WO2023185831A1 - Compound containing thiazole ring - Google Patents

Compound containing thiazole ring Download PDF

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Publication number
WO2023185831A1
WO2023185831A1 PCT/CN2023/084374 CN2023084374W WO2023185831A1 WO 2023185831 A1 WO2023185831 A1 WO 2023185831A1 CN 2023084374 W CN2023084374 W CN 2023084374W WO 2023185831 A1 WO2023185831 A1 WO 2023185831A1
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Prior art keywords
alkyl
alternatively
ring
membered
alkynyl
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PCT/CN2023/084374
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French (fr)
Chinese (zh)
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张寅生
刘保民
黄雨
计磊
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正大天晴药业集团股份有限公司
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Publication of WO2023185831A1 publication Critical patent/WO2023185831A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to compounds containing thiazole rings, their preparation methods, pharmaceutical compositions containing the compounds, and their use in the treatment of cancer and other diseases.
  • DNA damage response plays an important role in maintaining cellular genome stability and organism survival.
  • DNA double-strand breaks (DSBs) are the most serious form of DNA damage.
  • Homologous recombination repair is one of the important mechanisms involved in the repair of DSBs damage in vivo, in which the recombinant protein RAD51 is the core factor in repairing DNA double-strand breaks (DSBs) through homologous recombination.
  • RAD51 is a eukaryotic gene.
  • the protein encoded by this gene is a member of the RAD51 protein family, which helps repair DNA double-strand breaks.
  • RAD51 is a 339-amino acid protein that plays an important role in DNA homologous recombination during double-strand break (DSB) repair.
  • RAD51 catalyzes strand transfer between the broken sequence and its unbroken homolog to allow resynthesis of the damaged region.
  • AID activation-induced cytidine deaminase
  • AID activation-induced cytidine deaminase
  • RAD51 RAD51 to repair DNA damage caused by cytosine deaminase.
  • RAD51 has low or no expression in normal tissues, but is overexpressed in a variety of human cancer cells, such as breast cancer, non-small cell lung cancer, prostate cancer, etc., and is associated with tumor metastasis and progression.
  • RAD51 highly expressed RAD51 promotes homologous recombination repair in cancer cells, thereby inducing resistance of cancer cells to radiotherapy and chemotherapy that can cause DNA damage. It has been reported in the literature that RAD51 inhibitors can enhance the sensitivity of cancer cells to chemotherapy and radiotherapy. Related research results support the use of RAD51 as an anti-tumor drug target to develop small molecule RAD51 inhibitors to enhance the lethality of chemotherapy or radiotherapy to cancer cells.
  • MCTs Monocarboxylate transporters
  • MCT1 is a high-affinity lactate transporter that efficiently imports and exports lactate.
  • Cancer cell metabolism requires lactate transport to support their high proliferation rate.
  • MCTs are frequently upregulated in cancer, leading to poor prognosis and increased mortality.
  • Inhibiting MCT results in downstream reductions in several proteins important for cell cycle regulation, including RAD51, which may explain the effects seen in homologous recombination analyses. Effects seen in group analyses.
  • MCT-mediated lactate transport is critical for cancer cell survival and tumorigenesis, making it an attractive target for cancer therapy and drug development.
  • R 1 is selected from 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-15 membered heterocyclyl, phenyl, 3-10 membered cycloalkyl, C 2-10 alkenyl or C 2- 10 alkynyl;
  • the 3-10-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-15-membered heterocyclyl, phenyl or 3-10-membered cycloalkyl is optionally substituted by one or more R c ;
  • the C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
  • R a is selected from deuterated C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -C 1-3 alkyl-CON(C 1-6 alkyl) 2 , the deuterated C 1-6 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1- 3 alkyl) 2 substituted;
  • R b is selected from halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl or halo C 1-6 alkyl;
  • R c is selected from C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, oxo, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) Or -N(C 1-3 alkyl) 2 , the C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2. -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
  • R d and R e are independently selected from H, halogen, CN or C 1-6 alkyl;
  • L is selected from bond or NR f ;
  • R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • X 1 and X 2 are independently selected from NR g or O;
  • Y is selected from CH 2 , N or O;
  • R f and R g are independently selected from H or C 1-3 alkyl
  • R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • R 4 and R 5 are each independently selected from H, OH, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substitution.
  • R 1 is selected from 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-13 membered heterocyclyl, phenyl, 3-8 membered cycloalkyl, C 2 -8 alkenyl or C 2-8 alkynyl;
  • the 3-8-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-13-membered heterocyclyl, phenyl or 3-8-membered cycloalkyl is optionally substituted by one or more R c ;
  • the C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens or OH.
  • R 1 is selected from 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-11 membered heterocyclyl, phenyl, 4-6 membered cycloalkyl, C 3 -6 alkenyl or C 3-6 alkynyl;
  • the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-11 membered heterocyclyl, phenyl or 4-6 membered cycloalkyl is optionally substituted by one or more R c .
  • the R 1 is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl, 11-membered heterocyclyl or C 4-5 alkynyl;
  • the 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c .
  • R1 is selected from the group consisting of 5-membered heteroaryl, 8-membered heterocyclyl containing a fused ring, 10-membered heterocyclyl containing a fused ring and a spiro ring, 10-membered heterocyclyl containing a fused ring and a spiro ring, 11-membered heterocyclyl or C 4-5 alkynyl;
  • the 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
  • the 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c .
  • the heteroatom of the above-mentioned heterocycloalkyl, heteroaryl or heterocyclyl group is selected from nitrogen, oxygen or sulfur; alternatively, the heteroatom of the heterocyclyl group is selected from nitrogen or oxygen.
  • the number of heteroatoms may be selected from 1, 2, 3, 4, 5 or 6, or the number of heteroatoms may be selected from 2, 3 or 4, or the number of heteroatoms may be selected from 2 or 3 .
  • the heterocyclyl group contains at least 2 heteroatoms, selected from nitrogen or oxygen; in some specific embodiments, the heteroatoms of the heterocyclyl group are 2 nitrogen atoms, or 3 nitrogen atoms , or 2 nitrogen atoms and 1 oxygen atom.
  • the heterocyclyl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heterocyclyl group is selected from bicyclic or tricyclic rings. Furthermore, the bicyclic or tricyclic rings may be connected through fused rings, bridged rings or spiro rings. In some embodiments, the heterocyclyl group is selected from a bicyclic ring or a tricyclic ring, the bicyclic ring is connected through a fused ring, and the tricyclic ring is connected through a spiro ring and a fused ring.
  • the heterocyclyl group is selected from bicyclic or tricyclic rings, in which the ring directly connected to the NH site is an aromatic ring or a heteroaromatic ring.
  • the heterocyclyl group is selected from a bicyclic or tricyclic ring, and one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring; optionally, one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring.
  • the ring is selected from heteroaromatic rings; further, optionally, the bicyclic or tricyclic ring is directly connected to the NH position.
  • the attached ring is a heteroaromatic ring.
  • the heterocyclyl group is selected from the group consisting of a 5-membered ring fused to a 5-membered ring, a 3-membered spiro 6-membered ring fused to a 5-membered ring, or a 3-membered spiro 5-membered ring fused to a 5-membered ring.
  • R1 is selected from pyrazolyl, imidazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, Hydrogen-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b]pyrazol] base, 6',7'-dihydrospiro[cyclopropane-1,4'-pyrazolo[5,1-c][1,4]oxazine] base, 4'H,6 'H-spiro[cyclopropan-1,5'-pyrrolo[1,2-b]pyrazol]yl, pent-3-yn-2-yl or but-2-yn-1-yl,
  • the pyrazolyl, imidazolyl or triazolyl group is substituted by one or more R a , optionally substituted by one or more R b ;
  • the R1 is selected from
  • the R1 is selected from
  • R a is selected from deuterated C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-3 alkyl-CON(C 1-3 alkyl) 2.
  • the deuterated C 1-4 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl groups are optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 substitution.
  • R a is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkyl-CON(C 1-3 alkyl) 2.
  • the C 2-6 alkenyl or C 2-6 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-2 alkyl, CN, NH 2 , -NH (C 1-2 alkyl ) or -N(C 1-2 alkyl) 2 replace.
  • R a is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CH 2 CON(C 1-2 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl is optionally substituted with one or more fluorine, chlorine, bromine or OH.
  • R a is selected from deuterated methyl, vinyl, propenyl, ethynyl, propynyl, -CH 2 CON(CH 3 ) 2 , said vinyl, propenyl, ethynyl, or propynyl.
  • Alkynyl groups are optionally substituted with one or more fluorine or OH.
  • R a is selected from optionally modified by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1 -3 alkyl) 2 substituted In some embodiments, R is selected from optionally substituted with one or more halogens, OH, CN, or NH
  • Ra is selected from deuterated methyl
  • R b is selected from halogen, OH, CN, NH 2 , C 1-3 alkyl, C 3-4 cycloalkyl, or haloC 1-3 alkyl;
  • R b is selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 3-4 cycloalkyl, or haloC 1-3 alkyl.
  • R b is selected from fluorine, chlorine, methyl, cyclopropyl, or -CHF 2 .
  • R c is selected from C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
  • R c is selected from C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-6 alkenyl or C 2-6 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
  • R c is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
  • R c is selected from C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, CN or NH 2 , the C 2-4 alkenyl, C 2-4 alkynyl is optionally replaced by one or more halogen, OH, CN or NH 2 substitution.
  • R c is selected from Halogen, OH, CN or NH 2 .
  • R c is selected from Fluorine, chlorine or bromine. In some embodiments, R c is selected from Or fluorine.
  • R d and R e are each independently selected from hydrogen, halogen, CN, or C 1-3 alkyl.
  • R d and R e are each independently selected from hydrogen, fluorine, chlorine, CN, or methyl. In some embodiments, R d and Re are hydrogen.
  • the R1 is selected from The definitions of R a , R b or R c are independently as described above.
  • the R1 is selected from
  • L is selected from bond or NH. In some embodiments, L is selected from bonds.
  • R 2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl Or 3-5 membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN, NH2 or C1-3 alkoxy group.
  • R2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl, or 4-membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl, or 4-membered heterocycloalkyl
  • a membered heterocycloalkyl group is optionally substituted with one or more OH, halogen, CN or NH .
  • R is selected from ethyl, cyclopropyl, dicyclopentyl, or 4-membered heterocycloalkyl, optionally Substituted by one or more fluorine, chlorine or bromine.
  • R is selected from ethyl, cyclopropyl, bicyclopentyl, or a 4-membered heterocycloalkyl containing 1 heteroatom selected from N or O.
  • Pentyl or 4-membered heterocycloalkyl is optionally substituted with one or more fluorine, chlorine or bromine.
  • R is selected from ethyl, dicyclopentyl, oxetanyl, or cyclopropyl optionally substituted with one or more fluorine.
  • R is selected from ethyl
  • R is selected from C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, which is optionally replaced by a Or multiple OH, halogen, CN or NH substitutions. In some embodiments, R is selected from C 3-5 cycloalkyl, which is optionally substituted with one or more OH, halogen, CN , or NH . In some embodiments, R2 is selected from C3-4 cycloalkyl. In some embodiments, R is selected from
  • X 1 and X 2 are each independently selected from NH or O. In some embodiments, X1 is selected from NH and X2 is selected from O.
  • Y is selected from CH2 or O. In some embodiments, Y is selected from CH2 .
  • R f and R g are each independently selected from H or methyl. In some embodiments, Rf and Rg are H.
  • R 3 is selected from C 1-4 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-4 alkyl, C 3-5 cycloalkyl Or 3-5 membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN, NH2 or C1-3 alkoxy group.
  • R 3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl, said C 1-4 alkyl, C 3-4 cycloalkyl Or 3-4 membered heterocycloalkyl optionally substituted with one or more OH, halogen, CN or NH .
  • R3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl, or 3-4 membered heterocycloalkyl.
  • R 3 is selected from C 1-4 alkyl. In some embodiments, R3 is selected from C3-4 alkyl.
  • R3 is selected from isopropyl.
  • R 4 and R 5 are each independently selected from hydrogen, OH, halogen, CN, NH 2 , C 1-3 alkyl, or C 1-3 alkoxy.
  • R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-3 alkyl, or C 1-3 alkoxy.
  • R 4 and R 5 are each independently selected from hydrogen.
  • structural fragments Selected from Further, the structure fragment Selected from
  • structural fragments Selected from In some embodiments, structural fragments Selected from In some embodiments, structural fragments Selected from
  • R1 is selected from pyrazolyl, imidazolyl, or triazolyl substituted with one or more Ra , optionally with one or Multiple R b substitutions.
  • the R1 is selected from pyrazolyl substituted with one or more Ra , optionally substituted with one or more Rb .
  • Ra is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, which C 2-6 alkenyl or C 2-6 alkynyl is optionally Ground is substituted by one or more halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl) 2 .
  • Ra is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, which C 2-4 alkenyl or C 2-4 alkynyl is optionally Ground is substituted by one or more fluorine, chlorine, bromine or OH.
  • R is selected from deuterated methyl, vinyl, propenyl, or propynyl optionally substituted with one or more fluorine or OH.
  • Ra is selected from deuterated methyl or C 2-4 alkynyl optionally substituted with one or more fluorine or OH.
  • R is selected from deuterated methyl or propynyl, which is optionally substituted with one or more fluorine or OH.
  • Ra is selected from deuterated methyl
  • R is selected from C 2-6 alkenyl or C 2-6 alkynyl, which is optionally replaced by one or more halogen, OH , OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl) 2 substitution.
  • R is selected from C 2-4 alkenyl or C 2-4 alkynyl, which is optionally replaced by one or more fluorine, chlorine , bromine or OH substitution.
  • R is selected from vinyl, propenyl, or propynyl, which is optionally substituted with one or more fluorine or OH.
  • Ra is selected from
  • the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkenes base, C 2-6 alkynyl or deuterated C 1-3 alkyl, when it is substituted by two R a , one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, the other R a is selected from deuterated C 1-3 alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 substitution.
  • the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkenes base or C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 Alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl ) or N(C 1-3 alkyl) 2 substitution.
  • the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkynes group, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl group, and the other R a is selected from deuterated C 1-3 alkyl group, the C 2-6 alkynyl group is optionally Substituted by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 .
  • the above-mentioned pyrazolyl, imidazolyl or triazolyl group is substituted by one or two R a , optionally substituted by one or more R b , when it is substituted by one R a , the R a Selected from C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 alkyl, the C 2 -6 Alkynyl is optionally substituted with one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 .
  • the above heterocyclyl group is substituted by one or two R c , and when substituted by one R c , R c is selected from C 2-4 alkenyl, or C 2-4 alkynyl; when substituted by two R c , one R c is selected from C 2-4 alkenyl or C 2-4 alkynyl, the other R c is selected from halogen, OH, CN or NH 2 ; the C 2-4 alkenyl or C 2-4 alkynyl is optionally replaced by a or more selected from halogen, OH, CN or NH substitution .
  • the above-mentioned heterocyclyl group is optionally substituted by one or two R c .
  • R c is selected from When replaced by two R c , one of which is selected from The other R c is selected from halogen.
  • the compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of compounds of Formula IA or Formula I-A', its stereoisomer or its pharmaceutically acceptable salt. of salt,
  • R 1 , L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as defined in this application.
  • structural fragments and is defined as described in this application.
  • the compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of a compound of Formula II, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as described in this application;
  • R' is selected from hydrogen, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • R 6 is each independently selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, halogen, OH, CN, NH 2 , C 3-6 cycloalkyl, OC 1-3 alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
  • Ring A is selected from 5-6 membered heteroaryl or 8-15 membered heterocyclyl
  • n is selected from 0, 1, 2, 3 or 4.
  • the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of a compound of formula III, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R c are as described in this application;
  • Ring B is selected from absence, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl;
  • Ring C is selected from 5-6 membered heterocycloalkyl
  • Ring D is selected from 5-6 membered heteroaryl
  • n is selected from 0, 1, 2, 3 or 4.
  • the R' is selected from hydrogen, halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl ) 2 ;
  • R' is selected from hydrogen, fluorine, chlorine, bromine or OH;
  • R' is selected from hydrogen, fluorine, bromine or OH;
  • R' is selected from hydrogen, fluorine or OH.
  • each R 6 is independently selected from C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen, OH, CN, NH 2 , C 3- 4 cycloalkyl, OC 1-3 alkyl, -NH (C 1-3 alkyl) or -N (C 1-3 alkyl) 2 ; or, R 6 is each independently selected from C 1-3 alkyl , deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen or C 3-4 cycloalkyl; or, R 6 is each independently selected from methyl, deuterated methyl, halomethyl , fluorine, chlorine, bromine or cyclopropyl; alternatively, R 6 is each independently selected from methyl, -CD 3 , -CHF 2 , fluorine, chlorine or cyclopropyl.
  • the ring A is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl;
  • Ring A is selected from the group consisting of a 5-membered heteroaryl group, an 8-membered heterocyclyl group containing a fused ring, a 10-membered heterocyclyl group containing a fused ring and a spiro ring, and an 11-membered heterocyclyl group containing a fused ring and a spiro ring. ;
  • Ring A is selected from 5-membered heteroaryl
  • Ring A is selected from 5-membered nitrogen-containing heteroaryl
  • Ring A is selected from pyrazolyl, imidazolyl or triazolyl;
  • Ring A is selected from pyrazole.
  • Ring B is selected from Absence or C 3-4 cycloalkyl; or Ring B is selected from Absence or cyclopropyl.
  • the ring C is selected from pyrrolidinyl or morpholinyl.
  • Ring D is selected from 5-membered heteroaryl; or Ring D is selected from pyrazolyl or triazolyl.
  • Ring B is absent
  • Ring C is pyrrolidinyl
  • Ring D is selected from pyrazolyl or triazolyl.
  • the ring B is cyclopropyl
  • ring C is selected from pyrrolidinyl or morpholinyl
  • ring D is pyrazolyl
  • structural fragments and is defined as described in this application.
  • n is selected from 0, 1, 2, or 3; alternatively, m is selected from 0 or 1.
  • n is selected from 0, 1, 2, or 3.
  • the compound of Formula I, Formula IA or Formula II, its stereoisomer or its pharmaceutically acceptable salt described in the present application is selected from the group consisting of the compound of Formula II-A, its stereoisomer or its pharmaceutically acceptable salt. acceptable salt,
  • R', ring A, m, L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R 6 are as defined in this application.
  • the compound of Formula I, Formula IA or Formula III, its stereoisomer or its pharmaceutically acceptable salt described in the present application is selected from the group consisting of the compound of Formula III-A, its stereoisomer or its pharmaceutically acceptable salt. acceptable salt,
  • ring B, ring C, ring D, n, L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R c are as described in this application.
  • the compounds of Formula I, or Formula II, their stereoisomers, or pharmaceutically acceptable salts thereof described in the present application are selected from the group consisting of compounds of Formula IV, their stereoisomers, or their pharmaceutically acceptable salts ,
  • R', m, L, R 2 , R 3 , R 4 , R 5 and R 6 are as described in this application.
  • the compounds of Formula I, Formula IA, Formula II, Formula II-A or Formula IV, their stereoisomers or their pharmaceutically acceptable salts described in the present application are selected from the group consisting of compounds of Formula IV-A, their Stereoisomers or pharmaceutically acceptable salts thereof,
  • R', m, L, R 2 , R 3 , R 4 , R 5 and R 6 are as described in this application.
  • the compounds of Formula I or Formula III, their stereoisomers, or pharmaceutically acceptable salts thereof described in the present application are selected from the group consisting of compounds of Formula V, their stereoisomers, or their pharmaceutically acceptable salts,
  • n, L, R 2 , R 3 , R 4 , R 5 and R c are as described in this application.
  • the compounds of Formula I, Formula IA, Formula III, Formula III-A or V, their stereoisomers or their pharmaceutically acceptable salts described in the present application are selected from the group consisting of compounds of Formula VA, their stereoisomers body or a pharmaceutically acceptable salt thereof,
  • n, L, R 2 , R 3 , R 4 , R 5 and R c are as described in this application.
  • substituent ranges are disclosed in the specific embodiments and/or claims for any particular L, X1 , X2 , Y, R1 , R2 , R3 , R4 or R5 substituent, It is understood that one or more substituents may be deleted from this range and the remaining substituent ranges shall also be considered embodiments of the present application.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application relates to a method for treating cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases in mammals, comprising administering a therapeutically effective amount of the above compounds, their stereoisomers, to mammals in need of such treatment, preferably humans. body or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of medicines for preventing or treating cancer, autoimmune diseases, immune deficiencies or neurodegenerative diseases. uses in.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in preventing or treating cancer, autoimmune diseases, immune deficiencies or neurodegenerative diseases.
  • the present application relates to the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases.
  • the cancer is selected from lymphoma, leukemia, or solid tumors.
  • the solid tumor is selected from lung cancer, breast cancer, and the like.
  • the present application relates to a method of treating a mammal with a disease mediated by RAD51 and/or MCT, comprising administering a therapeutically effective amount of the above compound, a stereoisomer thereof or a mammal in need of the treatment, preferably a human.
  • Pharmaceutically acceptable salts, or pharmaceutical compositions thereof are provided.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs for preventing or treating diseases mediated by RAD51 and/or MCT.
  • the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in preventing or treating diseases mediated by RAD51 and/or MCT.
  • the present application relates to the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating RAD51 and/or MCT-mediated diseases.
  • the above-mentioned RAD51 and/or MCT-mediated diseases are selected from cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases.
  • the cancer is selected from lymphoma, leukemia, or solid tumors.
  • the solid tumor is selected from lung cancer, breast cancer, and the like.
  • the compound of the present application has at least one of the following effects: improved or excellent inhibitory activity on Daudi cells; compared with WI38-VA13 cells, it has selective inhibitory activity on Daudi cells; improved or excellent in vivo efficacy; in vitro various
  • the liver microsomal metabolism of species for example, rats, dogs, monkeys, mice and humans
  • mice or rats, dogs
  • Generation kinetic data (such as AUC, C max or t 1/2 , etc.).
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • the term "optionally” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance.
  • the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), or poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • One or more in this article refers to an integer ranging from one to ten. For example, “one or more” refers to one, two, three, four, five, six, seven, eight, nine or ten; or “one or more” refers to one, two , three, four, five or six; alternatively, "one or more” means one, two or three.
  • C mn as used herein means that the part has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • any variable e.g., R
  • its definition in each instance is independent. So, for example, if a group is replaced by 2 R's, there are separate options for each R.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • substituents bond When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • structural unit Indicates that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbyl group having the general formula C n H 2n+1 .
  • the alkyl group may be straight chain or branched.
  • C 1 -6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl refers to an alkyl group containing 1 to 5 carbon atoms
  • C 1 - 4 alkyl referring to an alkyl group containing 1 to 4 carbon atoms
  • C 1 - 3 Alkyl refers to an alkyl group containing 1 to 3 carbon atoms.
  • alkyl portion ie, alkyl of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
  • alkoxy refers to -O-alkyl
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring (eg, a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring).
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.
  • heterocyclyl refers to a partially unsaturated (but not fully unsaturated heteroaromatic) non-aromatic ring.
  • the "heterocyclyl” may be a single ring or a polycyclic ring (including but not limited to bicyclic or tricyclic rings).
  • the heterocycle is generally a 3- to 15-membered ring (e.g., 3-membered, 4-membered 1, 5, 6, or 7-membered rings).
  • Non-limiting examples of heterocyclyl include, but are not limited to, dihydrofuryl, dihydropyrrolyl, 2H-pyranyl, wait.
  • the term "monocyclic” refers to a cyclic group containing one ring, which may be fully saturated, partially saturated or aromatic.
  • the monocyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example.
  • bicyclic refers to a cyclic group containing two rings, which may be fully saturated, partially saturated, or aromatic.
  • the bicyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example.
  • the bicyclic ring may be a fused ring, a bridged ring or a spiro ring.
  • tricyclic refers to a cyclic group containing three rings, which may be fully saturated, partially saturated, or aromatic.
  • the tricyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example. Any two adjacent single rings in the three rings may be fused rings, bridged rings or spiro rings.
  • fused ring refers to a polycyclic compound formed by the fusion of two or more carbocyclic or heterocyclic rings with two atoms in common, including fully saturated, partially saturated and aromatic. Unless otherwise indicated, the fused ring has 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. Non-limiting examples of fused rings include, but are not limited to, naphthalene, anthracene, phenanthrene, wait.
  • bridged ring refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5-14 yuan, preferably 6-14 yuan, more preferably 6-10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic.
  • one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) n (where n is 0, 1 or 2) ), the remaining ring atoms are carbon atoms.
  • spiro ring refers to a fully saturated or partially unsaturated polycyclic system in which a single carbon atom (called a spiro atom) is shared between single rings, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the spiro ring is 5 to 20 members, preferably 6 to 14 members, more preferably 9 to 14 members.
  • the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) n (where n is 0, 1 or 2) ), the remaining ring atoms are carbon atoms.
  • heterocycloalkyl refers to a fully saturated cyclic group.
  • the “heterocycloalkyl” may be a single ring or a polycyclic ring (including but not limited to bicyclic or tricyclic rings).
  • the heterocycle is generally a 3- to 10-membered ring (e.g., 3-membered, 4-membered 1, 5, 6, or 7-membered rings).
  • 3-membered heterocycloalkyl include, but are not limited to, oxirane, ethylene sulfide, and aziridyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane.
  • Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxeptanyl, and thiopanyl. Preference is given to monocyclic heterocycloalkyl groups with 5 or 6 ring atoms.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, such as 1, 2 or 3 ring atoms selected from N, O, S Ring atoms, the remaining ring atoms are C, and it has at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5 to 8 membered ring (eg 4, 5, 6, 7 or 8 membered ring) or contain 6 to 14, especially 6 to 10 (or 9) rings Multiple fused rings of atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • hetero refers to heteroatoms including, for example, oxygen (O), nitrogen (N), or sulfur (S).
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • treating means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when such disease A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
  • solvate refers to a compound formed by combining a compound of the invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid, etc.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • hydrate refers to a solvate including a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of water.
  • the compounds of the present invention may also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. Since prodrugs are known to enhance numerous desirable properties of drugs (eg, solubility, bioavailability, preparation, etc.), the compounds of the invention can be delivered in the form of prodrugs. Accordingly, the present invention is intended to encompass prodrugs of the presently claimed compounds, methods of delivery thereof, and compositions containing the prodrugs.
  • prodrug is intended to include any covalently bound carrier that releases the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject.
  • the prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved to the parent compound during routine manipulation or in vivo.
  • the term "individual” includes humans and animals, for example, mammals (such as primates, cattle, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep and birds, etc.).
  • the term "active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • mammals include mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens.
  • Valence tautomers include tautomers by reorganization of some of the bonding electrons. Exemplary tautomers are shown below But not limited to this.
  • the present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the present application can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements) and, therefore, in certain situations
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • Exemplary deuterated compounds are shown below But not limited to this.
  • Stereoisomers of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • the stereoisomers respectively include, but are not limited to ( represents a five-membered heteroaryl group).
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients.
  • they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • dosages of 0.01 to 200 mg/kg body weight are administered per day, in single or divided doses.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.
  • the compound of Formula I of the present application can be prepared by those skilled in the field of organic synthesis through the following route:
  • R 1 , L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as defined in this application.
  • Boc represents tert-butoxycarbonyl
  • DMSO dimethyl sulfoxide
  • TBS represents tert-butyldimethylsilyl
  • BrettPhos Pd G3 represents methane sulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy Palladium(II) (2'-amino-1,1'-biphenyl-2-yl)(2'-amino-1,1'-biphenyl-2-yl)
  • Lawson's reagent represents 2,4-bis(p-methoxyphenyl)-1,3-dithiodiphosphatane-2,4 sulfide
  • TBSO represents tert-butyldimethylsiloxy.
  • intermediate 1-2 (220g), 2-methyl-tetrahydrofuran (1300mL), sodium carbonate (96g) and Lawson's reagent (202g) to the single-neck bottle respectively, and raise the temperature to 80°C for 3 hours.
  • the reaction solution was cooled to room temperature, poured into water (1L), extracted with ethyl acetate (1L ⁇ 2), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain intermediate 1-3 (260g). It was used directly in the next reaction without further purification.
  • intermediate 2-7 (6.8g) and 1,4-dioxane (10mL) in sequence, add dropwise 4M dioxane hydrochloride solution (60.0mL) under stirring, complete the addition, and stir at room temperature. 4h.
  • Pour the reaction solution into ice water (100 mL), add sodium bicarbonate to adjust the pH to neutral, extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane:methanol 50:1) to obtain intermediate 2-8 (4.6g).
  • intermediate 4-2 (12g), benzyl bromide (12.3g), potassium carbonate (21.3g) and acetonitrile (75mL) in sequence, and stir and react at room temperature for 1 hour.
  • intermediate 4-5 (3.87g), intermediate 1-A (3g), sodium carbonate (2.73g), and 1,1'-bis(diphenylphosphino)ferrocene dichloride in sequence.
  • Palladium (II) (0.63g), 1,4-dioxane (50mL) and water (5mL) were reacted at 100°C for 12 hours under a nitrogen atmosphere.
