护下，向3-溴-4-氟-N-(4-甲氧基苄基)-N-甲基苯磺酰胺(A6-2)(12g,30.9mmol)和双联频哪醇硼酸酯(11.77g,46.4mmol)的1,4-二氧六环(20mL)溶液中加入无水醋酸钾(6.07g,61.8mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.262g,3.09mmol)。反应混合物在110℃下搅拌12小时。反应结束后，将反应液冷却到室温，反应液用硅藻土过滤，滤液浓缩得到粗品，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝100:1-1:1)得到白色固体4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯磺酰胺(A6-3)(10.0g,收率74.7％)。Under nitrogen protection at 25°C, anhydrous potassium acetate (6.07 g, 61.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.262 g, 3.09 mmol) were added to a solution of 3-bromo-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (A6-2) (12 g, 30.9 mmol) and bis-pinacol borate (11.77 g, 46.4 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 110°C for 12 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 100:1-1:1) to obtain a white solid 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A6-3) (10.0 g, yield 74.7%).
第一步：(R)-5,6-二溴-2-甲基-2,3-二氢咪唑并[2,1-b]恶唑(A6-5)的合成
Step 1: Synthesis of (R)-5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (A6-5)
将2,4,5-三溴-1H-咪唑(17.74g,58.2mmol)溶于无水四氢呋喃(85mL)，氮气保护，-78℃滴加正丁基锂(2.5M,23.3mL,58.2mmol)，滴完后继续-78℃搅拌45分钟，再加入(R)-2-甲基环氧乙烷(33.8g,582mmol)，自然恢复至室温搅拌，反应2天，0℃加40mL饱和氯化铵淬灭反应，乙酸乙酯(100mL x 3)萃取，有机相用无水Na2SO4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝3:1)得到白色固体(R)-5,6-二溴-2-甲基-2,3-二氢咪唑并[2,1-b]恶唑(A6-5)(13.01g，产率：79％)。2,4,5-tribromo-1H-imidazole (17.74 g, 58.2 mmol) was dissolved in anhydrous tetrahydrofuran (85 mL), and n-butyl lithium (2.5 M, 23.3 mL, 58.2 mmol) was added dropwise at -78°C under nitrogen protection. After the addition was complete, stirring was continued at -78°C for 45 minutes, and (R)-2-methyloxirane (33.8 g, 582 mmol) was added. The temperature was naturally restored to room temperature and stirred. The reaction was reacted for 2 days, and 40 mL of saturated ammonium chloride was added at 0°C to quench the reaction. The organic phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (R)-5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (A6-5) (13.01 g, yield: 79%).
LC-MS,M/Z(ESI):282.80[M+H]+。LC-MS, M/Z (ESI): 282.80 [M+H] + .
第二步：(R)-6-溴-2-甲基-2,3-二氢咪唑[2,1-b]恶唑(A6-6)的合成
Step 2: Synthesis of (R)-6-bromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (A6-6)
将(R)-5,6-二溴-2-甲基-2,3-二氢咪唑并[2,1-b]恶唑(13.0g,46.1mmol)溶解于无水四氢呋喃(72ml)中，-78℃滴加正丁基锂(2.5M,18.4mL,46.1mmol)，-78℃反应2小时，0℃加25mL饱和氯化铵淬灭反应，乙酸乙酯(50mL x 3)萃取，有机相用无水Na2SO4干燥，过滤，浓缩得到粗品。粗品用硅胶色谱柱纯化(石油醚:乙酸乙酯＝3:1)得到白色固体(R)-6-溴-2-甲基-2,3-二氢咪唑[2,1-b]恶唑(A6-6)(6.88g，产率：73.4％)。 (R)-5,6-dibromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (13.0 g, 46.1 mmol) was dissolved in anhydrous tetrahydrofuran (72 ml), and n-butyl lithium (2.5 M, 18.4 mL, 46.1 mmol) was added dropwise at -78°C, and the reaction was allowed to proceed for 2 hours at -78°C. 25 mL of saturated ammonium chloride was added at 0°C to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (R)-6-bromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (A6-6) (6.88 g, yield: 73.4%).
LC-MS,M/Z(ESI):202.9[M+H]+。LC-MS, M/Z (ESI): 202.9 [M+H] + .
第三步：(R)-4-氟-N-(4-甲氧基苄基)-N-甲基-3-(2-甲基-2,3-二氢咪唑[2,1-b]恶唑-6-基)苯磺酰胺(A6)的合成
Step 3: Synthesis of (R)-4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)benzenesulfonamide (A6)
将4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯磺酰胺(2.28g,5.25mmol)与(R)-6-溴-2-甲基-2,3-二氢咪唑[2,1-b]恶唑(1.06g,5.25mmol)溶于1,4-二氧六环(20mL)，再加入1,1’-双二苯基膦二茂铁二氯化钯(0.38g,0.52mmol)、碳酸钠(1.38g,12.98mmol)、水(4mL)。氮气置换3次，氮气保护于100℃反应21小时。冷却至室温，减蒸除去反应溶剂，加水(40mL)，乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥。硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1-1:2)，得到(R)-4-氟-N-(4-甲氧基苄基)-N-甲基-3-(2-甲基-2,3-二氢咪唑[2,1-b]恶唑-6-基)苯磺酰胺(A6)(1.104g，产率：48.8％)。Dissolve 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (2.28 g, 5.25 mmol) and (R)-6-bromo-2-methyl-2,3-dihydroimidazole [2,1-b] oxazole (1.06 g, 5.25 mmol) in 1,4-dioxane (20 mL), and then add 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (0.38 g, 0.52 mmol), sodium carbonate (1.38 g, 12.98 mmol), and water (4 mL). Replace with nitrogen three times, and react at 100 ° C for 21 hours under nitrogen protection. Cool to room temperature, remove the reaction solvent by evaporation, add water (40 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether:ethyl acetate=1:1-1:2) gave (R)-4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)benzenesulfonamide (A6) (1.104 g, yield: 48.8%).
LC-MS,M/Z(ESI):432.3[M+H]+。LC-MS, M/Z (ESI): 432.3 [M+H] + .
中间体A7的制备Preparation of intermediate A7
合成路线如下所示：
The synthetic route is as follows:
第一步：2-(苯甲硫基)-5-氯吡嗪(A7-2)的合成
Step 1: Synthesis of 2-(phenylmethylthio)-5-chloropyrazine (A7-2)
将苯甲基硫醇(13.8g,111mmol)溶解在四氢呋喃(200mL)中，在0℃下分批加入氢化钠(6.67g,166mmol)，在0℃搅拌2小时，再将2,5-二氯吡嗪(18.2g,122mmol)分批加入到反应液中，反应液继续于0℃反应2小时。缓慢滴加饱和氯化铵水溶液淬灭反应，用乙酸乙酯(100mL×2)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，再用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至0:1)，得到化合物2-(苯甲硫基)-5-氯吡嗪(A7-2)(25.0g，产率95.0％)。Benzyl mercaptan (13.8 g, 111 mmol) was dissolved in tetrahydrofuran (200 mL), sodium hydride (6.67 g, 166 mmol) was added in batches at 0°C, and the mixture was stirred at 0°C for 2 hours. 2,5-dichloropyrazine (18.2 g, 122 mmol) was added in batches to the reaction solution, and the reaction solution was continued to react at 0°C for 2 hours. Saturated aqueous ammonium chloride solution was slowly added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL×2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1 to 0:1) to obtain compound 2-(phenylmethylthio)-5-chloropyrazine (A7-2) (25.0 g, yield 95.0%).
第二步：5-氯吡嗪-2-磺酰氯(A7-3)的合成
Step 2: Synthesis of 5-chloropyrazine-2-sulfonyl chloride (A7-3)
将2-(苯甲硫基)-5-氯吡嗪(16.0g,67.6mmol)和二氯化硫酰(72.9g,540mmol)溶解在水(100mL)和二氯甲烷(100mL)中，0℃反应2小时。将反应液分液，水相用二氯甲烷(100mL)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得到化合物5-氯吡嗪-2-磺酰氯(A7-3)(14.0g，产率97.2％)。2-(Benzylthio)-5-chloropyrazine (16.0 g, 67.6 mmol) and sulfuryl dichloride (72.9 g, 540 mmol) were dissolved in water (100 mL) and dichloromethane (100 mL) and reacted at 0°C for 2 hours. The reaction solution was separated, the aqueous phase was extracted with dichloromethane (100 mL), the organic phases were combined, washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 5-chloropyrazine-2-sulfonyl chloride (A7-3) (14.0 g, yield 97.2%).
第三步：5-氯-N-甲基-吡嗪-2-磺酰胺(A7)的合成
Step 3: Synthesis of 5-chloro-N-methyl-pyrazine-2-sulfonamide (A7)
将5-氯吡嗪-2-磺酰氯(14.0g,65.7mmol)溶解在二氯甲烷(90.0mL)中，加入N,N-二异丙基乙胺(25.5g,197mmol)和甲胺盐酸盐(5.32g,78.8mmol)，然后在25℃搅拌反应2小时。把反应液加到水(100mL)中，然后用二氯甲烷(100mL)萃取，用饱和食盐水(100mL×2)洗涤有机相，无水硫酸钠干燥，过滤浓 缩得到粗品，再用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-0:1)，得到化合物5-氯-N-甲基-吡嗪-2-磺酰胺(A7)(3.00g，产率21.9％)。Dissolve 5-chloropyrazine-2-sulfonyl chloride (14.0 g, 65.7 mmol) in dichloromethane (90.0 mL), add N,N-diisopropylethylamine (25.5 g, 197 mmol) and methylamine hydrochloride (5.32 g, 78.8 mmol), and then stir at 25°C for 2 hours. Add the reaction solution to water (100 mL), then extract with dichloromethane (100 mL), wash the organic phase with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter and concentrate. The crude product was obtained by condensation, and then separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V) = 5:1-0:1) to obtain compound 5-chloro-N-methyl-pyrazine-2-sulfonamide (A7) (3.00 g, yield 21.9%).
中间体A8的制备Preparation of intermediate A8
合成路线如下所示：
The synthetic route is as follows:
第一步：N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(A8-1)的合成
Step 1: Synthesis of N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A8-1)
将5-氯-N-甲基-吡嗪-2-磺酰胺(A7，1.00g,4.82mmol)和(4-(三氟甲基)苯基)甲胺(1.01g,5.78mmol)溶解在N,N-二甲基甲酰胺(50.0mL)中，加N,N-二异丙基乙胺(3.11g,14.4mmol)，25℃搅拌反应2小时。将反应液加到水(200mL)中，然后用乙酸乙酯(100mL×3)萃取，有机相合并，无水硫酸钠干燥，过滤浓缩得到化合物N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(A8-1)(1.20g，产率71.9％)。5-Chloro-N-methyl-pyrazine-2-sulfonamide (A7, 1.00 g, 4.82 mmol) and (4-(trifluoromethyl)phenyl)methylamine (1.01 g, 5.78 mmol) were dissolved in N,N-dimethylformamide (50.0 mL), and N,N-diisopropylethylamine (3.11 g, 14.4 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was added to water (200 mL), and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A8-1) (1.20 g, yield 71.9%).
第二步：6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(A8)
Step 2: 6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A8)
将N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(300mg,866μmol)溶解在乙腈(8mL)中，加N-溴琥珀酰胺(154mg,866μmol)和四氯化碳(2mL)，0℃搅拌反应2小时。将反应液倒入水(50mL)中，用乙酸乙酯(50mL×2)萃取，合并有机相，浓缩得到粗品，再用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1至0:1)，得到化合物6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(A8)(200mg，产率54.3％)。N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (300 mg, 866 μmol) was dissolved in acetonitrile (8 mL), and N-bromosuccinamide (154 mg, 866 μmol) and carbon tetrachloride (2 mL) were added, and the mixture was stirred at 0°C for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phases were combined and concentrated to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V) = 5:1 to 0:1) to obtain compound 6-bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A8) (200 mg, yield 54.3%).
中间体A9的制备Preparation of intermediate A9
合成路线如下所示：
The synthetic route is as follows:
第一步：N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(A9-1)的合成Step 1: Synthesis of N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A9-1)
将5-氯-N-甲基吡嗪-2-磺酰胺(93mg,0.45mmol)溶解于二甲基亚砜(2mL)中，加入(3-(三氟甲基)苯基)甲胺(236.5mg，1.35mmol)，微波150℃反应1.5小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，依次用水洗(20mL)和无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得到化合物N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(A9-1)(121.3mg，产率：78.2％)。5-Chloro-N-methylpyrazine-2-sulfonamide (93 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), (3-(trifluoromethyl)phenyl)methylamine (236.5 mg, 1.35 mmol) was added, and the mixture was reacted at 150°C for 1.5 hours in a microwave oven. After the reaction was completed, the mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3:1) to obtain compound N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A9-1) (121.3 mg, yield: 78.2%).
LC-MS,M/Z(ESI):347.1[M+H]+。LC-MS, M/Z (ESI): 347.1 [M+H] + .
第二步：6-溴-N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(A9)的合成Step 2: Synthesis of 6-bromo-N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A9)
将N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(121.3mg,0.35mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N-溴代琥珀酰亚胺(90.8mg，0.51mmol)，室温反应过夜。反应结束后，加水(20mL)，再加乙 酸乙酯(20mL×3)萃取，合并有机相，水(20mL)洗，无水硫酸钠干燥有机相，硅胶柱层析纯化(石油醚:乙酸乙酯＝4:1)，得到化合物6-溴-N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(A9)(118.4mg，产率：79.5％)。Dissolve N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (121.3 mg, 0.35 mmol) in N,N-dimethylformamide (10 mL), add N-bromosuccinimide (90.8 mg, 0.51 mmol), and react at room temperature overnight. After the reaction is completed, add water (20 mL) and then add ethyl acetate. The residue was extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate. The organic phase was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 6-bromo-N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (A9) (118.4 mg, yield: 79.5%).
LC-MS,M/Z(ESI):425.1[M+H]+。LC-MS, M/Z (ESI): 425.1 [M+H] + .
中间体A10的制备Preparation of intermediate A10
合成路线如下所示：
The synthetic route is as follows:
第一步：3-氮杂双环[3.1.0]己烷-2-酮(A10-2)的合成
Step 1: Synthesis of 3-azabicyclo[3.1.0]hexane-2-one (A10-2)
参照专利CN114728167A合成方法，以3-氮杂双环[3.1.0]己烷盐酸盐(A10-1)为原料进行合成，得到白色固体3-氮杂双环[3.1.0]己烷-2-酮(A10-2)。Referring to the synthesis method of patent CN114728167A, 3-azabicyclo[3.1.0]hexane hydrochloride (A10-1) was used as a raw material to synthesize 3-azabicyclo[3.1.0]hexane-2-one (A10-2), a white solid.
1H NMR(400MHz,DMSO-d6)δ7.02(s,1H),3.37-3.33(m,1H),3.14(d,1H),1.90(dq,1H),1.61(tddd,1H),1.00(dt,1H),0.44(q,1H). 1 H NMR (400 MHz, DMSO-d6) δ7.02 (s, 1H), 3.37-3.33 (m, 1H), 3.14 (d, 1H), 1.90 (dq, 1H), 1.61 (tddd, 1H), 1.00 (dt, 1H), 0.44 (q, 1H).
第二步：2-(2-氧代-3-氮杂双环[3.1.0]己-3-基)乙酸甲酯(A10-3)的合成
Step 2: Synthesis of methyl 2-(2-oxo-3-azabicyclo[3.1.0]hex-3-yl)acetate (A10-3)
氮气保护下，0℃向四氢呋喃(25mL)中加入氢化钠(480mg,12.0mmol,60％)，再滴加3-氮杂双环[3.1.0]己烷-2-酮(A10-2)(0.97g,10.0mmol)的无水四氢呋喃(20ml)中，滴加完毕后，室温搅拌30分钟，再加入溴乙酸甲酯(1.84g,12.0mmol),室温搅拌3小时。反应结束后，0℃加水(20mL)淬灭反应，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，浓缩，得液体2-(2-氧代-3-氮杂双环[3.1.0]己-3-基)乙酸甲酯(A10-3)(1.37g，产率：81.0％)，直接用于下一步反应。Under nitrogen protection, sodium hydride (480 mg, 12.0 mmol, 60%) was added to tetrahydrofuran (25 mL) at 0°C, and then 3-azabicyclo[3.1.0]hexane-2-one (A10-2) (0.97 g, 10.0 mmol) was added dropwise to anhydrous tetrahydrofuran (20 ml). After the addition was complete, the mixture was stirred at room temperature for 30 minutes, and then methyl bromoacetate (1.84 g, 12.0 mmol) was added and stirred at room temperature for 3 hours. After the reaction was completed, water (20 mL) was added at 0°C to quench the reaction, and ethyl acetate was extracted (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain liquid 2-(2-oxo-3-azabicyclo[3.1.0]hex-3-yl)acetic acid methyl ester (A10-3) (1.37 g, yield: 81.0%), which was directly used in the next step.
第三步：2-(2-氧代-3-氮杂双环[3.1.0]己烷-3-基)乙酰胺(A10-4)的合成
Step 3: Synthesis of 2-(2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)acetamide (A10-4)
将2-(2-氧代-3-氮杂双环[3.1.0]己-3-基)乙酸甲酯(A10-3)(1.37g，8.10mmol)加至氨甲醇溶液(40mL，7M)，60℃反应4小时。反应结束后，浓缩，得固体2-(2-氧代-3-氮杂双环[3.1.0]己烷-3-基)乙酰胺(A10-4)(1.23g，产率：98.5％)，直接用于下一步反应。Methyl 2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)acetate (A10-3) (1.37 g, 8.10 mmol) was added to ammonia methanol solution (40 mL, 7 M) and reacted at 60° C. for 4 hours. After the reaction was completed, the mixture was concentrated to obtain solid 2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)acetamide (A10-4) (1.23 g, yield: 98.5%), which was directly used in the next step.
LC-MS,M/Z(ESI):155.1[M+H]+。LC-MS, M/Z (ESI): 155.1 [M+H] + .
第四步：2-溴-5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑(A10)的合成
Step 4: Synthesis of 2-bromo-5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazole (A10)
将-(2-氧代-3-氮杂双环[3.1.0]己烷-3-基)乙酰胺(A10-4)(1.23g,8.0mmol)溶于乙腈(15mL)，再加入三 溴氧磷(4.59g,16.0mmol)，加热至80℃反应3小时，再室温搅拌过夜。反应结束后，浓缩，粗品加入二氯甲烷(50mL)，用饱和碳酸钠水溶液调节pH至8，分液，水相二氯甲烷萃取(50mL×2)，合并有机相，无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯＝2:1)，得到黄色油状2-溴-5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑(A10)(0.65g，产率：41.0％)。LC-MS,M/Z(ESI):199.1[M+H]+。-(2-Oxo-3-azabicyclo[3.1.0]hexane-3-yl)acetamide (A10-4) (1.23 g, 8.0 mmol) was dissolved in acetonitrile (15 mL), and then three Phosphorus oxybromide (4.59 g, 16.0 mmol) was heated to 80°C for 3 hours and then stirred at room temperature overnight. After the reaction was completed, the crude product was concentrated, dichloromethane (50 mL) was added, and the pH was adjusted to 8 with a saturated sodium carbonate aqueous solution. The aqueous phase was extracted with dichloromethane (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a yellow oily 2-bromo-5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazole (A10) (0.65 g, yield: 41.0%). LC-MS, M/Z (ESI): 199.1 [M+H] + .
中间体5A的制备Preparation of intermediate 5A
合成路线如下所示：
The synthetic route is as follows:
将(2R)-6-溴-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑(5.0g,24.6mmol)溶解在四氢呋喃(30.0mL)中，在-70℃氮气保护下缓慢加入正丁基锂(2.5M,19.7mmol),并在-70℃下反应1小时。然后在-70℃氮气保护下缓慢加入三丁基氯化锡(12.0g,36.9mmol)，并缓慢升温至25℃反应2小时。反应完毕后，将反应液用饱和氯化铵溶液(100mL)淬灭，乙酸乙酯(100mL)萃取，有机相用无水硫酸钠干燥，过滤浓缩得到粗品，通过柱层析硅胶纯化(石油醚/乙酸乙酯(V/V)＝3/1至0/1)，得到化合物三丁基-[(2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基]锡烷(6.00g，产率59.0％)。Dissolve (2R)-6-bromo-2-methyl-2,3-dihydroimidazo[2,1-b]oxazole (5.0 g, 24.6 mmol) in tetrahydrofuran (30.0 mL), slowly add n-butyl lithium (2.5 M, 19.7 mmol) at -70°C under nitrogen protection, and react at -70°C for 1 hour. Then slowly add tributyltin chloride (12.0 g, 36.9 mmol) at -70°C under nitrogen protection, and slowly heat to 25°C to react for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (V/V) = 3/1 to 0/1) to obtain the compound tributyl-[(2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl]stannane (6.00 g, yield 59.0%).
实施例1化合物I-1的制备Example 1 Preparation of Compound I-1
合成路线如下所示：
The synthetic route is as follows:
第一步：5-溴-N-[(4-甲氧苯基)甲基]-N-甲基-6-[[4-(五氟-λ6-巯基)苯基]甲基氨基]吡啶-3-磺酰胺(B1-2)的合成
Step 1: Synthesis of 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[4-(pentafluoro- λ 6 -mercapto)phenyl]methylamino]pyridine-3-sulfonamide (B1-2)
将5-溴-6-氯-N-(4-甲氧苄基)-N-甲基吡啶-3-磺酰胺(中间体A1)(2.00g,10.0mmol)和(4-(五氟-λ6-硫烷基)苯基)甲胺(1.99g,7.39mmol)溶于N,N-二甲基甲酰胺(15.0mL)中，加入N,N-二异丙基乙基胺(3.82g,29.6mmol)，反应液升温至60℃反应6小时。反应结束后，将反应液直接过滤浓缩，并用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1到0:1)得到5-溴-N-[(4-甲氧苯基)甲基]-N-甲基-6-[[4-(五氟-λ6-巯基)苯基]甲基氨基]吡啶-3-磺酰胺(B1-2)(2.40g,产率53.9％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (intermediate A1) (2.00 g, 10.0 mmol) and (4-(pentafluoro- λ 6 -sulfanyl)phenyl)methylamine (1.99 g, 7.39 mmol) were dissolved in N,N-dimethylformamide (15.0 mL), and N,N-diisopropylethylamine (3.82 g, 29.6 mmol) was added. The reaction solution was heated to 60°C for 6 hours. After the reaction, the reaction solution was directly filtered and concentrated, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[4-(pentafluoro- λ 6 -mercapto)phenyl]methylamino]pyridine-3-sulfonamide (B1-2) (2.40 g, yield 53.9%).
第二步：N-[(4-甲氧苯基)甲基]-N-甲基-5-(1-甲基咪唑-4-基)-6-[[3-(五氟-λ6-巯基)苯基]甲氧基]吡啶-3-磺酰胺(B1-3)的合成
Step 2: Synthesis of N-[(4-methoxyphenyl)methyl]-N-methyl-5-(1-methylimidazol-4-yl)-6-[[3-(pentafluoro- λ 6 -mercapto)phenyl]methoxy]pyridine-3-sulfonamide (B1-3)
将5-溴-N-[(4-甲氧苯基)甲基]-N-甲基-6-[[4-(五氟-λ6-巯基)苯基]甲基氨基]吡啶-3-磺酰胺(B1-2)(200mg,331μmol)，三丁基-(1-甲基咪唑-4-基)锡烷(123mg,331μmol)溶于甲苯(20.0mL)中，加入四(三苯基膦)钯(38.3mg,33.2μmol)，氮气置换三次，并于110℃下反应6小时。反应完毕后，将反应液直接过滤浓缩。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1到0:1)，得到N-[(4-甲氧苯基)甲基]-N-甲基-5-(1-甲基咪 唑-4-基)-6-[[3-(五氟-λ6-巯基)苯基]甲氧基]吡啶-3-磺酰胺(B1-3)(150mg,产率74.9％)。5-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[4-(pentafluoro-λ 6 -mercapto)phenyl]methylamino]pyridine-3-sulfonamide (B1-2) (200 mg, 331 μmol), tributyl-(1-methylimidazol-4-yl)stannane (123 mg, 331 μmol) were dissolved in toluene (20.0 mL), tetrakis(triphenylphosphine)palladium (38.3 mg, 33.2 μmol) was added, nitrogen was replaced three times, and the reaction was carried out at 110°C for 6 hours. After the reaction was completed, the reaction solution was directly filtered and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain N-[(4-methoxyphenyl)methyl]-N-methyl-5-(1-methylimidazol-4-yl)stannane. oxazol-4-yl)-6-[[3-(pentafluoro-λ6-mercapto)phenyl]methoxy]pyridine-3-sulfonamide (B1-3) (150 mg, yield 74.9%).
LC-MS,M/Z(ESI):604.1[M+H]+ LC-MS, M/Z(ESI):604.1[M+H] +
第三步：N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(I-1)的合成
Step 3: Synthesis of N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-1)
将N-[(4-甲氧苯基)甲基]-N-甲基-5-(1-甲基咪唑-4-基)-6-[[3-(五氟-λ6-巯基)苯基]甲氧基]吡啶-3-磺酰胺(B1-3)(150mg,248μmol)溶解于三氟乙酸(5.00mL)中，反应液于60℃下搅拌2小时。反应完毕后，反应液冷至室温，加到水(50.0mL)中，用饱和碳酸氢钠溶液调节溶液pH值约为7，然后用乙酸乙酯(50mL×2)萃取，有机相用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品通过制备高效液相色谱分离纯化(柱子：Phenomenex luna C18 150*25mm*10μm；溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：35％-65％，10分钟)，得到化合物N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-l6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(I-1)(70.0mg，产率37.8％)。N-[(4-methoxyphenyl)methyl]-N-methyl-5-(1-methylimidazol-4-yl)-6-[[3-(pentafluoro- λ 6 -mercapto)phenyl]methoxy]pyridine-3-sulfonamide (B1-3) (150 mg, 248 μmol) was dissolved in trifluoroacetic acid (5.00 mL), and the reaction solution was stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, added to water (50.0 mL), and the pH value of the solution was adjusted to about 7 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (50 mL×2), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; solvent: A=water+formic acid (0.05%), B=acetonitrile; gradient: 35%-65%, 10 minutes) to obtain compound N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro-16-sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-1) (70.0 mg, yield 37.8%).
LC-MS,M/Z(ESI):484.1[M+H]+ LC-MS, M/Z(ESI):484.1[M+H] +
1H NMR(CDCl3,400MHz)δ9.80(br s,1H),8.46(d,1H),7.95(d,1H),7.70(d,2H),7.45–7.49(m,3H),7.34(d,1H),4.90(d,2H),4.26–4.32(m,1H),3.79(s,3H),2.68(d,3H). 1 H NMR (CDCl 3 , 400 MHz) δ 9.80 (br s, 1H), 8.46 (d, 1H), 7.95 (d, 1H), 7.70 (d, 2H), 7.45–7.49 (m, 3H), 7.34 (d, 1H), 4.90 (d, 2H), 4.26–4.32 (m, 1H), 3.79 (s, 3H), 2.68 (d, 3H).
实施例2化合物I-2的制备Example 2 Preparation of Compound I-2
合成路线如下所示：
The synthetic route is as follows:
第一步：5-溴-N-(4-甲氧苄基)-N-甲基-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(B2-2)的合成
Step 1: Synthesis of 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-2)
将5-溴-6-氯-N-(4-甲氧苄基)-N-甲基吡啶-3-磺酰胺(中间体A1)(900mg,2.22mmol)和(3-(五氟-λ6-硫烷基)苯基)甲胺(598mg,2.22mmol)溶于四氢呋喃(5mL)中，加入N,N-二异丙基乙基胺(1.15g,8.87mmol)，反应液升温至55℃搅拌6小时。反应结束后，将反应液直接过滤浓缩，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1到0:1)，得到5-溴-N-(4-甲氧苄基)-N-甲基-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(B2-2)(1.00g,收率74.8％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (intermediate A1) (900 mg, 2.22 mmol) and (3-(pentafluoro- λ 6 -sulfanyl)phenyl)methylamine (598 mg, 2.22 mmol) were dissolved in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (1.15 g, 8.87 mmol) was added. The reaction solution was heated to 55°C and stirred for 6 hours. After the reaction was completed, the reaction solution was directly filtered and concentrated, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-2) (1.00 g, yield 74.8%).
第二步：N-(4-甲氧苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(B2-3)的合成
Step 2: Synthesis of N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-3)
将5-溴-N-(4-甲氧苄基)-N-甲基-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(B2-2)(200mg,331 μmol)，三丁基-(1-甲基咪唑-4-基)锡烷(123mg,331μmol)溶于甲苯(20mL)中，加入四(三苯基膦)钯(38.3mg,33.2μmol)，氮气置换三次，并于110℃下搅拌6小时。反应完毕后，将反应液直接过滤浓缩。用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1到0:1)，得到N-(4-甲氧苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(B2-3)(150mg,收率74.9％)。5-Bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-2) (200 mg, 331 μmol), tributyl-(1-methylimidazol-4-yl)stannane (123 mg, 331 μmol) was dissolved in toluene (20 mL), tetrakis(triphenylphosphine)palladium (38.3 mg, 33.2 μmol) was added, nitrogen was replaced three times, and stirred at 110°C for 6 hours. After the reaction was completed, the reaction solution was directly filtered and concentrated. It was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-3) (150 mg, yield 74.9%).
LC-MS,M/Z(ESI):604.1[M+H]+ LC-MS, M/Z(ESI):604.1[M+H] +
第三步：N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(I-2)的合成
Step 3: Synthesis of N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-2)
将N-(4-甲氧苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((4-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(B2-3)(150mg,248μmol)溶于三氟乙酸(5.00mL)中，于60℃搅拌2小时。反应完毕后，把反应液加到水(50mL)中，用饱和碳酸氢钠水溶液调节溶液pH约7，然后用乙酸乙酯(50mL×2)萃取，有机相用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，浓缩得到粗品。然后通过制备高效液相色谱法进行分离(柱子：Phenomenex luna C18 150*25mm*10μm；溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：36％-66％，10分钟)，得到化合物N-甲基-5-(1-甲基-1H-咪唑-4-基)-6-((3-(五氟-λ6-硫烷基)苯甲基)氨基)吡啶-3-磺酰胺(I-2)(32.0mg，产率17.4％)。N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((4-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (B2-3) (150 mg, 248 μmol) was dissolved in trifluoroacetic acid (5.00 mL) and stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was added to water (50 mL), the pH of the solution was adjusted to about 7 with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (50 mL×2), and the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Then, separation was carried out by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10μm; solvent: A=water+formic acid (0.05%), B=acetonitrile; gradient: 36%-66%, 10 minutes) to obtain compound N-methyl-5-(1-methyl-1H-imidazol-4-yl)-6-((3-(pentafluoro- λ 6 -sulfanyl)benzyl)amino)pyridine-3-sulfonamide (I-2) (32.0 mg, yield 17.4%).
LC-MS,M/Z(ESI):484.1[M+H]+ LC-MS, M/Z(ESI):484.1[M+H] +
1H NMR(DMSO,400MHz)δ9.86(m,1H),8.22(d,1H),8.01(d,1H),7.83–7.88(m,3H),7.76(d,1H),7.53–7.64(m,2H),7.15–7.22(m,1H),4.87(d,2H),3.75(s,3H),2.40(d,3H). 1 H NMR (DMSO, 400 MHz) δ9.86 (m, 1H), 8.22 (d, 1H), 8.01 (d, 1H), 7.83–7.88 (m, 3H), 7.76 (d, 1H), 7.53–7.64 (m, 2H), 7.15–7.22 (m, 1H), 4.87 (d, 2H), 3.75 (s, 3H), 2.40 (d, 3H).
实施例3化合物I-5的制备Example 3 Preparation of Compound I-5
合成路线如下所示：
The synthetic route is as follows:
第一步：(R)-N-(4-甲氧基苄基)-N-甲基-3-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基))苄基)氨基)苯磺酰胺(B5-2)的合成
Step 1: Synthesis of (R)-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl))benzyl)amino)benzenesulfonamide (B5-2)
将(R)-4-氟-N-(4-甲氧基苄基)-N-甲基-3-(2-甲基-2,3-二氢咪唑[2,1-b]恶唑-6-基)苯磺酰胺(A6)(350mg,0.81mmol)与(4-(三氟甲基)苯基)甲胺(709mg,4.05mmol)溶于二甲基亚砜(3mL)，140℃微波反应2小时。冷却至室温，加入水(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，依次用水(15mL)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥，减压浓缩，得到粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1至1:2)，得到化合物(R)-N-(4-甲氧基苄基)-N-甲基-3-(2-甲基-2,3-二氢咪唑并[2,1-b]恶唑-6-基)-4-((4-(三氟甲基))苄基)氨基)苯磺酰胺(B5-2)(0.19g，产率38.9％)。(R)-4-Fluoro-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)benzenesulfonamide (A6) (350 mg, 0.81 mmol) and (4-(trifluoromethyl)phenyl)methanamine (709 mg, 4.05 mmol) were dissolved in dimethyl sulfoxide (3 mL) and reacted in a microwave oven at 140 °C for 2 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (15 mL) and saturated brine (15 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1 to 1:2) to obtain compound (R)-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl))benzyl)amino)benzenesulfonamide (B5-2) (0.19 g, yield 38.9%).
LC-MS,M/Z(ESI):587.2[M+H]+ LC-MS, M/Z(ESI):587.2[M+H] +
第二步：(R)-N-甲基-3-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苄基)氨基)苯磺酰胺(I-5)的合成
Step 2: Synthesis of (R)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (I-5)
将(R)-N-(4-甲氧基苄基)-N-甲基-3-(2-甲基-2,3-二氢咪唑并[2,1-b]恶唑-6-基)-4-((4-(三氟甲基))苄基)氨基)苯磺酰胺(B5-2)(185mg,0.32mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温搅拌1小时。反应结束后，将反应液浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液洗涤(20mL×3)，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到化合物(R)-N-甲基-3-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苄基)氨基)苯磺酰胺(I-5)(59mg，产率40.2％)。(R)-N-(4-methoxybenzyl)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl))benzyl)amino)benzenesulfonamide (B5-2) (185 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (20 mL×3), and the crude product was purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain compound (R)-N-methyl-3-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (I-5) (59 mg, yield 40.2%).
LC-MS,M/Z(ESI):467.4[M+H]+。LC-MS, M/Z (ESI): 467.4 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.55(t,1H),7.75–7.67(m,3H),7.55(d,2H),7.35–7.28(m,2H),6.99(q,1H),6.59(d,1H),5.50–5.40(m,1H),4.61(d,2H),4.38(dd,1H),3.85(dd,1H),2.34(d,3H),1.53(d,3H). 1 H NMR (400 MHz, DMSO-d6) δ8.55 (t, 1H), 7.75–7.67 (m, 3H), 7.55 (d, 2H), 7.35–7.28 (m, 2H), 6.99 (q, 1H), 6.59 (d, 1H), 5.50–5.40 (m, 1H), 4.61 (d, 2H), 4.38 (dd, 1H), 3.85 (dd, 1H), 2.34 (d, 3H), 1.53 (d, 3H).
实施例4化合物I-6的制备Example 4 Preparation of Compound I-6
合成路线如下所示：
The synthetic route is as follows:
第一步：5-溴-N-(4-甲氧苄基)-N-甲基-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B6-2)的合成
Step 1: Synthesis of 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-2)
将5-溴-6-氯-N-(4-甲氧苄基)-N-甲基吡啶-3-磺酰胺(中间体A1)(3.00g,7.39mmol)溶于二甲基亚砜(40.0mL)中，加入N,N-二异丙基乙胺(2.87g,22.1mmol)和(4-(三氟甲基)苯基)甲胺(1.68g,9.61mmol)，反应液于90℃搅拌8小时。向反应液中加入水(200mL)，然后用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，减压浓缩,得到化合物5-溴-N-(4-甲氧苄基)-N-甲基-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B6-2)(3.80g，产率94.4％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (Intermediate A1) (3.00 g, 7.39 mmol) was dissolved in dimethyl sulfoxide (40.0 mL), and N,N-diisopropylethylamine (2.87 g, 22.1 mmol) and (4-(trifluoromethyl)phenyl)methylamine (1.68 g, 9.61 mmol) were added, and the reaction solution was stirred at 90°C for 8 hours. Water (200 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5-bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-2) (3.80 g, yield 94.4%).
LC-MS,M/Z(ESI):545.1[M+H]+.LC-MS, M/Z(ESI):545.1[M+H] + .
第二步：(R)-N-(4-甲氧苄基)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B6-3)的合成
Step 2: Synthesis of (R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-3)
将5-溴-N-(4-甲氧苄基)-N-甲基-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B6-2)(527mg,968μmol)和三丁基-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)锡烷(中间体5A，438mg,1.06mmol)溶解在甲苯(5mL)中，加入四(三苯基膦)钯(111mg,96.8μmol)，在氮气保护下于110℃搅拌4小时。把反应液加到水(200mL)中，然后用乙酸乙酯(200mL)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩得到粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1到0:1)得到化合物(R)-N-(4-甲氧苄基)-N- 甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B6-3)(250mg，产率43.9％)5-Bromo-N-(4-methoxybenzyl)-N-methyl-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-2) (527 mg, 968 μmol) and tributyl-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)stannane (Intermediate 5A, 438 mg, 1.06 mmol) were dissolved in toluene (5 mL), tetrakis(triphenylphosphine)palladium (111 mg, 96.8 μmol) was added, and the mixture was stirred at 110 °C for 4 hours under nitrogen protection. The reaction solution was added to water (200 mL), then extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1 to 0:1) to obtain compound (R)-N-(4-methoxybenzyl)-N- Methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B6-3) (250 mg, yield 43.9%)
LC-MS,M/Z(ESI):588.1[M+H]+ LC-MS, M/Z(ESI):588.1[M+H] +
第三步：(R)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(I-6)
Step 3: (R)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (I-6)
将(R)-N-(4-甲氧苄基)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(150mg,255μmol)溶解在三氟乙酸(3mL)中，60℃搅拌2小时。把反应液加入饱和碳酸钾水溶液中，用1M稀盐酸调节pH至7，然后用乙酸乙酯(30mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩得到粗品。粗品通过制备高效液相色谱进行分离纯化(柱子：YMC Triart C18 150*25mm*5μm；溶剂：A＝水+0.05体积甲酸(99％)，B＝乙腈；梯度：51％-81％，8.5分钟)，得到化合物(R)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((4-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(I-6)(29.8mg，产率23.7％)。(R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (150 mg, 255 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 60°C for 2 hours. The reaction solution was added to a saturated aqueous potassium carbonate solution, the pH was adjusted to 7 with 1M dilute hydrochloric acid, and then extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: YMC Triart C18 150*25mm*5μm; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 51%-81%, 8.5 minutes) to obtain compound (R)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((4-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (I-6) (29.8 mg, yield 23.7%).
LC-MS,M/Z(ESI):468.2[M+H]+ LC-MS, M/Z(ESI):468.2[M+H] +
1H NMR(DMSO-d6)δ9.18(m,1H),8.20(d,1H),7.92(d,1H),7.69(d,2H),7.53(d,2H),7.49(s,1H),7.19(m,1H),5.37–5.55(m,1H),4.83(d,2H),4.39(m,1H),3.86(m,1H),2.41(d,3H),1.53(d,3H) 1 H NMR (DMSO-d 6 )δ9.18(m,1H),8.20(d,1H),7.92(d,1H),7.69(d,2H),7.53(d,2H),7.49(s,1H),7.19(m,1H),5.37–5.55(m,1H),4.83(d,2H),4.39(m,1H),3.86(m,1H),2.41(d,3H),1.53(d,3H)
实施例5：化合物I-7的制备Example 5: Preparation of Compound I-7
合成路线如下所示：
The synthetic route is as follows:
第一步：5-溴-N-[(4-甲氧苯基)甲基]-N-甲基-6-[[3-(三氟甲基)苯基]甲基氨基]吡啶-3-磺酰胺(B7-2)的合成
Step 1: Synthesis of 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[3-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (B7-2)
将5-溴-6-氯-N-[(4-甲氧苯基)甲基]-N-甲基-吡啶-3-磺酰胺(中间体A1)(600mg,1.48mmol)和[3-(三氟甲基)苯基]甲胺(285mg,1.63mmol)溶于二甲基亚砜(5.00mL)中，加入N,N-二异丙基乙基胺(573mg,4.44mmol)，升温至90℃反应2小时。反应结束后，将反应液用乙酸乙酯(50.0mL)萃取，有机相用饱和食盐水(80.0mL)洗涤，硫酸钠干燥，浓缩得到棕色油状化合物5-溴-N-[(4-甲氧苯基)甲基]-N-甲基-6-[[3-(三氟甲基)苯基]甲基氨基]吡啶-3-磺酰胺(B7-2)(800mg,产率99.3％)。 5-Bromo-6-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-pyridine-3-sulfonamide (Intermediate A1) (600 mg, 1.48 mmol) and [3-(trifluoromethyl)phenyl]methylamine (285 mg, 1.63 mmol) were dissolved in dimethyl sulfoxide (5.00 mL), N,N-diisopropylethylamine (573 mg, 4.44 mmol) was added, and the temperature was raised to 90°C for 2 hours. After the reaction, the reaction solution was extracted with ethyl acetate (50.0 mL), the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to obtain a brown oily compound 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[3-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (B7-2) (800 mg, yield 99.3%).
第二步：(R)-N-(4-甲氧苄基)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((3-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B7-3)的合成
Step 2: Synthesis of (R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B7-3)
将5-溴-N-[(4-甲氧苯基)甲基]-N-甲基-6-[[3-(三氟甲基)苯基]甲基氨基]吡啶-3-磺酰胺(B7-2)(800mg,1.47mmol)和三丁基-[(2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基]锡烷(667mg,1.62mmol)溶于甲苯(5mL)中，加入四(三苯基膦)钯(169mg,146μmol)，升温至100℃反应6小时。反应结束后，将反应液直接过滤浓缩，并用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1至0:1)得到化合物(R)-N-(4-甲氧苄基)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((3-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B7-3)(600mg,产率69.5％)。5-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[3-(trifluoromethyl)phenyl]methylamino]pyridine-3-sulfonamide (B7-2) (800 mg, 1.47 mmol) and tributyl-[(2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl]stannane (667 mg, 1.62 mmol) were dissolved in toluene (5 mL), tetrakis(triphenylphosphine)palladium (169 mg, 146 μmol) was added, and the temperature was raised to 100 ° C for 6 hours. After the reaction, the reaction solution was directly filtered and concentrated, and separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain compound (R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B7-3) (600 mg, yield 69.5%).
第三步：(R)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((3-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(I-7)的合成
Step 3: Synthesis of (R)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (I-7)
将(R)-N-(4-甲氧苄基)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((3-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(B7-3)(600mg,1.02mmol)溶解于三氟乙酸(10mL)中，于60℃搅拌2小时。反应完毕后，把反应液加到水(50mL)中，用饱和碳酸钾水溶液调节pH至7，然后用乙酸乙酯(50mL*2)萃取，有机相合并，用饱和食盐水(80mL)洗涤，硫酸钠干燥，浓缩得到粗品。然后通过制备高效液相色谱法进行分离纯化，分离方法为(柱子：YMC Triart C18 150*25mm*5um；溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：50％-70％，10分钟)，得到化合物(R)-N-甲基-5-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-6-((3-(三氟甲基)苯甲基)氨基)吡啶-3-磺酰胺(I-7)(200mg，产率39.4％)。(R)-N-(4-methoxybenzyl)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (B7-3) (600 mg, 1.02 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was added to water (50 mL), the pH was adjusted to 7 with saturated potassium carbonate aqueous solution, and then extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (80 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Then, it was separated and purified by preparative high performance liquid chromatography (column: YMC Triart C18 150*25mm*5um; solvent: A=water+formic acid (0.05%), B=acetonitrile; gradient: 50%-70%, 10 minutes) to obtain compound (R)-N-methyl-5-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-6-((3-(trifluoromethyl)benzyl)amino)pyridine-3-sulfonamide (I-7) (200 mg, yield 39.4%).