  • intermediate 8-2 (0.37g), tetrahydrofuran (10mL) and tetrabutylammonium fluoride (0.56g) in sequence, and stir and react at room temperature for 1 hour.
  • the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL).
  • the organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • intermediate 9-4 (0.15g), tetrahydrofuran (5mL) and tetrabutylammonium fluoride tetrahydrofuran solution (1M, 1.12mL, 1.12mmol) in sequence, and stir the reaction solution at room temperature for 1 hour.
  • intermediate 14-1 (3.9g), phthalic anhydride (3.37g) and acetic acid (40mL) in sequence, and mix under nitrogen protection. The mixture was heated to 120°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered with suction. The filter cake was washed with methyl tert-butyl ether (100 mL). The solid was collected and dried to obtain intermediate 14-2 (5.57g).
  • 1 H-NMR 500MHz, DMSO-d 6 ) ⁇ 14.20-13.81(m,1H),8.04(s,2H),7.97(s,2H).MS(ESI)m/z: 309.85[MH] - .
  • intermediate 14-2 (5.57g), potassium carbonate (2.73g) and N,N-dimethylformamide (45mL) in sequence; the resulting mixture is stirred in an ice water bath and cooled to 5°C.
  • Methyl iodide (2.55g) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature overnight.
  • the reaction solution was poured into water (50 mL) and stirred vigorously for 10 minutes, filtered with suction, and the filter cake was washed with water (50 mL). The solid was collected and dried to obtain intermediate 14-3 (1.14 g).
  • intermediate 14-3 (0.6g), ethanol (20mL) and hydrazine hydrate (0.463g) in sequence, heat the reaction solution to 70°C and stir for 1.5 hours. At the end of the reaction, the reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated to dryness. Add methyl tert-butyl ether (10 mL) to the residue, stir vigorously for 10 minutes, filter with suction, and concentrate the filtrate to obtain intermediate 14-4. (0.33g).
  • 1 H-NMR 500MHz, DMSO-d 6 ) ⁇ 4.95 (s, 2H), 3.52 (s, 3H).
  • intermediate 15-2 (1g) and tetrahydrofuran (40mL) in sequence.
  • the reaction solution is stirred and cooled to -75°C.
  • n-butyllithium (2.54g, 2.54mL) is added dropwise to it. Keep it until the dropwise addition is completed.
  • Temperature reaction 1h. Add iodine (1.341g) to it. After adding, keep the temperature and stir for 10 seconds. min, then transferred to room temperature and stirred for 1 h.
  • intermediate 15-4 (0.5g), copper iodide (0.080g), bistriphenylphosphorus palladium dichloride (0.148g) and trifluoroacetic acid (1.708g, 2.352mL) in sequence , N,N-dimethylformamide (10mL), then bubble nitrogen into the mixture for five minutes, add tert-butyldimethyl (2-propynyloxy)silane (0.719g), and put in the microwave
  • the reactor was heated to 80°C for 2 hours. After the reaction is completed, pour the reaction solution into 100 mL of saturated sodium chloride solution, extract with ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The residue was separated and purified using a silica gel column to obtain an intermediate (0.42g). MS(ESI)m/z: 280.23[M+H] + .
  • intermediate 16-1 (4.0g), potassium tert-butoxide (2.06g), and N,N-dimethylformamide (30mL) in sequence.
  • the mixture is cooled to 0°C and stirred under nitrogen protection.
  • the reaction was carried out for 10 minutes, and difluorobromomethyltrimethylsilane (4.06g) was added dropwise. After the dropwise addition was completed, the reaction solution was stirred and reacted at 0°C for 1 hour. After the reaction is completed, pour the reaction solution into water (200 mL), add ethyl acetate (100 mL), and extract.
  • intermediate 16-4 (320 mg), tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (0.56 g) were added in sequence, and the mixture was stirred and reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain intermediate 2-L (0.12g).
  • intermediate 1-B (0.15g), tert-butanol (5mL), cesium carbonate (0.334g), intermediate 2-I (0.036g) and BrettPhos Pd G3 (0.026g), nitrogen gas Replaced three times, the mixture was heated to 85°C for 12 hours under nitrogen protection.
  • the compounds of the present disclosure have improved or excellent inhibitory activity on Daudi cells; and compared with WI38-VA13 cells, they have selective inhibitory activity on Daudi cells.
  • the sample was added to an acetonitrile solution containing an internal standard and subjected to protein precipitation to prepare a supernatant, which was diluted and used for LC/MS/MS measurement.
  • test results show that the test compound of the present disclosure has stable metabolism in vitro (for example, the remaining amount is relatively large in 60 minutes), and the remaining amount in 60 minutes in the metabolism of human and/or mouse liver microparticles exceeds 50%.
  • ICR mice weighing 18 to 22 g, were randomly divided into groups of 9 after adapting for 3 to 5 days, and the test compound solution was orally administered at a dose of 10 mg/kg.
  • Blood collection time points are 15min, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h. Blood is collected from the orbit to prepare plasma samples to be tested.
  • Noncompartmental models were used to fit pharmacokinetic parameters.
  • test results show that the compounds of the present disclosure show good properties in pharmacokinetic tests, including but not limited to advantages in bioavailability, AUC, C max , t 1/2 , T max and other aspects.

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Abstract

The present application relates to a compound containing a thiazole ring, and specifically to a compound of formula I, a preparation method therefor, a pharmaceutical composition comprising same, and use thereof in treating diseases such as cancer.

Description

含有噻唑环的化合物Compounds containing thiazole rings
相关申请的交叉引用Cross-references to related applications
本申请要求向中国国家知识产权局提交的下述中国专利申请的优先权和权益，所述中国专利申请的内容通过援引整体并入本文：于2022年03月29日提交的第202210322374.X号中国专利申请。This application claims the priority and rights of the following Chinese patent application filed with the State Intellectual Property Office of China, the contents of which are incorporated herein by reference in their entirety: No. 202210322374.X filed on March 29, 2022 Chinese patent application.
技术领域Technical field
本申请涉及含有噻唑环的化合物、其制备方法、含有该化合物的药物组合物、以及其在治疗癌症等疾病中的用途。The present application relates to compounds containing thiazole rings, their preparation methods, pharmaceutical compositions containing the compounds, and their use in the treatment of cancer and other diseases.
背景技术Background technique
DNA损伤反应在维持细胞基因组稳定性和机体存活方面发挥重要作用。DNA双链断裂(Double strand breaks,DSBs)是DNA损伤最严重的形式。同源重组修复是体内参与DSBs损伤修复的重要机制之一，其中重组蛋白RAD51是通过同源重组来修复DNA双链断裂(double-strand breaks,DSBs)的核心因子。DNA damage response plays an important role in maintaining cellular genome stability and organism survival. DNA double-strand breaks (DSBs) are the most serious form of DNA damage. Homologous recombination repair is one of the important mechanisms involved in the repair of DSBs damage in vivo, in which the recombinant protein RAD51 is the core factor in repairing DNA double-strand breaks (DSBs) through homologous recombination.
RAD51是真核生物基因，由该基因编码的蛋白是RAD51蛋白家族的成员，其有助于DNA双链断裂的修复。在人类中，RAD51是339个氨基酸的蛋白，其在双链断裂(DSB)修复期间在DNA同源重组中起重要作用。RAD51催化断裂序列和其未破坏的同源物之间的链转移，以允许损伤区域的再合成活化诱导的胞苷脱氨酶(AID)或其他胞苷脱氨酶的过表达会导致大量B细胞恶性肿瘤患者和部分实体瘤患者的DNA损伤率升高(突变，双链DNA断裂和染色体重排)。过量表达AID和其他胞嘧啶脱氨酶的癌细胞依靠RAD51来修复由胞嘧啶脱氨酶引起的DNA损伤。RAD51在正常组织中低表达或不表达，在多种人类癌细胞中过度表达，如乳腺癌、非小细胞肺癌、***癌等，与肿瘤的转移和恶化相关。高度表达的RAD51促进癌细胞中的同源重组修复，从而诱发癌细胞对可引起DNA损伤的放疗和化疗的抵抗。已有文献报道RAD51抑制剂可以增强癌细胞对化疗和放疗的敏感性，相关研究结果支持RAD51作为一种抗肿瘤药物靶点开发小分子RAD51抑制剂提升化疗或放疗对癌细胞的杀伤力。RAD51 is a eukaryotic gene. The protein encoded by this gene is a member of the RAD51 protein family, which helps repair DNA double-strand breaks. In humans, RAD51 is a 339-amino acid protein that plays an important role in DNA homologous recombination during double-strand break (DSB) repair. RAD51 catalyzes strand transfer between the broken sequence and its unbroken homolog to allow resynthesis of the damaged region. Overexpression of activation-induced cytidine deaminase (AID) or other cytidine deaminase results in large amounts of B Patients with cellular malignancies and some solid tumors have increased rates of DNA damage (mutations, double-stranded DNA breaks, and chromosomal rearrangements). Cancer cells that overexpress AID and other cytosine deaminase enzymes rely on RAD51 to repair DNA damage caused by cytosine deaminase. RAD51 has low or no expression in normal tissues, but is overexpressed in a variety of human cancer cells, such as breast cancer, non-small cell lung cancer, prostate cancer, etc., and is associated with tumor metastasis and progression. Highly expressed RAD51 promotes homologous recombination repair in cancer cells, thereby inducing resistance of cancer cells to radiotherapy and chemotherapy that can cause DNA damage. It has been reported in the literature that RAD51 inhibitors can enhance the sensitivity of cancer cells to chemotherapy and radiotherapy. Related research results support the use of RAD51 as an anti-tumor drug target to develop small molecule RAD51 inhibitors to enhance the lethality of chemotherapy or radiotherapy to cancer cells.
单羧酸转运蛋白(Monocarboxylate transporters，MCTs)是一个蛋白质家族，可双向转运关键代谢中间体，例如乳酸、丙酮酸和酮体。MCT1是一种高亲和力的乳酸转运蛋白，可有效地导入和导出乳酸。癌细胞代谢需要乳酸转运以支持其高增殖率。MCTs在癌症中经常被上调，导致预后不良和死亡率增加。抑制MCT会导致下游几种对细胞周期调节很重要的蛋白质减少，包括RAD51，这可以解释在同源重组分析中看到的效果。组分析中看到的效果。MCT介导的乳酸转运对于癌细胞存活和肿瘤发生至关重要，使其成为癌症治疗和药物开发的有吸引力的靶点。Monocarboxylate transporters (MCTs) are a family of proteins that bidirectionally transport key metabolic intermediates such as lactate, pyruvate, and ketone bodies. MCT1 is a high-affinity lactate transporter that efficiently imports and exports lactate. Cancer cell metabolism requires lactate transport to support their high proliferation rate. MCTs are frequently upregulated in cancer, leading to poor prognosis and increased mortality. Inhibiting MCT results in downstream reductions in several proteins important for cell cycle regulation, including RAD51, which may explain the effects seen in homologous recombination analyses. Effects seen in group analyses. MCT-mediated lactate transport is critical for cancer cell survival and tumorigenesis, making it an attractive target for cancer therapy and drug development.
发明内容Contents of the invention
本申请涉及式I化合物、其立体异构体或其药学上可接受的盐，
The present application relates to compounds of formula I, their stereoisomers or pharmaceutically acceptable salts thereof,
其中，in,
R1选自3-10元杂环烷基、5-6元杂芳基、8-15元杂环基、苯基、3-10元环烷基、C2-10烯基或C2-10炔基；R 1 is selected from 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-15 membered heterocyclyl, phenyl, 3-10 membered cycloalkyl, C 2-10 alkenyl or C 2- 10 alkynyl;
所述3-10元杂环烷基或5-6元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 3-10-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
所述8-15元杂环基、苯基或3-10元环烷基任选地被一个或多个Rc取代；The 8-15-membered heterocyclyl, phenyl or 3-10-membered cycloalkyl is optionally substituted by one or more R c ;
所述C2-10烯基或C2-10炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；The C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
Ra选自氘代C1-6烷基、C2-10烯基、C2-10炔基、-C1-3烷基-CON(C1-6烷基)2，所述氘代C1-6烷基、C2-10 烯基、C2-10炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R a is selected from deuterated C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -C 1-3 alkyl-CON(C 1-6 alkyl) 2 , the deuterated C 1-6 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1- 3 alkyl) 2 substituted;
Rb选自卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)、-N(C1-3烷基)2、C1-6烷基、C3-6环烷基或者卤代C1-6烷基；R b is selected from halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl or halo C 1-6 alkyl;
Rc选自C1-6烷基、C2-10烯基、C2-10炔基、氧代、卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2，所述C2-10烯基或C2-10炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R c is selected from C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, oxo, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) Or -N(C 1-3 alkyl) 2 , the C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2. -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
Rd及Re分别独立地选自H、卤素、CN或C1-6烷基；R d and R e are independently selected from H, halogen, CN or C 1-6 alkyl;
L选自键或NRf；L is selected from bond or NR f ;
R2选自C1-6烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、C3-6环烷基或3-6元杂环烷基任选地被一个或多个OH、OC1-3烷基、卤素、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
X1及X2分别独立地选自NRg或O；X 1 and X 2 are independently selected from NR g or O;
Y选自CH2、N或O；Y is selected from CH 2 , N or O;
Rf及Rg分别独立地选自H或C1-3烷基；R f and R g are independently selected from H or C 1-3 alkyl;
R3选自C1-6烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、C3-6环烷基或3-6元杂环烷基任选地被一个或多个OH、OC1-3烷基、卤素、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
R4及R5分别独立地选自H、OH、卤素、CN、NH2、C1-6烷基或C1-6烷氧基取代。R 4 and R 5 are each independently selected from H, OH, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substitution.
在一些实施方案中，所述R1选自3-8元杂环烷基、5-6元杂芳基、8-13元杂环基、苯基、3-8元环烷基、C2-8烯基或C2-8炔基；In some embodiments, R 1 is selected from 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-13 membered heterocyclyl, phenyl, 3-8 membered cycloalkyl, C 2 -8 alkenyl or C 2-8 alkynyl;
所述3-8元杂环烷基或5-6元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 3-8-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
所述8-13元杂环基、苯基或3-8元环烷基任选地被一个或多个Rc取代；The 8-13-membered heterocyclyl, phenyl or 3-8-membered cycloalkyl is optionally substituted by one or more R c ;
所述C2-8烯基或C2-8炔基任选地被一个或多个卤素或OH取代。The C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens or OH.
在一些实施方案中，所述R1选自4-6元杂环烷基、5-6元杂芳基、8-11元杂环基、苯基、4-6元环烷基、C3-6烯基或C3-6炔基；In some embodiments, R 1 is selected from 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-11 membered heterocyclyl, phenyl, 4-6 membered cycloalkyl, C 3 -6 alkenyl or C 3-6 alkynyl;
所述4-6元杂环烷基或5-6元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
所述8-11元杂环基、苯基或4-6元环烷基任选地被一个或多个Rc取代。The 8-11 membered heterocyclyl, phenyl or 4-6 membered cycloalkyl is optionally substituted by one or more R c .
在一些实施方案中，所述R1选自5元杂芳基、8元杂环基、10元杂环基、11元杂环基或C4-5炔基；In some embodiments, the R 1 is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl, 11-membered heterocyclyl or C 4-5 alkynyl;
所述5元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
所述8元杂环基、10元杂环基或11元杂环基任选地被一个或多个Rc取代。The 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c .
在一些实施方案中，所述R1选自5元杂芳基、含有稠合环的8元杂环基、含有稠合环及螺环的10元杂环基、含有稠合环及螺环的11元杂环基或C4-5炔基；In some embodiments, R1 is selected from the group consisting of 5-membered heteroaryl, 8-membered heterocyclyl containing a fused ring, 10-membered heterocyclyl containing a fused ring and a spiro ring, 10-membered heterocyclyl containing a fused ring and a spiro ring, 11-membered heterocyclyl or C 4-5 alkynyl;
所述5元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
所述8元杂环基、10元杂环基或11元杂环基任选地被一个或多个Rc取代。The 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c .
上述杂环烷基、杂芳基或杂环基的杂原子选自氮、氧或硫；或者，所述杂环基的杂原子选自氮或氧。所述杂原子的个数可以选自1、2、3、4、5或6个，或者杂原子的个数选自2、3或4个，或者杂原子的个数选自2或3个。The heteroatom of the above-mentioned heterocycloalkyl, heteroaryl or heterocyclyl group is selected from nitrogen, oxygen or sulfur; alternatively, the heteroatom of the heterocyclyl group is selected from nitrogen or oxygen. The number of heteroatoms may be selected from 1, 2, 3, 4, 5 or 6, or the number of heteroatoms may be selected from 2, 3 or 4, or the number of heteroatoms may be selected from 2 or 3 .
在一些实施方案中，所述杂环基至少包含2个杂原子，选自氮或氧；在一些具体实施方案中，所述杂环基的杂原子为2个氮原子、或者3个氮原子、或者2个氮原子及1个氧原子。In some embodiments, the heterocyclyl group contains at least 2 heteroatoms, selected from nitrogen or oxygen; in some specific embodiments, the heteroatoms of the heterocyclyl group are 2 nitrogen atoms, or 3 nitrogen atoms , or 2 nitrogen atoms and 1 oxygen atom.
在一些方案中，所述杂环基可以是单环、双环或三环。在一些实施方案中，所述杂环基选自双环或三环。进一步，所述双环或三环之间可以通过稠合环、桥环或螺环形式连接。在一些实施方案中，所述杂环基选自双环或三环，双环通过稠合环方式连接，三环通过螺环和稠合环方式连接。In some embodiments, the heterocyclyl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heterocyclyl group is selected from bicyclic or tricyclic rings. Furthermore, the bicyclic or tricyclic rings may be connected through fused rings, bridged rings or spiro rings. In some embodiments, the heterocyclyl group is selected from a bicyclic ring or a tricyclic ring, the bicyclic ring is connected through a fused ring, and the tricyclic ring is connected through a spiro ring and a fused ring.
在一些具体方案中，所述杂环基选自双环或三环，其中与NH部位直接连接的环是芳香环或杂芳环。In some embodiments, the heterocyclyl group is selected from bicyclic or tricyclic rings, in which the ring directly connected to the NH site is an aromatic ring or a heteroaromatic ring.
在一些具体方案中，所述杂环基选自双环或三环，所述双环或三环中有一个环选自杂芳环或芳香环；可选地，所述双环或三环中有一个环选自杂芳环；进一步，可选地，所述双环或三环中与NH部位直接连 接的环是杂芳环。In some specific embodiments, the heterocyclyl group is selected from a bicyclic or tricyclic ring, and one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring; optionally, one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring. The ring is selected from heteroaromatic rings; further, optionally, the bicyclic or tricyclic ring is directly connected to the NH position. The attached ring is a heteroaromatic ring.
在一些实施方案中，其中杂环基选自5元环稠合5元环、3元环螺6元环稠合5元环、或3元环螺5元环稠合5元环。In some embodiments, the heterocyclyl group is selected from the group consisting of a 5-membered ring fused to a 5-membered ring, a 3-membered spiro 6-membered ring fused to a 5-membered ring, or a 3-membered spiro 5-membered ring fused to a 5-membered ring.
在一些实施方案中，所述R1选自吡唑基、咪唑基、***基、5,6-二氢-4H-吡咯并[1,2-b]吡唑基、6,7-二氢-5H-吡咯并[1,2-b][1,2,4]***基、5',6'-二氢螺环[环丙烷-1,4'-吡咯并[1,2-b]吡唑]基、6',7'-二氢螺[环丙烷-1,4'-吡唑并[5,1-c][1,4]噁嗪]基、4'H,6'H-螺[环丙烷-1,5'-吡咯并[1,2-b]吡唑]基、戊-3-炔-2-基或丁-2-炔-1-基，In some embodiments, R1 is selected from pyrazolyl, imidazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, Hydrogen-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2- b]pyrazol] base, 6',7'-dihydrospiro[cyclopropane-1,4'-pyrazolo[5,1-c][1,4]oxazine] base, 4'H,6 'H-spiro[cyclopropan-1,5'-pyrrolo[1,2-b]pyrazol]yl, pent-3-yn-2-yl or but-2-yn-1-yl,
所述吡唑基、咪唑基或***基被一个或多个Ra取代，任选地被一个或多个Rb取代；The pyrazolyl, imidazolyl or triazolyl group is substituted by one or more R a , optionally substituted by one or more R b ;
所述5,6-二氢-4H-吡咯并[1,2-b]吡唑基、6,7-二氢-5H-吡咯并[1,2-b][1,2,4]***基、5',6'-二氢螺环[环丙烷-1,4'-吡咯并[1,2-b]吡唑]基、6',7'-二氢螺[环丙烷-1,4'-吡唑并[5,1-c][1,4]噁嗪]基、4'H,6'H-螺[环丙烷-1,5'-吡咯并[1,2-b]吡唑]基任选地被一个或多个Rc取代。The 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]tri Azolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-b]pyrazol]yl, 6',7'-dihydrospiro[cyclopropane-1 ,4'-pyrazolo[5,1-c][1,4]oxazin]yl, 4'H,6'H-spiro[cyclopropane-1,5'-pyrrolo[1,2-b ]pyrazol] group is optionally substituted with one or more R c .
在一些实施方案中，所述R1选自 In some embodiments, the R1 is selected from
所述被一个或多个Ra取代，任选地被一个或多个Rb取代；described Substituted by one or more Ra , optionally substituted by one or more Rb ;
所述任选地被一个或多个Rc取代。described Optionally substituted by one or more Rc .
在一些实施方案中，所述R1选自 In some embodiments, the R1 is selected from
所述被一个或多个Ra取代，任选地被一个或多个Rb取代；described Substituted by one or more Ra , optionally substituted by one or more Rb ;
所述任选地被一个或多个Rc取代。described Optionally substituted by one or more Rc .
在一些实施方案中，Ra选自氘代C1-4烷基、C2-8烯基、C2-8炔基、-C1-3烷基-CON(C1-3烷基)2，所述氘代C1-4烷基、C2-8烯基、C2-8炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代。In some embodiments, R a is selected from deuterated C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-3 alkyl-CON(C 1-3 alkyl) 2. The deuterated C 1-4 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl groups are optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 substitution.
在一些实施方案中，Ra选自氘代C1-3烷基、C2-6烯基、C2-6炔基、-C1-2烷基-CON(C1-3烷基)2，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-2烷基、CN、NH2、-NH(C1-2烷基)或-N(C1-2烷基)2 取代。In some embodiments, R a is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkyl-CON(C 1-3 alkyl) 2. The C 2-6 alkenyl or C 2-6 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-2 alkyl, CN, NH 2 , -NH (C 1-2 alkyl ) or -N(C 1-2 alkyl) 2 replace.
在一些实施方案中，Ra选自氘代C1-3烷基、C2-4烯基、C2-4炔基、-CH2CON(C1-2烷基)2，所述C2-4烯基或C2-4炔基任选地被一个或多个氟、氯、溴或OH取代。In some embodiments, R a is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CH 2 CON(C 1-2 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl is optionally substituted with one or more fluorine, chlorine, bromine or OH.
在一些实施方案中，Ra选自氘代甲基、乙烯基、丙烯基、乙炔基、丙炔基、-CH2CON(CH3)2，所述乙烯基、丙烯基、乙炔基或丙炔基任选地被一个或多个氟或OH取代。In some embodiments, R a is selected from deuterated methyl, vinyl, propenyl, ethynyl, propynyl, -CH 2 CON(CH 3 ) 2 , said vinyl, propenyl, ethynyl, or propynyl. Alkynyl groups are optionally substituted with one or more fluorine or OH.
在一些实施方案中，Ra选自任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代的在一些实施方案中，Ra选自任选地被一个或多个卤素、OH、CN或NH2取代的 In some embodiments, R a is selected from optionally modified by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1 -3 alkyl) 2 substituted In some embodiments, R is selected from optionally substituted with one or more halogens, OH, CN, or NH
在一些实施方案中，Ra选自氘代甲基、 In some embodiments, Ra is selected from deuterated methyl,
在一些实施方案中，Rb选自卤素、OH、CN、NH2、C1-3烷基、C3-4环烷基或者卤代C1-3烷基；In some embodiments, R b is selected from halogen, OH, CN, NH 2 , C 1-3 alkyl, C 3-4 cycloalkyl, or haloC 1-3 alkyl;
在一些实施方案中，Rb选自氟、氯、溴、C1-3烷基、C3-4环烷基或者卤代C1-3烷基。In some embodiments, R b is selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 3-4 cycloalkyl, or haloC 1-3 alkyl.
在一些实施方案中，Rb选自氟、氯、甲基、环丙基或-CHF2。In some embodiments, R b is selected from fluorine, chlorine, methyl, cyclopropyl, or -CHF 2 .
在一些实施方案中，Rc选自C1-4烷基、C2-8烯基、C2-8炔基、卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2，所述C2-8烯基或C2-8炔基任选地被一个或多个卤素、OH、CN或NH2取代。In some embodiments, R c is selected from C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
在一些实施方案中，Rc选自C1-3烷基、C2-6烯基、C2-6炔基、卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、CN或NH2取代。In some embodiments, R c is selected from C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-6 alkenyl or C 2-6 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
在一些实施方案中，Rc选自C1-3烷基、C2-4烯基、C2-4炔基、卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2，所述C2-4烯基或C2-4炔基任选地被一个或多个卤素、OH、CN或NH2取代。In some embodiments, R c is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 .
在一些实施方案中，Rc选自C2-4烯基、C2-4炔基、卤素、OH、CN或NH2，所述C2-4烯基、C2-4炔基任选地被一个或多个卤素、OH、CN或NH2取代。In some embodiments, R c is selected from C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, CN or NH 2 , the C 2-4 alkenyl, C 2-4 alkynyl is optionally replaced by one or more halogen, OH, CN or NH 2 substitution.
在一些实施方案中，Rc选自卤素、OH、CN或NH2。 In some embodiments, R c is selected from Halogen, OH, CN or NH 2 .
在一些实施方案中，Rc选自氟、氯或溴。在一些实施方案中，Rc选自或氟。In some embodiments, R c is selected from Fluorine, chlorine or bromine. In some embodiments, R c is selected from Or fluorine.
在一些实施方案中，Rd及Re分别独立地选自氢、卤素、CN或C1-3烷基。In some embodiments, R d and R e are each independently selected from hydrogen, halogen, CN, or C 1-3 alkyl.
在一些实施方案中，Rd及Re分别独立地选自氢、氟、氯、CN或甲基。在一些实施方案中，Rd及Re为氢。In some embodiments, R d and R e are each independently selected from hydrogen, fluorine, chlorine, CN, or methyl. In some embodiments, R d and Re are hydrogen.
在一些实施方案中，所述R1选自 其中Ra、Rb或Rc的定义分别独立地如前所述。In some embodiments, the R1 is selected from The definitions of R a , R b or R c are independently as described above.
在一些实施方案中，所述R1选自 In some embodiments, the R1 is selected from
在一些实施方案中，L选自键或NH。在一些实施方案中，L选自键。In some embodiments, L is selected from bond or NH. In some embodiments, L is selected from bonds.
在一些实施方案中，R2选自C1-3烷基、C3-5环烷基或3-5元杂环烷基，所述C1-3烷基、C3-5环烷基或3-5元杂环烷基任选地被一个或多个OH、卤素、CN、NH2或C1-3烷氧基取代。In some embodiments, R 2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl Or 3-5 membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN, NH2 or C1-3 alkoxy group.
在一些实施方案中，R2选自C1-3烷基、C3-5环烷基或4元杂环烷基，所述C1-3烷基、C3-5环烷基或4元杂环烷基任选地被一个或多个OH、卤素、CN或NH2取代。In some embodiments, R2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl, or 4-membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl, or 4-membered heterocycloalkyl A membered heterocycloalkyl group is optionally substituted with one or more OH, halogen, CN or NH .
在一些实施方案中，R2选自乙基、环丙基、双环戊基或4元杂环烷基，所述乙基、环丙基、双环戊基或4元杂环烷基任选地被一个或多个氟、氯或溴取代。In some embodiments, R is selected from ethyl, cyclopropyl, dicyclopentyl, or 4-membered heterocycloalkyl, optionally Substituted by one or more fluorine, chlorine or bromine.
在一些实施方案中，R2选自乙基、环丙基、双环戊基或含有1个选自N或O的杂原子的4元杂环烷基，所述乙基、环丙基、双环戊基或4元杂环烷基任选地被一个或多个氟、氯或溴取代。In some embodiments, R is selected from ethyl, cyclopropyl, bicyclopentyl, or a 4-membered heterocycloalkyl containing 1 heteroatom selected from N or O. Pentyl or 4-membered heterocycloalkyl is optionally substituted with one or more fluorine, chlorine or bromine.
在一些实施方案中，R2选自乙基、双环戊基、氧杂环丁基或任选地被一个或多个氟取代的环丙基。In some embodiments, R is selected from ethyl, dicyclopentyl, oxetanyl, or cyclopropyl optionally substituted with one or more fluorine.