LC-MS,M/Z(ESI):468.1[M+H]+ LC-MS, M/Z(ESI):468.1[M+H] +
1H NMR(CDCl3,400MHz)δ8.53(s,1H),7.96-8.07(m,1H),7.40-7.71(m,6H),7.27(s,1H),7.11-7.15(m,1H),5.44-5.50(m,1H),4.95(s,2H),4.38(br d,1H),3.85(br d,1H),2.71(s,3H),1.68(d,3H). 1 H NMR (CDCl 3 , 400 MHz) δ 8.53 (s, 1H), 7.96-8.07 (m, 1H), 7.40-7.71 (m, 6H), 7.27 (s, 1H), 7.11-7.15 (m, 1H), 5.44-5.50 (m, 1H), 4.95 (s, 2H), 4.38 (br d, 1H), 3.85 (br d, 1H), 2.71 (s, 3H), 1.68 (d, 3H).
实施例6：化合物I-11的制备Example 6: Preparation of Compound I-11
合成路线如下所示：
The synthetic route is as follows:
第一步：2-(3-氧代吗啉)乙酸甲酯(B11-2)的合成
Step 1: Synthesis of methyl 2-(3-oxomorpholino)acetate (B11-2)
将吗啉-3-酮(B11-1)(10.0g,98.9mmol)溶解在四氢呋喃(100mL)中，分批加入钠氢(4.35g,109mmol)，反应液在25℃下搅拌1小时，再将溴乙酸甲酯(16.6g,109mmol)加到反应液中，在25℃下搅拌9小时。向反应液中缓慢加入水(200mL)，然后用二氯甲烷(200mL)萃取，用饱和食盐水(100mL)洗涤有机相，无水硫酸钠干燥，过滤浓缩，得到粗品2-(3-氧代吗啉)乙酸甲酯(B11-2)(15.0g，收率87.6％)。Morpholine-3-one (B11-1) (10.0 g, 98.9 mmol) was dissolved in tetrahydrofuran (100 mL), sodium hydrogen (4.35 g, 109 mmol) was added in batches, the reaction solution was stirred at 25°C for 1 hour, and then methyl bromoacetate (16.6 g, 109 mmol) was added to the reaction solution, and stirred at 25°C for 9 hours. Water (200 mL) was slowly added to the reaction solution, and then extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 2-(3-oxomorpholine)acetic acid methyl ester (B11-2) (15.0 g, yield 87.6%).
第二步：2-(3-氧代吗啉)乙酰胺(B11-3)的合成
Step 2: Synthesis of 2-(3-oxomorpholino)acetamide (B11-3)
将2-(3-氧代吗啉)乙酸甲酯(B11-2)(3.00g,17.3mmol)溶解在甲醇(10.0mL)中，再将氨甲醇(7M,30mL)加到反应液中，在60℃下反应4小时。将反应液直接浓缩得到粗品2-(3-氧代吗啉)乙酰胺(B11-3)(1.20g,收率43.8％)。2-(3-oxomorpholino)acetate methyl ester (B11-2) (3.00 g, 17.3 mmol) was dissolved in methanol (10.0 mL), and ammonia methanol (7 M, 30 mL) was added to the reaction solution, and the reaction was carried out at 60°C for 4 hours. The reaction solution was directly concentrated to obtain crude 2-(3-oxomorpholino)acetamide (B11-3) (1.20 g, yield 43.8%).
第三步：2-溴-6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪(B11-4)的合成
Step 3: Synthesis of 2-bromo-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine (B11-4)
将2-(3-氧代吗啉)乙酰胺(B11-3)(1.00g,6.32mmol)溶解在乙腈(10.0mL)中，在氮气保护下，加入三溴氧磷(9.06g,31.6mmol),90℃反应2小时。将反应液中加入饱和碳酸钾溶液(100mL),然后用乙酸乙酯(100mL)萃取，用饱和食盐水(100mL)洗涤有机相，无水硫酸钠干燥，过滤浓缩，得到粗品2-溴-6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪(B11-4)(800mg,收率62.3％)。2-(3-Oxomorpholine)acetamide (B11-3) (1.00 g, 6.32 mmol) was dissolved in acetonitrile (10.0 mL), and phosphorus oxybromide (9.06 g, 31.6 mmol) was added under nitrogen protection, and the mixture was reacted at 90°C for 2 hours. Saturated potassium carbonate solution (100 mL) was added to the reaction solution, and then extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 2-bromo-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine (B11-4) (800 mg, yield 62.3%).
LC-MS,M/Z(ESI):203.0[M+H]+。LC-MS, M/Z (ESI): 203.0 [M+H]+.
第四步：3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-4-氟-N-(4-甲氧苄基)-N-甲基苯磺酰胺(B11-5)的合成
Step 4: Synthesis of 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B11-5)
将2-溴-6,8-二氢-5Η-咪唑并[2,1-c][1,4]噁嗪(B11-4)(476mg,2.34mmol)和4-氟-N-(4-甲氧苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯磺酰胺(A6-3)(1.02g,2.34mmol)溶解在乙腈(10.0mL)和水(5.0mL)中，加入碳酸钾(648mg,4.69mmol)和1,1-双(二苯基膦)二茂铁氯化钯(171mg,234μmol)，然后在氮气保护下于95℃搅拌反应10小时。将反应液浓缩得到粗品，然后通过制备高效液相色谱法进行分离(柱子：3PhenomenexLuna C18 150*40mm*15μm；溶剂：A＝水+三氟乙酸(0.05％)，B＝乙腈；梯度：20％-50％,11分钟)，得到3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-4-氟-N-(4-甲氧苄基)-N-甲基苯磺酰胺(B11-5)(200mg，收率19.8％)。2-Bromo-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazine (B11-4) (476 mg, 2.34 mmol) and 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A6-3) (1.02 g, 2.34 mmol) were dissolved in acetonitrile (10.0 mL) and water (5.0 mL), potassium carbonate (648 mg, 4.69 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (171 mg, 234 μmol) were added, and then the reaction was stirred at 95 ° C under nitrogen protection for 10 hours. The reaction solution was concentrated to obtain a crude product, which was then separated by preparative HPLC (column: 3PhenomenexLuna C18 150*40mm*15μm; solvent: A = water + trifluoroacetic acid (0.05%), B = acetonitrile; gradient: 20%-50%, 11 minutes) to obtain 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B11-5) (200 mg, yield 19.8%).
第五步：3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-N-(4-甲氧苄基)-N-甲基-4-(((4-(三氟甲基)苯基)甲基)氨基)苯磺酰胺(168-6)的合成
Step 5: Synthesis of 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-(4-methoxybenzyl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (168-6)
将5-(三氟甲基)吡啶-2-胺(147mg,904μmol)和3-(5,6-二氢-8H-咪唑并[2,1-c][1,4]噁嗪-2-基)-4-氟-Ν-(4-甲氧苄基)-N-甲基苯磺酰胺(B11-5)(195mg,452μιmol)溶解在N,N-二甲基甲酰胺(5.0mL)中，在0℃下加入氢化钠(27.1mg,678mol)，氮气保护下20℃反应1小时。把反应液滴加到1M盐酸(100mL)中，用饱和碳酸氢钠溶液中和，然后用乙酸乙酯(100mL)萃取，用饱和食盐水(80.0mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。然后通过硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至5:1)，得到3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-N-(4-甲氧苄基)-N-甲基-4-(((4-(三氟甲基)苯基)甲基)氨基)苯磺酰胺(B11-6)(150mg，收率57.9％)。5-(Trifluoromethyl)pyridin-2-amine (147 mg, 904 μmol) and 3-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-4-fluoro-N-(4-methoxybenzyl)-N-methylbenzenesulfonamide (B11-5) (195 mg, 452 μmol) were dissolved in N,N-dimethylformamide (5.0 mL), sodium hydride (27.1 mg, 678 mol) was added at 0°C, and the mixture was reacted at 20°C for 1 hour under nitrogen protection. The reaction solution was added dropwise to 1M hydrochloric acid (100 mL), neutralized with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, and concentrated to obtain a crude product. Then, the mixture was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V) = 50:1 to 5:1) to obtain 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-(4-methoxybenzyl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (B11-6) (150 mg, yield 57.9%).
第六步：3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-N-甲基-4-(((4-(三氟甲基)苯基)甲基)氨基)苯磺酰胺(I-11)
Step 6: 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (I-11)
将3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-N-(4-甲氧苄基)-N-甲基-4-(((4-(三氟甲基)苯基)甲基)氨基)苯磺酰胺(200mg,349μmol)溶解在三氟乙酸(7.70mg,67.5mmol)中，60℃反应2小时。将反应液加到水(40.0mL)中，用饱和碳酸氢钠溶液中和，然后用乙酸乙酯(40.0mL)萃取，用饱和食盐水(80.0mL)洗涤有机相，无水硫酸钠干燥，过滤浓缩得到粗品。然后通过反相制备高效液相色谱法进行分离(柱子：3_PhenomenexLuna C18 150*25mm*10μm；溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：32％-62％,9分钟)，得到3-(6,8-二氢-5H-咪唑并[2,1-c][1,4]噁嗪-2-基)-N-甲基-4-(((4-(三氟甲基)苯基)甲基)氨基)苯磺酰胺(I-11)(35.0mg，收率31.4％)。3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-(4-methoxybenzyl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (200 mg, 349 μmol) was dissolved in trifluoroacetic acid (7.70 mg, 67.5 mmol) and reacted at 60°C for 2 hours. The reaction solution was added to water (40.0 mL), neutralized with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (40.0 mL). The organic phase was washed with saturated brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Then, it was separated by reverse phase preparative HPLC (column: 3_Phenomenex Luna C18 150*25mm*10μm; solvent: A=water+formic acid (0.05%), B=acetonitrile; gradient: 32%-62%, 9 minutes) to obtain 3-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-2-yl)-N-methyl-4-(((4-(trifluoromethyl)phenyl)methyl)amino)benzenesulfonamide (I-11) (35.0 mg, yield 31.4%).
LC-MS,M/Z(ESI):467.2[M+H]+。LC-MS, M/Z (ESI): 467.2 [M+H] + .
1HNMR(400MHz,CDCl3)δ7.87(d,1H),7.58(d,2H),7.49-7.46(m,3H),7.28(s,1H),6.52(d,1H),4.86(s,2H),4.59(s,2H),4.24(b,1H),4.11(s,4H),2.61(s,3H),。 1 HNMR (400 MHz, CDCl3) δ7.87 (d, 1H), 7.58 (d, 2H), 7.49-7.46 (m, 3H), 7.28 (s, 1H), 6.52 (d, 1H), 4.86 (s, 2H), 4.59 (s, 2H), 4.24 (b, 1H), 4.11 (s, 4H), 2.61 (s, 3H),.
实施例7：化合物I-14的制备Example 7: Preparation of Compound I-14
合成路线如下所示：
The synthetic route is as follows:
第一步：6-((((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B14-2)的合成
Step 1: Synthesis of 6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B14-2)
将5-溴-6-((((1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺胺(中间体A2)(100mg,0.19mmol)溶解N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(70.5mg，0.19mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护，120℃搅拌过夜。反应结束后，反应液冷却至室温，加饱和氟化钾水溶液(5mL)，室温搅拌30分钟，然后再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，依次用水洗(20mL)、无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到化合物6-((((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B14-2)(80mg，产率79.8％)。5-Bromo-6-((((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (Intermediate A2) (100 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-methyl-4-(tri-n-butyltin)imidazole (70.5 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added. The mixture was protected by argon and stirred at 120°C overnight. After the reaction, the reaction solution was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Water (20 mL) was then added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL) in turn, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain compound 6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B14-2) (80 mg, yield 79.8%).
LC-MS,M/Z(ESI):518.3[M+H]+ LC-MS, M/Z(ESI):518.3[M+H] +
第二步：6-((((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-14)的合成
Step 2: Synthesis of 6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-14)
将6-((((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B14-2)(80mg,0.15mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温搅拌1小时。反应结束后，反应液减压浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液洗至水相pH为7-8，有机相减压浓缩，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到6-((((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-14)(28mg，产率45.6％)。6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B14-2) (80 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and dichloromethane (30 mL) was added to dissolve it, and the aqueous phase was washed with saturated sodium bicarbonate solution until the pH of the aqueous phase was 7-8. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain 6-((((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-14) (28 mg, yield 45.6%).
LC-MS,M/Z(ESI):398.3[M+H]+ LC-MS, M/Z(ESI):398.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.51(t,1H),8.23(d,1H),7.94(d,1H),7.85(s,1H),7.81(d,1H),7.14(q,1H),3.74(s,3H),3.49(t,2H),2.41(d,3H),2.29–2.18(m,1H),2.14–2.03(m,4H),1.83–1.72(m,2H). 1 H NMR (400 MHz, DMSO-d6) δ9.51 (t, 1H), 8.23 (d, 1H), 7.94 (d, 1H), 7.85 (s, 1H), 7.81 (d, 1H), 7.14 (q, 1H), 3.74 (s, 3H), 3.49 (t, 2H), 2.41 (d, 3H), 2.29–2.18 (m, 1H), 2.14–2.03 (m, 4H), 1.83–1.72 (m, 2H).
实施例8化合物I-15的制备
Example 8 Preparation of Compound I-15
参考化合物I-14的制备方法，将中间体A2替换为中间体A3，得到化合物6-((((1R，3r，5S)-6,6-二氟双环[3.1.0]己基-3-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-15).Referring to the preparation method of compound I-14, intermediate A2 was replaced with intermediate A3 to obtain compound 6-((((1R, 3r, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-15).
LC-MS,M/Z(ESI):398.3[M+H]+ LC-MS, M/Z(ESI):398.3[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.46(t,1H),8.23(d,1H),7.95–7.92(d,1H),7.84(s,1H),7.81(d,1H),3.74(s,3H),3.42(dd,2H),2.75(dd,1H),2.41(d,3H),2.28–2.16(m,3H),2.15–2.00(m,2H),1.83–1.71(m,1H),1.48–1.41(m,1H). 1 H NMR (400 MHz, DMSO-d6) δ9.46 (t, 1H), 8.23 (d, 1H), 7.95–7.92 (d, 1H), 7.84 (s, 1H), 7.81 (d, 1H), 3.74 (s, 3H), 3.42 (dd, 2H), 2.75 (dd, 1H), 2.41 (d, 3H), 2.28–2.16 (m, 3H), 2.15–2.00 (m, 2H), 1.83–1.71 (m, 1H), 1.48–1.41 (m, 1H).
实施例9化合物I-16的制备Example 9 Preparation of Compound I-16
合成路线如下所示：
The synthetic route is as follows:
第一步：6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B16-2)的合成
Step 1: Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B16-2)
将5-溴-6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(中间体A4)(95.5mg,0.19mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(70.5mg，0.19mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护，120℃反应过夜。反应结束后，反应液冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B16-2)(68mg，产率：71.1％)。5-Bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (Intermediate A4) (95.5 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-methyl-4-(tri-n-butyltin)imidazole (70.5 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added. The mixture was protected by argon and reacted at 120°C overnight. After the reaction, the reaction solution was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, stirred for 30 minutes, and then water (20 mL) was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B16-2) (68 mg, yield: 71.1%).
LC-MS,M/Z(ESI):504.2[M+H]+ LC-MS, M/Z(ESI):504.2[M+H] +
第二步：6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-16)的合成
Step 2: Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-16)
将6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B16-2)(68mg,0.14mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温搅拌1小时。反应结束后，浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液洗至水相pH为7-8，有机相减压浓缩，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1),得到化合物6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-16)(31mg，产率59.9％)。6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B16-2) (68 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, the mixture is concentrated and dichloromethane (30 mL) is added to dissolve the mixture. The mixture is washed with saturated sodium bicarbonate solution until the pH of the aqueous phase is 7-8. The organic phase is concentrated under reduced pressure and the crude product is purified by silica gel chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain compound 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-16) (31 mg, yield 59.9%).
LC-MS,M/Z(ESI):384.5[M+H]+。LC-MS, M/Z (ESI): 384.5 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.47(d,1H),8.26(d,1H),7.94(d,1H),7.83(s,1H),7.81(d,1H),7.15(q,1H),4.50(dt,1H),3.74(s,3H),2.48–2.42(m,2H),2.41(d,3H),2.23–2.20(m,1H),2.18(d,1H),1.90(ddd,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (d, 1H), 8.26 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.81 (d, 1H), 7.15 (q, 1H), 4.50 (dt, 1H), 3.74 (s, 3H), 2.48–2.42 (m, 2H), 2.41 (d, 3H), 2.23–2.20 (m, 1H), 2.18 (d, 1H), 1.90 (ddd, 2H).
实施例10化合物I-17的制备
Example 10 Preparation of Compound I-17
参考化合物I-16的制备方法，将中间体A4替换为中间体A5，得到化合物6-(((1R，3r，5S)-6,6-二氟双环[3.1.0]己基-3-基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-17).Referring to the preparation method of compound I-16, intermediate A4 was replaced with intermediate A5 to obtain compound 6-(((1R, 3r, 5S)-6,6-difluorobicyclo[3.1.0]hexyl-3-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-17).
LC-MS,M/Z(ESI):384.1[M+H]+。 LC-MS, M/Z (ESI): 384.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.58(d,1H),8.25(d,1H),7.93(d,1H),7.83(s,1H),7.79(d,1H),7.16(q,1H),4.88–4.74(m,1H),3.73(s,3H),2.71–2.57(m,2H),2.41(d,3H),2.27–2.22(m,1H),2.21–2.16(m,1H),1.51(dd,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.58 (d, 1H), 8.25 (d, 1H), 7.93 (d, 1H), 7.83 (s, 1H), 7.79 (d, 1H), 7.16 (q, 1H), 4.88–4.74 (m, 1H), 3.73 (s, 3H), 2.71–2.57 (m, 2H), 2.41 (d, 3H), 2.27–2.22 (m, 1H), 2.21–2.16 (m, 1H), 1.51 (dd, 2H).
实施例11：化合物I-24的制备Example 11: Preparation of Compound I-24
合成路线如下所示：
The synthetic route is as follows:
第一步：(1R,5S,6r)-3,3-二氟环[3.1.0]己烷-6-甲酸乙酯(B24-2)的合成
Step 1: Synthesis of (1R,5S,6r)-3,3-difluorocyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B24-2)
化合物(1R,5S,6r)-3,3-二氟环[3.1.0]己烷-6-甲酸乙酯(B24-2)的合成参考专利US20150023913A1，以环戊-3-烯-1-醇为原料进行合成。The synthesis of the compound (1R,5S,6r)-3,3-difluorocyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B24-2) was carried out according to patent US20150023913A1, using cyclopent-3-ene-1-ol as raw material.
第二步：(1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-甲酰胺(B24-3)的合成
Step 2: Synthesis of (1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-carboxamide (B24-3)
将(1R,5S,6r)-3,3-二氟环[3.1.0]己烷-6-甲酸乙酯(B24-2)(1.0g,5.3mmol)溶解在氨甲醇溶液(10mL,7M)中，室温搅拌两天。反应结束后，减压浓缩，得化合物(1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-甲酰胺(B24-3)(0.84g，收率99.0％)，直接用于下一步反应。Dissolve (1R,5S,6r)-3,3-difluorocyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B24-2) (1.0 g, 5.3 mmol) in ammonia methanol solution (10 mL, 7 M) and stir at room temperature for two days. After the reaction is completed, concentrate under reduced pressure to obtain compound (1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-carboxamide (B24-3) (0.84 g, yield 99.0%), which is directly used in the next step reaction.
第三步：((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲胺(B24-4)的合成
Step 3: Synthesis of ((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B24-4)
将(1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-甲酰胺(B24-3)(0.84g,5.2mmol)溶解在无水四氢呋喃(10mL)中，氩气保护下于0℃缓慢加入四氢铝锂(0.40g,10.4mmol),反应液升温至60℃搅拌过夜。反应结束后，反应液冷却至室温，0℃下加水(1mL)淬灭，搅拌15分钟，再加15％氢氧化钠溶液(0.5mL)，室温搅拌15分钟，过滤，乙酸乙酯(50mL)洗涤滤饼，滤液水洗(10mL)，再用无水硫酸钠干燥，过滤浓缩，得化合物((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲胺(B24-4)(0.57g，收率75.0％)。(1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-carboxamide (B24-3) (0.84 g, 5.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (0.40 g, 10.4 mmol) was slowly added at 0°C under argon protection, and the reaction solution was heated to 60°C and stirred overnight. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (1 mL) at 0°C, stirred for 15 minutes, and then 15% sodium hydroxide solution (0.5 mL) was added, stirred at room temperature for 15 minutes, filtered, and the filter cake was washed with ethyl acetate (50 mL), and the filtrate was washed with water (10 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound ((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B24-4) (0.57 g, yield 75.0%).
第四步：5-溴-6-((((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B24-5)的合成
Step 4: Synthesis of 5-bromo-6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B24-5)
将5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(A1)(182mg,0.45mmol)溶解于二甲基亚砜(2mL)中，加入((1R，5S，6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲胺(66mg，0.45mmol)与N,N-二异丙基乙胺(174mg，1.35mmol)，微波下120℃反应1小时。反应结束后，反应液冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再用无水硫酸钠干燥，过滤浓缩，粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:2)，得到化合物5-溴-6-(2-(1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B24-5)(105mg，产率45.0％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (A1) (182 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), ((1R, 5S, 6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methanamine (66 mg, 0.45 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added, and the mixture was reacted at 120 ° C under microwave for 1 hour. After the reaction, the reaction solution was cooled to room temperature, water (10 mL) was added, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined, washed with water (20 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3:2) to obtain compound 5-bromo-6-(2-(1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B24-5) (105 mg, yield 45.0%).
LC-MS,M/Z(ESI):517.1[M+H]+。LC-MS, M/Z (ESI): 517.1 [M+H] + .
第五步：6-((((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B24-6)的合成
Step 5: Synthesis of 6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B24-6)
将5-溴-6-(2-(1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B24-5)(100mg,0.19mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(70.5mg，0.19mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护下于120℃反应过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，先用水洗(20mL)，再用无水硫酸钠干燥，过滤浓缩，得到粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到化合物6-((((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B24-6)(80mg，产率79.8％)。5-Bromo-6-(2-(1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B24-5) (100 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-methyl-4-(tri-n-butyltin)imidazole (70.5 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added, and the reaction was carried out at 120 ° C under argon protection overnight. After the reaction, the mixture was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, and the mixture was stirred for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain compound 6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B24-6) (80 mg, yield 79.8%).
LC-MS,M/Z(ESI):518.3[M+H]+。LC-MS, M/Z (ESI): 518.3 [M+H] + .
第六步：6-((((1R，5S，6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-24)的合成
Step 6: Synthesis of 6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-24)
将6-((((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(80mg,0.15mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温搅拌1小时。反应结束后，反应液浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液(30mL*3)洗涤，有机相减压浓缩，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到化合物6-((((1R,5S,6r)-3,3-二氟双环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-24)(28mg，产率45.6％)。6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-yl)methyl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (80 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, and dichloromethane (30 mL) was added to dissolve it, and it was washed with a saturated sodium bicarbonate solution (30 mL*3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain compound 6-((((1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-24) (28 mg, yield 45.6%).
LC-MS,M/Z(ESI):398.3[M+H]+。LC-MS, M/Z (ESI): 398.3 [M+H] + .
1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.44(d,1H),7.90(d,1H),7.49(s,1H),7.30(d,1H),4.58(d,1H),3.75(s,3H),3.45(dd,2H),2.65(d,3H),2.44–2.29(m,2H),2.25–2.14(m,2H),1.39(s,2H),1.22–1.15(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 8.44 (d, 1H), 7.90 (d, 1H), 7.49 (s, 1H), 7.30 (d, 1H), 4.58 (d, 1H), 3.75 (s, 3H), 3.45 (dd, 2H), 2.65 (d, 3H), 2.44–2.29 (m, 2H), 2.25–2.14 (m, 2H), 1.39 (s, 2H), 1.22–1.15 (m, 1H).
实施例12：化合物I-25的合成 Example 12: Synthesis of Compound I-25
合成路线如下所示
The synthetic route is shown below
第一步：5-溴-6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B25-1)的合成
Step 1: Synthesis of 5-bromo-6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B25-1)
将5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(中间体A1)(182mg,0.45mmol)溶解于二甲基亚砜(2mL)中，加入Rel-(1R,5S,6r)-3,3-二氟双环[3.1.0]己-6-胺(WO2017202742)(66mg，0.45mmol)与N,N-二异丙基乙胺(174mg，1.35mmol)，微波下120℃搅拌1小时。反应结束后，反应液冷却至室温，加水(10mL)、乙酸乙酯(20mL×3)萃取，合并有机相，先用水洗(20mL)，再用无水硫酸钠干燥，过滤浓缩，得到粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:2)，得到化合物5-溴-6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B25-1)(105mg，产率45.0％)。5-Bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (Intermediate A1) (182 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and Rel-(1R,5S,6r)-3,3-difluorobicyclo[3.1.0]hexan-6-amine (WO2017202742) (66 mg, 0.45 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added, and the mixture was stirred at 120 ° C for 1 hour under microwave. After the reaction, the reaction solution was cooled to room temperature, extracted with water (10 mL) and ethyl acetate (20 mL×3), and the organic phases were combined, washed with water (20 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3:2) to obtain compound 5-bromo-6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B25-1) (105 mg, yield 45.0%).
第五步：6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B25-2)的合成
Step 5: Synthesis of 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B25-2)
将5-溴-6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(100mg,0.19mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(70.5mg，0.19mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护下于120℃反应过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，先用水洗(20mL)，再用无水硫酸钠干燥，过滤浓缩，得到粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到化合物6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B25-2)(80mg，产率79.8％)。5-Bromo-6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (100 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-methyl-4-(tri-n-butyltin)imidazole (70.5 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added, and the reaction was carried out at 120 ° C under argon protection overnight. After the reaction, the mixture was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, and the mixture was stirred for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain compound 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B25-2) (80 mg, yield 79.8%).
第六步：6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-25)的合成
Step 6: Synthesis of 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-25)
将6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(80mg,0.15mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温搅拌1小时。反应结束后，反应液浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液(30mL*3)洗涤，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到化合物6-((3,3-二氟双环[3.1.0]己烷-6-基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-25)(28mg，产率45.6％)。 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (80 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, and dichloromethane (30 mL) was added to dissolve it, and it was washed with saturated sodium bicarbonate solution (30 mL*3). The crude product was purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain compound 6-((3,3-difluorobicyclo[3.1.0]hexane-6-yl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-25) (28 mg, yield 45.6%).
LC-MS,M/Z(ESI):383.2[M+H]+。LC-MS, M/Z (ESI): 383.2 [M+H] + .
1H NMR(400MHz,CDCl3)δ9.44(d,1H),8.30(d,1H),7.94(d,1H),7.80(s,2H),7.17-7.14(m,1H),3.71(s,3H),2.73(s,1H),2.49-2.47(m,2H),2.40(d,3H),2.30–2.26(m,2H),1.57(s,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.44 (d, 1H), 8.30 (d, 1H), 7.94 (d, 1H), 7.80 (s, 2H), 7.17-7.14 (m, 1H), 3.71 (s, 3H), 2.73 (s, 1H), 2.49-2.47 (m, 2H), 2.40 (d, 3H), 2.30–2.26 (m, 2H), 1.57 (s, 2H).
实施例13：目标化合物I-28的制备Example 13: Preparation of target compound I-28
合成路线如下所示：
The synthetic route is as follows:
第一步：((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲醇(B28-2)的合成
Step 1: Synthesis of ((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methanol (B28-2)
将(1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-甲酸甲酯(A2-2a)(0.98g,5.6mmol)溶解在无水四氢呋喃(10mL)中，氩气保护，0℃加入四氢铝锂(0.43g,11.2mmol),再回流反应过夜。反应结束后，冷却至室温，0℃加水(1mL)淬灭，搅拌15分钟，再加15％氢氧化钠溶液(0.5mL)，室温搅拌15分钟，过滤，乙酸乙酯洗滤饼，滤液水洗(10mL)，再无水硫酸钠干燥，有机相减压浓缩，得黄色油状粗品((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲醇(B28-2)(0.6g，收率72.2％)，直接用于下一步反应。(1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid methyl ester (A2-2a) (0.98 g, 5.6 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium aluminum tetrahydride (0.43 g, 11.2 mmol) was added at 0°C under argon protection, and the reaction was refluxed overnight. After the reaction was completed, it was cooled to room temperature, quenched with water (1 mL) at 0°C, stirred for 15 minutes, and then 15% sodium hydroxide solution (0.5 mL) was added, stirred at room temperature for 15 minutes, filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with water (10 mL), and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a yellow oily crude product ((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methanol (B28-2) (0.6 g, yield 72.2%), which was directly used in the next step.
第二步：5-溴-6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己-3-基)甲氧基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B28-3)的合成
Step 2: Synthesis of 5-bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B28-3)
将((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲醇(B28-2)(67mg,0.45mmol)溶解于N,N-二甲基甲酰胺(5mL)，氩气保护，0℃搅拌，加入钠氢(54mg，1.35mmol,60％)，搅拌30分钟，加入5-溴-6-氯-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(182mg,0.45mmol)，室温搅拌2小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再用无水硫酸钠干燥，有机相减压浓缩，粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:2)，得到白色固体5-溴-6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己-3-基)甲氧基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B28-3)(103mg，产率：44.2％)。Dissolve ((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methanol (B28-2) (67 mg, 0.45 mmol) in N,N-dimethylformamide (5 mL), protect with argon, stir at 0°C, add sodium hydrogen sulfide (54 mg, 1.35 mmol, 60%), stir for 30 minutes, add 5-bromo-6-chloro-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (182 mg, 0.45 mmol), and stir at room temperature for 2 hours. After the reaction, the mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3:2) to obtain a white solid 5-bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B28-3) (103 mg, yield: 44.2%).
LC-MS,M/Z(ESI):517.2[M+H]+。LC-MS, M/Z (ESI): 517.2 [M+H] + .
第三步：6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲氧基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B28-4)的合成
Step 3: Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B28-4)
将5-溴-6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己-3-基)甲氧基)-N-(4-甲氧基苄基)-N-甲基吡啶-3-磺酰胺(B28-3)(98mg,0.19mmol)溶解于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(70.5mg，0.19mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护下于120℃搅拌过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，过滤浓缩，粗品用硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲氧基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B28-4)(79.8mg，产率：81.2％)。LC-MS,M/Z(ESI):519.3[M+H]+。5-Bromo-6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hex-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methylpyridine-3-sulfonamide (B28-3) (98 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-methyl-4-(tri-n-butyltin)imidazole (70.5 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added, and the mixture was stirred at 120 °C overnight under argon protection. After the reaction, the mixture was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, stirred for 30 minutes, water (20 mL) was added, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B28-4) (79.8 mg, yield: 81.2%). LC-MS, M/Z (ESI): 519.3 [M+H] + .
第四步：6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲氧基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺胺(I-28)的合成
Step 4: Synthesis of 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-28)
将6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲氧基)-N-(4-甲氧基苄基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(B28-4)(79.8mg,0.15mmol)溶解在二氯甲烷(5mL)中，加入三氟乙酸(3mL)，室温搅拌1小时。反应结束后，浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液洗至水相pH＝7-8，有机相减压浓缩，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1)，得到化合物6-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)甲氧基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺胺(I-28)(31.4mg，产率：51.2％)。6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-(4-methoxybenzyl)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (B28-4) (79.8 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, the mixture is concentrated and dissolved in dichloromethane (30 mL). The mixture is washed with saturated sodium bicarbonate solution until the aqueous phase has a pH of 7-8. The organic phase is concentrated under reduced pressure and the crude product is purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain compound 6-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)methoxy)-N-methyl-5-(1-methyl-1H-imidazole-4-yl)pyridine-3-sulfonamide (I-28) (31.4 mg, yield: 51.2%).
LC-MS,M/Z(ESI):399.2[M+H]+ LC-MS, M/Z(ESI):399.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.67(d,1H),8.34(d,1H),7.77(d,1H),7.61–7.51(m,2H),4.41(d,2H),3.75(s,3H),2.47(s,1H),2.43(d,3H),2.23–2.12(m,4H),1.98–1.88(m,2H). 1 H NMR (400 MHz, DMSO-d6) δ8.67 (d, 1H), 8.34 (d, 1H), 7.77 (d, 1H), 7.61–7.51 (m, 2H), 4.41 (d, 2H), 3.75 (s, 3H), 2.47 (s, 1H), 2.43 (d, 3H), 2.23–2.12 (m, 4H), 1.98–1.88 (m, 2H).
实施例14：化合物I-30的制备Example 14: Preparation of Compound I-30
合成路线如下所示：
The synthetic route is as follows:
第一步：5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基吡嗪-2-磺酰胺(30-2)的合成
Step 1: Synthesis of 5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (30-2)
将5-氯-N-甲基吡嗪-2-磺酰胺(A7，93mg,0.45mmol)溶解于二甲基亚砜(2mL)中，加入粗品(1R,3s,5S)-6,6-二氟双环[3.1.0]己烷-3-胺盐酸盐(84.8mg，0.5mmol)与N,N-二异丙基乙胺(174mg，1.35mmol)，微波 120℃反应1.5小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，依次水洗(20mL)和无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得到化合物5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基吡嗪-2-磺酰胺(B30-1)(103mg，产率75.2％)。5-Chloro-N-methylpyrazine-2-sulfonamide (A7, 93 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and crude (1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-amine hydrochloride (84.8 mg, 0.5 mmol) and N,N-diisopropylethylamine (174 mg, 1.35 mmol) were added and heated under microwave evaporation. The mixture was reacted at 120°C for 1.5 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3:1) to obtain compound 5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (B30-1) (103 mg, yield 75.2%).
LC-MS,M/Z(ESI):305.1[M+H]+ LC-MS, M/Z(ESI):305.1[M+H] +
第二步：6-溴-5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基吡嗪-2-磺酰胺(B30-2)的合成
Step 2: Synthesis of 6-bromo-5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (B30-2)
将5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基吡嗪-2-磺酰胺(B30-1，103mg,0.34mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N-溴代琥珀酰亚胺(90.8mg，0.51mmol)，室温反应过夜。反应结束后，加水(20mL)，再加乙酸乙酯(20mL×3)萃取，合并有机相，依次用水(20mL)洗和无水硫酸钠干燥，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝4:1)，得到化合物6-溴-5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基吡嗪-2-磺酰胺(B30-2)(101.8mg，产率：78.5％)。5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (B30-1, 103 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (10 mL), N-bromosuccinimide (90.8 mg, 0.51 mmol) was added, and the reaction was allowed to react at room temperature overnight. After the reaction, water (20 mL) was added, followed by extraction with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 4:1) to obtain compound 6-bromo-5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (B30-2) (101.8 mg, yield: 78.5%).
LC-MS,M/Z(ESI):383.1[M+H]+。LC-MS, M/Z (ESI): 383.1 [M+H] + .
第三步：5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡嗪-2-磺酰胺(I-30)的合成
Step 3: Synthesis of 5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-30)
将6-溴-5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基吡嗪-2-磺酰胺(101.8mg,0.27mmol)溶解于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(118.7mg，0.32mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护下于120℃反应过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，混合液用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水洗(20mL)和无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到化合物5-(((1R，3s，5S)-6,6-二氟双环[3.1.0]己烷-3-基)氨基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡嗪-2-磺酰胺(I-30)(58mg，产率：56.8％)。6-Bromo-5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methylpyrazine-2-sulfonamide (101.8 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-methyl-4-(tri-n-butyltin)imidazole (118.7 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added, and the reaction was carried out at 120 ° C overnight under argon protection. After the reaction, the mixture was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, stirred for 30 minutes, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain compound 5-(((1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-yl)amino)-N-methyl-6-(1-methyl-1H-imidazole-4-yl)pyrazine-2-sulfonamide (I-30) (58 mg, yield: 56.8%).
LC-MS,M/Z(ESI):385.2[M+H]+。LC-MS, M/Z (ESI): 385.2 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.79(d,1H),8.31(s,1H),7.90(s,2H),7.35(q,1H),4.43(dt,1H),3.79(s,3H),2.56(d,3H),2.50–2.43(m,2H),2.22(dt,2H),1.96(ddd,2H). 1 H NMR (400 MHz, DMSO-d6) δ9.79 (d, 1H), 8.31 (s, 1H), 7.90 (s, 2H), 7.35 (q, 1H), 4.43 (dt, 1H), 3.79 (s, 3H), 2.56 (d, 3H), 2.50–2.43 (m, 2H), 2.22 (dt, 2H), 1.96 (ddd, 2H).
实施例15：化合物I-36的制备Example 15: Preparation of Compound I-36
合成路线如下所示：
The synthetic route is as follows:
第一步：N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(B36-2)的合成
Step 1: Synthesis of N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (B36-2)
将5-氯-N-甲基-吡嗪-2-磺酰胺(中间体A7，200mg,963μmol)和(3-(三氟甲基)苯基)甲胺(B36-1，168mg,963μmol)溶解在N,N-二甲基甲酰胺(10.0mL)中，加N,N-二异丙基乙胺(373mg,2.89mmol)，25℃搅拌反应2小时。将反应液加到水(200mL)中，然后用乙酸乙酯(100mL×3)萃取，无水硫酸钠干燥，过滤浓缩得到粗品化合物N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰(B36-2)(200mg，产率59.9％)。5-Chloro-N-methyl-pyrazine-2-sulfonamide (intermediate A7, 200 mg, 963 μmol) and (3-(trifluoromethyl)phenyl)methylamine (B36-1, 168 mg, 963 μmol) were dissolved in N,N-dimethylformamide (10.0 mL), and N,N-diisopropylethylamine (373 mg, 2.89 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was added to water (200 mL), and then extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonyl (B36-2) (200 mg, yield 59.9%).
第二步：6-溴-N-甲基-5-((3-(三氟甲基)苄基)氨基]吡嗪-2-磺酰胺(B36-3)
Step 2: 6-Bromo-N-methyl-5-((3-(trifluoromethyl)benzyl)amino]pyrazine-2-sulfonamide (B36-3)
将N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(B36-2，200mg,577μmol)和二异丙基乙胺(224mg,1.73mmol)溶解在N,N-二甲基甲酰胺(10mL)中，加N-溴琥珀酰胺(102mg,577μmol)，25℃搅拌反应2小时。将反应液倒入水中(50mL)，用乙酸乙酯(50mL×2)萃取，有机相干燥浓缩，得到粗品化合物6-溴-N-甲基-5-[[3-(三氟甲基)苯基]甲基氨基]吡嗪-2-磺酰胺(B36-3)(150mg，产率61.1％)。N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (B36-2, 200 mg, 577 μmol) and diisopropylethylamine (224 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinamide (102 mg, 577 μmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was dried and concentrated to obtain a crude compound 6-bromo-N-methyl-5-[[3-(trifluoromethyl)phenyl]methylamino]pyrazine-2-sulfonamide (B36-3) (150 mg, yield 61.1%).
第三步：6-(6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)-N-甲基-5-((3-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(化合物I-36)
Step 3: 6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (Compound I-36)
将6-溴-N-甲基-5-[[3-(三氟甲基)苯基]甲基氨基]吡嗪-2-磺酰胺(B36-3，100mg,235μmol)和2-(三丁基甲锡烷基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑(93.4mg,235μmol)溶解在甲苯(15mL)中，加入四(三苯基膦)钯(27.2mg,23.5μmol)，氮气置换三次，并于100℃下，反应6小时。反应液直接浓缩得到粗品，然后通过制备高效液相色谱进行纯化(柱子：Phenomenex luna C18 150*25mm*10um；溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：52％-82％，7分钟)，得到化合物6-(6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)-N-甲基-5-((3-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(化合物I-36)(13.0mg，产率10.5％)。6-Bromo-N-methyl-5-[[3-(trifluoromethyl)phenyl]methylamino]pyrazine-2-sulfonamide (B36-3, 100 mg, 235 μmol) and 2-(tributylstannyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (93.4 mg, 235 μmol) were dissolved in toluene (15 mL), tetrakis(triphenylphosphine)palladium (27.2 mg, 23.5 μmol) was added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 6 hours. The reaction solution was directly concentrated to obtain a crude product, which was then purified by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 52%-82%, 7 minutes) to obtain compound 6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (Compound I-36) (13.0 mg, yield 10.5%).
LC-MS,M/Z(ESI):453.3[M+H]+ LC-MS, M/Z(ESI):453.3[M+H] +
1H NMR(CDCl3,400MHz)δppm 8.44(s,1H),7.76(s,1H),7.69(s,1H),7.53-7.61(m,3H),7.44-7.51(m,2H),4.83(d,2H),4.09-4.26(m,2H),2.92-3.14(m,2H),2.66-2.76(m,5H)。 1 H NMR (CDCl 3 , 400 MHz) δ ppm 8.44 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.53-7.61 (m, 3H), 7.44-7.51 (m, 2H), 4.83 (d, 2H), 4.09-4.26 (m, 2H), 2.92-3.14 (m, 2H), 2.66-2.76 (m, 5H).
实施例16：化合物I-54的制备Example 16: Preparation of Compound I-54
合成路线如下所示：
The synthetic route is as follows:
将6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(80.0mg,154μmol)溶解在甲苯(20mL)中，加入四(三苯基膦)钯(17.8mg,15.4μmol)和三丁基-[(2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基]锡烷(116mg,169μmol)，氮气置换三次，并于100℃下，反应6小时。把反应液直接浓缩得到粗品，然后通过制备 高效液相色谱法进行纯化(柱子：Phenomenex luna C18 150*25mm*10μm；溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：52％-82％，7分钟)，得到化合物(R)-N-甲基-6-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(I-54)(15.0mg，产率19.9％)。6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (80.0 mg, 154 μmol) was dissolved in toluene (20 mL), tetrakis(triphenylphosphine)palladium (17.8 mg, 15.4 μmol) and tributyl-[(2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl]stannane (116 mg, 169 μmol) were added, nitrogen was replaced three times, and the reaction was carried out at 100°C for 6 hours. The reaction solution was directly concentrated to obtain a crude product, which was then prepared by Purification was performed by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10μm; solvent: A=water+formic acid (0.05%), B=acetonitrile; gradient: 52%-82%, 7 minutes) to obtain compound (R)-N-methyl-6-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (I-54) (15.0 mg, yield 19.9%).
1H NMR(DMSO-d6)δ:8.47(s,2H),8.23(s,1H),7.69(d,2H),7.64(s,1H),7.52-7.57(m,2H),5.45-5.52(m,1H),4.84(d,2H),4.41-4.47(m,1H),3.91(m,1H),2.57(br s,3H),1.54(d,3H) 1 H NMR (DMSO-d 6 )δ:8.47(s,2H),8.23(s,1H),7.69(d,2H),7.64(s,1H),7.52-7.57(m,2H),5.45-5.52(m,1H),4.84(d,2H),4.41-4.47(m,1H),3.91(m,1H),2.57(br s,3H),1.54(d,3H)
LC-MS,M/Z(ESI):469.1[M+H]+ LC-MS, M/Z(ESI):469.1[M+H] +
实施例17：化合物I-55的制备Example 17: Preparation of Compound I-55
合成路线如下所示：
The synthetic route is as follows:
将6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(100.0mg,235μmol)溶解在N,N-二甲基甲酰胺(1.0mL)中，加入四(三苯基膦)钯(27.2mg,23.5μmol)和N-甲基-4-(三丁基锡)咪唑(104.7mg,282.2μmol)，氩气置换三次，反应液于110℃下反应16小时。反应液冷却至室温，向其中加入饱和氟化钾水溶液(5mL)和乙酸乙酯(5mL)，搅拌30分钟后过滤，滤饼用乙酸乙酯(10mL)淋洗，收集滤液，分层，有机相水洗(5mL×2)，饱和食盐水洗(5mL)，无水硫酸钠干燥，过滤浓缩后用硅胶柱纯化(二氯甲烷：乙酸乙酯(V/V)＝5：1)后得到化合物N-甲基-6-(1-甲基-1-氢咪唑-4-基)-5-((4-(三氟甲基)苯甲基)氨基)吡嗪-2-磺酰胺(化合物I-55)(69.0mg，产率68.5％)。6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (100.0 mg, 235 μmol) was dissolved in N,N-dimethylformamide (1.0 mL), tetrakis(triphenylphosphine)palladium (27.2 mg, 23.5 μmol) and N-methyl-4-(tributyltin)imidazole (104.7 mg, 282.2 μmol) were added, and the argon atmosphere was replaced three times. The reaction solution was reacted at 110°C for 16 hours. The reaction solution was cooled to room temperature, and saturated potassium fluoride aqueous solution (5 mL) and ethyl acetate (5 mL) were added thereto. The mixture was stirred for 30 minutes and then filtered. The filter cake was rinsed with ethyl acetate (10 mL). The filtrate was collected and layered. The organic phase was washed with water (5 mL×2) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by silica gel column (dichloromethane: ethyl acetate (V/V) = 5:1) to obtain compound N-methyl-6-(1-methyl-1-hydroimidazole-4-yl)-5-((4-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (Compound I-55) (69.0 mg, yield 68.5%).