在一些实施方案中，R2选自乙基、 In some embodiments, R is selected from ethyl,
在一些实施方案中，R2选自C3-5环烷基或3-5元杂环烷基，所述C3-5环烷基或3-5元杂环烷基任选地被一个或多个OH、卤素、CN或NH2取代。在一些实施方案中，R2选自C3-5环烷基，所述C3-5环烷基任选地被一个或多个OH、卤素、CN或NH2取代。在一些实施方案中，R2选自C3-4环烷基。在一些实施方案中，R2选自 In some embodiments, R is selected from C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, which is optionally replaced by a Or multiple OH, halogen, CN or NH substitutions. In some embodiments, R is selected from C 3-5 cycloalkyl, which is optionally substituted with one or more OH, halogen, CN , or NH . In some embodiments, R2 is selected from C3-4 cycloalkyl. In some embodiments, R is selected from
在一些实施方案中，X1及X2分别独立地选自NH或O。在一些实施方案中，X1选自NH，X2选自O。In some embodiments, X 1 and X 2 are each independently selected from NH or O. In some embodiments, X1 is selected from NH and X2 is selected from O.
在一些实施方案中，Y选自CH2或O。在一些实施方案中，Y选自CH2。In some embodiments, Y is selected from CH2 or O. In some embodiments, Y is selected from CH2 .
在一些实施方案中，Rf及Rg分别独立地选自H或甲基。在一些实施方案中，Rf及Rg为H。In some embodiments, R f and R g are each independently selected from H or methyl. In some embodiments, Rf and Rg are H.
在一些实施方案中，R3选自C1-4烷基、C3-5环烷基或3-5元杂环烷基，所述C1-4烷基、C3-5环烷基或3-5元杂环烷基任选地被一个或多个OH、卤素、CN、NH2或C1-3烷氧基取代。In some embodiments, R 3 is selected from C 1-4 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl, said C 1-4 alkyl, C 3-5 cycloalkyl Or 3-5 membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN, NH2 or C1-3 alkoxy group.
在一些实施方案中，R3选自C1-4烷基、C3-4环烷基或3-4元杂环烷基，所述C1-4烷基、C3-4环烷基或3-4元杂环烷基任选地被一个或多个OH、卤素、CN或NH2取代。In some embodiments, R 3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl, said C 1-4 alkyl, C 3-4 cycloalkyl Or 3-4 membered heterocycloalkyl optionally substituted with one or more OH, halogen, CN or NH .
在一些实施方案中，R3选自C1-4烷基、C3-4环烷基或3-4元杂环烷基。In some embodiments, R3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl, or 3-4 membered heterocycloalkyl.
在一些实施方案中，R3选自C1-4烷基。在一些实施方案中，R3选自C3-4烷基。In some embodiments, R 3 is selected from C 1-4 alkyl. In some embodiments, R3 is selected from C3-4 alkyl.
在一些实施方案中，R3选自异丙基。In some embodiments, R3 is selected from isopropyl.
在一些实施方案中，R4及R5分别独立地选自氢、OH、卤素、CN、NH2、C1-3烷基或C1-3烷氧基。In some embodiments, R 4 and R 5 are each independently selected from hydrogen, OH, halogen, CN, NH 2 , C 1-3 alkyl, or C 1-3 alkoxy.
在一些实施方案中，R4及R5分别独立地选自氢、卤素、C1-3烷基或C1-3烷氧基。In some embodiments, R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-3 alkyl, or C 1-3 alkoxy.
在一些实施方案中，R4及R5分别独立地选自氢。In some embodiments, R 4 and R 5 are each independently selected from hydrogen.
在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from
在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from
在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from
在一些实施方案中，结构片段选自进一步，结构片段 选自 In some embodiments, structural fragments Selected from Further, the structure fragment Selected from
在一些实施方案中，结构片段选自在一些具体实施方案中，结构片段选自在一些具体实施方案中，结构片段选自 In some embodiments, structural fragments Selected from In some embodiments, structural fragments Selected from In some embodiments, structural fragments Selected from
在一些实施方案中，所述R1选自吡唑基、咪唑基或***基，所述吡唑基、咪唑基或***基被一个或多个Ra取代，任选地被一个或多个Rb取代。In some embodiments, R1 is selected from pyrazolyl, imidazolyl, or triazolyl substituted with one or more Ra , optionally with one or Multiple R b substitutions.
在一些实施方案中，所述R1选自吡唑基，所述吡唑基被一个或多个Ra取代，任选地被一个或多个Rb取代。In some embodiments, the R1 is selected from pyrazolyl substituted with one or more Ra , optionally substituted with one or more Rb .
在一些实施方案中，Ra选自氘代C1-3烷基、C2-6烯基或C2-6炔基，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-2烷基、CN、NH2、-NH(C1-2烷基)或-N(C1-2烷基)2取代。In some embodiments, Ra is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, which C 2-6 alkenyl or C 2-6 alkynyl is optionally Ground is substituted by one or more halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl) 2 .
在一些实施方案中，Ra选自氘代C1-3烷基、C2-4烯基或C2-4炔基，所述C2-4烯基或C2-4炔基任选地被一个或多个氟、氯、溴或OH取代。In some embodiments, Ra is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, which C 2-4 alkenyl or C 2-4 alkynyl is optionally Ground is substituted by one or more fluorine, chlorine, bromine or OH.
在一些实施方案中，Ra选自氘代甲基、乙烯基、丙烯基或丙炔基，所述乙烯基、丙烯基或丙炔基任选地被一个或多个氟或OH取代。 In some embodiments, R is selected from deuterated methyl, vinyl, propenyl, or propynyl optionally substituted with one or more fluorine or OH.
在一些实施方案中，Ra选自氘代甲基或C2-4炔基，所述C2-4炔基任选地被一个或多个氟或OH取代。In some embodiments, Ra is selected from deuterated methyl or C 2-4 alkynyl optionally substituted with one or more fluorine or OH.
在一些实施方案中，Ra选自氘代甲基或丙炔基，所述丙炔基任选地被一个或多个氟或OH取代。In some embodiments, R is selected from deuterated methyl or propynyl, which is optionally substituted with one or more fluorine or OH.
在一些实施方案中，Ra选自氘代甲基、 In some embodiments, Ra is selected from deuterated methyl,
在一些实施方案中，Ra选自C2-6烯基或C2-6炔基，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-2烷基、CN、NH2、-NH(C1-2烷基)或-N(C1-2烷基)2取代。In some embodiments, R is selected from C 2-6 alkenyl or C 2-6 alkynyl, which is optionally replaced by one or more halogen, OH , OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl) 2 substitution.
在一些实施方案中，Ra选自C2-4烯基或C2-4炔基，所述C2-4烯基或C2-4炔基任选地被一个或多个氟、氯、溴或OH取代。In some embodiments, R is selected from C 2-4 alkenyl or C 2-4 alkynyl, which is optionally replaced by one or more fluorine, chlorine , bromine or OH substitution.
在一些实施方案中，Ra选自乙烯基、丙烯基或丙炔基，所述乙烯基、丙烯基或丙炔基任选地被一个或多个氟或OH取代。In some embodiments, R is selected from vinyl, propenyl, or propynyl, which is optionally substituted with one or more fluorine or OH.
在一些实施方案中，Ra选自 In some embodiments, Ra is selected from
在一些实施方案中，上述杂芳基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6烯基、C2-6炔基或氘代C1-3烷基，当其被两个Ra取代，其中一个Ra选自C2-6烯基或C2-6炔基，另一个Ra选自氘代C1-3烷基，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代。In some embodiments, the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkenes base, C 2-6 alkynyl or deuterated C 1-3 alkyl, when it is substituted by two R a , one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, the other R a is selected from deuterated C 1-3 alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 substitution.
在一些实施方案中，上述杂芳基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6烯基或C2-6炔基，当其被两个Ra取代，其中一个Ra选自C2-6烯基或C2-6炔基，另一个Ra选自氘代C1-3烷基，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代。In some embodiments, the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkenes base or C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 Alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl ) or N(C 1-3 alkyl) 2 substitution.
在一些实施方案中，上述杂芳基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6炔基，当其被两个Ra取代，其中一个Ra选自C2-6炔基，另一个Ra选自氘代C1-3烷基，所述C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代。In some embodiments, the heteroaryl group described above is substituted with one or two Ra , optionally substituted with one or more R , and when it is substituted with one Ra , the Ra is selected from C 2-6 alkynes group, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl group, and the other R a is selected from deuterated C 1-3 alkyl group, the C 2-6 alkynyl group is optionally Substituted by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 .
在一些实施方案中，上述吡唑基、咪唑基或***基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6炔基，当其被两个Ra取代，其中一个Ra选自C2-6炔基，另一个Ra选自氘代C1-3烷基，所述C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代。In some embodiments, the above-mentioned pyrazolyl, imidazolyl or triazolyl group is substituted by one or two R a , optionally substituted by one or more R b , when it is substituted by one R a , the R a Selected from C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 alkyl, the C 2 -6 Alkynyl is optionally substituted with one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 .
在一些实施方案中，上述杂环基被一个或两个Rc取代，当被一个Rc取代，Rc选自C2-4烯基、或C2-4炔基；当被两个Rc取代，其中一个Rc选自C2-4烯基、或C2-4炔基，另一个Rc选自卤素、OH、CN或NH2；所述C2-4烯基或C2-4炔基任选地被一个或多个选自卤素、OH、CN或NH2取代。In some embodiments, the above heterocyclyl group is substituted by one or two R c , and when substituted by one R c , R c is selected from C 2-4 alkenyl, or C 2-4 alkynyl; when substituted by two R c , one R c is selected from C 2-4 alkenyl or C 2-4 alkynyl, the other R c is selected from halogen, OH, CN or NH 2 ; the C 2-4 alkenyl or C 2-4 alkynyl is optionally replaced by a or more selected from halogen, OH, CN or NH substitution .
在一些实施方案中，上述杂环基任选被一个或两个Rc取代，当被一个Rc取代，Rc选自当被两个Rc取代，其中一个Rc选自另一个Rc选自卤素。In some embodiments, the above-mentioned heterocyclyl group is optionally substituted by one or two R c . When substituted by one R c , R c is selected from When replaced by two R c , one of which is selected from The other R c is selected from halogen.
在一些方案中，本申请所述的式I化合物、其立体异构体或其药学上可接受的盐选自式I-A或式I-A’化合物、其立体异构体或其药学上可接受的盐,
In some embodiments, the compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of compounds of Formula IA or Formula I-A', its stereoisomer or its pharmaceutically acceptable salt. of salt,
其中，R1、L、R2、X1、X2、Y、R3、R4及R5的定义如本申请所述。Among them, R 1 , L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as defined in this application.
在一些实施方案中，结构片段及的定义如本申请所述。In some embodiments, structural fragments and is defined as described in this application.
在一些方案中，本申请所述的式I化合物、其立体异构体或其药学上可接受的盐选自式II化合物、其立体异构体或其药学上可接受的盐,
In some embodiments, the compound of Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of a compound of Formula II, its stereoisomer or a pharmaceutically acceptable salt thereof,
其中，in,
L、R2、X1、X2、Y、R3、R4及R5的定义如本申请所述；The definitions of L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as described in this application;
R’选自氢、卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2；R' is selected from hydrogen, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
R6各自独立地选自C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、卤素、OH、CN、NH2、C3-6环烷基、OC1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2；R 6 is each independently selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, halogen, OH, CN, NH 2 , C 3-6 cycloalkyl, OC 1-3 alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
环A选自5-6元杂芳基或8-15元杂环基；Ring A is selected from 5-6 membered heteroaryl or 8-15 membered heterocyclyl;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
在一些方案中，本申请所述的式I化合物、其立体异构体或其药学上可接受的盐选自式III化合物、其立体异构体或其药学上可接受的盐,
In some embodiments, the compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof described in the present application is selected from the group consisting of a compound of formula III, its stereoisomer or a pharmaceutically acceptable salt thereof,
其中，in,
L、R2、X1、X2、Y、R3、R4、R5及Rc的定义如本申请所述；The definitions of L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R c are as described in this application;
环B选自不存在、C3-4环烷基或3-4元杂环烷基；Ring B is selected from absence, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl;
环C选自5-6元杂环烷基；Ring C is selected from 5-6 membered heterocycloalkyl;
环D选自5-6元杂芳基；Ring D is selected from 5-6 membered heteroaryl;
n选自0、1、2、3或4。n is selected from 0, 1, 2, 3 or 4.
在一些实施方案中，所述R’选自氢、卤素、OH、OC1-2烷基、CN、NH2、-NH(C1-2烷基)或-N(C1-2烷基)2；In some embodiments, the R' is selected from hydrogen, halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH(C 1-2 alkyl) or -N(C 1-2 alkyl ) 2 ;
或者，R’选自选自氢、氟、氯、溴或OH；Alternatively, R' is selected from hydrogen, fluorine, chlorine, bromine or OH;
或者，R’选自选自氢、氟、溴或OH； Alternatively, R' is selected from hydrogen, fluorine, bromine or OH;
或者，R’选自选自氢、氟或OH。Alternatively, R' is selected from hydrogen, fluorine or OH.
在一些实施方案中，R6各自独立地选自C1-3烷基、氘代C1-3烷基、卤代C1-3烷基、卤素、OH、CN、NH2、C3-4环烷基、OC1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2；或者，R6各自独立地选自C1-3烷基、氘代C1-3烷基、卤代C1-3烷基、卤素或C3-4环烷基；或者，R6各自独立地选自甲基、氘代甲基、卤代甲基、氟、氯、溴或环丙基；或者，R6各自独立地选自甲基、-CD3、-CHF2、氟、氯或环丙基。In some embodiments, each R 6 is independently selected from C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen, OH, CN, NH 2 , C 3- 4 cycloalkyl, OC 1-3 alkyl, -NH (C 1-3 alkyl) or -N (C 1-3 alkyl) 2 ; or, R 6 is each independently selected from C 1-3 alkyl , deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen or C 3-4 cycloalkyl; or, R 6 is each independently selected from methyl, deuterated methyl, halomethyl , fluorine, chlorine, bromine or cyclopropyl; alternatively, R 6 is each independently selected from methyl, -CD 3 , -CHF 2 , fluorine, chlorine or cyclopropyl.
在一些实施方案中，所述环A选自5元杂芳基、8元杂环基、10元杂环基或11元杂环基；In some embodiments, the ring A is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl;
或者，环A选自5元杂芳基、含有稠合环的8元杂环基、含有稠合环及螺环的10元杂环基、含有稠合环及螺环的11元杂环基；Alternatively, Ring A is selected from the group consisting of a 5-membered heteroaryl group, an 8-membered heterocyclyl group containing a fused ring, a 10-membered heterocyclyl group containing a fused ring and a spiro ring, and an 11-membered heterocyclyl group containing a fused ring and a spiro ring. ;
或者，环A选自5元杂芳基；Alternatively, Ring A is selected from 5-membered heteroaryl;
或者，环A选自5元含氮杂芳基；Alternatively, Ring A is selected from 5-membered nitrogen-containing heteroaryl;
或者，环A选自吡唑基、咪唑基或***基；Alternatively, Ring A is selected from pyrazolyl, imidazolyl or triazolyl;
或者，环A选自吡唑。Alternatively, Ring A is selected from pyrazole.
在一些实施方案中，所述环B选自不存在或C3-4环烷基；或者环B选自不存在或环丙基。In some embodiments, Ring B is selected from Absence or C 3-4 cycloalkyl; or Ring B is selected from Absence or cyclopropyl.
在一些实施方案中，所述环C选自吡咯烷基或吗啉基。In some embodiments, the ring C is selected from pyrrolidinyl or morpholinyl.
在一些实施方案中，环D选自5元杂芳基；或者环D选自吡唑基或***基。In some embodiments, Ring D is selected from 5-membered heteroaryl; or Ring D is selected from pyrazolyl or triazolyl.
在一些实施方案中，所述环B为不存在，环C为吡咯烷基，环D选自吡唑基或***基。In some embodiments, Ring B is absent, Ring C is pyrrolidinyl, and Ring D is selected from pyrazolyl or triazolyl.
在一些实施方案中，所述环B为环丙基、环C选自吡咯烷基或吗啉基，环D为吡唑基。In some embodiments, the ring B is cyclopropyl, ring C is selected from pyrrolidinyl or morpholinyl, and ring D is pyrazolyl.
在一些实施方案中，结构片段选自 In some embodiments, structural fragments Selected from
在一些实施方案中，结构片段及的定义如本申请所述。In some embodiments, structural fragments and is defined as described in this application.
在一些实施方案中，m选自0、1、2或3；或者，m选自0或1。In some embodiments, m is selected from 0, 1, 2, or 3; alternatively, m is selected from 0 or 1.
在一些实施方案中，n选自0、1、2或3。In some embodiments, n is selected from 0, 1, 2, or 3.
在一些方案中，本申请所述的式I、式I-A或式II化合物、其立体异构体或其药学上可接受的盐选自式II-A化合物、其立体异构体或其药学上可接受的盐，
In some embodiments, the compound of Formula I, Formula IA or Formula II, its stereoisomer or its pharmaceutically acceptable salt described in the present application is selected from the group consisting of the compound of Formula II-A, its stereoisomer or its pharmaceutically acceptable salt. acceptable salt,
其中，R’、环A、m、L、R2、X1、X2、Y、R3、R4、R5及R6的定义如本申请所述。Among them, R', ring A, m, L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R 6 are as defined in this application.
在一些方案中，本申请所述的式I、式I-A或式III化合物、其立体异构体或其药学上可接受的盐选自式III-A化合物、其立体异构体或其药学上可接受的盐，
In some embodiments, the compound of Formula I, Formula IA or Formula III, its stereoisomer or its pharmaceutically acceptable salt described in the present application is selected from the group consisting of the compound of Formula III-A, its stereoisomer or its pharmaceutically acceptable salt. acceptable salt,
其中，环B、环C、环D、n、L、R2、X1、X2、Y、R3、R4、R5及Rc的定义如本申请所述。Among them, the definitions of ring B, ring C, ring D, n, L, R 2 , X 1 , X 2 , Y, R 3 , R 4 , R 5 and R c are as described in this application.
在一些方案中，结构片段及的定义如本申请所述。In some scenarios, structural fragments and is defined as described in this application.
在一些方案中，本申请所述的式I、或式II化合物、其立体异构体或其药学上可接受的盐选自式IV化合物、其立体异构体或其药学上可接受的盐，
In some embodiments, the compounds of Formula I, or Formula II, their stereoisomers, or pharmaceutically acceptable salts thereof described in the present application are selected from the group consisting of compounds of Formula IV, their stereoisomers, or their pharmaceutically acceptable salts ,
其中，R’、m、L、R2、R3、R4、R5及R6的定义如本申请所述。Among them, the definitions of R', m, L, R 2 , R 3 , R 4 , R 5 and R 6 are as described in this application.
在一些方案中，本申请所述的式I、式I-A、式II、式II-A或式IV化合物、其立体异构体或其药学上可接受的盐选自式IV-A化合物、其立体异构体或其药学上可接受的盐，
In some embodiments, the compounds of Formula I, Formula IA, Formula II, Formula II-A or Formula IV, their stereoisomers or their pharmaceutically acceptable salts described in the present application are selected from the group consisting of compounds of Formula IV-A, their Stereoisomers or pharmaceutically acceptable salts thereof,
其中，R’、m、L、R2、R3、R4、R5及R6的定义如本申请所述。Among them, the definitions of R', m, L, R 2 , R 3 , R 4 , R 5 and R 6 are as described in this application.
在一些方案中，本申请所述的式I或式III化合物、其立体异构体或其药学上可接受的盐选自式V化合物、其立体异构体或其药学上可接受的盐，
In some embodiments, the compounds of Formula I or Formula III, their stereoisomers, or pharmaceutically acceptable salts thereof described in the present application are selected from the group consisting of compounds of Formula V, their stereoisomers, or their pharmaceutically acceptable salts,
其中，n、L、R2、R3、R4、R5及Rc的定义如本申请所述。Among them, the definitions of n, L, R 2 , R 3 , R 4 , R 5 and R c are as described in this application.
在一些方案中，本申请所述的式I、式I-A、式III、式III-A或V化合物、其立体异构体或其药学上可接受的盐选自式V-A化合物、其立体异构体或其药学上可接受的盐，
In some embodiments, the compounds of Formula I, Formula IA, Formula III, Formula III-A or V, their stereoisomers or their pharmaceutically acceptable salts described in the present application are selected from the group consisting of compounds of Formula VA, their stereoisomers body or a pharmaceutically acceptable salt thereof,
其中，n、L、R2、R3、R4、R5及Rc的定义如本申请所述。Among them, the definitions of n, L, R 2 , R 3 , R 4 , R 5 and R c are as described in this application.
应理解，如以上所述的本申请的化合物的任何实施方案和本文关于如以上所述的本公开的化合物中的特定L、X1、X2、Y、R1、R2、R3、R4或R5取代基所阐述的任何具体取代基可以独立地与本申请的其它实施方案和/或化合物的取代基组合以形成以上未具体阐述的本发明的实施方案。此外，在具体实施方案和/或权利要求中关于任何特定L、X1、X2、Y、R1、R2、R3、R4或R5取代基公开了取代基范围的情况下，应理解，可以从该范围中删除一个或多个取代基，并且剩余的取代基范围也应被认为是本申请的实施方案。It will be understood that any embodiment of the compounds of the present application as described above and herein with respect to specific L, X 1 , X 2 , Y, R 1 , R 2 , R 3 , Any specific substituent set forth for the R 4 or R 5 substituent may independently be combined with substituents of other embodiments and/or compounds of this application to form embodiments of the invention not specifically set forth above. Furthermore, where substituent ranges are disclosed in the specific embodiments and/or claims for any particular L, X1 , X2 , Y, R1 , R2 , R3 , R4 or R5 substituent, It is understood that one or more substituents may be deleted from this range and the remaining substituent ranges shall also be considered embodiments of the present application.
本申请提供以下化合物、其立体异构体或其药学上可接受的盐，


This application provides the following compounds, their stereoisomers or their pharmaceutically acceptable salts,


另一方面，本申请涉及药物组合物，其包含上述化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。In another aspect, the present application relates to a pharmaceutical composition comprising the above-described compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
另一方面，本申请涉及治疗哺乳动物癌症、自身免疫疾病、免疫缺陷或神经退行性疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to a method for treating cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases in mammals, comprising administering a therapeutically effective amount of the above compounds, their stereoisomers, to mammals in need of such treatment, preferably humans. body or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
另一方面，本申请涉及上述的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗癌症、自身免疫疾病、免疫缺陷或神经退行性疾病的药物中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of medicines for preventing or treating cancer, autoimmune diseases, immune deficiencies or neurodegenerative diseases. uses in.
另一方面，本申请涉及上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗癌症、自身免疫疾病、免疫缺陷或神经退行性疾病中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in preventing or treating cancer, autoimmune diseases, immune deficiencies or neurodegenerative diseases.
另一方面，本申请涉及预防或者治疗癌症、自身免疫疾病、免疫缺陷或神经退行性疾病的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases.
在本申请的部分实施方案中，所述癌症选自淋巴瘤、白血病或实体瘤。在部分实施方案中，所述实体瘤选自肺癌或乳腺癌等。In some embodiments of the present application, the cancer is selected from lymphoma, leukemia, or solid tumors. In some embodiments, the solid tumor is selected from lung cancer, breast cancer, and the like.
另一方面，本申请涉及治疗哺乳动物由RAD51和/或MCT介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to a method of treating a mammal with a disease mediated by RAD51 and/or MCT, comprising administering a therapeutically effective amount of the above compound, a stereoisomer thereof or a mammal in need of the treatment, preferably a human. Pharmaceutically acceptable salts, or pharmaceutical compositions thereof.
另一方面，本申请涉及上述的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗RAD51和/或MCT介导的疾病的药物中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in the preparation of drugs for preventing or treating diseases mediated by RAD51 and/or MCT.
另一方面，本申请涉及上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗RAD51和/或MCT介导的疾病中的用途。On the other hand, the present application relates to the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions in preventing or treating diseases mediated by RAD51 and/or MCT.
另一方面，本申请涉及预防或者治疗RAD51和/或MCT介导的疾病的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。On the other hand, the present application relates to the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions for preventing or treating RAD51 and/or MCT-mediated diseases.
上述RAD51和/或MCT介导的疾病选自癌症、自身免疫疾病、免疫缺陷或神经退行性疾病。在本申请的部分实施方案中，所述癌症选自淋巴瘤、白血病或实体瘤。在部分实施方案中，所述实体瘤选自肺癌或乳腺癌等。The above-mentioned RAD51 and/or MCT-mediated diseases are selected from cancer, autoimmune diseases, immunodeficiency or neurodegenerative diseases. In some embodiments of the present application, the cancer is selected from lymphoma, leukemia, or solid tumors. In some embodiments, the solid tumor is selected from lung cancer, breast cancer, and the like.
技术效果Technical effect
本申请化合物具备以下效果中的至少一种：改善的或优异的Daudi细胞抑制活性；相较于WI38-VA13细胞，对Daudi细胞具有选择性抑制活性；改善的或优异的体内药效；体外各种属(例如，大鼠、犬、猴、小鼠和人)肝微粒体代谢稳定；具备良好的体内外药代动力学性质，例如小鼠(或者，大鼠、犬)体内具有良好的药代动力学数据(如AUC，Cmax或t1/2等)。The compound of the present application has at least one of the following effects: improved or excellent inhibitory activity on Daudi cells; compared with WI38-VA13 cells, it has selective inhibitory activity on Daudi cells; improved or excellent in vivo efficacy; in vitro various The liver microsomal metabolism of species (for example, rats, dogs, monkeys, mice and humans) is stable; they have good pharmacokinetic properties in vitro and in vivo. For example, mice (or rats, dogs) have good pharmacokinetic properties in vivo. Generation kinetic data (such as AUC, C max or t 1/2 , etc.).
定义definition
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。 Unless otherwise stated, the following terms used in this application have the following meanings. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and absence of the stated event or circumstance. For example, the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), or poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
本文中的“一个或多个”指一个至十个以内的整数。例如“一个或多个”指一个、两个、三个、四个、五个、六个、七个、八个、九个或十个；或者，“一个或多个”指一个、两个、三个、四个、五个或六个；或者，“一个或多个”指一个、两个或三个。“One or more” in this article refers to an integer ranging from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or "one or more" refers to one, two , three, four, five or six; alternatively, "one or more" means one, two or three.
本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。C mn as used herein means that the part has an integer number of carbon atoms in the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. So, for example, if a group is replaced by 2 R's, there are separate options for each R.
当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为共价键。When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表共价键时表示该结构实际上是A-Z。When one of the variables is selected from a covalent bond, it means that the two groups it is connected to are directly connected. For example, when L in A-L-Z represents a covalent bond, it means that the structure is actually A-Z.
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元表示其可在环己基或者环己二烯上的任意一个位置发生取代。When a substituent's bond is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, structural unit Indicates that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。其他例如，术语“C1-5烷基”指含有1至5个碳原子的烷基、术语“C1-4烷基”指含有1至4个碳原子的烷基、“C1-3烷基”指含有1至3个碳原子的烷基。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。The term "alkyl" refers to a hydrocarbyl group having the general formula C n H 2n+1 . The alkyl group may be straight chain or branched. For example, the term "C 1 -6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Other examples include the term "C 1 - 5 alkyl" referring to an alkyl group containing 1 to 5 carbon atoms, the term "C 1 - 4 alkyl" referring to an alkyl group containing 1 to 4 carbon atoms, "C 1 - 3 "Alkyl" refers to an alkyl group containing 1 to 3 carbon atoms. Similarly, the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。The term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-Butadiynyl (-C≡CC≡CH), etc.
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环(例如3元、4元、5元、6元、7元、8元、9元或10元环)。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring (eg, a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.
术语“杂环基”是指部分不饱和的(但不是完全不饱和的杂芳族)的非芳族环。所述“杂环基”可以是单环，也可以是多环(包括但不限于双环、三环)。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至15元环(例如3元、4元、5元、6元或7元环)。杂环基的非限制性实例包括但不限于二氢呋喃基、二氢吡咯基、2H-吡喃基、 等。The term "heterocyclyl" refers to a partially unsaturated (but not fully unsaturated heteroaromatic) non-aromatic ring. The "heterocyclyl" may be a single ring or a polycyclic ring (including but not limited to bicyclic or tricyclic rings). Unless otherwise indicated, the heterocycle is generally a 3- to 15-membered ring (e.g., 3-membered, 4-membered 1, 5, 6, or 7-membered rings). Non-limiting examples of heterocyclyl include, but are not limited to, dihydrofuryl, dihydropyrrolyl, 2H-pyranyl, wait.
术语“单环”指含有一个环的环状基团，其可以是完全饱和、部分饱和或芳香的。所述单环可以全部由C原子组成，可以含有一个或多个例如选自N、O或S的杂原子。The term "monocyclic" refers to a cyclic group containing one ring, which may be fully saturated, partially saturated or aromatic. The monocyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example.