LC-MS,M/Z(ESI):427.0[M+H]+ LC-MS, M/Z(ESI):427.0[M+H] +
1H NMR(DMSO-d6)δ10.14(t,1H),8.26(s,1H),7.91(d,2H),7.67(d,2H),7.54(d,2H),7.35(q,1H),4.86(d,2H),3.78(s,3H),2.56(d,3H). 1 H NMR (DMSO-d6) δ 10.14 (t, 1H), 8.26 (s, 1H), 7.91 (d, 2H), 7.67 (d, 2H), 7.54 (d, 2H), 7.35 (q, 1H), 4.86 (d, 2H), 3.78 (s, 3H), 2.56 (d, 3H).
实施例18：化合物I-56的制备Example 18: Preparation of Compound I-56
合成路线如下所示：
The synthetic route is as follows:
将6-溴-N-甲基-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(118.4mg,0.28mmol)溶解于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(118.7mg，0.32mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护，120℃反应过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到N-甲基-6-(1-甲基-1H-咪唑-4-基)-5-((3-(三氟甲基)苄基)氨基)吡嗪-2-磺酰胺(I-56)(77.5mg，产率：65.3％)。Dissolve 6-bromo-N-methyl-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (118.4 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL), add N-methyl-4-(tri-n-butyltin)imidazole (118.7 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), protect with argon, and react at 120°C overnight. After the reaction, the mixture was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, and the mixture was stirred for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain N-methyl-6-(1-methyl-1H-imidazol-4-yl)-5-((3-(trifluoromethyl)benzyl)amino)pyrazine-2-sulfonamide (I-56) (77.5 mg, yield: 65.3%).
LC-MS,M/Z(ESI):427.1[M+H]+。LC-MS, M/Z (ESI): 427.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.15(t,1H),8.29(s,1H),7.94(d,1H),7.92(s,1H),7.72(s,1H),7.66(d,1H),7.62(d,1H),7.57(t,1H),7.38(q,1H),4.88(d,2H),3.80(s,3H),2.58(d,3H). 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (t, 1H), 8.29 (s, 1H), 7.94 (d, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.57 (t, 1H), 7.38 (q, 1H), 4.88 (d, 2H), 3.80 (s, 3H), 2.58 (d, 3H).
实施例19：目标化合物I-57的制备Example 19: Preparation of target compound I-57
合成路线如下所示：
The synthetic route is as follows:
第一步：3-(二氟甲基)-4-氟苯甲腈(B57-2)的合成
Step 1: Synthesis of 3-(difluoromethyl)-4-fluorobenzonitrile (B57-2)
将4-氟-3-甲酰基苯甲腈(1g,6.71mmol)溶于二氯甲烷(20mL)，0℃加入二乙胺基三氟化硫(3.24g,20.13mmol)，室温搅拌过夜。反应结束后，将反应液缓慢滴加至饱和碳酸氢钠水溶液，0℃搅拌20分钟，分液，水相用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩，得3-(二氟甲基)-4-氟苯甲腈(B57-2)(1.09g，产率：95.0％)，直接用于下一步反应。Dissolve 4-fluoro-3-formylbenzonitrile (1 g, 6.71 mmol) in dichloromethane (20 mL), add diethylaminosulfur trifluoride (3.24 g, 20.13 mmol) at 0°C, and stir at room temperature overnight. After the reaction is completed, slowly add the reaction solution dropwise to a saturated sodium bicarbonate aqueous solution, stir at 0°C for 20 minutes, separate the liquids, extract the aqueous phase with dichloromethane (20 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain 3-(difluoromethyl)-4-fluorobenzonitrile (B57-2) (1.09 g, yield: 95.0%), which is directly used in the next step.
第二步：(3-(二氟甲基)-4-氟苯基)甲胺(B57-3)的合成
Step 2: Synthesis of (3-(difluoromethyl)-4-fluorophenyl)methylamine (B57-3)
将3-(二氟甲基)-4-氟苯甲腈(B57-2)(1.09g，6.4mmol)溶于甲醇(20mL)，氮气保护下，加入湿的镍粉(0.2g)，氮气置换3次，再氢气置换3次，氢气球下室温反应过夜。反应结束后，过滤，滤液浓缩，得液体(3-(二氟甲基)-4-氟苯基)甲胺(B57-3)(1.03g，产率：92.3％)，直接用于下一步反应。3-(Difluoromethyl)-4-fluorobenzonitrile (B57-2) (1.09 g, 6.4 mmol) was dissolved in methanol (20 mL). Under nitrogen protection, wet nickel powder (0.2 g) was added, and the nitrogen was replaced 3 times, and then hydrogen was replaced 3 times. The reaction was carried out at room temperature under a hydrogen balloon overnight. After the reaction was completed, the filtrate was filtered and concentrated to obtain liquid (3-(difluoromethyl)-4-fluorophenyl)methylamine (B57-3) (1.03 g, yield: 92.3%), which was directly used for the next step reaction.
LC-MS,M/Z(ESI):176.2[M+H]+。LC-MS, M/Z (ESI): 176.2 [M+H] + .
第三步：5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B57-4)的合成
Step 3: Synthesis of 5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-4)
将5-氯-N-甲基吡嗪-2-磺酰胺(93mg,0.45mmol)溶解二甲基亚砜(2mL)中，加入(3-(二氟甲基)-4-氟苯基)甲胺(236.5mg，1.35mmol)与三乙胺(136.6mg,1.35mmol)，微波70℃反应1小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝3:1)，得到无色液体5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B57-4)(135.9mg，产率：87.2％)。5-Chloro-N-methylpyrazine-2-sulfonamide (93 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), (3-(difluoromethyl)-4-fluorophenyl)methylamine (236.5 mg, 1.35 mmol) and triethylamine (136.6 mg, 1.35 mmol) were added, and the mixture was reacted at 70°C for 1 hour in a microwave oven. After the reaction was completed, the mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 3:1) to obtain a colorless liquid 5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-4) (135.9 mg, yield: 87.2%).
LC-MS,M/Z(ESI):347.1[M+H]+。LC-MS, M/Z (ESI): 347.1 [M+H] + .
第四步：6-溴-5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B57-5)的合成
Step 4: Synthesis of 6-bromo-5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-5)
将5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基吡嗪-2-磺酰胺(121.3mg,0.35mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N-溴代琥珀酰亚胺(90.8mg，0.51mmol)，室温反应过夜。反应结束后，加水(20mL)，再加乙酸乙酯(20mL×3)萃取，合并有机相，水(20mL)洗，无水硫酸钠干燥有机相，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝4:1)，得到化合物6-溴-5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B57-5)(118.4mg，产率：79.5％)。5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (121.3 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (90.8 mg, 0.51 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was completed, water (20 mL) was added, and then ethyl acetate (20 mL×3) was added for extraction. The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 4:1) to obtain compound 6-bromo-5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-5) (118.4 mg, yield: 79.5%).
LC-MS,M/Z(ESI):425.1[M+H]+。LC-MS, M/Z (ESI): 425.1 [M+H] + .
第五步：5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡嗪-2-磺酰胺(I-57)的合成
Step 5: Synthesis of 5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-57)
将6-溴-5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B57-5，118.4mg,0.28mmol)溶解于N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(118.7mg，0.32mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护，120℃反应过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟，再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1)，得到5-((3-(二氟甲基)-4-氟苄基)氨基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡嗪-2-磺酰胺(I-57)(89.4mg，产率：75.3％)。Dissolve 6-bromo-5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methylpyrazine-2-sulfonamide (B57-5, 118.4 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL), add N-methyl-4-(tri-n-butyltin)imidazole (118.7 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), protect with argon, and react at 120°C overnight. After the reaction, the mixture was cooled to room temperature, saturated potassium fluoride aqueous solution (5 mL) was added, and the mixture was stirred for 30 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain 5-((3-(difluoromethyl)-4-fluorobenzyl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-57) (89.4 mg, yield: 75.3%).
LC-MS,M/Z(ESI):427.1[M+H]+。LC-MS, M/Z (ESI): 427.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.11(t,1H),8.30(s,1H),7.93(d,1H),7.91(s,1H),7.66–7.55(m,2H),7.41–7.31(m,2H),7.18(t,1H),4.81(d,2H),3.80(s,3H),2.58(d,3H). 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (t, 1H), 8.30 (s, 1H), 7.93 (d, 1H), 7.91 (s, 1H), 7.66–7.55 (m, 2H), 7.41–7.31 (m, 2H), 7.18 (t, 1H), 4.81 (d, 2H), 3.80 (s, 3H), 2.58 (d, 3H).
实施例20：化合物I-58的制备Example 20: Preparation of Compound I-58
合成路线如下所示：
The synthetic route is as follows:
第一步：3-(二氟甲基)苯甲腈(B58-2)的合成
Step 1: Synthesis of 3-(difluoromethyl)benzonitrile (B58-2)
将3-甲酰基苯甲腈(B58-1，1g,6.71mmol)溶于二氯甲烷(20mL)，0℃加入二乙胺基三氟化硫(3.24g,20.13mmol)，室温搅拌过夜。反应结束后，将反应液缓慢滴加至饱和碳酸氢钠水溶液，0℃搅拌20分钟， 分液，水相二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩，得3-(二氟甲基)苯甲腈(B58-2)(1.09g，产率：95.0％)，直接用于下一步反应。3-Formylbenzonitrile (B58-1, 1 g, 6.71 mmol) was dissolved in dichloromethane (20 mL), diethylaminosulfur trifluoride (3.24 g, 20.13 mmol) was added at 0°C, and stirred at room temperature overnight. After the reaction was completed, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution, and stirred at 0°C for 20 minutes. The liquids were separated, the aqueous phase was extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 3-(difluoromethyl)benzonitrile (B58-2) (1.09 g, yield: 95.0%), which was directly used in the next step reaction.
第二步：(3-(二氟甲基)苯基)甲胺(B58-3)的合成
Step 2: Synthesis of (3-(difluoromethyl)phenyl)methylamine (B58-3)
将3-(二氟甲基)苯甲腈(B58-2)(1.09g，6.4mmol)溶于甲醇(20mL)，氮气保护下，加入湿的镍粉(0.2g)，氮气置换3次，再氢气置换3次，氢气球下室温反应过夜。反应结束后，过滤，滤液浓缩，得液体(3-(二氟甲基)苯基)甲胺(B58-3)(1.03g，产率：92.3％)，直接用于下一步反应。LC-MS,M/Z(ESI):158.1[M+H]+。3-(Difluoromethyl)benzonitrile (B58-2) (1.09 g, 6.4 mmol) was dissolved in methanol (20 mL). Under nitrogen protection, wet nickel powder (0.2 g) was added, and the nitrogen was replaced 3 times, and then hydrogen was replaced 3 times. The reaction was carried out at room temperature overnight under a hydrogen balloon. After the reaction was completed, the filtrate was filtered and concentrated to obtain liquid (3-(difluoromethyl)phenyl)methylamine (B58-3) (1.03 g, yield: 92.3%), which was directly used for the next step reaction. LC-MS, M/Z (ESI): 158.1 [M+H] + .
第三步：5-((3-(二氟甲基)苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B58-4)的合成
Step 3: Synthesis of 5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-4)
将5-氯-N-甲基吡嗪-2-磺酰胺(B58-3)(93mg,0.45mmol)溶解二甲基亚砜(2mL)中，加入(3-(二氟甲基)苯基)甲胺(236.5mg，1.35mmol)与三乙胺(136.6mg,1.35mmol)，微波70℃反应1小时。反应结束后，冷却至室温，加水(10mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯＝3:1)，得到无色液体5-((3-(二氟甲基)苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B58-4)(135.9mg，产率：87.2％)。5-Chloro-N-methylpyrazine-2-sulfonamide (B58-3) (93 mg, 0.45 mmol) was dissolved in dimethyl sulfoxide (2 mL), and (3-(difluoromethyl)phenyl)methylamine (236.5 mg, 1.35 mmol) and triethylamine (136.6 mg, 1.35 mmol) were added, and the mixture was reacted at 70°C for 1 hour in a microwave oven. After the reaction was completed, the mixture was cooled to room temperature, and water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a colorless liquid 5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-4) (135.9 mg, yield: 87.2%).
LC-MS,M/Z(ESI):329.1[M+H]+。LC-MS, M/Z (ESI): 329.1 [M+H] + .
第四步：6-溴-5-((3-(二氟甲基)苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B58-5)的合成
Step 4: Synthesis of 6-bromo-5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-5)
将5-((3-(二氟甲基)苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B58-4)(121.3mg,0.35mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N-溴代琥珀酰亚胺(90.8mg，0.51mmol)，室温反应过夜。反应结束后，加水(20mL)，再加乙酸乙酯(20mL×3)萃取，合并有机相，水(20mL)洗，无水硫酸钠干燥有机相，硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝4:1)，得到化合物6-溴-5-((3-(二氟甲基)苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B58-5)(118.4mg，产率：79.5％)。5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-4) (121.3 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (90.8 mg, 0.51 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was completed, water (20 mL) was added, and then ethyl acetate (20 mL×3) was added for extraction, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 4:1) to obtain compound 6-bromo-5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-5) (118.4 mg, yield: 79.5%).
LC-MS,M/Z(ESI):407.0[M+H]+。LC-MS, M/Z (ESI): 407.0 [M+H] + .
第五步：5-((3-(二氟甲基)苄基)氨基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡嗪-2-磺酰胺(I-58)的合成
Step 5: Synthesis of 5-((3-(difluoromethyl)benzyl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-58)
将6-溴-5-((3-(二氟甲基)苄基)氨基)-N-甲基吡嗪-2-磺酰胺(B58-5)(118.4mg,0.28mmol)溶解N,N-二甲基甲酰胺(5mL)中，加入N-甲基-4-(三正丁基锡)咪唑(118.7mg，0.32mmol)与四(三苯基膦)钯(23mg，0.02mmol)，氩气保护，120℃反应过夜。反应结束后，冷却至室温，加饱和氟化钾水溶液(5mL)，搅拌30分钟， 再加水(20mL)，乙酸乙酯(20mL×3)萃取，合并有机相，水洗(20mL)，再无水硫酸钠干燥，浓缩，硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1)，得到5-((3-(二氟甲基)苄基)氨基)-N-甲基-6-(1-甲基-1H-咪唑-4-基)吡嗪-2-磺酰胺(I-58)(89.4mg，产率：75.3％)。Dissolve 6-bromo-5-((3-(difluoromethyl)benzyl)amino)-N-methylpyrazine-2-sulfonamide (B58-5) (118.4 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL), add N-methyl-4-(tri-n-butyltin)imidazole (118.7 mg, 0.32 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), protect with argon, and react at 120°C overnight. After the reaction is completed, cool to room temperature, add saturated potassium fluoride aqueous solution (5 mL), stir for 30 minutes, Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 5-((3-(difluoromethyl)benzyl)amino)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrazine-2-sulfonamide (I-58) (89.4 mg, yield: 75.3%).
LC-MS,M/Z(ESI):409.1[M+H]+。LC-MS, M/Z (ESI): 409.1 [M+H] + .
1H NMR(400MHz,DMSO)δ10.10(t,1H),8.27(s,1H),7.90(d,2H),7.53-7.42(m,4H),7.35(dd,1H),6.99(t,1H),4.83(d,2H),3.78(s,3H),2.56(d,3H). 1 H NMR (400 MHz, DMSO) δ 10.10 (t, 1H), 8.27 (s, 1H), 7.90 (d, 2H), 7.53-7.42 (m, 4H), 7.35 (dd, 1H), 6.99 (t, 1H), 4.83 (d, 2H), 3.78 (s, 3H), 2.56 (d, 3H).
实施例21：化合物I-59的制备Example 21: Preparation of Compound I-59
合成路线如下所示：
The synthetic route is as follows:
第一步：4-氟-N-(4-甲氧基苄基)-N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1，2-a]咪唑-2-基)苯磺酰胺(B59-1)的合成
Step 1: Synthesis of 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)benzenesulfonamide (B59-1)
将4-氟-N-(4-甲氧基苄基)-N-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯磺酰胺(A6-3)(1.14g,2.62mmol)与2-溴-5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑(0.52g,2.63mmol)溶于1,4-二氧六环(20mL)，再加入1,1’-双二苯基膦二茂铁二氯化钯(0.19g,0.26mmol)、碳酸钠(0.69g,6.49mmol)、水(4mL)。氮气置换3次，氮气保护下于100℃反应21小时。冷却至室温，减压浓缩除去溶剂，加水(40mL)，乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥。硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1至1:2)，得到化合物4-氟-N-(4-甲氧基苄基)-N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1，2-a]咪唑-2-基)苯磺酰胺(B59-1)(0.55g，产率：49.5％)。Dissolve 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (A6-3) (1.14 g, 2.62 mmol) and 2-bromo-5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazole (0.52 g, 2.63 mmol) in 1,4-dioxane (20 mL), and then add 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.19 g, 0.26 mmol), sodium carbonate (0.69 g, 6.49 mmol), and water (4 mL). Replace with nitrogen three times, and react at 100 ° C for 21 hours under nitrogen protection. Cool to room temperature, concentrate under reduced pressure to remove the solvent, add water (40 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V/V) = 1:1 to 1:2) gave compound 4-fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)benzenesulfonamide (B59-1) (0.55 g, yield: 49.5%).
LC-MS,M/Z(ESI):428.2[M+H]+。LC-MS, M/Z (ESI): 428.2 [M+H] + .
第二步：N-(4-甲氧基苄基)-N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑-2-基)-4-(4-(三氟甲基)苄基)氨基)苯磺酰胺(B59-2)的合成
Step 2: Synthesis of N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-(4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (B59-2)
将4-氟-N-(4-甲氧基苄基)-N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1，2-a]咪唑-2-基)苯磺酰胺(B59-1)(346.3mg,0.81mmol)与(4-(三氟甲基)苯基)甲胺(709mg,4.05mmol)溶于二甲基亚砜(3mL)，140℃微波反应2小时。冷却至室温，加入水(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，水洗(15mL)，饱和食盐水洗(15mL)，无水硫酸钠干燥。硅胶柱层析纯化(石油醚:乙酸乙酯(V/V)＝1:1至1:2)，得到化合物N-(4-甲氧基苄基)-N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑-2-基)-4-(4-(三氟甲基)苄基)氨基)苯磺酰胺(B59-2)(0.35g，产率：74.2％)。LC-MS,M/Z(ESI):583.2[M+H]+。4-Fluoro-N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)benzenesulfonamide (B59-1) (346.3 mg, 0.81 mmol) and (4-(trifluoromethyl)phenyl)methylamine (709 mg, 4.05 mmol) were dissolved in dimethyl sulfoxide (3 mL) and subjected to microwave reaction at 140°C for 2 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (15 mL), washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V/V) = 1:1 to 1:2) gave compound N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-(4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (B59-2) (0.35 g, yield: 74.2%). LC-MS, M/Z (ESI): 583.2 [M+H] + .
第三步：N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑-2-基)-4-((4-(三氟甲基)苄基)氨基)苯磺酰胺(I-59)的合成
Step 3: Synthesis of N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (I-59)
将N-(4-甲氧基苄基)-N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑-2-基)-4-(4-(三氟甲基)苄基)氨基)苯磺酰胺(B59-2)(0.35g,0.60mmol)溶解在二氯甲烷(20ml)中，加入三氟乙酸(20mL)，室温搅拌1小时。反应结束后，浓缩，再加二氯甲烷(30mL)溶解，用饱和碳酸氢钠溶液洗至水相pH为7至8，粗品用硅胶色谱柱纯化(二氯甲烷:甲醇(V/V)＝10:1)得到化合物N-甲基-3-(5,5a,6,6a-四氢环丙基[3,4]吡咯并[1,2-a]咪唑-2-基)-4-((4-(三氟甲基)苄基)氨基)苯磺酰胺(I-59)(136.7mg，产率：49.2％)。Dissolve N-(4-methoxybenzyl)-N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-(4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (B59-2) (0.35 g, 0.60 mmol) in dichloromethane (20 ml), add trifluoroacetic acid (20 mL), and stir at room temperature for 1 hour. After the reaction is completed, the mixture is concentrated and dissolved in dichloromethane (30 mL). The mixture is washed with saturated sodium bicarbonate solution until the pH of the aqueous phase is 7 to 8. The crude product is purified by silica gel column chromatography (dichloromethane: methanol (V/V) = 10:1) to obtain the compound N-methyl-3-(5,5a,6,6a-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]imidazol-2-yl)-4-((4-(trifluoromethyl)benzyl)amino)benzenesulfonamide (I-59) (136.7 mg, yield: 49.2%).