术语“双环”指含有两个环的环状基团，其可以是完全饱和、部分饱和或芳香的。所述双环可以全部由C原子组成，可以含有一个或多个例如选自N、O或S的杂原子。所述双环可以是稠合环、桥环或螺环。The term "bicyclic" refers to a cyclic group containing two rings, which may be fully saturated, partially saturated, or aromatic. The bicyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example. The bicyclic ring may be a fused ring, a bridged ring or a spiro ring.
术语“三环”指含有三个环的环状基团，其可以是完全饱和、部分饱和或芳香的。所述三环可以全部由C原子组成，可以含有一个或多个例如选自N、O或S的杂原子。所述三环中任意相邻的两个单环可以是稠合环、桥环或螺环。The term "tricyclic" refers to a cyclic group containing three rings, which may be fully saturated, partially saturated, or aromatic. The tricyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms selected from N, O or S, for example. Any two adjacent single rings in the three rings may be fused rings, bridged rings or spiro rings.
术语“稠合环”是指两个或两个以上碳环或杂环以共有两个原子骈合而形成的多环化合物，包括完全饱和的、部分饱和的和芳香的。除非另有指示，所述稠合环为5～20元，优选6～14元，更优选9～14元。稠合环的非限制性实例包括但不限于萘、蒽、菲、 等。The term "fused ring" refers to a polycyclic compound formed by the fusion of two or more carbocyclic or heterocyclic rings with two atoms in common, including fully saturated, partially saturated and aromatic. Unless otherwise indicated, the fused ring has 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. Non-limiting examples of fused rings include, but are not limited to, naphthalene, anthracene, phenanthrene, wait.
术语“桥环”是指两个环共用三个或三个以上原子的完全饱和、或部分不饱和的多环***，包括碳环和杂环。除非另有指示，所述桥环为5～14元，优选6～14元，更优选6～10元。根据成环的数目可以分为双环、三环、四环或多环桥环，优选为双环或三环，更优选为双环。当桥环为杂环时，该多环中一个或多个环原子选自N、O、S(O)n(其中n为0、1或2)的杂原子(优选1或2个杂原子)，其余环原子为碳原子。The term "bridged ring" refers to a fully saturated or partially unsaturated polycyclic system in which two rings share three or more atoms, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the bridged ring is 5-14 yuan, preferably 6-14 yuan, more preferably 6-10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged rings, preferably bicyclic or tricyclic, more preferably bicyclic. When the bridged ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) n (where n is 0, 1 or 2) ), the remaining ring atoms are carbon atoms.
术语“螺环”是指单环之间共用一个碳原子(称螺原子)的完全饱和、或部分不饱和的多环***，包括碳环和杂环。除非另有指示，所述螺环为5至20元，优选为6至14元，更优选为9至14元。当螺环为杂环时，该多环中一个或多个环原子选自N、O、S(O)n(其中n为0、1或2)的杂原子(优选1或2个杂原子)，其余环原子为碳原子。The term "spiro ring" refers to a fully saturated or partially unsaturated polycyclic system in which a single carbon atom (called a spiro atom) is shared between single rings, including carbocyclic and heterocyclic rings. Unless otherwise indicated, the spiro ring is 5 to 20 members, preferably 6 to 14 members, more preferably 9 to 14 members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring are selected from heteroatoms (preferably 1 or 2 heteroatoms) of N, O, S(O) n (where n is 0, 1 or 2) ), the remaining ring atoms are carbon atoms.
术语“杂环烷基”是指完全饱和的环状基团。所述“杂环烷基”可以是单环，也可以是多还(包括但不限于双环、三环)。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环(例如3元、4元、5元、6元或7元环)。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。The term "heterocycloalkyl" refers to a fully saturated cyclic group. The "heterocycloalkyl" may be a single ring or a polycyclic ring (including but not limited to bicyclic or tricyclic rings). Unless otherwise indicated, the heterocycle is generally a 3- to 10-membered ring (e.g., 3-membered, 4-membered 1, 5, 6, or 7-membered rings). Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, ethylene sulfide, and aziridyl. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane. Examples of cyclyl, thibutylcyclyl, and 5-membered heterocycloalkyl include but are not limited to tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, and thiazolidine 1, 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxeptanyl, and thiopanyl. Preference is given to monocyclic heterocycloalkyl groups with 5 or 6 ring atoms.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，例如含有1个、2个或3个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个5至8元环(例如4元、5元、6元、7元或8元环)，或包含6至14个，尤其是6至10个(或9个)环 原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、***基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, such as 1, 2 or 3 ring atoms selected from N, O, S Ring atoms, the remaining ring atoms are C, and it has at least one aromatic ring. Preferred heteroaryl groups have a single 5 to 8 membered ring (eg 4, 5, 6, 7 or 8 membered ring) or contain 6 to 14, especially 6 to 10 (or 9) rings Multiple fused rings of atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
除非另有规定，术语“杂”表示杂原子，例如包括氧(O)、氮(N)或硫(S)。Unless otherwise specified, the term "hetero" refers to heteroatoms including, for example, oxygen (O), nitrogen (N), or sulfur (S).
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i)抑制疾病或疾病状态，即遏制其发展；(i) To inhibit a disease or disease state, that is, to arrest its progression;
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "treating" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when such disease A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
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。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. .
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
术语“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括水，乙醇，乙酸等。溶剂化物包括化学计算量的溶剂合物和非化学计算量的溶剂合物。The term "solvate" refers to a compound formed by combining a compound of the invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, acetic acid, etc. Solvates include stoichiometric solvates and non-stoichiometric solvates.
术语“水合物”指的是一种溶剂化物，包括已披露或要求保护的化合物和化学计量或非化学计量数量的水。The term "hydrate" refers to a solvate including a disclosed or claimed compound and a stoichiometric or non-stoichiometric amount of water.
本发明的化合物还可以被制备成前药，如药学上可接受的前药。由于已知前药可提高药物的众多期望特性(如溶解性、生物利用度、制备等)，可以以前药的形式递送本发明的化合物。因此，本发明旨在涵盖当前主张的化合物的前药，其递送方法和含有前药的组合物。The compounds of the present invention may also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. Since prodrugs are known to enhance numerous desirable properties of drugs (eg, solubility, bioavailability, preparation, etc.), the compounds of the invention can be delivered in the form of prodrugs. Accordingly, the present invention is intended to encompass prodrugs of the presently claimed compounds, methods of delivery thereof, and compositions containing the prodrugs.
术语“前药”旨在包括任何共价结合的载体，当给予哺乳动物受试者这种前药时，该载体在体内释放本发明的活性母体药物。本发明的前药通过以这样一种方式修饰化合物中存在的官能团制备，使得该修饰物在常规操作中或在体内断裂成母体化合物。The term "prodrug" is intended to include any covalently bound carrier that releases the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved to the parent compound during routine manipulation or in vivo.
本发明中，术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。术语“活性代谢物”是指当化合物被代谢时形成的化合物的生物活性衍生物。In the present invention, the term "individual" includes humans and animals, for example, mammals (such as primates, cattle, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep and birds, etc.). The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
术语“个体”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。 The words "comprise" or "comprise" and their English variants such as compris or comprising should be understood in an open, non-exclusive sense, that is, "including but not limited to."
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。例示性的互变异构体如下所示但不限于此。The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens. Valence tautomers include tautomers by reorganization of some of the bonding electrons. Exemplary tautomers are shown below But not limited to this.
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。The present application also includes compounds of the present application that are the same as those described herein, but are isotopically labeled in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
某些同位素标记的本申请化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。Certain isotopically labeled compounds of the present application (eg, those labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。例示性的氘代化合物如下所示但不限于此。Furthermore, substitution with heavier isotopes such as deuterium (i.e. 2H ) may provide certain therapeutic advantages resulting from greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements) and, therefore, in certain situations The following may be preferred, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium. Exemplary deuterated compounds are shown below But not limited to this.
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。非限制性实例，的立体异构体的分别包括但不限于 (表示五元杂芳基)。Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples, The stereoisomers respectively include, but are not limited to ( represents a five-membered heteroaryl group).
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients. For example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，以单独或分开剂量的形式。In all methods of administration of the compounds of general formula I described herein, dosages of 0.01 to 200 mg/kg body weight are administered per day, in single or divided doses.
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent. The solvent must be suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compounds of the present application, those skilled in the art sometimes need to modify or select the synthesis steps or reaction procedures based on the existing embodiments.
本领域合成路线规划中的一个重要考量因素是为反应性官能团选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。An important consideration in the planning of synthetic routes in this field is the selection of appropriate protecting groups for reactive functional groups. For example, please refer to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. Referenced in this application All references to are incorporated into this application in their entirety.
在一些实施方案中，本申请通式I的化合物可以由有机合成领域技术人员通过以下路线来制备：

In some embodiments, the compound of Formula I of the present application can be prepared by those skilled in the field of organic synthesis through the following route:

其中，R1、L、R2、X1、X2、Y、R3、R4及R5的定义如本申请所述。Among them, R 1 , L, R 2 , X 1 , X 2 , Y, R 3 , R 4 and R 5 are as defined in this application.
本申请采用下述缩略词：This application uses the following abbreviations:
Boc代表叔丁氧基羰基；DMSO代表二甲基亚砜；TBS代表叔丁基二甲基硅烷基；BrettPhos Pd G3代表甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)；劳森试剂代表2,4-双(对甲氧苯基)-1,3-二硫一二磷杂环丁烷-2,4硫化物；TBSO代表叔丁基二甲基硅氧基。Boc represents tert-butoxycarbonyl; DMSO represents dimethyl sulfoxide; TBS represents tert-butyldimethylsilyl; BrettPhos Pd G3 represents methane sulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy Palladium(II) (2'-amino-1,1'-biphenyl-2-yl)(2'-amino-1,1'-biphenyl-2-yl); Lawson's reagent represents 2,4-bis(p-methoxyphenyl)-1,3-dithiodiphosphatane-2,4 sulfide; TBSO represents tert-butyldimethylsiloxy.
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有溶剂试剂是市售的，无需进一步纯化即可使用。For the sake of clarity, examples are further used to illustrate the invention, but the examples do not limit the scope of the application. All solvent reagents used in this application are commercially available and used without further purification.
具体实施方式Detailed ways
制备例1中间体1-A的制备
Preparation Example 1 Preparation of Intermediate 1-A
步骤一：中间体1-2的制备Step 1: Preparation of intermediate 1-2
向三口瓶中分别加入化合物1-1(250g)，氯化铵(82g)、乙腈(4000mL)、三乙胺(312g,3083mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(390g)，室温搅拌反应4小时。反应液过滤，石油醚洗涤，干燥，得中间体1-2(220g)。1H NMR(500MHz,DMSO-d6)δ7.33(s,2H),7.24–7.16(m,1H),3.14(m,1H),2.02–1.92(m,1H),1.81–1.68(m,4H),1.37(s,9H),1.36–1.26(m,2H),1.18–1.06(m,2H).Add compound 1-1 (250g), ammonium chloride (82g), acetonitrile (4000mL), triethylamine (312g, 3083mmol) and benzotriazole-N,N,N',N' to the three-necked flask. - Tetramethylurea hexafluorophosphate (390g), stir and react at room temperature for 4 hours. The reaction solution was filtered, washed with petroleum ether, and dried to obtain intermediate 1-2 (220g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.33(s,2H),7.24–7.16(m,1H),3.14(m,1H),2.02–1.92(m,1H),1.81–1.68(m ,4H),1.37(s,9H),1.36–1.26(m,2H),1.18–1.06(m,2H).
步骤二：中间体1-3的制备Step 2: Preparation of intermediate 1-3
向单口瓶中分别加入中间体1-2(220g)、2-甲基-四氢呋喃(1300mL)、碳酸钠(96g)和劳森试剂(202g)，升温至80℃反应3h。反应液降至室温，倒入水(1L)中，乙酸乙酯(1L×2)萃取，合并有机相，饱和食盐水洗涤，有机相减压浓缩得中间体1-3(260g)。未进一步纯化，直接用于下一步反应。1H NMR(500MHz,DMSO-d6):δ9.30(s,1H),9.03(s,1H),6.71(d,J＝8.1Hz,1H),3.25–2.94(m,1H),2.46–2.36(m,1H),1.82–1.65(m,4H),1.38(m,11H),1.26–1.09(m,2H).Add intermediate 1-2 (220g), 2-methyl-tetrahydrofuran (1300mL), sodium carbonate (96g) and Lawson's reagent (202g) to the single-neck bottle respectively, and raise the temperature to 80°C for 3 hours. The reaction solution was cooled to room temperature, poured into water (1L), extracted with ethyl acetate (1L × 2), the organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain intermediate 1-3 (260g). It was used directly in the next reaction without further purification. 1 H NMR (500MHz, DMSO-d 6 ): δ9.30 (s, 1H), 9.03 (s, 1H), 6.71 (d, J = 8.1Hz, 1H), 3.25–2.94 (m, 1H), 2.46 –2.36(m,1H),1.82–1.65(m,4H),1.38(m,11H),1.26–1.09(m,2H).
步骤三：中间体1-4的制备Step 3: Preparation of intermediates 1-4
向单口瓶中分别加入中间体1-3(260g)、乙醇(3L)、对甲苯磺酸(347g)和2-溴-1,1-二乙氧基-乙烷(397g)，升温至80℃反应6h，将反应液降至室温，用饱和碳酸钠水溶液调节至pH＝9，并添加二碳酸二叔丁酯(220g)，混合物在室温搅拌下反应过夜。将反应液减压浓缩后倒入水(3L)中，乙酸乙酯(2L×2)萃取，合并有机相，减压浓缩，残留物经硅胶柱层析分离(石油醚:乙酸乙酯＝20:1-10:1)，得中间体1-4(52g)。1H NMR(500MHz,DMSO-d6)δ7.69(d,J＝3.3Hz,1H),7.56(d,J＝3.3Hz,1H),6.79(d,J＝7.8Hz,1H),3.25(s,1H),2.95–2.85(m,1H),2.11–2.05(m,2H),1.90–1.85(m,2H),1.54–1.47(m,2H),1.38(m,11H).Add intermediate 1-3 (260g), ethanol (3L), p-toluenesulfonic acid (347g) and 2-bromo-1,1-diethoxy-ethane (397g) to the single-neck bottle respectively, and heat to 80 The reaction was carried out for 6 hours at ℃, the reaction solution was lowered to room temperature, adjusted to pH=9 with saturated sodium carbonate aqueous solution, and di-tert-butyl dicarbonate (220g) was added, and the mixture was allowed to react overnight with stirring at room temperature. The reaction solution was concentrated under reduced pressure and poured into water (3L). Extracted with ethyl acetate (2L×2). The organic phases were combined and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20 :1-10:1), and intermediate 1-4 (52g) was obtained. 1 H NMR (500MHz, DMSO-d 6 ) δ7.69 (d, J = 3.3 Hz, 1H), 7.56 (d, J = 3.3 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 3.25 (s,1H),2.95–2.85(m,1H),2.11–2.05(m,2H),1.90–1.85(m,2H),1.54–1.47(m,2H),1.38(m,11H).
步骤四：中间体1-5的制备Step 4: Preparation of intermediates 1-5
向单口瓶中加入中间体1-4(52g)、N,N-二甲基甲酰胺(520mL)和N-溴代丁二酰亚胺(13.6g)，室温反应过夜。将反应液倒入饱和氯化钠溶液(3L)中，乙酸乙酯(2L×2)萃取，合并有机相，减压浓缩，残留物经硅胶柱层析分离(石油醚:乙酸乙酯＝20:1-10:1)，得中间体1-5(22g)。MS(ESI):m/z 361.05[M+H]+.步骤五：中间体1-6的制备Intermediate 1-4 (52g), N,N-dimethylformamide (520mL) and N-bromosuccinimide (13.6g) were added to the one-neck bottle, and the reaction was carried out at room temperature overnight. Pour the reaction solution into a saturated sodium chloride solution (3L), extract with ethyl acetate (2L×2), combine the organic phases, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20 :1-10:1), and intermediate 1-5 (22g) was obtained. MS(ESI): m/z 361.05[M+H] + . Step 5: Preparation of intermediate 1-6
向单口瓶中加入中间体1-5(22g)和4M盐酸二氧六环溶液(300mL)，室温反应2h。将反应液减压浓缩，得中间体1-6(18g).Add intermediate 1-5 (22g) and 4M dioxane hydrochloride solution (300 mL) to the one-neck bottle, and react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate 1-6 (18g).
步骤六：中间体1-A的制备Step 6: Preparation of Intermediate 1-A
向单口瓶中分别加入中间体1-6(18g)、吡啶(27.3g)、4-二甲氨基吡啶(1.68g)和二氯甲烷(200mL)。冰浴下缓慢滴加入氯甲酸异丙酯(12.7g)，加毕，室温反应2小时。向反应液中加入二氯甲烷(100mL)，分别以1N的盐酸水溶液(200mL)、饱和碳酸钠水溶液、饱和氯化钠水溶液洗涤，有机相减压浓缩，残留物经硅胶柱层析分离(石油醚:乙酸乙酯＝15:1至10:1)得中间体1-A(19g)。ESI-MS m/z 347.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ7.74(s,1H),7.00(d,J＝7.9Hz,1H),4.77–4.72(m,1H),3.34–3.27(m,1H),2.94–2.84(m,1H),2.09–2.03(m,2H),1.91–1.87(m,2H),1.54–1.47(m,2H),1.34–1.27(m,2H),1.16(d,J＝6.3Hz,6H).Intermediate 1-6 (18g), pyridine (27.3g), 4-dimethylaminopyridine (1.68g) and dichloromethane (200mL) were added to the single-neck bottle respectively. Isopropyl chloroformate (12.7g) was slowly added dropwise in an ice bath. After the addition was completed, the reaction was carried out at room temperature for 2 hours. Dichloromethane (100 mL) was added to the reaction solution, and washed with 1N hydrochloric acid aqueous solution (200 mL), saturated sodium carbonate aqueous solution, and saturated sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum). Ether:ethyl acetate=15:1 to 10:1) to obtain intermediate 1-A (19g). ESI-MS m/z 347.1[M+H] + . 1 H NMR (500MHz, DMSO-d 6 ) δ7.74 (s, 1H), 7.00 (d, J = 7.9Hz, 1H), 4.77–4.72 ( m,1H),3.34–3.27(m,1H),2.94–2.84(m,1H),2.09–2.03(m,2H),1.91–1.87(m,2H),1.54–1.47(m,2H), 1.34–1.27(m,2H),1.16(d,J＝6.3Hz,6H).
制备例2中间体1-B的制备
Preparation Example 2 Preparation of Intermediate 1-B
步骤一：中间体2-2的制备Step 1: Preparation of intermediate 2-2
向三口瓶中，依次加入化合物2-1(50g)、N,N-二甲基甲酰胺(200mL)，冰浴降温至0℃，分批加入60wt％纯度的氢化钠(16.0g)，加毕，自然升至室温搅拌0.5h，随后加入环丙基溴(48.3g)的N,N-二甲基甲酰胺(100mL)溶液，加毕将反应瓶加热至100℃反应过夜。将反应液倒入水(3L)中，乙酸乙酯(500mL×2)萃取，合并有机相，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝80:20)，得中间体2-2(47g)。1H NMR(500MHz,DMSO-d6)δ6.94(t,J＝7.8Hz,1H),6.57(t,J＝1.9Hz,1H),6.48(dd,J＝7.7,0.7Hz,1H),6.40–6.30(m,1H),5.11(s,2H),2.22–2.11(m,1H),1.07–0.99(m,2H),0.59–0.49(m,2H)。MS(ESI):m/z 166.21[M+H]+.To the three-necked flask, add compound 2-1 (50g) and N,N-dimethylformamide (200mL) in sequence, cool down to 0°C in an ice bath, add 60wt% purity sodium hydride (16.0g) in batches, and add After completion, the mixture was naturally raised to room temperature and stirred for 0.5 h. Then a solution of cyclopropyl bromide (48.3g) in N,N-dimethylformamide (100mL) was added. After the addition was completed, the reaction flask was heated to 100°C for overnight reaction. Pour the reaction solution into water (3L), extract with ethyl acetate (500mL×2), combine the organic phases, wash with saturated brine (200mL), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product obtained is subjected to silica gel column chromatography. After separation and purification (petroleum ether:ethyl acetate=80:20), intermediate 2-2 (47g) was obtained. 1 H NMR (500MHz, DMSO-d 6 ) δ6.94 (t, J = 7.8 Hz, 1H), 6.57 (t, J = 1.9 Hz, 1H), 6.48 (dd, J = 7.7, 0.7 Hz, 1H) ,6.40–6.30(m,1H),5.11(s,2H),2.22–2.11(m,1H),1.07–0.99(m,2H),0.59–0.49(m,2H). MS(ESI):m/z 166.21[M+H] + .
步骤二：中间体2-3的制备Step 2: Preparation of intermediate 2-3
向三口瓶中，依次加入中间体2-2(42g)、甲醇(600mL)、二碳酸二叔丁酯(111g)，加毕，室温下搅拌过夜。将反应液倒入水(1L)中，乙酸乙酯(300mL×2)萃取，合并有机相，饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品经硅胶柱层析分离(石油醚:乙酸乙酯＝80:20)，得中间体2-3(67g)。1H NMR(500MHz,DMSO-d6)9.37(s,1H),7.52(s,1H),7.20(dt,J＝15.6,7.9Hz,2H),6.94(d,J＝7.5Hz,1H),2.29–2.12(m,1H),1.47(s,9H),1.07(d,J＝6.9Hz,2H),0.66–0.46(m,2H).To the three-necked flask, add intermediate 2-2 (42g), methanol (600mL), and di-tert-butyl dicarbonate (111g) in sequence. After the addition is completed, stir at room temperature overnight. Pour the reaction solution into water (1L), extract with ethyl acetate (300mL×2), combine the organic phases, wash with saturated brine (300mL), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product obtained is subjected to silica gel column chromatography. Separate (petroleum ether: ethyl acetate = 80:20) to obtain intermediate 2-3 (67g). 1 H NMR (500MHz, DMSO-d 6 )9.37(s,1H),7.52(s,1H),7.20(dt,J＝15.6,7.9Hz,2H),6.94(d,J＝7.5Hz,1H) ,2.29–2.12(m,1H),1.47(s,9H),1.07(d,J＝6.9Hz,2H),0.66–0.46(m,2H).
步骤三：中间体2-4的制备Step 3: Preparation of intermediate 2-4
向三口瓶中，依次加入中间体2-3(67g)、二氯甲烷(1300mL)，降温至-30℃，分批加入N-溴代丁二酰亚胺(44.9g)，加毕，-30℃下继续搅拌0.5h。停止搅拌，将反应液倒入水(1L)，二氯甲烷(500mL×3)萃取，合并有机相，饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品经硅胶柱层析分离(石油醚:乙酸乙酯＝20:1)，得中间体2-4(28.4g)。1H NMR(500MHz,DMSO-d6)δ8.51(s,1H),7.55(d,J＝8.4Hz,1H),7.52(d,J＝2.1Hz,1H),7.08(dd,J＝8.4,2.3Hz,1H),2.28-2.25(m,J＝7.3,4.3Hz,1H),1.46(s,9H),1.16–1.04(m,2H),0.62–0.50(m,2H).To the three-necked flask, add intermediate 2-3 (67g) and dichloromethane (1300mL) in sequence, cool to -30°C, add N-bromosuccinimide (44.9g) in batches, and complete the addition, - Continue stirring at 30°C for 0.5h. Stop stirring, pour the reaction solution into water (1L), extract with dichloromethane (500mL×3), combine the organic phases, wash with saturated brine (500mL), dry over anhydrous sodium sulfate, filter, and concentrate. The crude product obtained is passed through a silica gel column. Chromatographic separation (petroleum ether: ethyl acetate = 20:1) gave intermediate 2-4 (28.4g). 1 H NMR (500MHz, DMSO-d 6 ) δ8.51 (s, 1H), 7.55 (d, J = 8.4Hz, 1H), 7.52 (d, J = 2.1Hz, 1H), 7.08 (dd, J = 8.4, 2.3Hz, 1H), 2.28-2.25 (m, J＝7.3, 4.3Hz, 1H), 1.46 (s, 9H), 1.16–1.04 (m, 2H), 0.62–0.50 (m, 2H).
步骤四：中间体2-5的制备Step 4: Preparation of intermediate 2-5
向单口瓶中，依次加入中间体2-4(28.4g)、二氯甲烷(600mL)，分批缓慢加入间氯过氧苯甲酸(56.9g)，加毕，继续在室温下搅拌过夜。停止搅拌，过滤，滤液分别以饱和亚硫酸钠溶液(200mL)、饱和碳酸氢钠溶液(200mL)、饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品经硅胶柱层析分离(石油醚:乙酸乙酯＝50:50)，得中间体2-5(21g)。1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.25(s,1H),7.78(d,J＝8.6Hz,1H),7.60(d,J＝8.4Hz,1H),3.26–3.10(m,1H),1.48(s,9H),1.12-1.11(m,4H).To the single-neck bottle, add intermediate 2-4 (28.4g) and dichloromethane (600mL) in sequence, slowly add m-chloroperoxybenzoic acid (56.9g) in batches, complete the addition, and continue stirring at room temperature overnight. Stop stirring, filter, and the filtrate is washed with saturated sodium sulfite solution (200 mL), saturated sodium bicarbonate solution (200 mL), and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained is separated by silica gel column chromatography. (Petroleum ether:ethyl acetate=50:50), to obtain intermediate 2-5 (21g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.87 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.6Hz, 1H), 7.60 (d, J = 8.4Hz, 1H) ,3.26–3.10(m,1H),1.48(s,9H),1.12-1.11(m,4H).
步骤五：中间体2-6的制备Step 5: Preparation of intermediate 2-6
向单口瓶中，依次加入中间体2-5(21g)、1,4-二氧六环(300mL)、醋酸钾(16.43g)、双联频哪醇硼酸酯(18.42g)及二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II)(1.189g)，氮气保护下，将混合物加热至90℃反应8h。经冷却至室温的反应液倒入水(1L)中，乙酸乙酯(500mL×3)萃取，合并有机相，饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品经硅胶柱层析分离(石油醚:乙酸乙酯＝70:30)，得中间体2-6(28g)。1H NMR(500MHz,DMSO-d6)δ9.81(s,1H),8.05(s,1H),7.67(d,J＝8.0Hz,1H),7.48 (d,J＝8.1Hz,1H),2.96-2.91(m,1H),1.49(s,9H),1.31(s,12H),1.13–0.98(m,4H).To the single-neck bottle, add intermediate 2-5 (21g), 1,4-dioxane (300mL), potassium acetate (16.43g), double pinacol borate (18.42g) and dichloro Di-tert-butyl-(4-dimethylaminophenyl)phosphorus palladium (II) (1.189g), under nitrogen protection, heated the mixture to 90°C for 8 hours. The reaction solution cooled to room temperature was poured into water (1L), extracted with ethyl acetate (500mL×3), the organic phases were combined, washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained was Separate by silica gel column chromatography (petroleum ether:ethyl acetate=70:30) to obtain intermediate 2-6 (28g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.81 (s, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.48 (d,J＝8.1Hz,1H),2.96-2.91(m,1H),1.49(s,9H),1.31(s,12H),1.13–0.98(m,4H).
步骤六：中间体2-7的制备Step 6: Preparation of intermediate 2-7
向单口瓶中，依次加入中间体2-6(13.41g)、1,4-二氧六环(180mL)、水(20mL)、反式-(4-(5-溴噻唑-2-基)环己基)氨基甲酸异丙酯(10g)、碳酸钠(7.63g)及[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.632g)，氮气保护下，将混合物加热至100℃反应8h。将冷却至室温的反应液倒入水(500mL)中，乙酸乙酯(100mL×3)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩,所得粗品经硅胶柱层析分离(石油醚:乙酸乙酯＝50:50)，得中间体2-7(6.8g)。1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),8.28(d,J＝2.1Hz,1H),7.75–7.67(m,2H),7.46(d,J＝8.4Hz,1H),7.02(d,J＝7.7Hz,1H),4.74(dt,J＝12.4,6.2Hz,1H),2.93(tt,J＝11.8,3.5Hz,1H),2.43–2.34(m,1H),2.20–2.08(m,2H),1.93-1.90(m,2H),1.66–1.45(m,11H),1.38-1.30(m,2H),1.19-1.16(m,7H),1.02–0.93(m,2H),0.93–0.79(m,2H).MS(ESI):m/z 564.34[M+H]+.To the single-neck bottle, add intermediate 2-6 (13.41g), 1,4-dioxane (180mL), water (20mL), trans-(4-(5-bromothiazol-2-yl)) in sequence Cyclohexyl) isopropyl carbamate (10g), sodium carbonate (7.63g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.632g), under nitrogen protection, The mixture was heated to 100°C for 8 h. Pour the reaction solution cooled to room temperature into water (500 mL), extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50) to obtain intermediate 2-7 (6.8g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.92 (s, 1H), 8.28 (d, J = 2.1Hz, 1H), 7.75–7.67 (m, 2H), 7.46 (d, J = 8.4Hz, 1H),7.02(d,J＝7.7Hz,1H),4.74(dt,J＝12.4,6.2Hz,1H),2.93(tt,J＝11.8,3.5Hz,1H),2.43–2.34(m,1H ),2.20–2.08(m,2H),1.93-1.90(m,2H),1.66–1.45(m,11H),1.38-1.30(m,2H),1.19-1.16(m,7H),1.02–0.93 (m,2H),0.93–0.79(m,2H).MS(ESI):m/z 564.34[M+H] + .
步骤七：中间体2-8的制备Step 7: Preparation of intermediate 2-8
向单口瓶中，依次加入中间体2-7(6.8g)和1,4-二氧六环(10mL)，搅拌下滴加4M盐酸二氧六环溶液(60.0mL)，加毕，室温搅拌4h。将反应液倒入冰水(100mL)，加入碳酸氢钠调pH至中性，乙酸乙酯(50mL×3)萃取，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物经硅胶柱层析分离(二氯甲烷:甲醇＝50:1)，得中间体2-8(4.6g)。1H NMR(500MHz,DMSO-d6)δ7.59(s,1H),7.23(d,J＝2.4Hz,1H),7.15(d,J＝8.3Hz,1H),7.01(d,J＝7.7Hz,1H),6.80(dd,J＝8.3,2.5Hz,1H),5.94(s,2H),4.74(dt,J＝12.4,6.2Hz,1H),3.57(s,1H),2.90(tt,J＝11.8,3.5Hz,1H),2.39–2.27(m,1H),2.18–2.04(m,2H),1.91(d,J＝10.1Hz,2H),1.55(qd,J＝13.0,2.9Hz,2H),1.39–1.27(m,2H),1.20–1.07(m,6H),0.97–0.88(m,2H),0.88–0.73(m,2H).MS(ESI):m/z 464.39[M+H]+.To the single-neck bottle, add intermediate 2-7 (6.8g) and 1,4-dioxane (10mL) in sequence, add dropwise 4M dioxane hydrochloride solution (60.0mL) under stirring, complete the addition, and stir at room temperature. 4h. Pour the reaction solution into ice water (100 mL), add sodium bicarbonate to adjust the pH to neutral, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain intermediate 2-8 (4.6g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.59 (s, 1H), 7.23 (d, J = 2.4Hz, 1H), 7.15 (d, J = 8.3Hz, 1H), 7.01 (d, J = 7.7Hz,1H),6.80(dd,J＝8.3,2.5Hz,1H),5.94(s,2H),4.74(dt,J＝12.4,6.2Hz,1H),3.57(s,1H),2.90( tt,J＝11.8,3.5Hz,1H),2.39–2.27(m,1H),2.18–2.04(m,2H),1.91(d,J＝10.1Hz,2H),1.55(qd,J＝13.0, 2.9Hz,2H),1.39–1.27(m,2H),1.20–1.07(m,6H),0.97–0.88(m,2H),0.88–0.73(m,2H).MS(ESI):m/z 464.39[M+H] + .
步骤八：中间体1-B的制备Step 8: Preparation of intermediate 1-B
向三口瓶中，依次加入溴化铜(6.36g)、乙腈(50mL)和亚硝酸叔丁酯(1.468g)，冰浴降温至0℃，滴加中间体2-8(4.4g)的乙腈(100mL)溶液，加毕，在0-5℃下搅拌30分钟，随后自然升至室温搅拌1小时。将反应倒入水(100mL)中,然后搅拌下分别加入乙酸乙酯(80mL)、20％的稀盐酸(10mL),分层取有机相，分别用饱和碳酸氢钠溶液(30mL)、饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离(二氯甲烷:甲醇＝50:1)，得中间体1-B(4.6g)。1H NMR(500MHz,DMSO-d6)δ8.14(d,J＝2.1Hz,1H),7.98(dd,J＝8.2,2.1Hz,1H),7.78(s,1H),7.54(d,J＝8.2Hz,1H),7.02(d,J＝7.7Hz,1H),4.74(dt,J＝12.4,6.2Hz,1H),2.96(tt,J＝11.8,3.5Hz,1H),2.58–2.52(m,1H),2.19–2.10(m,2H),1.92(d,J＝10.2Hz,2H),1.57(qd,J＝13.0,3.0Hz,2H),1.34(qd,J＝12.9,3.2Hz,2H),1.16(d,J＝6.2Hz,7H),1.00(qd,J＝7.6,6.0Hz,2H),0.96–0.90(m,2H).MS(ESI):m/z 527.19[M+H]+.To the three-necked flask, add copper bromide (6.36g), acetonitrile (50mL) and tert-butyl nitrite (1.468g) in sequence, cool to 0°C in an ice bath, and add acetonitrile of intermediate 2-8 (4.4g) dropwise. (100 mL) solution, after addition, stir at 0-5°C for 30 minutes, then naturally rise to room temperature and stir for 1 hour. Pour the reaction into water (100 mL), then add ethyl acetate (80 mL) and 20% dilute hydrochloric acid (10 mL) with stirring. Take the organic phase and add saturated sodium bicarbonate solution (30 mL) and saturated salt respectively. Wash with water (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product is separated by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain intermediate 1-B (4.6g). 1 H NMR (500MHz, DMSO-d 6 ) δ8.14 (d, J = 2.1 Hz, 1H), 7.98 (dd, J = 8.2, 2.1 Hz, 1H), 7.78 (s, 1H), 7.54 (d, J＝8.2Hz,1H),7.02(d,J＝7.7Hz,1H),4.74(dt,J＝12.4,6.2Hz,1H),2.96(tt,J＝11.8,3.5Hz,1H),2.58– 2.52(m,1H),2.19–2.10(m,2H),1.92(d,J＝10.2Hz,2H),1.57(qd,J＝13.0,3.0Hz,2H),1.34(qd,J＝12.9, 3.2Hz,2H),1.16(d,J＝6.2Hz,7H),1.00(qd,J＝7.6,6.0Hz,2H),0.96–0.90(m,2H).MS(ESI):m/z 527.19 [M+H] + .
制备例3中间体1-C的制备
Preparation Example 3 Preparation of Intermediate 1-C
步骤一：中间体3-1的制备Step 1: Preparation of intermediate 3-1
向三口瓶中分别加入化合物2-1(60g)、N,N-二甲基甲酰胺(500mL)、3-溴氧杂环丁烷(72.2g)和 碳酸钾(72.9g)，混合物于120℃下搅拌反应12小时。反应液冷却至室温后倒入水(2L)中，乙酸乙酯(1L×2)萃取，合并有机相，减压浓缩，残留物经硅胶柱层析分离(石油醚：乙酸乙酯＝1:1)，得中间体3-1(74g)。1H NMR(500MHz,DMSO-d6)δ6.95(dd,J＝8.6,7.6Hz,1H),6.51–6.36(m,2H),6.36–6.24(m,1H),5.17(s,2H),5.03–4.90(m,2H),4.54–4.46(m,1H),4.43(t,J＝6.2Hz,2H).MS(ESI):m/z 182.21[M+H]+.Add compound 2-1 (60g), N,N-dimethylformamide (500mL), 3-bromooxetane (72.2g) and Potassium carbonate (72.9g), the mixture was stirred and reacted at 120°C for 12 hours. After cooling to room temperature, the reaction solution was poured into water (2L), extracted with ethyl acetate (1L × 2), the organic phases were combined, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1), to obtain intermediate 3-1 (74g). 1 H NMR (500MHz, DMSO-d 6 ) δ6.95 (dd, J＝8.6, 7.6Hz, 1H), 6.51–6.36 (m, 2H), 6.36–6.24 (m, 1H), 5.17 (s, 2H ),5.03–4.90(m,2H),4.54–4.46(m,1H),4.43(t,J＝6.2Hz,2H).MS(ESI):m/z 182.21[M+H] + .
步骤二：中间体3-2的制备Step 2: Preparation of intermediate 3-2
向三口瓶中，将中间体3-1(74g)溶于甲醇(1L)中，向体系中加入二碳酸二叔丁酯(178g)，室温下反应12小时。冰浴下向反应液中缓慢加入氨水(100mL)，搅拌一小时，将混合物倒入水(1L)中，二氯甲烷(500mL×2)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，残留物经硅胶柱层析分离(石油醚：乙酸乙酯＝20:1)，得中间体3-2(110g)。1H NMR(500MHz,DMSO-d6)δ9.40(s,1H),7.39–7.27(m,2H),7.20(t,J＝7.9Hz,1H),6.81–6.71(m,1H),5.00(t,J＝6.9Hz,2H),4.61–4.51(m,1H),4.44(t,J＝6.3Hz,2H),1.47(s,9H).MS(ESI):m/z 280.20[M-H]-.In a three-necked flask, dissolve intermediate 3-1 (74g) in methanol (1L), add di-tert-butyl dicarbonate (178g) to the system, and react at room temperature for 12 hours. Slowly add ammonia water (100mL) to the reaction solution under ice bath, stir for one hour, pour the mixture into water (1L), extract with dichloromethane (500mL×2), combine the organic phases, dry over anhydrous sodium sulfate, and reduce pressure Concentrate, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 3-2 (110 g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.40 (s, 1H), 7.39–7.27 (m, 2H), 7.20 (t, J = 7.9Hz, 1H), 6.81–6.71 (m, 1H), 5.00(t,J＝6.9Hz,2H),4.61–4.51(m,1H),4.44(t,J＝6.3Hz,2H),1.47(s,9H).MS(ESI):m/z 280.20[ MH] - .
步骤三：中间体3-3的制备Step 3: Preparation of intermediate 3-3
向三口瓶中，将中间体3-2(60g)溶于二氯甲烷(1L)，降温至-30℃，搅拌下分批加入N-溴代丁二酰亚胺(38g)，保持温度反应3小时。升至室温，加水(1L)，分取有机相，减压浓缩，残留物经硅胶柱层析分离(石油醚：二氯甲烷＝1:1)，得中间体3-3(27g)。1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),7.47(d,J＝8.7Hz,1H),7.30(dd,1H),7.05(d,J＝2.4Hz,1H),5.09(t,J＝6.7Hz,2H),4.53(q,J＝6.6Hz,1H),4.48(t,J＝6.2Hz,2H),1.48(s,9H).MS(ESI):m/z 360.06[M-H]-.In a three-necked flask, dissolve intermediate 3-2 (60g) in dichloromethane (1L), cool to -30°C, add N-bromosuccinimide (38g) in batches while stirring, and maintain the temperature for reaction. 3 hours. Raise to room temperature, add water (1L), separate the organic phase, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (petroleum ether: dichloromethane = 1:1) to obtain intermediate 3-3 (27g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.52 (s, 1H), 7.47 (d, J = 8.7Hz, 1H), 7.30 (dd, 1H), 7.05 (d, J = 2.4Hz, 1H) ,5.09(t,J＝6.7Hz,2H),4.53(q,J＝6.6Hz,1H),4.48(t,J＝6.2Hz,2H),1.48(s,9H).MS(ESI):m /z 360.06[MH] - .
步骤四：中间体3-4的制备Step 4: Preparation of intermediate 3-4
向三口瓶中，将中间体3-3(27g)溶于二氯甲烷(600mL)中，0℃下，向搅拌液中分批缓慢加入间氯过氧苯甲酸(60g)，加毕，升至室温反应16小时。抽滤，向滤液中加水(1L)，分取有机相，减压浓缩，残留物经硅胶柱层析分离(石油醚：二氯甲烷＝3:1)得中间体3-4(22g)。1H NMR(500MHz,DMSO-d6)δ9.93(s,1H),8.37(d,J＝2.7Hz,1H),7.78(d,J＝8.7Hz,1H),7.63(dd,J＝8.7,2.7Hz,1H),5.16–5.07(m,1H),4.83(t,J＝7.7Hz,2H),4.74(dd,J＝7.2,6.0Hz,2H),1.49(s,9H).MS(ESI):m/z 390.08[M-H]-.In a three-necked flask, dissolve intermediate 3-3 (27g) in dichloromethane (600mL). At 0°C, slowly add m-chloroperoxybenzoic acid (60g) to the stirring liquid in batches. After the addition is completed, liter React at room temperature for 16 hours. Filter with suction, add water (1L) to the filtrate, separate the organic phase, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (petroleum ether: dichloromethane = 3:1) to obtain intermediate 3-4 (22g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.93 (s, 1H), 8.37 (d, J = 2.7Hz, 1H), 7.78 (d, J = 8.7Hz, 1H), 7.63 (dd, J = 8.7, 2.7Hz, 1H), 5.16–5.07 (m, 1H), 4.83 (t, J＝7.7Hz, 2H), 4.74 (dd, J＝7.2, 6.0Hz, 2H), 1.49 (s, 9H). MS(ESI):m/z 390.08[MH] - .
步骤五：中间体3-5的制备Step 5: Preparation of intermediate 3-5
向三口瓶中分别加入中间体3-4(16g)、联硼酸频那醇酯(20.72g)、醋酸钾(12.01g)、1,4-二氧六环(160mL)和四(三苯基膦)钯(4.71g)，氮气保护下，加热至100℃反应10小时。向反应液中加水(200mL)，乙酸乙酯(100mL×2)萃取，合并有机相，减压浓缩，残留物经硅胶柱柱层析分离(石油醚：二氯甲烷＝3:1)得中间体3-5(14g)。1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.15(d,J＝2.1Hz,1H),7.72(dd,J＝8.2,2.1Hz,1H),7.52(d,J＝8.1Hz,1H),4.98–4.91(m,1H),4.80–4.73(m,4H),1.49(s,9H),1.30(s,12H).MS(ESI):m/z 438.31[M-H]-.Add intermediate 3-4 (16g), pinacol diborate (20.72g), potassium acetate (12.01g), 1,4-dioxane (160mL) and tetrakis(triphenyl) to the three-necked flask respectively. Phosphine) palladium (4.71g), heated to 100°C for 10 hours under nitrogen protection. Add water (200 mL) to the reaction solution, extract with ethyl acetate (100 mL × 2), combine the organic phases, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (petroleum ether: dichloromethane = 3:1) to obtain the intermediate Body 3-5(14g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.87 (s, 1H), 8.15 (d, J = 2.1Hz, 1H), 7.72 (dd, J = 8.2, 2.1Hz, 1H), 7.52 (d, J＝8.1Hz,1H),4.98–4.91(m,1H),4.80–4.73(m,4H),1.49(s,9H),1.30(s,12H).MS(ESI):m/z 438.31[ MH] - .
步骤六：中间体3-6的制备Step 6: Preparation of intermediate 3-6
向三口瓶中分别加入中间体3-5(5g)、反式-4-(5-溴噻唑-2-基)环己基)氨基甲酸异丙酯(4.15g)、碳酸钠(2.412g)、1,1'-二(二苯膦基)二茂铁二氯化钯(II)(0.833g)、1,4-二氧六环(50mL)和水(5mL)，氮气保护下，将混合物加热至80℃反应10小时。冷却至室温后加入水(100mL)，乙酸乙酯(100mL×2)萃取，合并有机相，减压浓缩，残留物经硅胶柱层析分离(二氯甲烷：甲醇＝40:1)得中间体3-6(5g)。1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.33(d,J＝2.4Hz,1H),7.74(dd,J＝8.5,2.4Hz,1H),7.67(s,1H),7.45(d,J＝8.4Hz,1H),7.02(d,J＝7.9Hz,1H),4.79–4.72(m,1H),4.61(d,J＝5.0Hz,2H),4.55–4.47(m,3H),3.31(d,J＝3.7Hz,1H),2.94(t,J＝11.1Hz,1H),2.19–2.10(m,2H),1.94–1.89(m,2H),1.57(dd,J＝12.5,3.2Hz,2H),1.50(s,9H),1.38–1.31(m,2H),1.17(d,J＝6.2Hz,6H).MS(ESI):m/z 580.38[M+H]+.Add intermediate 3-5 (5g), trans-4-(5-bromothiazol-2-yl)cyclohexyl)carbamic acid isopropyl ester (4.15g), sodium carbonate (2.412g), and 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.833g), 1,4-dioxane (50mL) and water (5mL), under nitrogen protection, the mixture was Heat to 80°C and react for 10 hours. After cooling to room temperature, water (100 mL) was added, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol = 40:1) to obtain the intermediate. 3-6(5g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.97 (s, 1H), 8.33 (d, J = 2.4Hz, 1H), 7.74 (dd, J = 8.5, 2.4Hz, 1H), 7.67 (s, 1H),7.45(d,J＝8.4Hz,1H),7.02(d,J＝7.9Hz,1H),4.79–4.72(m,1H),4.61(d,J＝5.0Hz,2H),4.55– 4.47(m,3H),3.31(d,J＝3.7Hz,1H),2.94(t,J＝11.1Hz,1H),2.19–2.10(m,2H),1.94–1.89(m,2H),1.57 (dd,J＝12.5,3.2Hz,2H),1.50(s,9H),1.38–1.31(m,2H),1.17(d,J＝6.2Hz,6H).MS(ESI):m/z 580.38 [M+H] + .
步骤七：中间体3-7的制备Step 7: Preparation of intermediate 3-7
向单口瓶中分别加入中间体3-6(5g)和二氯甲烷(150mL)，搅拌下缓慢加入三氟醋酸(50mL)，室温下搅拌过夜，减压浓缩，向残余物中加饱和碳酸氢钠溶液调节pH值至中性，二氯甲烷(40mL)萃取，有机相减压浓缩，残留物经硅胶柱层析分离(二氯甲烷：甲醇＝40:1)得中间体3-7(3.3g)。1H NMR(500MHz,DMSO-d6)δ7.56(s,1H),7.30(d,J＝2.4Hz,1H),7.14(d,J＝8.3Hz,1H),7.01(d,J＝7.8Hz,1H),6.83(dd,J＝8.3,2.5Hz,1H),6.02(s,2H),4.78–4.71(m,1H),4.60(t,J＝7.6Hz,2H),4.49(t,J＝6.5Hz,2H),4.45 –4.38(m,1H),3.31(d,J＝11.9Hz,1H),2.95–2.85(m,1H),2.17–2.09(m,2H),1.94–1.88(m,2H),1.59–1.50(m,2H),1.38–1.29(m,2H),1.16(d,J＝6.2Hz,6H).MS(ESI):m/z 480.35[M+H]+.Add intermediate 3-6 (5g) and dichloromethane (150mL) to the single-neck bottle respectively, slowly add trifluoroacetic acid (50mL) under stirring, stir at room temperature overnight, concentrate under reduced pressure, and add saturated hydrogen carbonate to the residue. The pH value of the sodium solution was adjusted to neutral, extracted with dichloromethane (40 mL), the organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol = 40:1) to obtain intermediate 3-7 (3.3 g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.56 (s, 1H), 7.30 (d, J = 2.4Hz, 1H), 7.14 (d, J = 8.3Hz, 1H), 7.01 (d, J = 7.8Hz,1H),6.83(dd,J＝8.3,2.5Hz,1H),6.02(s,2H),4.78–4.71(m,1H),4.60(t,J＝7.6Hz,2H),4.49( t,J＝6.5Hz,2H),4.45 –4.38(m,1H),3.31(d,J＝11.9Hz,1H),2.95–2.85(m,1H),2.17–2.09(m,2H),1.94–1.88(m,2H),1.59–1.50 (m,2H),1.38–1.29(m,2H),1.16(d,J＝6.2Hz,6H).MS(ESI):m/z 480.35[M+H] + .
步骤八：中间体1-C的制备Step 8: Preparation of intermediate 1-C
向单口瓶中分别加入亚硝酸叔丁酯(1.032g)、溴化铜(4.47g)和乙腈(50mL)，0℃下搅拌5min，接着向搅拌液中缓慢滴加中间体3-7(3.2g)的乙腈(50mL)溶液，保持该温度反应1小时。反应完毕，加稀盐酸(10mL)搅拌10min，升至室温，加入水(200mL)，乙酸乙酯(100mL×2)萃取，合并有机相，减压浓缩，残留物经硅胶柱层析分离(二氯甲烷：甲醇＝40:1)得中间体1-C(2.8g)。1H NMR(500MHz,DMSO-d6)δ8.19(d,J＝2.2Hz,1H),8.01(dd,J＝8.2,2.2Hz,1H),7.75(s,1H),7.52(d,J＝8.2Hz,1H),7.02(d,J＝7.8Hz,1H),4.74(q,J＝6.3Hz,1H),4.67–4.60(m,3H),4.54–4.50(m,2H),3.34–3.27(m,1H),3.01–2.91(m,1H),2.17–2.12(m,2H),1.92(dd,J＝13.2,4.0Hz,2H),1.62–1.53(m,2H),1.39–1.30(m,2H),1.17(d,J＝6.3Hz,6H).MS(ESI)m/z:543.09[M+H]+.Add tert-butyl nitrite (1.032g), copper bromide (4.47g) and acetonitrile (50mL) to the single-neck bottle respectively, stir at 0°C for 5 minutes, and then slowly add intermediate 3-7 (3.2 g) in acetonitrile (50 mL), maintain the temperature for 1 hour. After the reaction is completed, add dilute hydrochloric acid (10 mL) and stir for 10 min, raise to room temperature, add water (200 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, concentrate under reduced pressure, and the residue is separated by silica gel column chromatography (II Methyl chloride: methanol = 40:1) to obtain intermediate 1-C (2.8g). 1 H NMR (500MHz, DMSO-d 6 ) δ8.19 (d, J＝2.2Hz, 1H), 8.01 (dd, J＝8.2, 2.2Hz, 1H), 7.75 (s, 1H), 7.52 (d, J＝8.2Hz,1H),7.02(d,J＝7.8Hz,1H),4.74(q,J＝6.3Hz,1H),4.67–4.60(m,3H),4.54–4.50(m,2H), 3.34–3.27(m,1H),3.01–2.91(m,1H),2.17–2.12(m,2H),1.92(dd,J＝13.2,4.0Hz,2H),1.62–1.53(m,2H), 1.39–1.30(m,2H),1.17(d,J＝6.3Hz,6H).MS(ESI)m/z:543.09[M+H] + .
制备例4中间体1-D的制备
Preparation Example 4 Preparation of Intermediate 1-D
步骤一：中间体4-2的制备Step 1: Preparation of intermediate 4-2
在三口瓶中，将化合物4-1(20g)溶于甲苯(250mL)，向其中分批加入三苯基膦(61.1g)，100℃反应2小时。加入水(25mL)，继续100℃反应2小时。反应液冷却至室温，冰浴下加入10％氢氧化钠溶液(300mL)，过滤，滤液以乙酸乙酯(100mL)洗涤，分液，水相在冰浴下以6N的盐酸溶液调节pH至2.0，过滤，干燥，得中间体4-2(12.4g)。1H NMR(500MHz,DMSO-d6)δ8.55-8.47(m,1H),7.94-7.80(m,2H),6.74(s,1H).MS(ESI)m/z 231.93[M-H]-.In a three-necked flask, compound 4-1 (20g) was dissolved in toluene (250 mL), triphenylphosphine (61.1g) was added thereto in batches, and the reaction was carried out at 100°C for 2 hours. Water (25 mL) was added, and the reaction was continued at 100°C for 2 hours. The reaction solution was cooled to room temperature, 10% sodium hydroxide solution (300 mL) was added in an ice bath, and filtered. The filtrate was washed with ethyl acetate (100 mL) and separated. The aqueous phase was adjusted to pH 2.0 with 6N hydrochloric acid solution in an ice bath. , filtered and dried to obtain intermediate 4-2 (12.4g). 1 H NMR(500MHz, DMSO-d 6 )δ8.55-8.47(m,1H),7.94-7.80(m,2H),6.74(s,1H).MS(ESI)m/z 231.93[MH] - .
步骤二：中间体4-3的制备Step 2: Preparation of intermediate 4-3
向单口瓶中，依次加入中间体4-2(12g)、溴化苄(12.3g)、碳酸钾(21.3g)和乙腈(75mL)，室温搅拌反应1小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝10:1)，得到中间体4-3(13.5g)。1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝2Hz,1H),7.92-7.87(m,2H),7.49-7.46(m,2H),7.39-7.34(m,2H),7.31-7.27(m,1H),4.48(s,2H).To the single-neck bottle, add intermediate 4-2 (12g), benzyl bromide (12.3g), potassium carbonate (21.3g) and acetonitrile (75mL) in sequence, and stir and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain intermediate 4-3 (13.5g). 1 H NMR (500MHz, DMSO-d 6 ) δ8.11 (d, J = 2Hz, 1H), 7.92-7.87 (m, 2H), 7.49-7.46 (m, 2H), 7.39-7.34 (m, 2H) ,7.31-7.27(m,1H),4.48(s,2H).
步骤三：中间体4-4的制备Step 3: Preparation of intermediate 4-4
向单口瓶中，依次加入中间体4-3(10g,30.8mmol)、锌粉(54.5g,833mmol)、氯化铵(148g,2776mmol)、四氢呋喃(100mL)和乙醇(500mL)，室温搅拌反应1小时。过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1)，得中间体4-4(7g)。1H NMR(500MHz,DMSO-d6)δ7.44-7.40(m,2H),7.37-7.31(m,2H),7.30-7.24(m,1H),7.15(d,J＝8.5Hz,1H),6.65(d,J＝2.5Hz,1H),6.33-6.29(m,1H),5.32(s,2H),4.14(s,2H).MS(ESI)m/z 294.00[M+H]+.To the single-neck bottle, add intermediate 4-3 (10g, 30.8mmol), zinc powder (54.5g, 833mmol), ammonium chloride (148g, 2776mmol), tetrahydrofuran (100mL) and ethanol (500mL) in sequence, and stir the reaction at room temperature. 1 hour. Filter, and the filtrate is concentrated under reduced pressure. The obtained crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 4-4 (7g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.44-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.30-7.24 (m, 1H), 7.15 (d, J = 8.5Hz, 1H ),6.65(d,J＝2.5Hz,1H),6.33-6.29(m,1H),5.32(s,2H),4.14(s,2H).MS(ESI)m/z 294.00[M+H] + .
步骤四：中间体4-5的制备Step 4: Preparation of intermediate 4-5
向单口瓶中，依次加入中间体4-4(7g)、联硼酸频那醇酯(12.08g)、双三苯基磷二氯化钯(1.67g)、醋酸钾(7.01g)和1,4-二氧六环(100mL)，氮气氛围下，80℃反应16小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1)，得中间体4-5(6g)。MS(ESI)m/z 342.16[M+H]+.步骤五：中间体4-6的制备 To the single-neck bottle, add intermediate 4-4 (7g), pinacol diborate (12.08g), triphenylphosphonium dichloride (1.67g), potassium acetate (7.01g) and 1, 4-Dioxane (100 mL), react at 80°C for 16 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 4-5 (6 g). MS(ESI)m/z 342.16[M+H] + .Step 5: Preparation of intermediate 4-6
向单口瓶中，依次加入中间体4-5(3.87g)、中间体1-A(3g)、碳酸钠(2.73g)、1,1'-二(二苯膦基)二茂铁二氯化钯(II)(0.63g)、1,4-二氧六环(50mL)和水(5mL)，氮气氛围下，100℃反应12小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝40:1)，得中间体4-6(2.2g)。1H NMR(500MHz,DMSO-d6)δ7.53(s,1H),7.32-7.27(m,4H),7.26-7.21(m,1H),7.06(d,J＝8.2Hz,1H),7.00(d,J＝7.9Hz,1H),6.72(d,J＝2.2Hz,1H),6.43(dd,J＝8.3,2.3Hz,1H),5.44(s,2H),4.77-4.71(m,1H),4.05(s,2H),3.32-3.25(m,1H),2.88-2.82(m,1H),2.11-2.06(m,2H),1.91-1.86(m,2H),1.56-1.48(m,2H),1.35-1.27(m,2H),1.16(d,J＝6.2Hz,6H).MS(ESI)m/z 482.27[M+H]+。To the single-neck bottle, add intermediate 4-5 (3.87g), intermediate 1-A (3g), sodium carbonate (2.73g), and 1,1'-bis(diphenylphosphino)ferrocene dichloride in sequence. Palladium (II) (0.63g), 1,4-dioxane (50mL) and water (5mL) were reacted at 100°C for 12 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain intermediate 4-6 (2.2g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.53 (s, 1H), 7.32-7.27 (m, 4H), 7.26-7.21 (m, 1H), 7.06 (d, J = 8.2Hz, 1H), 7.00(d,J＝7.9Hz,1H),6.72(d,J＝2.2Hz,1H),6.43(dd,J＝8.3,2.3Hz,1H),5.44(s,2H),4.77-4.71(m ,1H),4.05(s,2H),3.32-3.25(m,1H),2.88-2.82(m,1H),2.11-2.06(m,2H),1.91-1.86(m,2H),1.56-1.48 (m,2H),1.35-1.27(m,2H),1.16(d,J＝6.2Hz,6H).MS(ESI)m/z 482.27[M+H] + .