LC-MS,M/Z(ESI):463.0[M+H]+。LC-MS, M/Z (ESI): 463.0 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.24(t,1H),7.75(d,1H),7.71(d,2H),7.56(d,2H),7.50(s,1H),7.30(dd,1H),6.97(d,1H),6.58(d,1H),4.66(d,2H),4.25–4.14(m,1H),4.04(d,1H),2.46–2.38(m,2H),2.33(d,3H),1.25(dd,1H),0.61(d,1H). 1 H NMR (400 MHz, DMSO-d6) δ9.24 (t, 1H), 7.75 (d, 1H), 7.71 (d, 2H), 7.56 (d, 2H), 7.50 (s, 1H), 7.30 (dd, 1H), 6.97 (d, 1H), 6.58 (d, 1H), 4.66 (d, 2H), 4.25–4.14 (m, 1H), 4.04 (d, 1H), 2.46–2.38 (m, 2H), 2.33 (d, 3H), 1.25 (dd, 1H), 0.61 (d, 1H).
实施例22：化合物I-60的制备Example 22: Preparation of Compound I-60
合成路线如下所示：
The synthetic route is as follows:
第一步：2,4-二氟-N-((4-甲氧基苯基)甲基)-N-甲基-苯磺酰胺(B60-2)的合成
Step 1: Synthesis of 2,4-difluoro-N-((4-methoxyphenyl)methyl)-N-methyl-benzenesulfonamide (B60-2)
将2,4-二氟苯磺酰氯(B60-1)(10.0g,47.0mmol)溶解在二氯甲烷(100mL)中，加入三乙胺(14.2g,141mmol)和1-(4-甲氧基苯基)-N-甲基-甲胺(7.47g,49.3mmol)，反应液在20℃下搅拌1小时。反应结束后，向反应液中加入1M盐酸(100mL)，用二氯甲烷(200mL)萃取，有机相用饱和食盐水(200mL)洗涤，然后用无水硫酸钠干燥，过滤浓缩得到粗品化合物2,4-二氟-N-((4-甲氧基苯基)甲基)-N-甲基-苯磺酰胺(B60-2)(15.0g,产率97.4％)。2,4-difluorobenzenesulfonyl chloride (B60-1) (10.0 g, 47.0 mmol) was dissolved in dichloromethane (100 mL), triethylamine (14.2 g, 141 mmol) and 1-(4-methoxyphenyl)-N-methyl-methylamine (7.47 g, 49.3 mmol) were added, and the reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, 1M hydrochloric acid (100 mL) was added to the reaction solution, and it was extracted with dichloromethane (200 mL). The organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound 2,4-difluoro-N-((4-methoxyphenyl)methyl)-N-methyl-benzenesulfonamide (B60-2) (15.0 g, yield 97.4%).
第二步：2,4-二氟-3-碘-N-((4-甲氧基苯基)甲基)-N-甲基-苯磺酰胺(B60-3)的合成
Step 2: Synthesis of 2,4-difluoro-3-iodo-N-((4-methoxyphenyl)methyl)-N-methyl-benzenesulfonamide (B60-3)
将2,4-二氟-N-((4-甲氧基苯基)甲基)-N-甲基-苯磺酰胺(B60-2)(3.00g,9.16mmol)溶于四氢呋喃(60mL)中，降温至-70℃，在氮气保护下缓慢加入二异丙基氨基锂(5.50mL,2M)，反应液继续搅拌0.5小时，随后将碘(3.49g,13.7mmol)溶解在四氢呋喃(10.0mL)中，滴加到反应液中。反应液缓慢升温至0℃搅拌0.5小时。 反应结束后，将反应液倒入饱和氯化铵(100mL)中，用乙酸乙酯(100mL)萃取，用饱和食盐水(80.0mL)洗涤有机相，用硫酸钠干燥，过滤浓缩得到粗品化合物2,4-二氟-3-碘-N(-((4-甲氧基苯基)甲基))-N-甲基-苯磺酰胺(B60-3)(4.00g,产率96.3％)。Dissolve 2,4-difluoro-N-((4-methoxyphenyl)methyl)-N-methyl-benzenesulfonamide (B60-2) (3.00 g, 9.16 mmol) in tetrahydrofuran (60 mL), cool to -70°C, slowly add lithium diisopropylamide (5.50 mL, 2 M) under nitrogen protection, continue stirring the reaction solution for 0.5 hours, then dissolve iodine (3.49 g, 13.7 mmol) in tetrahydrofuran (10.0 mL) and add dropwise to the reaction solution. Slowly heat the reaction solution to 0°C and stir for 0.5 hours. After the reaction, the reaction solution was poured into saturated ammonium chloride (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (80.0 mL), dried over sodium sulfate, filtered and concentrated to give a crude compound 2,4-difluoro-3-iodo-N(-((4-methoxyphenyl)methyl))-N-methyl-benzenesulfonamide (B60-3) (4.00 g, yield 96.3%).
第三步：2,4-二氟-3-碘-N-甲基-苯磺酰胺(B60-4)的合成
Step 3: Synthesis of 2,4-difluoro-3-iodo-N-methyl-benzenesulfonamide (B60-4)
将2,4-二氟-3-碘-N(-((4-甲氧苯基)甲基))-N-甲基-苯磺酰胺(B60-3)(3.00g,6.62mmol)溶于三氟乙酸(30.0mL)中，反应液加热至70℃搅拌1小时。反应完毕后，把反应液加到碳酸钠溶液中(200mL)，然后用二氯甲烷(200mL)萃取，用饱和食盐水(200mL)洗涤有机相，然后用硫酸钠干燥，过滤浓缩得到粗品化合物2,4-二氟-3-碘-N-甲基-苯磺酰胺(B60-4)(2.00g,产率90.7％)。2,4-difluoro-3-iodo-N(-((4-methoxyphenyl)methyl))-N-methyl-benzenesulfonamide (B60-3) (3.00 g, 6.62 mmol) was dissolved in trifluoroacetic acid (30.0 mL), and the reaction solution was heated to 70°C and stirred for 1 hour. After the reaction was completed, the reaction solution was added to a sodium carbonate solution (200 mL), and then extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine (200 mL), and then dried with sodium sulfate, filtered and concentrated to obtain a crude compound 2,4-difluoro-3-iodo-N-methyl-benzenesulfonamide (B60-4) (2.00 g, yield 90.7%).
第四步：2-氟-3-碘-N-甲基-4((-((4-(三氟甲基)苯基))甲基氨基))苯磺酰胺(B60-5)的合成
Step 4: Synthesis of 2-fluoro-3-iodo-N-methyl-4-((-((4-(trifluoromethyl)phenyl))methylamino))benzenesulfonamide (B60-5)
将2,4-二氟-3-碘-N-甲基-苯磺酰胺(B66-4)(1.50g,4.50mmol)和(4-(三氟甲基)苯基)甲胺(788mg,4.50mmol)溶于二甲亚砜(20.0mL)中，加入N,N-二异丙基乙胺(2.33g,33.9μmol)，反应液在氮气保护下于105℃搅拌6小时。反应完毕后，把反应液加到1M盐酸(100mL)中，然后用乙酸乙酯(200mL)萃取，有机相用饱和食盐水(200mL)洗涤，然后用无水硫酸钠干燥，过滤浓缩得到粗品化合物2-氟-3-碘-N-甲基-4((-((4-(三氟甲基)苯基))甲基氨基))苯磺酰胺(B66-5)(400mg,产率18.1％)。2,4-difluoro-3-iodo-N-methyl-benzenesulfonamide (B66-4) (1.50 g, 4.50 mmol) and (4-(trifluoromethyl)phenyl)methylamine (788 mg, 4.50 mmol) were dissolved in dimethyl sulfoxide (20.0 mL), and N,N-diisopropylethylamine (2.33 g, 33.9 μmol) was added. The reaction solution was stirred at 105°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to 1M hydrochloric acid (100 mL), and then extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound 2-fluoro-3-iodo-N-methyl-4 ((-((4-(trifluoromethyl)phenyl))methylamino))benzenesulfonamide (B66-5) (400 mg, yield 18.1%).
第五步：2-氟-N-甲基-3(-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基))-4((-((4-(三氟甲基)苯基))甲基氨基))苯磺酰胺(I-60)的合成
Step 5: Synthesis of 2-fluoro-N-methyl-3(-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl))-4((-((4-(trifluoromethyl)phenyl))methylamino))benzenesulfonamide (I-60)
将2-氟-3-碘-N-甲基-4((-((4-(三氟甲基)苯基))甲基氨基))苯磺酰胺(B60-5)(100mg,204μmol)和三丁基-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)锡烷(84.6mg,204μmol)溶解于甲苯(40.0mL)中，氮气保护下加入四(三苯基膦)钯(23.6mg,20.4μmol)，反应液在氮气保护下于100℃搅拌3小时。反应完后将反应液冷至室温，直接浓缩得到粗品，然后通过制备高效液相色谱法进行分离(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+氨水，B＝乙腈；梯度：43％-73％)，得到化合物2-氟-N-甲基-3-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(I-60)(30.0mg，产率30.1％)。2-Fluoro-3-iodo-N-methyl-4-((-((4-(trifluoromethyl)phenyl))methylamino))benzenesulfonamide (B60-5) (100 mg, 204 μmol) and tributyl-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)stannane (84.6 mg, 204 μmol) were dissolved in toluene (40.0 mL), and tetrakis(triphenylphosphine)palladium (23.6 mg, 20.4 μmol) was added under nitrogen protection, and the reaction solution was stirred at 100 ° C for 3 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature and directly concentrated to obtain a crude product, which was then separated by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; solvent: A=water+ammonia water, B=acetonitrile; gradient: 43%-73%) to obtain compound 2-fluoro-N-methyl-3-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-60) (30.0 mg, yield 30.1%).
LC-MS,M/Z(ESI):483.1(M-H)+ LC-MS,M/Z(ESI):483.1(MH) +
1H NMR(CDCl3,400MHz)δ:7.59(br d,2H),7.45-7.50(m,3H),7.11(d,1H),6.27(d,1H),5.41-5.51(m,1H),4.57(s,2H),4.34-4.45(m,2H),3.86(m,1H),2.64(d,3H),1.68(d,3H) 1 H NMR (CDCl 3 , 400 MHz) δ: 7.59 (br d, 2H), 7.45-7.50 (m, 3H), 7.11 (d, 1H), 6.27 (d, 1H), 5.41-5.51 (m, 1H), 4.57 (s, 2H), 4.34-4.45 (m, 2H), 3.86 (m, 1H), 2.64 (d, 3H), 1.68 (d, 3H)
实施例23：化合物I-61的制备Example 23: Preparation of Compound I-61
合成路线如下所示：
The synthetic route is as follows:
第一步：5-溴-2,4-二氟-N-甲基-苯磺酰胺(B61-2)的合成
Step 1: Synthesis of 5-bromo-2,4-difluoro-N-methyl-benzenesulfonamide (B61-2)
将5-溴-2,4-二氟-苯磺酰氯(B61-1)(10.0g,64.3mmol)溶解在二氯甲烷(100mL)中，加入三乙胺(10.4g,102mmol)和甲胺盐酸盐(2.36g,34.9mmol)，反应液在20℃下搅拌1小时。反应结束后，向反应液中加入水(200mL)，用二氯甲烷(200mL)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，过滤浓缩得到粗品化合物5-溴-2,4-二氟-N-甲基-苯磺酰胺(B61-2)(8.0g,产率81.5％)。5-Bromo-2,4-difluoro-benzenesulfonyl chloride (B61-1) (10.0 g, 64.3 mmol) was dissolved in dichloromethane (100 mL), triethylamine (10.4 g, 102 mmol) and methylamine hydrochloride (2.36 g, 34.9 mmol) were added, and the reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, water (200 mL) was added to the reaction solution, extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, filtered and concentrated to obtain a crude compound 5-bromo-2,4-difluoro-N-methyl-benzenesulfonamide (B61-2) (8.0 g, yield 81.5%).
第二步：5-溴-2-氟-N-甲基-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(B61-3)的合成
Step 2: Synthesis of 5-bromo-2-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B61-3)
将5-溴-2,4-二氟-N-甲基-苯磺酰胺(B61-2)(3.00g,10.4mmol)和(4-(三氟甲基)苯基)甲胺(2.02g,11.5mmol)溶于二甲亚砜(20.0mL)中，加入N,N-二异丙基乙胺(5.42g,41.9μmol)，反应液在氮气保护下于100℃搅拌2小时。反应完毕后，把反应液加到碳酸钠溶液中(200mL)，然后用乙酸乙酯(200mL)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，过滤浓缩得到粗品化合物5-溴-2-氟-N-甲基-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(B61-3)(1.00g,产率21.6％)。5-Bromo-2,4-difluoro-N-methyl-benzenesulfonamide (B61-2) (3.00 g, 10.4 mmol) and (4-(trifluoromethyl)phenyl)methylamine (2.02 g, 11.5 mmol) were dissolved in dimethyl sulfoxide (20.0 mL), and N,N-diisopropylethylamine (5.42 g, 41.9 μmol) was added. The reaction solution was stirred at 100°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to sodium carbonate solution (200 mL), then extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, filtered and concentrated to obtain a crude compound 5-bromo-2-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B61-3) (1.00 g, yield 21.6%).
第三步：2-氟-N-甲基-5-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(I-61)的合成
Step 3: Synthesis of 2-fluoro-N-methyl-5-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-61)
将5-溴-2-氟-N-甲基-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(B61-3)(200mg,453μmol)和三丁基-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)锡烷(224mg,543μmol)溶解于甲苯(40.0mL)中，氮气保护下加入四(三苯基膦)钯(53.3mg,45.3μmol)，氮气保护下于100℃搅拌3小时。反应完后将反应液冷至室温，直接减压浓缩得到粗品，然后通过制备高效液相色谱法进行分离(柱子：Phenomenex lμna C18 150*25mm*10μm；溶剂：A＝水+三氟乙酸，B＝乙腈；梯度：38％-68％)，得到化合物2-氟-N-甲基-5-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(I-61)(30.0mg，产率12.3％)。5-Bromo-2-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B61-3) (200 mg, 453 μmol) and tributyl-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)stannane (224 mg, 543 μmol) were dissolved in toluene (40.0 mL), tetrakis(triphenylphosphine)palladium (53.3 mg, 45.3 μmol) was added under nitrogen protection, and the mixture was stirred at 100 °C for 3 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature and directly concentrated under reduced pressure to obtain a crude product, which was then separated by preparative high performance liquid chromatography (column: Phenomenex lμna C18 150*25mm*10μm; solvent: A=water+trifluoroacetic acid, B=acetonitrile; gradient: 38%-68%) to obtain compound 2-fluoro-N-methyl-5-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-61) (30.0 mg, yield 12.3%).
LC-MS,M/Z(ESI):485.2[M+H]+ LC-MS, M/Z(ESI):485.2[M+H] +
1H NMR(CDCl3,400MHz)δ:7.78(d,1H),7.61(br d,2H),7.48(br d,2H),6.93(s,1H),6.19(d,1H),5.36-5.53(m,1H),4.50-4.57(m,2H),4.46(br s,1H),4.32-4.40(m,1H),3.83(m,1H),2.66(s,3H),1.69(d,3H) 1 H NMR (CDCl 3 , 400 MHz) δ: 7.78 (d, 1H), 7.61 (br d, 2H), 7.48 (br d, 2H), 6.93 (s, 1H), 6.19 (d, 1H), 5.36-5.53 (m, 1H), 4.50-4.57 (m, 2H), 4.46 (br s, 1H), 4.32-4.40 (m, 1H), 3.83 (m, 1H), 2.66 (s, 3H), 1.69 (d, 3H)
实施例24：化合物I-62的制备Example 24: Preparation of Compound I-62
合成路线如下所示：
The synthetic route is as follows:
第一步：3-溴-4,5-二氟-苯磺酰氯(B62-2)的合成
Step 1: Synthesis of 3-bromo-4,5-difluoro-benzenesulfonyl chloride (B62-2)
第一部分：将氯化亚铜(142mg,1.44mmol)加入水(10.0mL)中，控制温度在-5℃至5℃，向其中滴加氯化亚砜(8.58g,72.1mmol)，反应1小时。第二部分：将3-溴-4,5-二氟苯胺(B62-1)(3.00g,14.4mmol)分批加到浓盐酸(40.0mL，12M)中，将亚硝酸钠(1.09g,15.8mmol)溶解到盐酸(6.0mL,12M)中滴加到上述反应液，滴加过程控制温度在-5℃至5℃之间，继续搅拌0.5小时。将第二部分的反应液加入到第一部分反应液中，反应过程控制温度在-5℃至5℃之间，反应液继续搅拌1小时。反应结束后，将反应液倒入水(30.0mL)中，用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(200mL)洗涤，然后用无水硫酸钠干燥，过滤浓缩得到化合物3-溴-4,5-二氟-苯磺酰氯(B62-2)(4.00g,产率95.1％)。Part 1: Add cuprous chloride (142 mg, 1.44 mmol) to water (10.0 mL), control the temperature between -5°C and 5°C, add thionyl chloride (8.58 g, 72.1 mmol) dropwise, and react for 1 hour. Part 2: Add 3-bromo-4,5-difluoroaniline (B62-1) (3.00 g, 14.4 mmol) to concentrated hydrochloric acid (40.0 mL, 12 M) in batches, dissolve sodium nitrite (1.09 g, 15.8 mmol) in hydrochloric acid (6.0 mL, 12 M) and add dropwise to the above reaction solution, control the temperature between -5°C and 5°C during the addition process, and continue stirring for 0.5 hours. Add the reaction solution of the second part to the reaction solution of the first part, control the temperature between -5°C and 5°C during the reaction process, and continue stirring the reaction solution for 1 hour. After the reaction, the reaction solution was poured into water (30.0 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 3-bromo-4,5-difluoro-benzenesulfonyl chloride (B62-2) (4.00 g, yield 95.1%).
第二步：3-溴-4,5-二氟-N-甲基-苯磺酰胺(B62-3)的合成
Step 2: Synthesis of 3-bromo-4,5-difluoro-N-methyl-benzenesulfonamide (B62-3)
将3-溴-4,5-二氟-苯磺酰氯(B62-2)(4.00g,13.7mmol)溶于二氯甲烷(10.0mL)中，加入N,N-二异丙基乙胺(5.55g,42.9mmol)和盐酸甲胺(1.02g,15.0mmol)，反应液在20℃下反应1小时。反应结束后，向反应液中加入盐酸(1mol/L，100mL)，用二氯甲烷(200mL)萃取，有机相用饱和食盐水(200mL)洗涤，然后用硫酸钠干燥，过滤浓缩得到粗品化合物3-溴-4,5-二氟-N-甲基-苯磺酰胺(B62-3)(2.30g,产率58.5％)。3-Bromo-4,5-difluoro-benzenesulfonyl chloride (B62-2) (4.00 g, 13.7 mmol) was dissolved in dichloromethane (10.0 mL), and N,N-diisopropylethylamine (5.55 g, 42.9 mmol) and methylamine hydrochloride (1.02 g, 15.0 mmol) were added, and the reaction solution was reacted at 20°C for 1 hour. After the reaction was completed, hydrochloric acid (1 mol/L, 100 mL) was added to the reaction solution, and it was extracted with dichloromethane (200 mL), and the organic phase was washed with saturated brine (200 mL), then dried with sodium sulfate, filtered and concentrated to obtain a crude compound 3-bromo-4,5-difluoro-N-methyl-benzenesulfonamide (B62-3) (2.30 g, yield 58.5%).
第三步：3-溴-5-氟-N-甲基-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(B62-4)的合成
Step 3: Synthesis of 3-bromo-5-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B62-4)
将3-溴-4,5-二氟-N-甲基-苯磺酰胺(B62-3)(1.2g,4.19mmol)溶于二甲亚砜(20.0mL)中，加入N,N-二异丙基乙胺(1.63g,12.5mmol)和(4-(三氟甲基)苯基)甲胺(734mg,4.19mmol)，反应液在氮气保护下于120℃搅拌2小时。反应完毕后，把反应液加到盐酸(1mol/L，100mL)中，然后用乙酸乙酯(200mL)萃取，用饱和食盐水(200mL)洗涤有机相，无水硫酸钠干燥，减压浓缩得到粗品化合物3-溴-5-氟-N-甲基-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(B62-4)(1.50g,产率81.0％)。3-Bromo-4,5-difluoro-N-methyl-benzenesulfonamide (B62-3) (1.2 g, 4.19 mmol) was dissolved in dimethyl sulfoxide (20.0 mL), and N,N-diisopropylethylamine (1.63 g, 12.5 mmol) and (4-(trifluoromethyl)phenyl)methylamine (734 mg, 4.19 mmol) were added. The reaction solution was stirred at 120°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was added to hydrochloric acid (1 mol/L, 100 mL), then extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude compound 3-bromo-5-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B62-4) (1.50 g, yield 81.0%).
第五步：3-氟-N-甲基-5-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(I-62)的合成
Step 5: Synthesis of 3-fluoro-N-methyl-5-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-62)
将3-溴-5-氟-N-甲基-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(B62-4)(400mg,906μmol)和三丁基-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)锡烷(374mg,906μmol)溶解于甲苯(40.0mL)中，氮气保护下加入四(三苯基膦)钯(10.6mg,9.04μmol)，反应液在氮气保护下于100℃搅拌3小时。反应完毕后直接浓缩得到粗品，然后用制备高效液相色谱法进行分离(柱子：3_PhenomenexLuna C18 150*25mm*10μm；溶剂：A＝水+甲酸，B＝乙腈；梯度：55％-85％，7分钟)，得到化合物3-氟-N-甲基-5-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-4-((4-(三氟甲基)苯基)甲基氨基)苯磺酰胺(I-62)(30.0mg，产率6.23％)。3-Bromo-5-fluoro-N-methyl-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (B62-4) (400 mg, 906 μmol) and tributyl-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)stannane (374 mg, 906 μmol) were dissolved in toluene (40.0 mL), and tetrakis(triphenylphosphine)palladium (10.6 mg, 9.04 μmol) was added under nitrogen protection, and the reaction solution was stirred at 100 ° C for 3 hours under nitrogen protection. After the reaction is completed, the crude product is directly concentrated and then separated by preparative HPLC (column: 3_PhenomenexLuna C18 150*25mm*10μm; solvent: A=water+formic acid, B=acetonitrile; gradient: 55%-85%, 7 minutes) to obtain compound 3-fluoro-N-methyl-5-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-4-((4-(trifluoromethyl)phenyl)methylamino)benzenesulfonamide (I-62) (30.0 mg, yield 6.23%).