步骤六：中间体4-7的制备Step 6: Preparation of intermediate 4-7
在单口瓶中，将中间体4-6(2.1g)溶于乙腈(80mL)，0℃下向其中依次加入亚硝酸异戊酯(0.67)和溴化亚铜(0.75)，加热至60℃反应3小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3:1)，得中间体4-7(0.62g)。1H NMR(500MHz,DMSO-d6)δ7.76(s,1H),7.63(d,J＝2.0Hz,1H),7.43(dd,J＝8.3,2.0Hz,1H),7.37-7.29(m,5H),7.27-7.24(m,1H),7.01(d,J＝7.8Hz,1H),4.78-4.71(m,1H),4.28(s,2H),3.32-3.22(m,1H),2.95-2.87(m,1H),2.13-2.07(m,2H),1.93-1.87(m,2H),1.59-1.50(m,2H),1.36-1.28(m,2H),1.16(d,J＝6.2Hz,6H).MS(ESI)m/z 545.08[M+H]+.In a single-neck bottle, dissolve intermediate 4-6 (2.1g) in acetonitrile (80mL), add isoamyl nitrite (0.67) and copper bromide (0.75) successively to it at 0°C, and heat to 60°C. Reaction takes 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 4-7 (0.62g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.76 (s, 1H), 7.63 (d, J = 2.0Hz, 1H), 7.43 (dd, J = 8.3, 2.0Hz, 1H), 7.37-7.29 ( m,5H),7.27-7.24(m,1H),7.01(d,J＝7.8Hz,1H),4.78-4.71(m,1H),4.28(s,2H),3.32-3.22(m,1H) ,2.95-2.87(m,1H),2.13-2.07(m,2H),1.93-1.87(m,2H),1.59-1.50(m,2H),1.36-1.28(m,2H),1.16(d, J＝6.2Hz,6H).MS(ESI)m/z 545.08[M+H] + .
步骤七：中间体4-8的制备Step 7: Preparation of intermediate 4-8
向单口瓶中，依次加入中间体4-7(200mg)、乙腈(10mL)、乙酸(1.5mL)和水(1mL)，0℃下向其中加入1,3-二氯-5,5-二甲基海因(108mg,0.550mmol)，室温搅拌反应3小时。反应液减压浓缩得中间体4-8(0.2g)。未经纯化，直接用于下一步反应。MS(ESI)m/z 520.97[M+H]+.To a single-neck bottle, add intermediate 4-7 (200 mg), acetonitrile (10 mL), acetic acid (1.5 mL) and water (1 mL) in sequence, and add 1,3-dichloro-5,5-bis at 0°C. Methylhydantoin (108 mg, 0.550 mmol), stir and react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate 4-8 (0.2g). It was used directly in the next reaction without purification. MS(ESI)m/z 520.97[M+H] + .
步骤八：中间体1-D的制备Step 8: Preparation of intermediate 1-D
在单口瓶中，将中间体4-8的制备(200mg)溶于二氯甲烷(10mL)中，0℃下依次加入环丙胺(32.8mg)和4-二甲氨基吡啶(9.4mg)，室温搅拌反应1小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝40:1)，得中间体1-D(140mg)。1H NMR(500MHz,DMSO-d6)δ8.13(d,J＝2.1Hz,1H),8.05(d,J＝2.0Hz,1H),7.90(dd,J＝8.2,2.2Hz,1H),7.70(s,1H),7.47(d,J＝8.2Hz,1H),7.27-7.22(m,1H),4.77-4.72(m,1H),3.32-3.27(m,1H),2.95-2.89(m,1H),2.24-2.19(m,1H),2.16-2.11(m,2H),1.94-1.90(m,2H),1.61-1.53(m,2H),1.36-1.30(m,2H),1.16(d,J＝6.2Hz,6H),0.49-0.44(m,2H),0.32-0.28(m,2H).MS(ESI)m/z 542.04[M+H]+.In a single-neck bottle, the preparation of intermediate 4-8 (200 mg) was dissolved in dichloromethane (10 mL), cyclopropylamine (32.8 mg) and 4-dimethylaminopyridine (9.4 mg) were added in sequence at 0°C, and the mixture was heated to room temperature. Stir the reaction for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 40:1) to obtain intermediate 1-D (140 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ8.13(d,J＝2.1Hz,1H),8.05(d,J＝2.0Hz,1H),7.90(dd,J＝8.2,2.2Hz,1H) ,7.70(s,1H),7.47(d,J＝8.2Hz,1H),7.27-7.22(m,1H),4.77-4.72(m,1H),3.32-3.27(m,1H),2.95-2.89 (m,1H),2.24-2.19(m,1H),2.16-2.11(m,2H),1.94-1.90(m,2H),1.61-1.53(m,2H),1.36-1.30(m,2H) ,1.16(d,J＝6.2Hz,6H),0.49-0.44(m,2H),0.32-0.28(m,2H).MS(ESI)m/z 542.04[M+H] + .
制备例5中间体2-A的制备
Preparation Example 5 Preparation of Intermediate 2-A
步骤一：中间体5-2的制备Step 1: Preparation of intermediate 5-2
向三口瓶中依次加入化合物5-1(20g)，碳酸钾(48.9g)，烯丙基溴(23.5g)，溶于N,N-二甲基甲酰胺(200mL)中，氮气保护下，室温反应30分钟后加热至80℃反应1.5h。将反应液用水稀释(600mL)，乙酸乙酯萃取(200mL×3)，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得中间体5-2(25g)。1H NMR(500MHz,DMSO-d6)δ8.88(s,1H),8.28(s,1H),6.18–5.84(m,1H),5.36–5.15(m,2H),4.84(dt,J＝5.9,1.5Hz,2H).Add compound 5-1 (20g), potassium carbonate (48.9g), and allyl bromide (23.5g) to the three-necked flask in sequence, and dissolve in N,N-dimethylformamide (200mL) under nitrogen protection. React at room temperature for 30 minutes and then heat to 80°C for 1.5 hours. The reaction solution was diluted with water (600mL), extracted with ethyl acetate (200mL×3), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 5-2 (25g) . 1 H NMR (500MHz, DMSO-d 6 ) δ8.88(s,1H),8.28(s,1H),6.18–5.84(m,1H),5.36–5.15(m,2H),4.84(dt,J =5.9,1.5Hz,2H).
步骤二：中间体2-A的制备Step 2: Preparation of intermediate 2-A
向单口瓶中依次加入中间体5-2(25g)、氯化铵(43.7g)、还原铁粉(45.6g)、甲醇(300mL)、和水(75mL)，氮气保护下,混合物加热至65℃反应5h。反应液通过硅藻土过滤，减压蒸除溶剂，加入水和二氯甲烷，有机相分离，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱(二氯甲烷：甲醇＝42：58)分离纯化得中间体2-A(6.5g)。1H NMR(500MHz,DMSO-d6)δ6.98(s,1H),6.91(s,1H),5.93(ddt,J＝17.2,10.2,5.7Hz,1H),5.13(dd,J＝10.2,1.5Hz,1H),5.07(dd,J＝17.1,1.8Hz,1H),4.54(d,J＝5.8Hz,2H),3.83(s,2H).Add intermediate 5-2 (25g), ammonium chloride (43.7g), reduced iron powder (45.6g), methanol (300mL), and water (75mL) to the single-neck bottle in sequence. Under nitrogen protection, the mixture is heated to 65 ℃ reaction for 5h. The reaction solution was filtered through diatomaceous earth, the solvent was evaporated under reduced pressure, water and dichloromethane were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was passed through a silica gel column (dichloromethane: methanol = 42 :58) was isolated and purified to obtain intermediate 2-A (6.5g). 1 H NMR (500MHz, DMSO-d 6 ) δ6.98 (s, 1H), 6.91 (s, 1H), 5.93 (ddt, J = 17.2, 10.2, 5.7Hz, 1H), 5.13 (dd, J = 10.2 ,1.5Hz,1H),5.07(dd,J＝17.1,1.8Hz,1H),4.54(d,J＝5.8Hz,2H),3.83(s,2H).
制备例6中间体2-B的制备
Preparation Example 6 Preparation of Intermediate 2-B
步骤一：中间体6-2的制备Step 1: Preparation of intermediate 6-2
向单口瓶中依次加入化合物6-1(4g)、2,5-己二酮(2.59g)、甲苯(70mL)和冰醋酸(0.341g)，将混合物加热至110℃反应过夜。将反应液倒入水(20mL)中，乙酸乙酯(20mL×2)萃取，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物经硅胶柱分离纯化(石油醚:乙酸乙酯＝94:6)，得到中间体6-2(5.5g)。MS(ESI)m/z:254.21[M+H]+.Compound 6-1 (4g), 2,5-hexanedione (2.59g), toluene (70mL) and glacial acetic acid (0.341g) were sequentially added to the single-neck bottle, and the mixture was heated to 110°C for reaction overnight. Pour the reaction solution into water (20 mL), extract with ethyl acetate (20 mL =94:6), and intermediate 6-2 (5.5g) was obtained. MS(ESI)m/z:254.21[M+H] + .
步骤二：中间体6-3的制备Step 2: Preparation of intermediate 6-3
向三口瓶中依次加入中间体6-2(5.8g)和干燥四氢呋喃(200mL)，反应液搅拌降温至-75℃，向其中缓慢滴加正丁基锂正己烷溶液(9.13mL,22.8mmol)，滴加完毕保持温度反应10分钟。向反应液中分别加入N,N-二甲基甲酰胺(1.668g,22.8mmol)和(氟代甲基)三苯基鏻四氟硼酸盐(8.72g)，加毕保持温度搅拌反应5分钟后转移至室温搅拌反应2h。随后向反应液中加入叔丁醇钾(2.56g)，加毕室温反应2h。向反应液中加入冰水(200mL)，分液，有机相以饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物经硅胶柱分离纯化(石油醚:乙酸乙酯＝92:8)，得到中间体6-3(1.44g)。1H NMR(500MHz,DMSO-d6)δ7.65(dd,J＝82.6,11.2Hz,1H),6.71(dd,J＝18.6,11.2Hz,1H),6.44(s,1H),5.74(s,2H),3.81(s,3H),2.02(s,6H).MS(ESI)m/z:220.16[M+H]+.Add intermediate 6-2 (5.8g) and dry tetrahydrofuran (200mL) to the three-necked flask in sequence. The reaction solution is stirred and cooled to -75°C, and n-butyllithium n-hexane solution (9.13mL, 22.8mmol) is slowly added dropwise. , after the dropwise addition, maintain the temperature for 10 minutes. Add N,N-dimethylformamide (1.668g, 22.8mmol) and (fluoromethyl)triphenylphosphonium tetrafluoroborate (8.72g) to the reaction solution respectively. After the addition is completed, the temperature is maintained and the reaction is stirred for 5 seconds. Minutes later, the mixture was transferred to room temperature and stirred for 2 h. Then potassium tert-butoxide (2.56g) was added to the reaction solution, and the reaction was completed at room temperature for 2 hours. Ice water (200 mL) was added to the reaction solution, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified on a silica gel column (petroleum ether: ethyl acetate = 92:8 ) to obtain intermediate 6-3 (1.44g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.65 (dd, J＝82.6, 11.2Hz, 1H), 6.71 (dd, J＝18.6, 11.2Hz, 1H), 6.44 (s, 1H), 5.74 ( s,2H),3.81(s,3H),2.02(s,6H).MS(ESI)m/z:220.16[M+H] + .
步骤三:中间体2-B的制备Step 3: Preparation of intermediate 2-B
向单口瓶中加入中间体6-3(1g)、盐酸羟胺(3.17g)、无水乙醇(8mL)、三乙胺(1.846g,18.24mmol)，混合物加热至90℃反应3h。将反应液冷却至室温，缓慢滴加入0℃下的1M稀盐酸中(120mL)，乙酸乙酯(50mL)洗涤。水相用饱和碳酸氢钠水溶液调pH至8，乙酸乙酯(50mL×2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物以硅胶柱分离纯化(二氯甲烷:甲醇＝97:3)，得到中间体2-B(80mg)。1H NMR(500MHz,DMSO-d6)δ7.47(dd,J＝83.4,11.2Hz,1H),6.49(dd,J＝19.1,11.2Hz,1H),5.50(s,1H),4.52(s,2H),3.51(s,3H).MS(ESI)m/z:142[M+H]+.Add intermediate 6-3 (1g), hydroxylamine hydrochloride (3.17g), absolute ethanol (8mL), and triethylamine (1.846g, 18.24mmol) to the single-neck bottle, and heat the mixture to 90°C for 3 hours. The reaction solution was cooled to room temperature, slowly added dropwise to 1 M dilute hydrochloric acid at 0°C (120 mL), and washed with ethyl acetate (50 mL). The aqueous phase was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified on a silica gel column ( Dichloromethane:methanol=97:3) to obtain intermediate 2-B (80 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ7.47 (dd, J＝83.4, 11.2Hz, 1H), 6.49 (dd, J＝19.1, 11.2Hz, 1H), 5.50 (s, 1H), 4.52 ( s,2H),3.51(s,3H).MS(ESI)m/z:142[M+H] + .
制备例7中间体2-C的制备
Preparation Example 7 Preparation of Intermediate 2-C
步骤一：中间体7-2的制备Step 1: Preparation of intermediate 7-2
向三口瓶中，依次加入化合物7-1(3.00g)、4-溴-1-丁烯(3.75g)、乙腈(40mL)和碳酸钾(7.68g)，氮气保护下加热至50℃搅拌反应5小时。反应液倒入水(100mL)中，乙酸乙酯(100mL)萃取。有机相分别用水(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品用硅胶柱层析分离(石油醚:乙酸乙酯＝80:20)，得到中间体7-2(1.4g)。MS(ESI)m/z:216.17[M+H]+.To the three-necked flask, add compound 7-1 (3.00g), 4-bromo-1-butene (3.75g), acetonitrile (40mL) and potassium carbonate (7.68g) in sequence, and heat to 50°C under nitrogen protection to stir the reaction. 5 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20) to obtain the intermediate. 7-2(1.4g). MS(ESI)m/z:216.17[M+H] + .
步骤二：中间体2-C的制备Step 2: Preparation of intermediate 2-C
向微波管中，依次加入中间体7-2(450mg)，醋酸钯(70mg)，乙腈(10mL)，三乙胺(632mg)和三苯基膦(164mg)，氮气鼓泡5分钟后，微波加热至80℃搅拌反应3小时。反应液浓缩，所得粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇＝97:3)，得中间体2-C(114mg)。1H NMR(500MHz,DMSO-d6)δ5.43(s,1H),5.23(t,J＝2.5Hz,1H),4.97(d,J＝2.2Hz,1H),4.69(s,2H),3.95(t,J＝6.5Hz,2H),3.12-3.02(m,2H)。MS(ESI)m/z:136.07[M+H]+.To the microwave tube, add intermediate 7-2 (450 mg), palladium acetate (70 mg), acetonitrile (10 mL), triethylamine (632 mg) and triphenylphosphine (164 mg) in sequence. After bubbling nitrogen for 5 minutes, microwave Heat to 80°C and stir for 3 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=97:3) to obtain intermediate 2-C (114 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ5.43 (s, 1H), 5.23 (t, J = 2.5Hz, 1H), 4.97 (d, J = 2.2Hz, 1H), 4.69 (s, 2H) ,3.95(t,J＝6.5Hz,2H),3.12-3.02(m,2H). MS(ESI)m/z:136.07[M+H] + .
制备例8中间体2-D的制备
Preparation Example 8 Preparation of Intermediate 2-D
步骤一：中间体8-2的制备Step 1: Preparation of intermediate 8-2
向微波管中，依次加入化合物8-1(0.5g)，叔丁基二甲基(2-丙炔氧基)硅烷(0.463g)，碘化铜(0.069g)，双三苯基磷二氯化钯(0.127g)，三乙胺(1.47g)和N,N-二甲基甲酰胺(10mL)，氮气鼓泡5分钟后，微波加热至80℃搅拌反应2小时。反应液倒入水(100mL)中，加入乙酸乙酯(100mL)萃取。有机相分别用水(100mL)、饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯＝10:1)，得到中间体8-2(0.374g)。1H NMR(500MHz,DMSO-d6)δ9.68(s,1H),6.39(s,1H),4.61(s,2H),3.71(s,3H),1.43(s,9H),0.88(s,9H),0.13(s,6H).To the microwave tube, add compound 8-1 (0.5g), tert-butyldimethyl (2-propynyloxy)silane (0.463g), copper iodide (0.069g), and bistriphenylphosphine diphosphate in sequence. Palladium chloride (0.127g), triethylamine (1.47g) and N,N-dimethylformamide (10mL) were bubbled with nitrogen for 5 minutes, heated to 80°C in microwave and stirred for 2 hours. The reaction solution was poured into water (100 mL), and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the intermediate Body 8-2 (0.374g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.68(s,1H),6.39(s,1H),4.61(s,2H),3.71(s,3H),1.43(s,9H),0.88( s,9H),0.13(s,6H).
步骤二：中间体8-3的制备Step 2: Preparation of intermediate 8-3
向单口瓶中，依次加入中间体8-2(0.37g)，四氢呋喃(10mL)和四丁基氟化铵(0.56g)，室温搅拌反应1小时。反应液倒入水(20mL)中，乙酸乙酯(20mL)萃取。有机相分别用水(20mL)、饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯＝5:1)，得到中间体8-3(0.25g)。1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),6.37(s,1H),5.45(t,J＝6.5Hz,1H),4.35(d,J＝6Hz,2H),3.72(s,3H),1.43(s,9H).To the one-neck bottle, add intermediate 8-2 (0.37g), tetrahydrofuran (10mL) and tetrabutylammonium fluoride (0.56g) in sequence, and stir and react at room temperature for 1 hour. The reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the intermediate Body 8-3 (0.25g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.66 (s, 1H), 6.37 (s, 1H), 5.45 (t, J = 6.5Hz, 1H), 4.35 (d, J = 6Hz, 2H), 3.72(s,3H),1.43(s,9H).
步骤三：中间体2-D的制备Step 3: Preparation of intermediate 2-D
向微波管中，依次加入中间体8-3(0.25g)和六氟异丙醇(2mL)，微波加热至140℃搅拌反应2小时。反应液直接浓缩，所得粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇＝50:1)，得到中间体2-D(0.13g)。1H NMR(500MHz,DMSO-d6):δ5.58(s,1H),5.39(t,J＝6.5Hz,1H),4.67(s,2H),4.32(d,J＝6Hz,2H),3.59(s,3H).MS(ESI)m/z:152.23[M+H]+.Into the microwave tube, add intermediate 8-3 (0.25g) and hexafluoroisopropanol (2mL) in sequence, heat to 140°C under microwave and stir for 2 hours. The reaction solution was directly concentrated, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain intermediate 2-D (0.13g). 1 H NMR (500MHz, DMSO-d 6 ): δ5.58 (s, 1H), 5.39 (t, J = 6.5Hz, 1H), 4.67 (s, 2H), 4.32 (d, J = 6Hz, 2H) ,3.59(s,3H).MS(ESI)m/z:152.23[M+H] + .
制备例9中间体2-E的制备
Preparation Example 9 Preparation of Intermediate 2-E
步骤一：中间体9-1的制备Step 1: Preparation of intermediate 9-1
向单口瓶中，依次加入化合物7-1(13g)，邻苯二甲酸酐(12.48g)和冰醋酸(100mL)，氮气保护下，加热至120℃反应过夜。反应液冷却至室温，抽滤，滤饼用甲基叔丁基醚(100mL)洗涤，收集固体烘干，得到中间体9-1(21.4g)。1H NMR(500MHz,DMSO-d6)δ13.74(d,J＝123.8Hz,1H),8.08–7.86(m,4H),6.56(s,1H).MS(ESI):m/z＝291.94[M+H]+.To a single-neck bottle, compound 7-1 (13g), phthalic anhydride (12.48g) and glacial acetic acid (100mL) were added in sequence, and heated to 120°C to react overnight under nitrogen protection. The reaction solution was cooled to room temperature and filtered with suction. The filter cake was washed with methyl tert-butyl ether (100 mL). The solid was collected and dried to obtain intermediate 9-1 (21.4 g). 1 H NMR (500MHz, DMSO-d 6 ) δ13.74 (d, J＝123.8Hz, 1H), 8.08–7.86 (m, 4H), 6.56 (s, 1H). MS (ESI): m/z＝ 291.94[M+H] + .
步骤二：中间体9-2的制备Step 2: Preparation of intermediate 9-2
向三口瓶中依次加入中间体9-1(3g)、碳酸钾(1.703g)和N,N-二甲基甲酰胺(20mL)，反应液在冰水浴中搅拌降温至5℃，向其中滴加碘甲烷-d3(1.489g)，滴加完毕室温搅拌反应过夜。将反应液倒入水(50mL)中剧烈搅拌10分钟，抽滤，滤饼用水(50mL)洗涤，收集固体烘干，得到中间体9-2(2.81g)。MS(ESI):m/z＝308.93[M+H]+。Add intermediate 9-1 (3g), potassium carbonate (1.703g) and N,N-dimethylformamide (20mL) to the three-necked flask in sequence. Stir the reaction solution in an ice water bath and cool it to 5°C. Add drops into it. Add methyl iodide- d 3 (1.489g), and after the dropwise addition is completed, stir and react at room temperature overnight. The reaction solution was poured into water (50 mL), stirred vigorously for 10 minutes, filtered with suction, and the filter cake was washed with water (50 mL). The solid was collected and dried to obtain intermediate 9-2 (2.81 g). MS (ESI): m/z=308.93[M+H] + .
步骤三：中间体9-3的制备Step 3: Preparation of intermediate 9-3
向单口瓶中依次加入中间体9-2(2.81g)、乙醇(50mL)和水合肼(1.334g)，将反应液加热至70℃搅拌反应1.5小时。反应液冷却至室温，抽滤，滤液浓缩至干，向残留物中加入甲基叔丁基醚(10mL)，剧烈搅拌10分钟，抽滤，滤液浓缩，得中间体9-3(1.35g)，不经纯化直接用于下一步反应。MS(ESI):m/z＝178.98[M+H]+。 Intermediate 9-2 (2.81g), ethanol (50mL) and hydrazine hydrate (1.334g) were added in sequence to the one-neck bottle, and the reaction solution was heated to 70°C and stirred for 1.5 hours. The reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated to dryness. Methyl tert-butyl ether (10 mL) was added to the residue, stirred vigorously for 10 minutes, filtered with suction, and the filtrate was concentrated to obtain intermediate 9-3 (1.35g). , was used directly in the next reaction without purification. MS (ESI): m/z=178.98[M+H] + .
步骤四：中间体9-4的制备Step 4: Preparation of intermediate 9-4
向微波管中依次加入中间体9-3(0.8g)、叔丁基二甲基(2-丙炔氧基)硅烷(2.78g)、碘化亚铜(0.062g)、双三苯基磷二氯化钯(0.229g)、三乙胺(1.650g,2.273mL)和N,N-二甲基甲酰胺(10mL)，氮气鼓泡五分钟后，放入微波反应器中，加热至80℃反应3小时。反应液冷却至室温，用硅藻土抽滤，滤液倒入水(70mL)中，乙酸乙酯(30mL×2)萃取，合并有机相，以饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物分别以硅胶柱(石油醚:乙酸乙酯＝3:1)和C18柱(水:乙腈＝46:54)分离纯化，得到中间体9-4(0.17g)。1H NMR(500MHz,DMSO-d6)δ5.60(s,1H),4.71(s,2H),4.58(s,2H),0.89(s,9H),0.12(s,6H).MS(ESI):m/z＝269.22[M+H]+.Add intermediate 9-3 (0.8g), tert-butyldimethyl (2-propynyloxy)silane (2.78g), copper iodide (0.062g), and bistriphenylphosphonate to the microwave tube in sequence. Palladium dichloride (0.229g), triethylamine (1.650g, 2.273mL) and N,N-dimethylformamide (10mL) were placed in a microwave reactor after bubbling nitrogen for five minutes and heated to 80 ℃ reaction for 3 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was poured into water (70 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. , filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column (petroleum ether: ethyl acetate = 3:1) and C 18 column (water: acetonitrile = 46:54) to obtain intermediate 9-4 (0.17g ). 1 H NMR (500MHz, DMSO-d 6 ) δ5.60(s,1H),4.71(s,2H),4.58(s,2H),0.89(s,9H),0.12(s,6H).MS( ESI):m/z＝269.22[M+H] + .
步骤五：中间体2-E的制备Step 5: Preparation of intermediate 2-E
向单口瓶中，依次加入中间体9-4(0.15g)、四氢呋喃(5mL)及四丁基氟化铵的四氢呋喃溶液(1M，1.12mL,1.12mmol)，反应液在室温搅拌反应1小时。反应液减压浓缩，残留物用硅胶柱分离纯化(二氯甲烷:甲醇＝97:3)，得到中间体2-E(0.083g)。1H NMR(500MHz,DMSO-d6)δ5.58(s,1H),5.40(t,J＝6.0Hz,1H),4.68(s,2H),4.32(d,J＝5.9Hz,2H).MS(ESI):m/z＝155.09[M+H]+.To the single-neck bottle, add intermediate 9-4 (0.15g), tetrahydrofuran (5mL) and tetrabutylammonium fluoride tetrahydrofuran solution (1M, 1.12mL, 1.12mmol) in sequence, and stir the reaction solution at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column (dichloromethane:methanol=97:3) to obtain intermediate 2-E (0.083g). 1 H NMR (500MHz, DMSO-d 6 ) δ5.58 (s, 1H), 5.40 (t, J = 6.0Hz, 1H), 4.68 (s, 2H), 4.32 (d, J = 5.9Hz, 2H) .MS(ESI):m/z＝155.09[M+H] + .
制备例10中间体2-F的制备
Preparation Example 10 Preparation of Intermediate 2-F
步骤一：中间体10-2的制备Step 1: Preparation of intermediate 10-2
向单口瓶中，依次加入化合物10-1(150mg)、四氢呋喃(5mL)和N-氯代丁二酰亚胺(79mg)，室温搅拌反应16小时。反应液倒入水(50mL)中，乙酸乙酯(50mL×2)萃取。合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得残留物以硅胶柱层析分离纯化(石油醚:乙酸乙酯＝72:28)，得到中间体10-2(160mg)。1H NMR(500MHz,DMSO-d6)δ4.86(s,2H),4.50(s,2H),3.48(s,3H),0.75(s,9H),0.00(s,6H)。MS(ESI)m/z300.13[M+H]+.To a single-neck bottle, compound 10-1 (150 mg), tetrahydrofuran (5 mL) and N-chlorosuccinimide (79 mg) were added in sequence, and the reaction was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=72:28) to obtain intermediate 10-2 (160 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ 4.86 (s, 2H), 4.50 (s, 2H), 3.48 (s, 3H), 0.75 (s, 9H), 0.00 (s, 6H). MS(ESI)m/z300.13[M+H] + .
步骤二：中间体2-F的制备Step 2: Preparation of intermediate 2-F
向单口瓶中，依次加入中间体10-2(100mg)，四氢呋喃(3mL)和四丁基氟化铵(96mg)，室温搅拌反应45分钟。反应液减压浓缩，所得粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇＝95.6:4.4)，得到中间体2-F(56mg)。1H NMR(500MHz,DMSO-d6)δ5.36(s,1H),4.83(s,2H),4.24(s,2H),3.48(s,3H)。MS(ESI)m/z 186.09[M+H]+.To the one-neck bottle, add intermediate 10-2 (100 mg), tetrahydrofuran (3 mL) and tetrabutylammonium fluoride (96 mg) in sequence, and stir the reaction at room temperature for 45 minutes. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=95.6:4.4) to obtain intermediate 2-F (56 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ5.36 (s, 1H), 4.83 (s, 2H), 4.24 (s, 2H), 3.48 (s, 3H). MS(ESI)m/z 186.09[M+H] + .
制备例11中间体2-G的制备
Preparation Example 11 Preparation of Intermediate 2-G
向三口瓶中依次加入中间体6-1(300mg)、1mol/L的丙炔四氢呋喃溶液(8.52mL)、三乙胺(5mL)、双三苯基膦二氯化钯(179mg,0.256mmol)和碘化亚铜(48.7mg)，氮气保护下，将混合物加热至90℃反应16小时。将反应液用水(40mL)稀释，乙酸乙酯(10mL×3)萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物经硅胶柱分离纯化(二氯甲烷：甲醇＝96.3：3.7)得中间体2-G(104mg)。1H NMR(500MHz,DMSO-d6)5.51(s,1H),4.64(s,2H),3.56(s,3H),2.08(s,3H).To the three-necked flask, add intermediate 6-1 (300 mg), 1 mol/L propyne tetrahydrofuran solution (8.52 mL), triethylamine (5 mL), and bistriphenylphosphine palladium dichloride (179 mg, 0.256 mmol) in sequence. and copper iodide (48.7 mg), under nitrogen protection, the mixture was heated to 90°C for reaction for 16 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was separated and purified on a silica gel column. (Dichloromethane: methanol = 96.3: 3.7) Intermediate 2-G (104 mg) was obtained. 1 H NMR (500MHz, DMSO-d 6 )5.51(s,1H),4.64(s,2H),3.56(s,3H),2.08(s,3H).