LC-MS,M/Z(ESI):485.2[M+H]+ LC-MS, M/Z(ESI):485.2[M+H] +
1H NMR(DMSO-d6)δ:8.43-8.51(m,1H),7.68(d,2H),7.58(d,1H),7.51(d,2H),7.39(s,1H),7.15-7.22(m,2H),5.43-5.52(m,1H),4.65-4.74(m,2H),4.39(d,1H),3.82-3.90(m,1H),2.35-2.39(m,3H),1.54(d,3H) 1 H NMR (DMSO-d 6 )δ:8.43-8.51(m,1H),7.68(d,2H),7.58(d,1H),7.51(d,2H),7.39(s,1H),7.15-7.22(m,2H),5.43-5.52(m,1H),4.65-4.74(m,2H),4.39(d,1H),3.82-3.90(m,1H),2.35-2.39(m,3H),1.54(d,3H)
实施例25：化合物I-63的制备Example 25: Preparation of Compound I-63
合成路线如下所示：
The synthetic route is as follows:
第一步：2-溴-6-氟-3-碘吡啶(B63-2)的合成
Step 1: Synthesis of 2-bromo-6-fluoro-3-iodopyridine (B63-2)
将2-溴-6-氟吡啶-3-胺(B63-1)(7.00g,36.6mmol)和碘化亚铜(13.9g,73.3mmol)加入乙腈(100mL)中，在0℃下加入叔丁基亚硝酸酯(2.67g,54.9mmol)，反应液升温至80℃搅拌10小时。反应液冷至室温后加到水(200mL)中，然后用乙酸乙酯(300mL)萃取，有机相用无水硫酸钠干燥，过滤浓缩，得到粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:0至10:1)，得到化合物2-溴-6-氟-3-碘吡啶(B63-2)(7.00g，产率46.8％)。2-Bromo-6-fluoropyridin-3-amine (B63-1) (7.00 g, 36.6 mmol) and cuprous iodide (13.9 g, 73.3 mmol) were added to acetonitrile (100 mL), tert-butyl nitrite (2.67 g, 54.9 mmol) was added at 0°C, and the reaction solution was heated to 80°C and stirred for 10 hours. The reaction solution was cooled to room temperature and added to water (200 mL), then extracted with ethyl acetate (300 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 1:0 to 10:1) to obtain compound 2-bromo-6-fluoro-3-iodopyridine (B63-2) (7.00 g, yield 46.8%).
第二步：6-(苯甲硫基)-2-溴-3-碘吡啶(B63-3)
Step 2: 6-(Benzylthio)-2-bromo-3-iodopyridine (B63-3)
将钠氢(1.12g,17.5mmol，60％)加入到四氢呋喃(100mL)中，氮气保护下加苄硫醇(2.18g,17.5mmol)，反应液在0℃搅拌1小时，再将2-溴-6-氟-3-碘吡啶(B63-2)(6.50g,15.9mmol)滴加到反应液中，25℃继续搅拌1小时。将反应液加到HCl(200mL，1M)中，然后用乙酸乙酯(300mL)萃取，有机相用无水硫酸钠干燥，过滤浓缩，得到粗品化合物6-(苯甲硫基)-2-溴-3-碘吡啶(B63-3)(7.0g)。Sodium hydride (1.12 g, 17.5 mmol, 60%) was added to tetrahydrofuran (100 mL), and benzyl mercaptan (2.18 g, 17.5 mmol) was added under nitrogen protection. The reaction solution was stirred at 0°C for 1 hour, and then 2-bromo-6-fluoro-3-iodopyridine (B63-2) (6.50 g, 15.9 mmol) was added dropwise to the reaction solution, and stirring was continued at 25°C for 1 hour. The reaction solution was added to HCl (200 mL, 1 M), and then extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound 6-(phenylmethylthio)-2-bromo-3-iodopyridine (B63-3) (7.0 g).
第三步：6-溴-5-碘吡啶-2-磺酰氯(B63-4)
Step 3: 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4)
将6-(苯甲硫基)-2-溴-3-碘吡啶(B63-3)(5.00g,12.3mmol)加入到乙腈(20.0mL)中，依次加入乙酸(3.70g,61.5mmol)、水(1.11g,61.5mmol)和二氯二甲基乙内酰脲(4.85g,24.6mmol)，反应液在20℃搅拌1小时。将反应液加到水(200mL)中，然后用乙酸乙酯(300mL)萃取，用饱和食盐水(200mL)洗涤有机相，硫酸钠干燥，过滤浓缩，得到粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至0:1)，得到粗品化合物6-溴-5-碘吡啶-2-磺酰氯(B63-4)(3.10g，产率65.8％)。6-(Benzylthio)-2-bromo-3-iodopyridine (B63-3) (5.00 g, 12.3 mmol) was added to acetonitrile (20.0 mL), and acetic acid (3.70 g, 61.5 mmol), water (1.11 g, 61.5 mmol) and dichlorodimethylhydantoin (4.85 g, 24.6 mmol) were added in sequence, and the reaction solution was stirred at 20°C for 1 hour. The reaction solution was added to water (200 mL), and then extracted with ethyl acetate (300 mL), and the organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1 to 0:1) to obtain a crude compound 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4) (3.10 g, yield 65.8%).
第四步：6-溴-5-碘-N-甲基吡啶-2-磺酰胺(B63-5)
Step 4: 6-Bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5)
将盐酸甲胺(821mg,12.1mmol)和三乙胺(2.46g,24.3mmol)加入到二氯甲烷(20.0mL)中，再加入6-溴-5-碘吡啶-2-磺酰氯(B63-4)(3.10g,8.11mmol)，反应液在25℃搅拌4小时。将反应液直接浓缩，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1至0:1)，得到化合物6-溴-5-碘-N-甲基吡啶-2-磺酰胺(B63-5)(1.50g，产率49.0％)。Methylamine hydrochloride (821 mg, 12.1 mmol) and triethylamine (2.46 g, 24.3 mmol) were added to dichloromethane (20.0 mL), and then 6-bromo-5-iodopyridine-2-sulfonyl chloride (B63-4) (3.10 g, 8.11 mmol) was added, and the reaction solution was stirred at 25°C for 4 hours. The reaction solution was directly concentrated, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain compound 6-bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5) (1.50 g, yield 49.0%).
第五步：6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡啶-2-磺酰胺(B63-6)
Step 5: 6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (B63-6)
将6-溴-5-碘-N-甲基吡啶-2-磺酰胺(B63-5)(1.50g,3.98mmol)和4-(三氟甲基)苯甲基胺(836mg,4.77mmol)加入到甲苯溶液(30.0mL)中，依次加入三(联苯亚甲基丙酮)二钯(3.10g,8.11mmol)、(1,1'-联萘)-2,2'-叉基二(二苯基膦)(99.1mg,159μmol)和叔丁醇钾(669mg,5.97mmol)，反应液在氮气保护下于80℃搅拌8小时。反应液冷至室温后减压浓缩，然后通过制备高效液相色谱法进行分离(柱子：Waters Xbridge150*25mm*5μm；溶剂：A＝水+氨水，B＝乙腈；梯度：38％-68％)，得到化合物6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡啶-2-磺酰胺(B63-6)(50.0mg，产率2.96％)。6-Bromo-5-iodo-N-methylpyridine-2-sulfonamide (B63-5) (1.50 g, 3.98 mmol) and 4-(trifluoromethyl)benzylamine (836 mg, 4.77 mmol) were added to a toluene solution (30.0 mL), and tris(biphenylmethyleneacetone)dipalladium (3.10 g, 8.11 mmol), (1,1'-binaphthyl)-2,2'-di(diphenylphosphine) (99.1 mg, 159 μmol) and potassium tert-butoxide (669 mg, 5.97 mmol) were added in sequence. The reaction solution was stirred at 80 ° C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and then separated by preparative HPLC (column: Waters Xbridge 150*25mm*5μm; solvent: A = water + ammonia water, B = acetonitrile; gradient: 38%-68%) to obtain compound 6-bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (B63-6) (50.0 mg, yield 2.96%).
第六步：(R)-N-甲基-6-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-5-((4-(三氟甲基)苯甲基)氨基)吡啶-2-磺酰胺(I-63)
Step 6: (R)-N-methyl-6-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (I-63)
将6-溴-N-甲基-5-((4-(三氟甲基)苯甲基)氨基)吡啶-2-磺酰胺(20.0mg,47.1μmol)溶解在甲苯(20.0mL)中，加入四(三苯基膦)钯(544μg,0.471μmol)、碘化亚铜(897μg,4.71μmol)和三丁基-((2R)-2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)锡烷(23.3mg,56.5μmol)，反应液在氮气保护下于100℃搅拌6小时。把反应液直接浓缩得到粗品。然后通过制备高效液相色谱法进行分离(柱子：Phenomenex lμna C18 150*25mm*10μm；-溶剂：A＝水+甲酸(0.05％)，B＝乙腈；梯度：52％-82％，7分钟)，得到化合物(R)-N-甲基-6-(2-甲基-2,3-二氢咪唑并[2,1-b]噁唑-6-基)-5-((4-(三氟甲基)苯甲基)氨基)吡啶-2-磺酰胺(I-63)(2.51mg，产率10.5％)。6-Bromo-N-methyl-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (20.0 mg, 47.1 μmol) was dissolved in toluene (20.0 mL), tetrakis(triphenylphosphine)palladium (544 μg, 0.471 μmol), cuprous iodide (897 μg, 4.71 μmol) and tributyl-((2R)-2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)stannane (23.3 mg, 56.5 μmol) were added, and the reaction solution was stirred at 100°C for 6 hours under nitrogen protection. The reaction solution was directly concentrated to obtain a crude product. Then, separation was carried out by preparative high performance liquid chromatography (column: Phenomenex lμna C18 150*25mm*10μm; - solvent: A = water + formic acid (0.05%), B = acetonitrile; gradient: 52%-82%, 7 minutes) to obtain compound (R)-N-methyl-6-(2-methyl-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-5-((4-(trifluoromethyl)benzyl)amino)pyridine-2-sulfonamide (I-63) (2.51 mg, yield 10.5%).
LC-MS,M/Z(ESI):468.3[M+H]+ LC-MS, M/Z(ESI):468.3[M+H] +
1H NMR(CDCl3)δ:8.95-9.21(m,1H),7.54-7.64(m,3H),7.42-7.51(m,3H),6.66-6.80(m,1H),5.33-5.53(m,1H),4.49-4.64(m,3H),4.36(m,1H),3.77-3.92(m,1H),2.62-2.76(m,3H),1.37(d,3H) 1 H NMR (CDCl 3 )δ:8.95-9.21(m,1H),7.54-7.64(m,3H),7.42-7.51(m,3H),6.66-6.80(m,1H),5.33-5.53(m,1H),4.49-4.64(m,3H),4.36(m,1H),3.77-3.92(m,1H),2.62-2.76(m,3H),1.37(d,3H)
实施例26：化合物I-64的制备Example 26: Preparation of Compound I-64
合成路线如下所示：
The synthetic route is as follows:
第一步：(1R,5S,6R)-2-氧基二环[3.1.0]己烷-6-甲酸乙酯(B64-2)的合成
Step 1: Synthesis of (1R,5S,6R)-2-oxybicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-2)
将(乙氧羰基甲基)二甲基溴化锍(5.05g,43.8mmol)和四甲基胍(5.05g,43.8mmol)溶解在乙腈(30mL)中，在25℃下搅拌10分钟，加入2-环戊烯-1-酮(B64-1)(10.0g,43.8mmol)，反应液在25℃下搅拌4小时。反应结束后，将反应液直接浓缩，得到粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝50:1至3:1)，得到化合物(1R,5S,6R)-2-氧基二环[3.1.0]己烷-6-甲酸乙酯(B64-2)(5.00g,收率81.3％)。(Ethoxycarbonylmethyl) dimethylsulfonium bromide (5.05 g, 43.8 mmol) and tetramethylguanidine (5.05 g, 43.8 mmol) were dissolved in acetonitrile (30 mL), stirred at 25°C for 10 minutes, 2-cyclopentene-1-one (B64-1) (10.0 g, 43.8 mmol) was added, and the reaction solution was stirred at 25°C for 4 hours. After the reaction, the reaction solution was directly concentrated to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether: ethyl acetate (V/V) = 50:1 to 3:1) to obtain compound (1R, 5S, 6R)-2-oxybicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-2) (5.00 g, yield 81.3%).
第二步：(1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-甲酸乙酯(B64-3)的合成
Step 2: Synthesis of (1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-3)
将(1R,5S,6R)-2-氧基二环[3.1.0]己烷-6-甲酸乙酯(B64-2)(5.00g,29.7mmol)溶于二氯甲烷(20.0mL)中，加入二乙胺基三氟化硫(9.58g,59.5mmol)，反应液于25℃下搅拌4小时。反应完毕后，将反应液减压浓缩，粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1至0:1)，得到化合物(1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-甲酸乙酯(B64-3)(5.00g,收率88.4％)。(1R,5S,6R)-2-oxybicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-2) (5.00 g, 29.7 mmol) was dissolved in dichloromethane (20.0 mL), diethylaminosulfur trifluoride (9.58 g, 59.5 mmol) was added, and the reaction solution was stirred at 25°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1 to 0:1) to obtain compound (1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-3) (5.00 g, yield 88.4%).
第三步：(1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-甲酰胺(B64-4)的合成
Step 3: Synthesis of (1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxamide (B64-4)
将(1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-甲酸乙酯(B64-3)(6.00g,34.0mmol)溶于氨的甲醇溶液(50.0mL)中，反应液缓慢升温至80℃搅拌6小时。反应完毕后，将反应液冷至室温，减压浓缩得到粗品化合物(1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-甲酰胺(B64-4)(4.00g,收率94.4％)。(1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (B64-3) (6.00 g, 34.0 mmol) was dissolved in ammonia methanol solution (50.0 mL), and the reaction solution was slowly heated to 80°C and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude compound (1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxamide (B64-4) (4.00 g, yield 94.4%).
第四步：((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲胺(B64-5)的合成
Step 4: Synthesis of ((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B64-5)
将(1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-甲酰胺(B64-4)(500mg,31.0mmol)溶于四氢呋喃(10.0mL)中，在0℃下加入四氢铝锂(1.49mL,2.5M)，反应液缓慢升温至50℃搅拌4小时。反应完毕后，向反应液中加入十水硫酸钠(5.00g),过滤，滤饼用乙酸乙酯(100mL)洗涤，滤液用无水硫酸钠干燥，过滤浓缩得到粗品化合物((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲胺(B64-5)(450mg，产率98.7％)。(1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-carboxamide (B64-4) (500 mg, 31.0 mmol) was dissolved in tetrahydrofuran (10.0 mL), and lithium aluminum tetrahydride (1.49 mL, 2.5 M) was added at 0°C. The reaction solution was slowly heated to 50°C and stirred for 4 hours. After the reaction was completed, sodium sulfate decahydrate (5.00 g) was added to the reaction solution, filtered, the filter cake was washed with ethyl acetate (100 mL), the filtrate was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude compound ((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methylamine (B64-5) (450 mg, yield 98.7%).
第五步：5-溴-6-((((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基吡啶-3-磺酰胺(B64-7)的合成
Step 5: Synthesis of 5-bromo-6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methylpyridine-3-sulfonamide (B64-7)
将5-溴-6-氯-N-甲基吡啶-3-磺酰胺(B64-6)(850mg,2.98mmol)溶于N,N-二甲基甲酰胺(50.0mL)中，加入((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲胺(B64-5)(438mg,2.98mmol)和N,N-二异丙基乙胺(1.15g,8.93mmol)，反应液在100℃下搅拌6小时。反应结束后，反应液冷至室温，加入水(50mL)，用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(100mL)洗涤，然后用无水硫酸钠干燥，过滤浓缩得到粗品，再用制备高效液相色谱法进行分离(柱子：Waters Xbridge 150*25mm*5um；溶剂：A＝水+氨水，B＝乙腈；梯度：28％-58％)，得到化合物5-溴-6-((((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基吡啶-3-磺酰胺(B64-7)(200mg，产率16.9％)。5-Bromo-6-chloro-N-methylpyridine-3-sulfonamide (B64-6) (850 mg, 2.98 mmol) was dissolved in N,N-dimethylformamide (50.0 mL), ((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methanamine (B64-5) (438 mg, 2.98 mmol) and N,N-diisopropylethylamine (1.15 g, 8.93 mmol) were added, and the reaction solution was stirred at 100 ° C for 6 hours. After the reaction, the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated by preparative HPLC (column: Waters Xbridge 150*25mm*5um; solvent: A=water+ammonia water, B=acetonitrile; gradient: 28%-58%) to obtain compound 5-bromo-6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methylpyridine-3-sulfonamide (B64-7) (200 mg, yield 16.9%).
第六步：6-((((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-64)的合成
Step 6: Synthesis of 6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-sulfonamide (I-64)
将5-溴-6-((((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基吡啶-3-磺酰胺(B64-7)(200mg,504μmol)和三丁基-(1-甲基咪唑-4-基)锡烷(187mg,504μmol)溶解于甲苯(30.0mL)中，氮气保护下加入四(三苯基膦)钯(58.3mg,50.4μmol)，反应液在氮气保护下于100℃搅拌4小时。反应结束后，向反应液中加入水(50mL)，用乙酸乙酯(100mL)萃取，用饱和食盐水(100mL)洗涤有机相，无水硫酸钠干燥，过滤浓缩得到粗品，再通过制备高效液相色谱法进行分离(柱子：C18 150×30mm；溶剂：A＝水+甲酸，B＝乙腈；梯度：25％-55％，7分钟)，得到化合物6-((((1R,5R,6R)-2,2-二氟二环[3.1.0]己烷-6-基)甲基)氨基)-N-甲基-5-(1-甲基-1H-咪唑-4-基)吡啶-3-磺酰胺(I-64)(104mg，产率52.3％)。5-Bromo-6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methylpyridine-3-sulfonamide (B64-7) (200 mg, 504 μmol) and tributyl-(1-methylimidazol-4-yl)stannane (187 mg, 504 μmol) were dissolved in toluene (30.0 mL), and tetrakis(triphenylphosphine)palladium (58.3 mg, 50.4 μmol) was added under nitrogen protection. The reaction solution was stirred at 100 ° C for 4 hours under nitrogen protection. After the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated by preparative HPLC (column: C18 150×30 mm; solvent: A = water + formic acid, B = acetonitrile; gradient: 25%-55%, 7 minutes) to obtain compound 6-((((1R,5R,6R)-2,2-difluorobicyclo[3.1.0]hexane-6-yl)methyl)amino)-N-methyl-5-(1-methyl-1H-imidazole-4-yl)pyridine-3-sulfonamide (I-64) (104 mg, yield 52.3%).
LC-MS,M/Z(ESI):398.1[M+H]+ LC-MS, M/Z(ESI):398.1[M+H] +
1H NMR(CDCl3,400MHz)δ:9.39(br s,1H),8.46(d,1H),7.90(d,1H),7.50(s,1H),7.30(s,1H),4.41(br d,1H),3.77(s,3H),3.59-3.66(m,1H),3.39-3.46(m,1H),2.67(d,3H),1.98-2.02(m,1H),1.87-1.92(m,1H),1.64-1.74(m,4H),1.42(br d,1H) 1 H NMR (CDCl 3 , 400 MHz) δ: 9.39 (br s, 1H), 8.46 (d, 1H), 7.90 (d, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 4.41 (br d, 1H), 3.77 (s, 3H), 3.59-3.66 (m, 1H), 3.39-3.46 (m, 1H), 2.67 (d, 3H), 1.98-2.02 (m, 1H), 1.87-1.92 (m, 1H), 1.64-1.74 (m, 4H), 1.42 (br d, 1H)
实施例27Embodiment 27
以下化合物的制备参考以上实施例的制备方法得到。






The following compounds were prepared by referring to the preparation methods of the above examples.






测试例1：TEADs介导的转录抑制IC50评价试验Test Example 1: TEADs-mediated transcription inhibition IC 50 evaluation test
采用HEK293T-TEAD Reporter Assay检测小分子化合物对TEADs介导的转录抑制作用。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以DMEM+10％FBS+1％PS+200ug/ml Hygromycin为完全培养基进行培养，将处于对数期的细胞接种于384孔板中，2500cell/孔/35ul，37℃，5％CO2孵育过夜，第二天每孔加入5uL稀释好的化合物(DMSO终浓度为0.1％)，同时设置只加入DMSO的阳性对照组，并以2μM的Okacid acid信号值作为阴性对照组信号，然后37℃，5％CO2孵育48h，孵育完成后使用luciferase assay system(Promega，E2550)并按照供应商提供的说明书在Envision 2104Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率，然后以抑制剂的浓度Log值为X轴，抑制率为Y轴绘制曲线， 用Graphpad 7.0计算得出IC50。HEK293T-TEAD-LUC reporter cell line was cultured in DMEM+10% FBS+1% PS+200ug/ml Hygromycin as complete medium. Cells in the logarithmic phase were seeded in 384-well plates, 2500 cells/well/35ul, incubated overnight at 37°C, 5% CO 2. On the second day, 5uL of diluted compound was added to each well (the final concentration of DMSO was 0.1%). At the same time, a positive control group with only DMSO added was set up, and the signal value of 2μM Okacid acid was used as the signal of the negative control group. Then, it was incubated at 37°C, 5% CO 2 for 48h. After incubation, it was used luciferase assay system (Promega, E2550) and the fluorescence signal value was measured 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, IC50 was calculated using Graphpad 7.0.
Inhibition％＝(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100
表1测试化合物在HEK293T-TEAD-LUC reporter cell line细胞上的TEADs转录抑制活性
Table 1 TEADs transcriptional inhibition activity of test compounds in HEK293T-TEAD-LUC reporter cell line cells
HEK293T-TEAD Reporter Assay结果表明，本发明化合物在HEK293T-TEAD-LUC reporter cell line细胞上能明显抑制TEADs转录的活性。The results of 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.