制备例12中间体2-H的制备
Preparation Example 12 Preparation of Intermediate 2-H
步骤一：中间体12-2的制备Step 1: Preparation of intermediate 12-2
向三口瓶中依次加入化合物12-1(27.5g)、四氢呋喃(30mL)、乙醛的四氢呋喃溶液(5g,22.7mL)和钛酸四乙酯(51.8g)，氮气氛围下，25℃搅拌16小时。将反应液加入冰水中(500mL)，过滤，滤液以乙酸乙 酯(30mL×3)萃取，分液，有机相以饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物经硅胶柱层析分离(二氯甲烷：甲醇＝98.7：1.3)得中间体12-2(4.3g)。1H NMR(500MHz,DMSO-d6)δ7.95(q,J＝5.1Hz,1H),2.20(d,J＝5.0Hz,3H),1.10(s,9H).Add compound 12-1 (27.5g), tetrahydrofuran (30mL), acetaldehyde solution in tetrahydrofuran (5g, 22.7mL) and tetraethyl titanate (51.8g) to the three-necked flask in sequence, stir at 25°C for 16 Hour. The reaction solution was added to ice water (500 mL), filtered, and the filtrate was treated with ethyl acetate. The ester (30 mL Body 12-2 (4.3g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.95 (q, J = 5.1 Hz, 1H), 2.20 (d, J = 5.0 Hz, 3H), 1.10 (s, 9H).
步骤二：中间体12-3的制备Step 2: Preparation of intermediate 12-3
向三口瓶中依次加入中间体12-2(600mg)和二氯甲烷(2mL)，氮气保护下反应液搅拌降温至-5℃，向其中缓慢滴加1-丙炔溴化镁的四氢呋喃溶液(10.6mL,5.30mmol)，滴加完毕保持温度-5～0℃反应2h。冰浴下将水缓慢滴加至反应液，直至温度不发生变化，再加入乙酸乙酯(10mL×3)，搅拌后分液，有机相以饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物经硅胶柱层析分离(二氯甲烷：甲醇＝98.7：1.3)得中间体12-3(330mg)。1H NMR(500MHz,Chloroform-d)δ4.18–4.09(m,1H),3.32(d,J＝5.2Hz,1H),1.83(s,3H),1.40(d,J＝6.7Hz,3H),1.21(s,9H).Intermediate 12-2 (600 mg) and methylene chloride (2 mL) were added sequentially to the three-necked flask. The reaction solution was stirred and cooled to -5°C under nitrogen protection. A tetrahydrofuran solution of 1-propyne magnesium bromide (1-propyne magnesium bromide) was slowly added dropwise thereto. 10.6mL, 5.30mmol), after the dropwise addition, keep the temperature at -5~0°C for 2 hours. Slowly add water dropwise to the reaction solution under ice bath until the temperature does not change, then add ethyl acetate (10mL×3), stir and separate the liquids, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and reduce pressure Concentrate, and the residue is separated by silica gel column chromatography (dichloromethane: methanol = 98.7: 1.3) to obtain intermediate 12-3 (330 mg). 1 H NMR(500MHz,Chloroform-d)δ4.18–4.09(m,1H),3.32(d,J＝5.2Hz,1H),1.83(s,3H),1.40(d,J＝6.7Hz,3H ),1.21(s,9H).
步骤三：中间体2-H的制备Step 3: Preparation of intermediate 2-H
向单口瓶中依次加入中间体12-3(230mg)，甲醇(1mL)，氯化氢的1,4-二氧六环溶液(7.67mL,30.7mmol)，冰浴下搅拌10min后转至室温搅拌反应2h。反应液减压浓缩至干得中间体2-H(203mg)。1H NMR(500MHz,Methanol-d4)δ4.20–4.05(m,1H),1.86(d,J＝2.2Hz,3H),1.50(d,J＝6.8Hz,3H).Add intermediate 12-3 (230 mg), methanol (1 mL), and 1,4-dioxane solution of hydrogen chloride (7.67 mL, 30.7 mmol) to the single-neck bottle in sequence, stir in an ice bath for 10 min, and then turn to room temperature to stir the reaction. 2h. The reaction solution was concentrated to dryness under reduced pressure to obtain intermediate 2-H (203 mg). 1 H NMR (500MHz, Methanol-d4) δ4.20–4.05 (m, 1H), 1.86 (d, J = 2.2Hz, 3H), 1.50 (d, J = 6.8Hz, 3H).
制备例13中间体2-I的制备
Preparation Example 13 Preparation of Intermediate 2-I
步骤一：中间体13-2的制备Step 1: Preparation of intermediate 13-2
向单口瓶中，依次加入邻苯二甲酰亚胺(2g)、N,N-二甲基甲酰胺(50mL)、碳酸钾(2.07g)、四丁基溴化铵(0.09g)及化合物13-1(1.99g)，将混合物加热至80℃反应6h。停止搅拌，将反应液倒入水(250mL)中。二氯甲烷(80mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，向残留物中加入石油醚/乙酸乙酯(40mL，体积比3:1)打浆，过滤，得到中间体13-2(2.3g)。1H NMR(500MHz,DMSO-d6):δ7.97–7.83(m,4H),4.32(q,J＝2.3Hz,2H),1.76(t,J＝2.4Hz,3H).To the single-neck bottle, add phthalimide (2g), N,N-dimethylformamide (50mL), potassium carbonate (2.07g), tetrabutylammonium bromide (0.09g) and the compound in sequence 13-1 (1.99g), the mixture was heated to 80°C and reacted for 6 hours. Stop stirring and pour the reaction solution into water (250 mL). Extract with dichloromethane (80 mL Intermediate 13-2 (2.3g) was obtained. 1 H NMR (500MHz, DMSO-d 6 ): δ7.97–7.83 (m, 4H), 4.32 (q, J = 2.3Hz, 2H), 1.76 (t, J = 2.4Hz, 3H).
步骤二：中间体2-I的制备Step 2: Preparation of intermediate 2-I
向单口瓶中，依次加入中间体13-2(1g)、乙醇(50mL)和水合肼(0.568g)，加热至80℃搅拌4h。停止加热，冷却至室温，减压浓缩，向残留物中加入二氯甲烷(100mL)，然后加入4M的氢氧化钠溶液(100mL)，分层取有机相，无水硫酸钠干燥，过滤，滤液以4M的盐酸1,4-二氧六环溶液调pH＝5-6，浓缩得中间体2-I(0.5g)。1H NMR(500MHz,DMSO-d6):δ8.47(s,3H),3.63(s,2H),1.85(t,J＝2.5Hz,3H).To the single-neck bottle, add intermediate 13-2 (1g), ethanol (50mL) and hydrazine hydrate (0.568g) in sequence, heat to 80°C and stir for 4 hours. Stop heating, cool to room temperature, concentrate under reduced pressure, add methylene chloride (100mL) to the residue, then add 4M sodium hydroxide solution (100mL), take the organic phase by layer, dry over anhydrous sodium sulfate, filter, and remove the filtrate Adjust pH=5-6 with 4M 1,4-dioxane hydrochloric acid solution, and concentrate to obtain intermediate 2-I (0.5g). 1 H NMR (500MHz, DMSO-d 6 ): δ8.47 (s, 3H), 3.63 (s, 2H), 1.85 (t, J = 2.5Hz, 3H).
制备例14中间体2-J的制备
Preparation Example 14 Preparation of Intermediate 2-J
步骤一：中间体14-1的制备Step 1: Preparation of intermediate 14-1
向单口瓶中，依次加入化合物7-1(12g)、乙腈(120mL)和1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(13.12g)，室温搅拌反应1小时。反应结束，将反应液过滤，减压浓缩，所得粗品用硅胶柱层析分离纯化，得到中间体14-1(3.9g)。1H-NMR(500MHz,DMSO-d6)δ11.99(s,1H),5.28(s,2H).MS(ESI)m/z：181.90[M+H]+.To the single-neck bottle, add compound 7-1 (12g), acetonitrile (120mL) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) ) salt (13.12g), stir and react at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 14-1 (3.9g). 1 H-NMR (500MHz, DMSO-d 6 ) δ11.99 (s, 1H), 5.28 (s, 2H). MS (ESI) m/z: 181.90 [M+H] + .
步骤二：中间体14-2的制备Step 2: Preparation of intermediate 14-2
向单口瓶中，依次加入中间体14-1(3.9g)、邻苯二甲酸酐(3.37g)和醋酸(40mL)，氮气保护下，将混 合物加热至120℃反应2小时。反应结束，将反应液冷却至室温，抽滤，滤饼用甲基叔丁基醚(100mL)洗涤，收集固体并烘干，得到中间体14-2(5.57g)。1H-NMR(500MHz,DMSO-d6)δ14.20-13.81(m,1H),8.04(s,2H),7.97(s,2H).MS(ESI)m/z：309.85[M-H]-.To the single-neck bottle, add intermediate 14-1 (3.9g), phthalic anhydride (3.37g) and acetic acid (40mL) in sequence, and mix under nitrogen protection. The mixture was heated to 120°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered with suction. The filter cake was washed with methyl tert-butyl ether (100 mL). The solid was collected and dried to obtain intermediate 14-2 (5.57g). 1 H-NMR (500MHz, DMSO-d 6 ) δ14.20-13.81(m,1H),8.04(s,2H),7.97(s,2H).MS(ESI)m/z: 309.85[MH] - .
步骤三：中间体14-3的制备Step 3: Preparation of intermediate 14-3
向三口瓶中，依次加入中间体14-2(5.57g)、碳酸钾(2.73g)和N,N-二甲基甲酰胺(45mL)；所得混合物在冰水浴中搅拌降温至5℃，向其中滴加碘甲烷(2.55g)，滴加完毕室温搅拌反应过夜。反应结束，将反应液倒入水(50mL)中剧烈搅拌10分钟，抽滤，滤饼用水(50mL)洗涤，收集固体烘干，得到中间体14-3(1.14g)。1H-NMR(500MHz,DMSO-d6):δ8.05-8.00(m,2H),7.98-7.94(m,2H),3.89(s,3H).MS(ESI)m/z：325.86[M+H]+.To the three-necked flask, add intermediate 14-2 (5.57g), potassium carbonate (2.73g) and N,N-dimethylformamide (45mL) in sequence; the resulting mixture is stirred in an ice water bath and cooled to 5°C. Methyl iodide (2.55g) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature overnight. At the end of the reaction, the reaction solution was poured into water (50 mL) and stirred vigorously for 10 minutes, filtered with suction, and the filter cake was washed with water (50 mL). The solid was collected and dried to obtain intermediate 14-3 (1.14 g). 1 H-NMR (500MHz, DMSO-d 6 ): δ8.05-8.00(m,2H),7.98-7.94(m,2H),3.89(s,3H).MS(ESI)m/z: 325.86[ M+H] + .
步骤四：中间体14-4的制备Step 4: Preparation of intermediate 14-4
向单口瓶中，依次加入中间体14-3(0.6g)、乙醇(20mL)和水合肼(0.463g)，将反应液加热至70℃搅拌反应1.5小时。反应结束，将反应液冷却至室温，抽滤，滤液浓缩至干，向残留物中加入甲基叔丁基醚(10mL)，剧烈搅拌10分钟，抽滤，滤液浓缩，得中间体14-4(0.33g)。1H-NMR(500MHz,DMSO-d6)δ4.95(s,2H),3.52(s,3H).MS(ESI)m/z：194.09[M+H]+.To the single-neck bottle, add intermediate 14-3 (0.6g), ethanol (20mL) and hydrazine hydrate (0.463g) in sequence, heat the reaction solution to 70°C and stir for 1.5 hours. At the end of the reaction, the reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated to dryness. Add methyl tert-butyl ether (10 mL) to the residue, stir vigorously for 10 minutes, filter with suction, and concentrate the filtrate to obtain intermediate 14-4. (0.33g). 1 H-NMR (500MHz, DMSO-d 6 ) δ4.95 (s, 2H), 3.52 (s, 3H). MS (ESI) m/z: 194.09 [M+H] + .
步骤五：中间体14-5的制备Step 5: Preparation of intermediate 14-5
向微波管中依次加入中间体14-4(0.27g)、叔丁基二甲基(2-丙炔氧基)硅烷(0.948g)、碘化亚铜(0.053g)、双三苯基磷二氯化钯(0.098g)、三乙胺(1.127g,1.552mL)和N,N-二甲基甲酰胺(5mL)，向反应液中通入氮气鼓泡五分钟后，放入微波反应器中，加热至80℃反应3小时。反应结束，反应液冷却至室温，抽滤，将滤液倒入水(70mL)中，加入乙酸乙酯萃取，合并有机相，以饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物依次以硅胶柱和C18柱分离纯化，得到中间体14-5(0.08g)。1H-NMR(500MHz,DMSO-d6):δ4.88(s,2H),4.63(s,2H),3.55(s,3H),0.89(s,9H),0.13(s,6H).MS(ESI)m/z：284.11[M+H]+.Add intermediate 14-4 (0.27g), tert-butyldimethyl (2-propynyloxy)silane (0.948g), copper iodide (0.053g), and bistriphenylphosphine in sequence to the microwave tube. Palladium dichloride (0.098g), triethylamine (1.127g, 1.552mL) and N,N-dimethylformamide (5mL) were added to the reaction solution. After bubbling nitrogen for five minutes, put it into the microwave for reaction. In a container, heat to 80°C for 3 hours. At the end of the reaction, the reaction solution was cooled to room temperature, filtered, poured the filtrate into water (70 mL), added ethyl acetate for extraction, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified using a silica gel column and a C 18 column in sequence to obtain intermediate 14-5 (0.08g). 1 H-NMR (500MHz, DMSO-d 6 ): δ4.88 (s, 2H), 4.63 (s, 2H), 3.55 (s, 3H), 0.89 (s, 9H), 0.13 (s, 6H). MS(ESI)m/z: 284.11[M+H] + .
步骤六：中间体2-J的制备Step 6: Preparation of intermediate 2-J
向单口瓶中，依次加入中间体14-5(0.075g)、四氢呋喃(3mL)及四丁基氟化铵的四氢呋喃溶液(1M，0.291mL)，反应液在室温搅拌反应1小时。反应结束，将反应液减压浓缩，残留物用硅胶柱分离纯化，得到中间体2-J(0.044g)。1H-NMR(500MHz,DMSO-d6)δ5.46(t,J＝6Hz,1H),4.86(s,2H),4.37(d,J＝6Hz,2H),3.55(s,3H).MS(ESI)m/z 169.94[M+H]+.To the one-neck bottle, intermediate 14-5 (0.075g), tetrahydrofuran (3mL) and tetrabutylammonium fluoride tetrahydrofuran solution (1M, 0.291mL) were added in sequence, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified using a silica gel column to obtain Intermediate 2-J (0.044g). 1 H-NMR (500MHz, DMSO-d 6 ) δ5.46 (t, J = 6 Hz, 1H), 4.86 (s, 2H), 4.37 (d, J = 6 Hz, 2H), 3.55 (s, 3H). MS(ESI)m/z 169.94[M+H] + .
制备例15中间体2-K的制备
Preparation Example 15 Preparation of Intermediate 2-K
步骤一：中间体15-2的制备Step 1: Preparation of intermediate 15-2
向单口瓶中，依次加入化合物15-1(1g)、2,5-己烷二酮(2.465g)、甲苯(20mL)和4-甲基苯磺酸(0.155g)，反应液于110℃进行反应过夜。反应结束，将反应液倒入水(100mL)中，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物以硅胶柱分离纯化，得到中间体15-2(1.5g)。1H NMR(500MHz,DMSO-d6)δ7.61(s,1H),5.75(s,2H),3.80(s,3H),1.89(s,6H),1.73(s,3H).MS(ESI)m/z：190.19[M+H]+.To the single-neck bottle, add compound 15-1 (1g), 2,5-hexanedione (2.465g), toluene (20mL) and 4-methylbenzenesulfonic acid (0.155g) in sequence, and the reaction solution is heated at 110°C The reaction was carried out overnight. At the end of the reaction, pour the reaction solution into water (100 mL), extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified on a silica gel column to obtain intermediate 15. -2(1.5g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.61(s,1H),5.75(s,2H),3.80(s,3H),1.89(s,6H),1.73(s,3H).MS( ESI)m/z: 190.19[M+H] + .
步骤二：中间体15-3的制备Step 2: Preparation of intermediate 15-3
向三口瓶中，依次加入中间体15-2(1g)和四氢呋喃(40mL)，反应液搅拌降温至-75℃，向其中滴加正丁基锂(2.54g,2.54mL)，滴加完毕保持温度反应1h。向其中加入碘(1.341g)，加完毕保持温度搅拌反应10 min，后转移至室温搅拌反应1h。反应结束，将反应液倒入饱和亚硫酸钠水溶液(100mL)中，加入乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物以硅胶柱分离纯化，得到中间体15-3(1g)。1H NMR(500MHz,DMSO-d6)δ5.77(s,2H),3.87(s,3H),1.89(s,6H),1.71(s,3H).MS(ESI)m/z 315.98[M+H]+.To the three-necked flask, add intermediate 15-2 (1g) and tetrahydrofuran (40mL) in sequence. The reaction solution is stirred and cooled to -75°C. n-butyllithium (2.54g, 2.54mL) is added dropwise to it. Keep it until the dropwise addition is completed. Temperature reaction 1h. Add iodine (1.341g) to it. After adding, keep the temperature and stir for 10 seconds. min, then transferred to room temperature and stirred for 1 h. At the end of the reaction, pour the reaction solution into a saturated sodium sulfite aqueous solution (100 mL), add ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated and purified with a silica gel column to obtain the intermediate. 15-3(1g). 1 H NMR (500MHz, DMSO-d 6 ) δ5.77(s,2H),3.87(s,3H),1.89(s,6H),1.71(s,3H).MS(ESI)m/z 315.98[ M+H] + .
步骤三：中间体15-4的制备Step 3: Preparation of intermediate 15-4
向单口瓶中，依次加入中间体15-3(1g)，水(40.0mL)和乙醇(40mL)，向反应液中加氢氧化钾(0.890g)和盐酸羟胺(2.205g)，加毕升高温度至90℃反应过夜。反应结束，将反应液倒入饱和食盐水(100mL)中，加入乙酸乙酯萃取，有机相合并，减压浓缩，残留物以硅胶柱分离纯化，得到中间体15-4(0.6g)。1H NMR(500MHz,DMSO-d6)δ4.58(s,2H),3.56(s,3H),1.77(s,3H).MS(ESI)m/z 238.00[M+H]+.To the single-neck bottle, add intermediate 15-3 (1g), water (40.0mL) and ethanol (40mL) in sequence, add potassium hydroxide (0.890g) and hydroxylamine hydrochloride (2.205g) to the reaction solution, add Bi liters The reaction was carried out at high temperature to 90°C overnight. At the end of the reaction, the reaction solution was poured into saturated brine (100 mL), and ethyl acetate was added for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified on a silica gel column to obtain intermediate 15-4 (0.6 g). 1 H NMR (500MHz, DMSO-d 6 ) δ4.58(s,2H),3.56(s,3H),1.77(s,3H).MS(ESI)m/z 238.00[M+H] + .
步骤四：中间体15-5的制备Step 4: Preparation of intermediate 15-5
向微波管中，依次加入中间体15-4(0.5g)、碘化亚铜(0.080g)、双三苯基磷二氯化钯(0.148g)和三氟乙酸(1.708g,2.352mL)，N,N-二甲基甲酰胺(10mL)，然后向混合物中通入氮气鼓泡五分钟，加入叔丁基二甲基(2-丙炔氧基)硅烷(0.719g)，放入微波反应器加热至80℃反应2小时。反应结束，将反应液倒入100mL饱和氯化钠溶液中，用乙酸乙酯萃取，合并有机相，减压浓缩。残留物以硅胶柱分离纯化，得到中间体(0.42g)。MS(ESI)m/z：280.23[M+H]+.To the microwave tube, add intermediate 15-4 (0.5g), copper iodide (0.080g), bistriphenylphosphorus palladium dichloride (0.148g) and trifluoroacetic acid (1.708g, 2.352mL) in sequence , N,N-dimethylformamide (10mL), then bubble nitrogen into the mixture for five minutes, add tert-butyldimethyl (2-propynyloxy)silane (0.719g), and put in the microwave The reactor was heated to 80°C for 2 hours. After the reaction is completed, pour the reaction solution into 100 mL of saturated sodium chloride solution, extract with ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The residue was separated and purified using a silica gel column to obtain an intermediate (0.42g). MS(ESI)m/z: 280.23[M+H] + .
步骤五：中间体2-K的制备Step 5: Preparation of intermediate 2-K
向单口瓶中，依次加入中间体15-5(0.4g)、四氢呋喃(3mL)及四正丁基氟化铵(1.574g)，混合物在氮气保护下，室温搅拌反应1小时。反应结束，将反应液直接减压浓缩，残留物以硅胶柱分离纯化，得到中间体2-K(0.19g)。MS(ESI)m/z 166.13[M+H]+.To the single-neck bottle, add intermediate 15-5 (0.4g), tetrahydrofuran (3mL) and tetra-n-butylammonium fluoride (1.574g) in sequence, and stir the mixture at room temperature for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified on a silica gel column to obtain intermediate 2-K (0.19g). MS(ESI)m/z 166.13[M+H] + .
制备例16
Preparation Example 16
步骤一：中间体16-1的制备Step 1: Preparation of intermediate 16-1
向单口瓶中，依次加入中间体7-1(5g)、2,5-己二酮(3.70g)、甲苯(50mL)和冰醋酸(0.441mL)，将反应液置于110℃油浴搅拌反应3小时。反应结束，反应液冷却至室温，将反应液倒入水(100mL)中，乙酸乙酯(100mL)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得到中间体16-1(7.2g)。MS(ESI)m/z：242.08[M+H]+.To the single-neck bottle, add intermediate 7-1 (5g), 2,5-hexanedione (3.70g), toluene (50mL) and glacial acetic acid (0.441mL) in sequence, and place the reaction solution in a 110°C oil bath for stirring. Reaction takes 3 hours. At the end of the reaction, the reaction solution was cooled to room temperature, poured into water (100 mL), extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain Intermediate 16-1 (7.2g). MS(ESI)m/z: 242.08[M+H] + .
步骤二：中间体16-2的制备Step 2: Preparation of intermediate 16-2
向三口瓶中，依次加入中间体16-1(4.0g)、叔丁醇钾(2.06g)、N,N-二甲基甲酰胺(30mL)，混合物在氮气保护下，降温至0℃搅拌反应10分钟，向其中滴加二氟溴甲基三甲基硅烷(4.06g)，滴加完毕，反应液在0℃下搅拌反应1小时。反应完毕，将反应液倒入水(200mL)中，加入乙酸乙酯(100mL)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，残留物用硅胶柱分离纯化，得到中间体16-2(4g)。1H NMR(500MHz,DMSO-d6)δ7.94(t,J＝56.8Hz,1H),7.02(s,1H),5.82(s,2H),2.08(s,6H).MS(ESI)/z：289.97[M+H]+.To the three-necked flask, add intermediate 16-1 (4.0g), potassium tert-butoxide (2.06g), and N,N-dimethylformamide (30mL) in sequence. The mixture is cooled to 0°C and stirred under nitrogen protection. The reaction was carried out for 10 minutes, and difluorobromomethyltrimethylsilane (4.06g) was added dropwise. After the dropwise addition was completed, the reaction solution was stirred and reacted at 0°C for 1 hour. After the reaction is completed, pour the reaction solution into water (200 mL), add ethyl acetate (100 mL), and extract. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is separated on a silica gel column. Purification yielded intermediate 16-2 (4g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.94 (t, J = 56.8 Hz, 1H), 7.02 (s, 1H), 5.82 (s, 2H), 2.08 (s, 6H).MS (ESI) /z：289.97[M+H] + .
步骤三：中间体16-3的制备Step 3: Preparation of intermediate 16-3
向单口瓶中，加入盐酸羟胺(5.75g)和无水乙醇(24mL)，混合物在室温搅拌30分钟。向其中加入氢氧化钾(2.32g)、无水乙醇(2.5mL)和水(2.5mL)，再加入中间体16-2(4g)的乙醇(5mL)溶液，混合物于95℃搅拌反应过夜。反应结束，将反应液冷却至室温，抽滤，滤液浓缩至干，残留物用乙酸乙酯打浆，抽滤，滤液减压浓缩至干，残留物用硅胶柱分离纯化，得到中间体16-3(0.7g)。1H NMR(500MHz,DMSO-d6)δ7.49(t,J＝57.6Hz,1H),5.91(s,1H),5.44(s,2H).MS(ESI)m/z：213.3[M+H]+. To the one-neck bottle, add hydroxylamine hydrochloride (5.75g) and absolute ethanol (24 mL), and the mixture is stirred at room temperature for 30 minutes. Potassium hydroxide (2.32g), absolute ethanol (2.5mL) and water (2.5mL) were added thereto, and then a solution of intermediate 16-2 (4g) in ethanol (5mL) was added, and the mixture was stirred and reacted at 95°C overnight. At the end of the reaction, the reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated to dryness. The residue was slurried with ethyl acetate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated and purified with a silica gel column to obtain intermediate 16-3. (0.7g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.49 (t, J = 57.6Hz, 1H), 5.91 (s, 1H), 5.44 (s, 2H). MS (ESI) m/z: 213.3[M +H] + .
步骤四：中间体16-4的制备Step 4: Preparation of intermediate 16-4
向微波管中，依次加入中间体16-3(0.7g)、叔丁基二甲基(2-丙炔氧基)硅烷(4.50g,)、碘化亚铜(0.063g)、双三苯基磷二氯化钯(0.232g)和三乙胺(2.67g)，N,N-二甲基甲酰胺(4mL)，向混合物中通入氮气鼓泡1钟后，微波反应器加热至80℃反应2小时。反应结束，反应液抽滤，滤液倒入水(70mL)中剧烈搅拌，所得溶液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，残留物用硅胶柱、C18柱分离纯化，得到中间体16-4(0.35g)。1H NMR(500MHz,DMSO-d6)δ7.46(t,J＝58.0Hz,1H),5.96(s,1H),5.37(s,2H),4.59(s,2H),0.88(s,9H),0.12(s,6H).MS(ESI)m/z:302.18[M+H]+.To the microwave tube, add intermediate 16-3 (0.7g), tert-butyldimethyl (2-propynyloxy)silane (4.50g,), copper iodide (0.063g), and triphenyl in sequence. Palladium dichloride (0.232g), triethylamine (2.67g) and N,N-dimethylformamide (4mL) were added into the mixture. After bubbling nitrogen for 1 minute, the microwave reactor was heated to 80 ℃ reaction for 2 hours. At the end of the reaction, the reaction solution was filtered, and the filtrate was poured into water (70 mL) and stirred vigorously. The resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue Separate and purify using silica gel column and C18 column to obtain intermediate 16-4 (0.35g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.46 (t, J = 58.0Hz, 1H), 5.96 (s, 1H), 5.37 (s, 2H), 4.59 (s, 2H), 0.88 (s, 9H),0.12(s,6H).MS(ESI)m/z:302.18[M+H] + .
步骤五：中间体2-L的制备Step 5: Preparation of intermediate 2-L
向单口瓶中，依次加入中间体16-4(320mg)、四氢呋喃(10mL)及四丁基氟化铵(0.56g)，混合物室温搅拌反应30分钟。反应结束，将反应液直接减压浓缩，残留物用硅胶柱层析分离纯化，得到中间体2-L(0.12g)。1H NMR(500MHz,DMSO-d6)δ7.48(t,J＝57.9Hz,1H),5.94(s,1H),5.46(t,J＝6.0Hz,1H),5.37(s,2H),4.34(d,J＝6.0Hz,2H).MS(ESI)m/z:188.11[M+H]+.To the single-neck bottle, intermediate 16-4 (320 mg), tetrahydrofuran (10 mL) and tetrabutylammonium fluoride (0.56 g) were added in sequence, and the mixture was stirred and reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain intermediate 2-L (0.12g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.48 (t, J = 57.9 Hz, 1H), 5.94 (s, 1H), 5.46 (t, J = 6.0 Hz, 1H), 5.37 (s, 2H) ,4.34(d,J＝6.0Hz,2H).MS(ESI)m/z:188.11[M+H] + .