测试例2：抑制恶性间皮瘤细胞增殖试验Test Example 2: Inhibition of malignant mesothelioma cell proliferation test
采用NF2突变的NCI-H226细胞增殖试验检测小分子化合物对恶性间皮瘤细胞增殖抑制作用。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)以RPMI1640+10％FBS+1％PS为完全培养基进行培养，将处于对数期的细胞接种于96孔板中，800cell/孔/195μL，37℃，5％CO2孵育过夜，第二天每孔加入5μL稀释好的化合物(DMSO终浓度为0.1％)，同时设置只加入DMSO的阳性对照组，并以1μM的Staurosporine信号值作为阴性对照组信号，然后37℃，5％CO2孵育6天，孵育完成后，吸出100μL培养基，使用Celltiter Glo assay kit(Promega，G7573)并按照供应商提供的说明书在Envision 2104Multilabel Reader上测定荧光信号值。通过以下公式计算抑制率，然后以抑制剂的浓度Log值为X轴，抑制率为Y轴绘制曲线，用Graphpad 7.0计算得出IC50。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 μL, incubated overnight at 37°C, 5% CO 2 , and 5 μL 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 μM Staurosporine signal value was used as the negative control group signal, and then incubated at 37°C, 5% CO 2 for 6 days. After the incubation was completed, 100 μL of culture medium was aspirated, and the fluorescence signal value was measured on Envision 2104 Multilabel Reader using Celltiter Glo assay kit (Promega, G7573) and according to the instructions provided by the supplier. The inhibition rate was calculated by the following formula, and then the concentration Log value of the inhibitor was plotted as the X-axis and the inhibition rate was plotted as the Y-axis, and the IC 50 was calculated using Graphpad 7.0.
Inhibition％＝(阳性对照组信号-测试孔信号)/(阳性对照组信号-阴性对照组信号)*100Inhibition% = (positive control group signal - test well signal) / (positive control group signal - negative control group signal) * 100
表2测试化合物对NCI-H226细胞增殖抑制活性
Table 2 Inhibitory activity of test compounds on NCI-H226 cell proliferation
NCI-H226细胞增殖试验结果表明，本发明化合物能明显抑制NCI-H226(ATCC，cat#CRL5826)的增殖。The results of the NCI-H226 cell proliferation test showed that the compounds of the present invention can significantly inhibit the proliferation of NCI-H226 (ATCC, cat#CRL5826).
测试例3：药代动力学试验Test Example 3: Pharmacokinetic Test
小鼠药代动力学试验，使用3只雄性ICR小鼠，20-25g，禁食过夜，口服灌胃给药(10mg/kg)。在给药前和给药后15、30分钟以及1、2、4、8、24小时采血。血液样品于6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。For the pharmacokinetic test in mice, three male ICR mice, 20-25 g, fasted overnight, were administered orally by gavage (10 mg/kg). Blood was collected before and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. The blood samples were centrifuged at 6800g, 2-8°C for 6 minutes, and the plasma was collected and stored at -80°C. The plasma at each time point was taken, mixed with 3-5 times the amount of acetonitrile solution containing the internal standard, vortexed for 1 minute, centrifuged at 13,000 rpm and 4°C for 10 minutes, the supernatant was taken, mixed with 3 times the amount of water, and an appropriate amount of the mixed solution was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
表2：小鼠药代动力学试验结果
Table 2: Results of pharmacokinetic studies in mice
小鼠药代动力学试验结果表明，本发明化合物表现出优良的药代动力学性质，成药性良好。The results of the mouse pharmacokinetic test showed that the compound of the present invention exhibited excellent pharmacokinetic properties and good drugability.
测试例4：NCI-H226间皮瘤小鼠荷瘤药效试验 Test Example 4: NCI-H226 mesothelioma mouse tumor efficacy test
Nu/Nu裸鼠(CRL)适应性饲养一周后，将处于对数期的NCI-H226细胞重悬于PBS，按100μL/只将5×106NCI-H226细胞接种于小鼠右侧后部处皮下，定期观察肿瘤生长情况，待肿瘤生长至平均体积80-100mm3时，根据肿瘤大小和小鼠体重随机分为模型组和给药组，给药前和给药过程中测量、记录肿瘤体积和动物体重，治疗结束后以模型组为对照组，统计给药组对肿瘤的生长抑制作用，计算TGI。After one week of adaptive feeding of Nu/Nu nude mice (CRL), NCI-H226 cells in the logarithmic phase were resuspended in PBS, and 5×10 6 NCI-H226 cells were inoculated subcutaneously at the right posterior part of the mice at 100 μL/mouse. The tumor growth was observed regularly. When the tumor grew to an average volume of 80-100 mm 3 , the mice were randomly divided into a model group and a treatment group according to the tumor size and mouse weight. The tumor volume and animal weight were measured and recorded before and during the treatment. After the treatment, the model group was used as the control group, and the tumor growth inhibition effect of the treatment group was statistically analyzed to calculate the TGI.
荷瘤小鼠药效试验结果表明，本发明化合物具有显著的抑制NCI-H226间皮瘤生长的作用。The results of the efficacy test on tumor-bearing mice showed that the compound of the present invention has a significant effect of inhibiting the growth of NCI-H226 mesothelioma.
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims (15)

  1. 一种式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    其中，    A compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    in,
    环A为6-10元芳环、5-10元杂芳环、6-12元双环或8-15元三环；Ring A is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;
    环B为6-10元芳环、5-10元杂芳环、6-12元双环或8-15元三环；Ring B is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring;
    X1、X2、X3各自独立地为N或CRa；X 1 , X 2 , and X 3 are each independently N or CR a ;
    W为O、NH；W is O, NH;
    L不存在或为-CH2-、-CH2CH2-、-CH2CH2CH2-；L is absent or is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
    R1、R2、Ra各自独立地为氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、-SF5、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基；所述C1-C6烷基、C1-C6烷氧基、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基任选地被1、2或3个相同或不同的选自下列的取代基取代：卤素、羟基、氨基、-SF5、C1-C6烷基；R 1 , R 2 , and Ra are each independently hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl are optionally substituted with 1, 2, or 3 identical or different substituents selected from the following: halogen, hydroxyl, amino, -SF 5 , and C 1 -C 6 alkyl;
    当R1为多个时，所述R1相同或不同；When R 1 is multiple, the R 1 are the same or different;
    当R2为多个时，所述R2相同或不同；When R 2 is multiple, the R 2 are the same or different;
    当Ra为多个时，所述Ra相同或不同；When Ra is multiple, the Ra are the same or different;
    R3、R4各自独立地选自：氢、C1-C6烷基、C1-C6卤代烷基；R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0、1、2或3。n is 0, 1, 2 or 3.
  2. 如权利要求1所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，式I所示化合物满足以下条件(1)至条件(11)中的一个或多个条件：The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound of formula I satisfies one or more of the following conditions (1) to (11):
    (1)为-W-L-为-NH-CH2-或-O-CH2-；(1) for -WL- is -NH-CH 2 - or -O-CH 2 -;
    (2)环A为6-12元双环饱和碳环；较佳地，环A为 (2) Ring A is a 6-12 membered bicyclic saturated carbocyclic ring; preferably, Ring A is
    (3)为 (3) for
    (4)环B为6-12元双环或8-15元三环，所述6-12元双环或8-15元三环为5元含N杂芳环并饱和杂环；较佳地，所述所述6-12元双环或8-15元三环为咪唑并饱和杂环；(4) Ring B is a 6-12 membered bicyclic ring or an 8-15 membered tricyclic ring, wherein the 6-12 membered bicyclic ring or the 8-15 membered tricyclic ring is a 5-membered N-containing heteroaromatic ring and a saturated heterocyclic ring; preferably, the 6-12 membered bicyclic ring or the 8-15 membered tricyclic ring is an imidazolyl saturated heterocyclic ring;
    (5)当环B为6-12元双环时，环B为其中，环B’为具有1、2、3或4个选自N、O、S的杂原子的5元杂芳环，当杂原子为多个时，所述杂原子相同或不同；环B”为具有1、2、3或4个选自N、O、S的杂原子的5元或6元饱和杂环，当杂原子为多个时，所述杂原子相同或不同； (5) When ring B is a 6-12 membered bicyclic ring, ring B is Wherein, Ring B' is a 5-membered heteroaromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, and when there are multiple heteroatoms, the heteroatoms are the same or different; Ring B" is a 5-membered or 6-membered saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S, and when there are multiple heteroatoms, the heteroatoms are the same or different;
    (6)当环B为6-12元双环时，环B为其中，环B”为具有1、2、3或4个选自N、O、S的杂原子的5元或6元饱和杂环，当杂原子为多个时，所述杂原子相同或不同；(6) When ring B is a 6-12 membered bicyclic ring, ring B is Wherein, Ring B" is a 5-membered or 6-membered saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
    (7)环B为6-12元双环，-L-W-不为-O-或者不为苯环或吡啶；(7) Ring B is a 6-12 membered bicyclic ring, -LW- is not -O- or It is not a benzene ring or pyridine;
    (8)为 (8) for
    (9)-W-L-为-NH-CH2-、-O-CH2-、-NH-、-O-；较佳地，-L-W-为-NH-CH2-或-O-CH2-；(9) -WL- is -NH-CH 2 -, -O-CH 2 -, -NH-, -O-; preferably, -LW- is -NH-CH 2 - or -O-CH 2 -;
    (10)当环B为8-15元三环时，环B为其中环B”’为6-10元并环；较佳地，环B”’为6-10元饱和并环，所述并环任选地含有1、2或3杂原子；较佳地，所述环B为 (10) When ring B is an 8-15 membered tricyclic ring, ring B is Wherein ring B'' is a 6-10 membered cyclic ring; preferably, ring B'' is a 6-10 membered saturated cyclic ring, the cyclic ring optionally contains 1, 2 or 3 heteroatoms; preferably, the ring B is
    (11)中不含有与氨基酸残基共价结合的基团；较佳地，其中，R2、R3、R4各自独立地为氢或C1-C6烷基；更佳地，R2、R3、R4各自独立地为氢或甲基。(11) It does not contain a group covalently bonded to an amino acid residue; preferably, R 2 , R 3 , and R 4 are each independently hydrogen or a C 1 -C 6 alkyl group; more preferably, R 2 , R 3 , and R 4 are each independently hydrogen or a methyl group.
  3. 如权利要求1所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，式I所示化合物具有结构：
    其中，    The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound of formula I has the structure:
    in,
    环A为6-10元芳环、6-10元杂芳环、6-12元双环；Ring A is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, or a 6-12 membered bicyclic ring;
    环B为6-10元芳环、6-10元杂芳环、6-12元双环；Ring B is a 6-10 membered aromatic ring, a 6-10 membered heteroaromatic ring, or a 6-12 membered bicyclic ring;
    X1、X2、X3各自独立地为N或CRa；X 1 , X 2 , and X 3 are each independently N or CR a ;
    W为O、NH；W is O, NH;
    L不存在或为-CH2-、-CH2CH2-、-CH2CH2CH2-；L is absent or is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -;
    R1、R2、Ra各自独立地为氢、卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基、-SF5、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基；所述C1-C6烷基、C1-C6烷氧基、3-6元环烷基、4-6元杂环烷基、6-10元芳基、6-10元杂芳基任选地被1、2或3个相同或不同的选自下列的取代基取代：卤素、羟基、氨基、-SF5、C1-C6烷基；R 1 , R 2 , and Ra are each independently hydrogen, halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -SF 5 , 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl are optionally substituted by 1, 2 or 3 identical or different substituents selected from the following: halogen, hydroxy, amino, -SF 5 , C 1 -C 6 alkyl;
    当R1为多个时，所述R1相同或不同；When R 1 is multiple, the R 1 are the same or different;
    当R2为多个时，所述R2相同或不同；When R 2 is multiple, the R 2 are the same or different;
    当Ra为多个时，所述Ra相同或不同；When Ra is multiple, the Ra are the same or different;
    R3、R4各自独立地选自：氢、C1-C6烷基、C1-C6卤代烷基；R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0、1、2或3； n is 0, 1, 2 or 3;
    较佳地，式I所示化合物满足以下一个或多个条件：Preferably, the compound represented by formula I satisfies one or more of the following conditions:
    i)R1为-SF5；i) R 1 is -SF 5 ;
    ii)X1、X2为N；ii) X 1 and X 2 are N;
    iii)环A为6-12元(较佳地为6或7元)双环；iii) Ring A is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;
    iv)环B为6-12元双环，且-L-W-不为-O-；iv) Ring B is a 6-12 membered bicyclic ring, and -L-W- is not -O-;
    较佳地，所述环A为饱和碳环；较佳地，所述环A为并环或螺环；Preferably, the ring A is a saturated carbocyclic ring; preferably, the ring A is a fused ring or a spiro ring;
    较佳地，环B为 Preferably, ring B is
    其中，环B’为具有1、2、3或4个选自N、O、S的杂原子的芳环，当杂原子为多个时，所述杂原子相同或不同；Wherein, ring B' is an aromatic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
    环B”为具有1、2、3或4个选自N、O、S的杂原子的饱和、不饱和或部分不饱和的杂环，当杂原子为多个时，所述杂原子相同或不同。Ring B" is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms may be the same or different.
  4. 如权利要求1或3所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，具有式II所示结构
    The compound of formula I as claimed in claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it has the structure shown in formula II
    其中，R21、R22各自独立地选自：氢、C1-C6烷基、C1-C6卤代烷基；或者，Wherein, R 21 and R 22 are each independently selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; or,
    R21、R22与它们共同连接的咪唑一起形成环B”；环B”为具有1、2、3或4个选自N、O、S的杂原子的饱和、不饱和或部分不饱和的杂环，当杂原子为多个时，所述杂原子相同或不同；R 21 , R 22 and the imidazole to which they are commonly connected together form a ring B"; the ring B" is a saturated, unsaturated or partially unsaturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
    所述环B”任选地被1、2或3个相同或不同的R2取代；所述R2选自卤素、C1-C6烷基、C1-C6卤代烷基；The ring B" is optionally substituted by 1, 2 or 3 identical or different R2; the R2 is selected from halogen, C1 - C6 alkyl, C1 - C6 haloalkyl;
    较佳地，式II所示化合物满足以下一个或多个条件：Preferably, the compound represented by formula II satisfies one or more of the following conditions:
    i)R1为-SF5；i) R 1 is -SF 5 ;
    ii)X1、X2为N；ii) X 1 and X 2 are N;
    iii)环A为6-12元(较佳地为6或7元)双环；iii) Ring A is a 6-12 membered (preferably 6 or 7 membered) bicyclic ring;
    iv)R2、R3与它们共同连接的基团一起形成环B”，且-L-W-不为-O-；iv) R 2 , R 3 and the group to which they are commonly attached together form a ring B″, and -LW- is not -O-;
    v)R1为氟代甲基、氟代乙基、氟代丙基；较佳地，所述氟代甲基为-CF3、CH2F、CHF2；v) R 1 is fluoromethyl, fluoroethyl, or fluoropropyl; preferably, the fluoromethyl is -CF 3 , CH 2 F, or CHF 2 ;
    vi)环A为苯环；vi) Ring A is a benzene ring;
    vii)R21为甲基，R22为H；vii) R 21 is methyl, R 22 is H;
    viii)-W-L-为-NH-CH2-；viii) -WL- is -NH-CH 2 -;
    较佳地，所述环A为饱和碳环；较佳地，所述环A为并环或螺环。Preferably, the ring A is a saturated carbocyclic ring; preferably, the ring A is a fused ring or a spiro ring.
  5. 如权利要求1-4任一所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，为 The compound of formula I as claimed in any one of claims 1 to 4, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: for
    较佳地，所述环A为 Preferably, the ring A is
    较佳地，所述环A为 Preferably, the ring A is
    较佳地，所述环A为 Preferably, the ring A is
    较佳地，基团为 Preferably, the group for
    较佳地，为 Preferably, for
    较佳地，为 Preferably, for
    较佳地，为 Preferably, for
    较佳地，R1各自独立地为F或甲基；Preferably, R 1 is each independently F or methyl;
    较佳地，为
    Preferably, for
    较佳地，为 Preferably, for
    较佳地，为 Preferably, for
    较佳地，为 Preferably, for
  6. 如权利要求1或3所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述式I所示化合物具有式Ia、式Ib或式Ic所示结构

    The compound of formula I as claimed in claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound of formula I has a structure shown in formula Ia, formula Ib or formula Ic

    其中，环A、R1、R21、R22、X1、X2、W、L、m、n的定义如权利要求1或3中所述；wherein ring A, R 1 , R 21 , R 22 , X 1 , X 2 , W, L, m, and n are as defined in claim 1 or 3;
    环B”为具有1、2、3或4个选自N、O、S的杂原子的饱和杂环，当杂原子为多个时，所述杂原子相同或不同；Ring B" is a saturated heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O and S. When there are multiple heteroatoms, the heteroatoms are the same or different;
    较佳地，R2为甲基、乙基、丙基、卤代甲基、卤代乙基、卤代丙基；Preferably, R2 is methyl, ethyl, propyl, halomethyl, haloethyl, or halopropyl;
    更佳地，R2为甲基。More preferably, R2 is methyl.
  7. 如权利要求6所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述式I所示化合物具有式Ic-1、式Ic-2或式Ic-3所示结构
    The compound of formula I as claimed in claim 6, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound of formula I has a structure shown in formula Ic-1, formula Ic-2 or formula Ic-3
    其中，环B”、R1、R2、X1、X2、W、L、n的定义如权利要求6中所述；wherein, Ring B", R 1 , R 2 , X 1 , X 2 , W, L, and n are as defined in claim 6;
    较佳地，为 Preferably, for
    较佳地，基团选自 Preferably, the group Selected from
    较佳地，为 Preferably, for
  8. 如权利要求1或3所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构Id
    The compound of formula I as claimed in claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it has structure Id
    较佳地，X1为N，X2为CH，R2为甲基、乙基或丙基，W为O、NH；Preferably, X1 is N, X2 is CH, R2 is methyl, ethyl or propyl, and W is O or NH;
    较佳地，R2为甲基；Preferably, R 2 is methyl;
    较佳地，L为-CH2-；Preferably, L is -CH 2 -;
    较佳地，为 Preferably, for
  9. 如权利要求1或3所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构If
    The compound of formula I as claimed in claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it has structure If
    其中，R1、R2、W、L的定义如权利要求1或3所述；Wherein, R 1 , R 2 , W, and L are as defined in claim 1 or 3;
    较佳地，R1为氟代甲基、氟代乙基、氟代丙基；较佳地，所述氟代甲基为-CF3、CFH2、CF2H；Preferably, R 1 is fluoromethyl, fluoroethyl, fluoropropyl; preferably, the fluoromethyl is -CF 3 , CFH 2 , CF 2 H;
    较佳地，环A为苯环；Preferably, ring A is a benzene ring;
    较佳地，R21为甲基，R22为H；Preferably, R 21 is methyl, and R 22 is H;
    较佳地，-W-L-为-NH-CH2-；Preferably, -WL- is -NH-CH 2 -;
    较佳地，为 Preferably, for
  10. 如权利要求1或3任一所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，X1、X2为N；或The compound of formula I as claimed in any one of claims 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that X 1 and X 2 are N; or
    X1为CRa，X2为N；或 X1 is CRa, X2 is N; or
    X1、X2为CRa； X1 and X2 are CRa;
    较佳地，Ra为氢或F。Preferably, Ra is hydrogen or F.
  11. 如权利要求1或3所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学 上可接受的盐或前药，其特征在于，具有结构Ie
    The compound of formula I as claimed in claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutical An acceptable salt or prodrug, characterized in that it has structure Ie
    其中，为8-15元三环；in, It is an 8-15 membered tricyclic ring;
    较佳地，为 Preferably, for
    较佳地，为 Preferably, for
    更佳地，为 More preferably, for
  12. 如权利要求1或3所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，选自： The compound of formula I as claimed in claim 1 or 3, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: Selected from:
    较佳地，为 Preferably, for
  13. 如权利要求1所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，选自：




    The compound of formula I as claimed in claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it is selected from:




  14. 一种药物组合物，包括如权利要求1-13任一所述所述式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，和药学上可接受的载体。A pharmaceutical composition comprising the compound of formula I as claimed in any one of claims 1 to 13, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier.
  15. 一种如权利要求1-13中任一所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的用途，或如权利要求14所述的药物组合物的用途，包括：A use of a compound of formula I as claimed in any one of claims 1 to 13, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a use of a pharmaceutical composition as claimed in claim 14, comprising:
    制备用于预防和/或治疗与TEAD表达增加相关的疾病的药物、药物组合物或制剂；和/或，Preparation of a medicament, pharmaceutical composition or formulation for preventing and/or treating a disease associated with increased TEAD expression; and/or,
    制备用于降低/抑制TEAD表达、TEAD活性增加的药物、药物组合物或制剂；和/或，Preparing a drug, pharmaceutical composition or formulation for reducing/inhibiting TEAD expression or increasing TEAD activity; and/or,
    制备用于降低/抑制Hippo信号通路的药物、药物组合物或制剂；Preparing a drug, pharmaceutical composition or preparation for reducing/inhibiting the Hippo signaling pathway;
    较佳地，所述TEAD包括：TEAD1、TEAD2、TEAD3和TEAD4；Preferably, the TEAD comprises: TEAD1, TEAD2, TEAD3 and TEAD4;
    较佳地，所述疾病是细胞增殖性病症；Preferably, the disease is a cell proliferative disorder;
    较佳地，所述细胞增殖性病症为癌症；Preferably, the cell proliferative disorder is cancer;
    较佳地，所述癌症选自：间皮瘤、卵巢癌、胆管癌、血液癌、淋巴瘤、骨髓瘤、白血病、神经系统癌症、皮肤癌、乳腺癌、前列腺癌、结直肠癌、肺癌、头颈癌、胃肠道癌、肝癌、胰腺癌、泌尿生殖系统癌、骨癌、肾癌和血管癌。 Preferably, the cancer is selected from mesothelioma, ovarian cancer, bile duct cancer, blood cancer, lymphoma, myeloma, leukemia, nervous system cancer, skin cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary system cancer, bone cancer, kidney cancer and vascular cancer.
PCT/CN2023/131008 2022-11-10 2023-11-10 Tead inhibitor WO2024099435A1 (en)

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