实施例1
Example 1
向单口瓶中，依次加入中间体1-B(0.2g)、甲苯(8mL)、中间体2-A(0.051g)、碳酸铯(0.148g)及4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.022g)、三(二亚苄基丙酮)二钯(0.017g)，氮气保护下，将混合物加热至100℃反应8小时。将反应液倒入水(50mL)中，乙酸乙酯(50mL×3)萃取，合并有机相并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物经硅胶柱层析分离纯化(二氯甲烷:甲醇＝50:1)，得到化合物1(0.05g)。1H NMR(500MHz,DMSO-d6)δ8.28(s,1H),7.74(s,1H),7.62(s,1H),7.44(s,1H),7.40(d,J＝2.5Hz,1H),7.28(d,J＝8.4Hz,1H),7.04–6.94(m,2H),6.03(ddt,J＝16.0,10.4,5.7Hz,1H),5.20(dd,J＝10.3,1.4Hz,1H),5.12(dd,J＝17.1,1.5Hz,1H),4.78–4.67(m,3H),2.91(tt,J＝11.8,3.5Hz,1H),2.40–2.32(m,1H),2.17–2.09(m,2H),1.91(d,J＝10.2Hz,2H),1.55(qd,J＝13.1,2.9Hz,2H),1.40–1.28(m,2H),1.24(s,1H),1.16(d,J＝6.2Hz,6H),0.98–0.91(m,2H),0.85(dt,J＝8.9,4.3Hz,2H).HRMS(ESI)calculated for C28H35N5O4S2([M+H]+)m/z:570.2203,found:570.2209.To the single-neck bottle, add intermediate 1-B (0.2g), toluene (8mL), intermediate 2-A (0.051g), cesium carbonate (0.148g) and 4,5-bisdiphenylphosphine-9 in sequence , 9-dimethylxanthene (0.022g), tris(dibenzylideneacetone) dipalladium (0.017g), under nitrogen protection, the mixture was heated to 100°C for 8 hours of reaction. Pour the reaction solution into water (50 mL), extract with ethyl acetate (50 mL Chromatography separation and purification (dichloromethane:methanol=50:1) gave compound 1 (0.05g). 1 H NMR (500MHz, DMSO-d 6 ) δ8.28 (s, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.44 (s, 1H), 7.40 (d, J = 2.5Hz, 1H),7.28(d,J＝8.4Hz,1H),7.04–6.94(m,2H),6.03(ddt,J＝16.0,10.4,5.7Hz,1H),5.20(dd,J＝10.3,1.4Hz ,1H),5.12(dd,J＝17.1,1.5Hz,1H),4.78–4.67(m,3H),2.91(tt,J＝11.8,3.5Hz,1H),2.40–2.32(m,1H), 2.17–2.09(m,2H),1.91(d,J＝10.2Hz,2H),1.55(qd,J＝13.1,2.9Hz,2H),1.40–1.28(m,2H),1.24(s,1H) ,1.16(d,J＝6.2Hz,6H),0.98–0.91(m,2H),0.85(dt,J＝8.9,4.3Hz,2H).HRMS(ESI)calculated for C 28 H 35 N 5 O 4 S 2 ([M+H] + )m/z:570.2203,found:570.2209.
实施例2
Example 2
向微波管中依次加入中间体1-B(0.1g)、中间体2-B(26.8mg)、乙酸钾(37.2mg)、四氢呋喃(3mL)和BrettPhos Pd G3(17.2mg)，氮气氛围下，加热至100℃反应3.5小时。将反应液以硅藻土做铺垫抽滤，滤液用水(30mL)稀释，乙酸乙酯(10mL×3)萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，所得粗品分别经硅胶柱(二氯甲烷：甲醇＝97.3：2.7)和C18柱(乙腈：水＝55:45)进行制备纯化，得到化合物2(26mg)。1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),7.99(d,J＝2.5Hz,1H),7.76–7.52(m,3H),7.36(d,J＝8.4Hz,1H),7.02(d,J＝7.8Hz,1H),6.64(dd,J＝18.8,11.1Hz,1H),6.00(s,1H),4.74(p,J＝6.2Hz,1H),3.72(s,3H),2.92(tt,J＝11.8,3.5Hz,1H),2.41(tq,J＝7.9,4.8,3.6Hz,1H),2.22–2.09(m,2H),1.98–1.85(m,2H),1.56(qd,J＝13.2,3.3Hz,2H),1.34(dt,J＝14.4,10.3Hz,2H),1.23(s,1H),1.16(d,J＝6.2Hz,6H),0.97(dd,J＝7.9,2.8Hz,2H),0.89(dd,J＝4.9,2.5Hz,2H).HRMS(ESI)calculated for C28H34FN5O4S2([M+H]+)m/z:588.2114，found 588.2112.Add Intermediate 1-B (0.1g), Intermediate 2-B (26.8mg), potassium acetate (37.2mg), tetrahydrofuran (3mL) and BrettPhos Pd G3 (17.2mg) in sequence to the microwave tube. Under nitrogen atmosphere, Heat to 100°C and react for 3.5 hours. The reaction solution was suction filtered using diatomaceous earth as a bed. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The crude product was preparatively purified through silica gel column (dichloromethane: methanol = 97.3: 2.7) and C 18 column (acetonitrile: water = 55:45) to obtain compound 2 (26 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ9.18 (s, 1H), 7.99 (d, J = 2.5Hz, 1H), 7.76–7.52 (m, 3H), 7.36 (d, J = 8.4Hz, 1H),7.02(d,J＝7.8Hz,1H),6.64(dd,J＝18.8,11.1Hz,1H),6.00(s,1H),4.74(p,J＝6.2Hz,1H),3.72( s,3H),2.92(tt,J＝11.8,3.5Hz,1H),2.41(tq,J＝7.9,4.8,3.6Hz,1H),2.22–2.09(m,2H),1.98–1.85(m, 2H),1.56(qd,J＝13.2,3.3Hz,2H),1.34(dt,J＝14.4,10.3Hz,2H),1.23(s,1H),1.16(d,J＝6.2Hz,6H), 0.97(dd,J＝7.9,2.8Hz,2H),0.89(dd,J＝4.9,2.5Hz,2H).HRMS(ESI)calculated for C 28 H 34 FN 5 O 4 S 2 ([M+H] + )m/z:588.2114, found 588.2112.
实施例3
Example 3
将中间体1-B(150mg)、中间体2-C(46.1mg)、1,4-二氧六环(5mL)、乙酸钾(84.0mg)和BrettPhos Pd G3(38.7mg)的混合物在氮气氛围下通过微波加热至100℃反应3小时。反应液减压浓缩，残留物经硅胶柱层析分离纯化(二氯甲烷:甲醇＝96.3:3.7)，得到化合物3(61.0mg)。1H NMR(500MHz,DMSO-d6)δ9.27(s,1H),7.98(d,J＝2.5Hz,1H),7.78–7.68(m,1H),7.66(s,1H),7.37(d,J＝8.4Hz,1H),7.02(d,J＝7.8Hz,1H),5.92(s,1H),5.44(t,J＝2.5Hz,1H),5.12(d,J＝2.1Hz,1H),4.75(h,J＝6.1Hz,1H),4.17(t,J＝6.6Hz,2H),3.32(d,J＝11.6Hz,1H),3.22–3.12(m,2H),2.97–2.87(m,1H),2.44–2.34(m,1H),2.17–2.09(m,2H),1.95–1.88(m,2H),1.61–1.51(m,2H),1.39–1.29(m,2H),1.16(d,J＝6.3Hz,6H),1.01–0.90(m,2H),0.92–0.82(m,2H)。HRMS(ESI)calculated for C29H35N5O4S2([M+H]+)m/z:582.2209,found:582.2209.A mixture of Intermediate 1-B (150 mg), Intermediate 2-C (46.1 mg), 1,4-dioxane (5 mL), potassium acetate (84.0 mg) and BrettPhos Pd G3 (38.7 mg) was heated under nitrogen. The mixture was heated to 100°C by microwave for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol=96.3:3.7) to obtain compound 3 (61.0 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ9.27 (s, 1H), 7.98 (d, J = 2.5Hz, 1H), 7.78–7.68 (m, 1H), 7.66 (s, 1H), 7.37 ( d,J＝8.4Hz,1H),7.02(d,J＝7.8Hz,1H),5.92(s,1H),5.44(t,J＝2.5Hz,1H),5.12(d,J＝2.1Hz, 1H),4.75(h,J＝6.1Hz,1H),4.17(t,J＝6.6Hz,2H),3.32(d,J＝11.6Hz,1H),3.22–3.12(m,2H),2.97– 2.87(m,1H),2.44–2.34(m,1H),2.17–2.09(m,2H),1.95–1.88(m,2H),1.61–1.51(m,2H),1.39–1.29(m,2H ),1.16(d,J＝6.3Hz,6H),1.01–0.90(m,2H),0.92–0.82(m,2H). HRMS(ESI)calculated for C 29 H 35 N 5 O 4 S 2 ([M+H] + )m/z:582.2209,found:582.2209.
实施例4
Example 4
向微波管中，依次加入中间体1-B(70mg)，中间体2-D(24.07mg)，四氢呋喃(4mL)，乙酸钾(26.0mg)和BrettPhos Pd G3(12.03mg)，氮气氛围下，加热至100℃反应2小时。反应液直接浓缩，所得粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇＝50:1)，得到化合物4(0.038g)。1H NMR(500MHz,DMSO-d6)δ9.26(s,1H),7.98(d,J＝2.5Hz,1H),7.68-7.63(m,2H),7.37(d,J＝8.5Hz,1H),7.02(d,J＝7.5Hz,1H),6.08(s,1H),5.47(t,J＝6Hz,1H),4.79-4.71(m,1H),4.37(d,J＝6Hz,2H),3.79(s,3H),2.96-2.88(m,1H),2.44-2.37(m,1H),2.18-2.08(m,2H),1.95-1.88(m,2H),1.63-1.52(m,2H),1.39-1.30(m,2H),1.27-1.22(m,1H),1.17(s,3H),1.16(s,3H),1.00-0.95(m,2H),0.91-0.87(m,2H).HRMS(ESI)calculated for C29H36N5O5S2([M+H]+)m/z:598.2158,found:598.2155.To the microwave tube, add Intermediate 1-B (70mg), Intermediate 2-D (24.07mg), tetrahydrofuran (4mL), potassium acetate (26.0mg) and BrettPhos Pd G3 (12.03mg) in sequence, under nitrogen atmosphere. Heat to 100°C and react for 2 hours. The reaction solution was directly concentrated, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain compound 4 (0.038g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.26 (s, 1H), 7.98 (d, J = 2.5Hz, 1H), 7.68-7.63 (m, 2H), 7.37 (d, J = 8.5Hz, 1H),7.02(d,J＝7.5Hz,1H),6.08(s,1H),5.47(t,J＝6Hz,1H),4.79-4.71(m,1H),4.37(d,J＝6Hz, 2H),3.79(s,3H),2.96-2.88(m,1H),2.44-2.37(m,1H),2.18-2.08(m,2H),1.95-1.88(m,2H),1.63-1.52( m,2H),1.39-1.30(m,2H),1.27-1.22(m,1H),1.17(s,3H),1.16(s,3H),1.00-0.95(m,2H),0.91-0.87( m,2H).HRMS(ESI)calculated for C 29 H 36 N 5 O 5 S 2 ([M+H] + )m/z:598.2158,found:598.2155.
实施例5
Example 5
向三口瓶中依次加入中间体1-B(100mg)、中间体2-E(35.1mg)、1,4-二氧六环(5mL)、乙酸钾(37.2mg)和BrettPhos Pd G3(17.19mg)，氮气保护下加热至100℃反应2小时。反应液冷却至室温，以硅藻土抽滤，滤液减压浓缩。残留物分别经硅胶柱(二氯甲烷:甲醇＝97：3)和C18柱(水：乙腈＝60:40)进行分离纯化，得到化合物5(0.048g)。1H NMR(500MHz,DMSO-d6)δ9.25(s,1H),7.98(d,J＝2.4Hz,1H),7.67–7.62(m,2H),7.37(d,J＝8.4Hz,1H),7.02(d,J＝7.7Hz,1H),6.08(s,1H),5.47(t,J＝6.0Hz,1H),4.77-4.72(m,1H),4.37(d,J＝6.0Hz,2H),2.95-2.89(m,1H),2.44–2.38(m,1H),2.14-2.12(m,2H),1.92-1.90(m,2H),1.62–1.51(m,2H),1.37-1.30(m,2H),1.24(s,1H),1.16(d,J＝6.2Hz,6H),1.00–0.95(m,2H),0.91–0.87(m,2H).HRMS(ESI)calculated for C29H32D3N5O5S2([M+H]+)m/z:601.2346,found 601.2350[M+H]+.Add intermediate 1-B (100mg), intermediate 2-E (35.1mg), 1,4-dioxane (5mL), potassium acetate (37.2mg) and BrettPhos Pd G3 (17.19mg) to the three-necked flask. ), heated to 100°C under nitrogen protection for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated and purified through a silica gel column (dichloromethane:methanol=97:3) and a C 18 column (water:acetonitrile=60:40) to obtain compound 5 (0.048g). 1 H NMR (500MHz, DMSO-d 6 ) δ9.25 (s, 1H), 7.98 (d, J = 2.4Hz, 1H), 7.67–7.62 (m, 2H), 7.37 (d, J = 8.4Hz, 1H),7.02(d,J＝7.7Hz,1H),6.08(s,1H),5.47(t,J＝6.0Hz,1H),4.77-4.72(m,1H),4.37(d,J＝6.0 Hz,2H),2.95-2.89(m,1H),2.44–2.38(m,1H),2.14-2.12(m,2H),1.92-1.90(m,2H),1.62–1.51(m,2H), 1.37-1.30(m,2H),1.24(s,1H),1.16(d,J＝6.2Hz,6H),1.00–0.95(m,2H),0.91–0.87(m,2H).HRMS(ESI) calculated for C 29 H 32 D 3 N 5 O 5 S 2 ([M+H] + )m/z:601.2346,found 601.2350[M+H] + .
实施例6
Example 6
向微波管中，依次加入中间体1-B(90mg)，1,4-二氧六环(5mL)，乙酸钾(50.0mg)和BrettPhos Pd  G3(23.2mg)和中间体2-F(31.7mg)，氮气氛围下，加热至100℃反应3小时。反应液减压浓缩，所得粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇＝96.3:3.7)，得到化合物6(18.0mg)。1H NMR(500MHz,Chloroform-d)δ7.94(d,J＝2.5Hz,1H),7.76(s,1H),7.77–7.67(m,1H),7.34(d,J＝8.4Hz,1H),6.23(s,1H),4.90(d,J＝7.8Hz,1H),4.60(s,2H),4.50(s,1H),3.87(s,3H),3.57(s,1H),3.08(s,1H),2.34–2.27(m,2H),2.27–2.15(m,3H),1.76–1.66(m,2H),1.38–1.32(m,1H),1.33–1.26(m,1H),1.24(d,J＝6.2Hz,6H),1.18–1.11(m,2H),0.95–0.85(m,2H)。HRMS(ESI)calculated for C29H34ClN5O5S2([M+H]+)m/z:632.1768,found:632.1773.To the microwave tube, add intermediate 1-B (90mg), 1,4-dioxane (5mL), potassium acetate (50.0mg) and BrettPhos Pd in sequence. G3 (23.2 mg) and intermediate 2-F (31.7 mg) were heated to 100°C for 3 hours in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=96.3:3.7) to obtain compound 6 (18.0 mg). 1 H NMR(500MHz,Chloroform-d)δ7.94(d,J＝2.5Hz,1H),7.76(s,1H),7.77–7.67(m,1H),7.34(d,J＝8.4Hz,1H ),6.23(s,1H),4.90(d,J＝7.8Hz,1H),4.60(s,2H),4.50(s,1H),3.87(s,3H),3.57(s,1H),3.08 (s,1H),2.34–2.27(m,2H),2.27–2.15(m,3H),1.76–1.66(m,2H),1.38–1.32(m,1H),1.33–1.26(m,1H) ,1.24(d,J＝6.2Hz,6H),1.18–1.11(m,2H),0.95–0.85(m,2H). HRMS(ESI)calculated for C 29 H 34 ClN 5 O 5 S 2 ([M+H] + )m/z:632.1768,found:632.1773.
实施例7
Example 7
-78℃下，将化合物4(0.1g)溶于二氯甲烷(10mL)，随后向其中加入二乙胺基三氟化硫(0.040g)，-78℃搅拌反应1小时。反应液倒入饱和碳酸氢钠溶液(20mL)中，乙酸乙酯(20mL)萃取。有机相分别用水(20mL)、饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇＝50:1)，得到化合物7(8mg)。1H NMR(500MHz,DMSO-d6)δ9.32(s,1H),7.99(d,J＝2.5Hz,1H),7.70-7.62(m,2H),7.38(d,J＝8.5Hz,1H),7.02(d,J＝8Hz,1H),6.21(s,1H),5.48(s,1H),5.39(s,1H),4.79-4.71(m,1H),3.82(s,3H),2.97-2.89(m,1H),2.45-2.39(m,1H),2.17-2.10(m,2H),1.95-1.88(m,2H),1.62-1.51(m,2H),1.41-1.32(m,2H),1.30-1.28(m,1H),1.17(s,3H),1.16(s,3H),1.00-0.96(m,2H),0.92-0.88(m,2H).HRMS(ESI)calculated for C29H34FN5O4S2([M+H]+)m/z:600.2114,found:600.2113.Compound 4 (0.1g) was dissolved in methylene chloride (10 mL) at -78°C, then diethylamine sulfur trifluoride (0.040g) was added thereto, and the reaction was stirred at -78°C for 1 hour. The reaction solution was poured into saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain compound 7. (8mg). 1 H NMR (500MHz, DMSO-d 6 ) δ9.32 (s, 1H), 7.99 (d, J = 2.5Hz, 1H), 7.70-7.62 (m, 2H), 7.38 (d, J = 8.5Hz, 1H),7.02(d,J＝8Hz,1H),6.21(s,1H),5.48(s,1H),5.39(s,1H),4.79-4.71(m,1H),3.82(s,3H) ,2.97-2.89(m,1H),2.45-2.39(m,1H),2.17-2.10(m,2H),1.95-1.88(m,2H),1.62-1.51(m,2H),1.41-1.32( m,2H),1.30-1.28(m,1H),1.17(s,3H),1.16(s,3H),1.00-0.96(m,2H),0.92-0.88(m,2H).HRMS(ESI) calculated for C 29 H 34 FN 5 O 4 S 2 ([M+H] + )m/z:600.2114,found:600.2113.
实施例8
Example 8
向三口瓶中依次加入中间体1-B(115mg)、碳酸铯(142mg)、中间体2-G(33.1mg)、1,4-二氧六环(5.5mL)和BrettPhos Pd G3(29.6mg)，氮气保护下，油浴加热至100℃反应1小时。将反应液用水稀释(40mL),乙酸乙酯萃取(10mL×3)萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，残留物分别经硅胶柱(二氯甲烷：甲醇＝97.5：2.5)和C18柱(乙腈：水＝60:40)分离纯化，得化合物8(80mg)。1H NMR(500MHz,DMSO-d6)δ9.25(s,1H),7.98(d,J＝2.4Hz,1H),7.65(q,J＝3.3,2.5Hz,2H),7.36(d,J＝8.4Hz,1H),7.01(d,J＝7.8Hz,1H),6.01(s,1H),4.74(s,1H),3.76(s,3H),3.00–2.84(m,1H),2.41(m,1H),2.14(s,3H),2.12(s,2H),1.96–1.85(m,2H),1.64–1.49(m,2H),1.40–1.29(m,2H),1.16(d,J＝6.2Hz,7H),0.97(m,2H),0.92–0.86(m,2H).HRMS(ESI)calculated for C29H35N5O4S2([M+H]+)m/z:582.2209,found m/z＝582.2209[M+H]+.Add intermediate 1-B (115mg), cesium carbonate (142mg), intermediate 2-G (33.1mg), 1,4-dioxane (5.5mL) and BrettPhos Pd G3 (29.6mg) to the three-necked flask. ), under nitrogen protection, heat the oil bath to 100°C for 1 hour. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. (Dichloromethane: methanol = 97.5: 2.5) and C18 column (acetonitrile: water = 60:40) were separated and purified to obtain compound 8 (80 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ9.25 (s, 1H), 7.98 (d, J = 2.4Hz, 1H), 7.65 (q, J = 3.3, 2.5Hz, 2H), 7.36 (d, J＝8.4Hz,1H),7.01(d,J＝7.8Hz,1H),6.01(s,1H),4.74(s,1H),3.76(s,3H),3.00–2.84(m,1H), 2.41(m,1H),2.14(s,3H),2.12(s,2H),1.96–1.85(m,2H),1.64–1.49(m,2H),1.40–1.29(m,2H),1.16( d,J＝6.2Hz,7H),0.97(m,2H),0.92–0.86(m,2H).HRMS(ESI)calculated for C29H35N5O4S2([M+H] + )m/z:582.2209,found m/ z＝582.2209[M+H] + .
实施例9
Example 9
向单口瓶中依次加入中间体1-B(300mg)、碳酸铯(741mg)、中间体2-H(102mg)、叔丁醇(10mL)和BrettPhos Pd G3(155mg)，氮气氛围下，加热至90℃反应16小时。反应液用水(50mL)稀释，乙酸乙酯萃取(10mL×3)，有机相以饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物分别经硅胶柱层析(二氯甲烷：甲醇＝97.3：2.7)和C18柱(乙腈：水＝62:38)进行分离纯化得化合物9(72mg)。1H NMR(500MHz,DMSO-d6)δ7.62(s,1H),7.30(d,J＝2.5Hz,1H),7.26(d,J＝8.4Hz,1H),7.01(d,J＝7.8Hz,1H),6.89(dd,J＝8.4,2.6Hz,1H),6.73(d,J＝7.3Hz,1H),4.86–4.62(m,1H),4.27–4.15(m,1H),2.96–2.86(m,1H),2.43–2.36(m,1H),2.12(d,J＝12.1Hz,2H),1.95–1.87(m,2H),1.75(d,J＝2.1Hz,3H),1.55(dd,J＝12.3,3.3Hz, 2H),1.42(d,J＝6.7Hz,3H),1.36–1.30(m,2H),1.24(s,1H),1.16(d,J＝6.2Hz,6H),0.95(dd,J＝10.1,6.9Hz,2H),0.91–0.84(m,2H).HRMS(ESI)calculated for C27H35N3O4S2([M+H]+)m/z:530.2147，found m/z＝530.2140[M+H]+.Add intermediate 1-B (300mg), cesium carbonate (741mg), intermediate 2-H (102mg), tert-butyl alcohol (10mL) and BrettPhos Pd G3 (155mg) to the single-neck bottle in sequence, and heat to React at 90°C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (10 mL : methanol = 97.3: 2.7) and C 18 column (acetonitrile: water = 62:38) were separated and purified to obtain compound 9 (72 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ7.62 (s, 1H), 7.30 (d, J = 2.5Hz, 1H), 7.26 (d, J = 8.4Hz, 1H), 7.01 (d, J = 7.8Hz,1H),6.89(dd,J＝8.4,2.6Hz,1H),6.73(d,J＝7.3Hz,1H),4.86–4.62(m,1H),4.27–4.15(m,1H), 2.96–2.86(m,1H),2.43–2.36(m,1H),2.12(d,J＝12.1Hz,2H),1.95–1.87(m,2H),1.75(d,J＝2.1Hz,3H) ,1.55(dd,J=12.3,3.3Hz, 2H),1.42(d,J＝6.7Hz,3H),1.36–1.30(m,2H),1.24(s,1H),1.16(d,J＝6.2Hz,6H),0.95(dd,J＝10.1 ,6.9Hz,2H),0.91–0.84(m,2H).HRMS(ESI)calculated for C27H35N3O4S2([M+H] + )m/z:530.2147, found m/z＝530.2140[M+H] + .
实施例10
Example 10
向单口瓶中，依次加入中间体1-B(0.15g)、叔丁醇(5mL)、碳酸铯(0.334g)、中间体2-I(0.036g)及BrettPhos Pd G3(0.026g)，氮气置换三次，氮气保护下，将混合物加热至85℃反应12小时。停止加热，冷却至室温，将反应液倒入水(50mL)中，乙酸乙酯(50mL×3)萃取，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物分别以硅胶柱(石油醚/乙酸乙酯＝50:50)和C18柱(水/乙腈＝50:50)分离纯化，得到化合物10(0.055g)。1HNMR(500MHz,DMSO-d6)δ7.61(s,1H),7.28-7.26(m,2H),7.01(d,J＝7.7Hz,1H),6.90–6.81(m,2H),4.74(dt,J＝12.4,6.2Hz,1H),3.92-3.90(m,2H),3.31–3.19(m,1H),2.94-2.87(m,1H),2.44–2.32(m,1H),2.13(d,J＝11.9Hz,2H),1.91(d,J＝10.3Hz,2H),1.77(t,J＝2.1Hz,3H),1.60-1.52(m,2H),1.37-1.30(m,2H),1.16(d,J＝6.2Hz,6H),0.99–0.91(m,2H),0.92–0.83(m,2H).HRMS(ESI)calculated for C29H36N5O5S2([M+H]+)m/z:516.1985,found:516.1984.To the single-neck bottle, add intermediate 1-B (0.15g), tert-butanol (5mL), cesium carbonate (0.334g), intermediate 2-I (0.036g) and BrettPhos Pd G3 (0.026g), nitrogen gas Replaced three times, the mixture was heated to 85°C for 12 hours under nitrogen protection. Stop heating, cool to room temperature, pour the reaction solution into water (50 mL), extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure After concentration, the resulting residue was separated and purified using a silica gel column (petroleum ether/ethyl acetate = 50:50) and a C 18 column (water/acetonitrile = 50:50) to obtain compound 10 (0.055g). 1 HNMR (500MHz, DMSO-d 6 ) δ7.61 (s, 1H), 7.28-7.26 (m, 2H), 7.01 (d, J = 7.7Hz, 1H), 6.90–6.81 (m, 2H), 4.74 (dt,J＝12.4,6.2Hz,1H),3.92-3.90(m,2H),3.31–3.19(m,1H),2.94-2.87(m,1H),2.44–2.32(m,1H),2.13 (d,J＝11.9Hz,2H),1.91(d,J＝10.3Hz,2H),1.77(t,J＝2.1Hz,3H),1.60-1.52(m,2H),1.37-1.30(m, 2H),1.16(d,J＝6.2Hz,6H),0.99–0.91(m,2H),0.92–0.83(m,2H).HRMS(ESI)calculated for C 29 H 36 N 5 O 5 S 2 ( [M+H] + )m/z:516.1985,found:516.1984.
实施例11
Example 11
向单口瓶中分别加入中间体1-C(150mg)、中间体2-A(40.8mg)、碳酸铯(108mg)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(31.9mg)、三(二亚苄基丙酮)二钯(25.3mg)和甲苯(6mL)，氮气保护下，100℃反应10小时。反应液减压浓缩，残留物经硅胶柱层析分离(二氯甲烷：甲醇＝20:1)得到化合物11(60mg)。1H NMR(500MHz,DMSO-d6)δ8.34(s,1H),7.76(s,1H),7.59(s,1H),7.44(d,J＝2.7Hz,2H),7.27(d,J＝8.4Hz,1H),7.07–6.95(m,2H),6.10–5.96(m,1H),5.25–5.18(m,1H),5.13(dd,J＝17.1,1.7Hz,1H),4.79–4.71(m,3H),4.63–4.57(m,2H),4.50–4.43(m,3H),3.32–3.26(m,1H),2.97–2.87(m,1H),2.16–2.08(m,2H),1.91(dd,J＝13.1,3.9Hz,2H),1.61–1.50(m,2H),1.39–1.29(m,2H),1.16(d,J＝6.2Hz,6H).HRMS(ESI)calculated for C28H36N5O5S2([M+H]+)m/z:586.2152,found:586.2151.Add intermediate 1-C (150 mg), intermediate 2-A (40.8 mg), cesium carbonate (108 mg), and 4,5-bisdiphenylphosphine-9,9-dimethyloxa to the single-neck bottle respectively. Anthracene (31.9 mg), tris(dibenzylideneacetone)dipalladium (25.3 mg) and toluene (6 mL) were reacted at 100°C for 10 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain compound 11 (60 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ8.34 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.44 (d, J = 2.7Hz, 2H), 7.27 (d, J＝8.4Hz,1H),7.07–6.95(m,2H),6.10–5.96(m,1H),5.25–5.18(m,1H),5.13(dd,J＝17.1,1.7Hz,1H),4.79 –4.71(m,3H),4.63–4.57(m,2H),4.50–4.43(m,3H),3.32–3.26(m,1H),2.97–2.87(m,1H),2.16–2.08(m, 2H),1.91(dd,J＝13.1,3.9Hz,2H),1.61–1.50(m,2H),1.39–1.29(m,2H),1.16(d,J＝6.2Hz,6H).HRMS(ESI )calculated for C 28 H 36 N 5 O 5 S 2 ([M+H] + )m/z:586.2152,found:586.2151.
实施例12
Example 12
向微波管中依次加入中间体1-C(100mg)、醋酸钾(36.1mg)、中间体2-B(26.0mg)、BrettPhos Pd G3(25.0mg)和四氢呋喃(4mL)，氮气保护下微波加热至100℃反应2h。反应液冷却至室温，以硅藻土抽滤，滤液减压浓缩，残留物分别经硅胶柱(二氯甲烷:甲醇＝98:2)和C18柱(乙腈：水＝50:50)进行分离纯化，得到化合物12(65mg)。1H NMR(500MHz,MeOD)δ8.11(d,J＝2.5Hz,1H),7.38(dd,J＝80,10Hz,1H),7.31(d,J＝10Hz,1H),6.48(dd,J＝17.5,11.2Hz,1H),5.98(s,1H),4.85–4.70(m,1H),4.71-4.65(m,4H),4.48–4.36(m,1H),3.75(s,3H),3.47-3.43(m,1H),3.1-2.97(m,1H),2.3-2.21(m,2H),2.08-2.05(m,2H),1.72-1.64(m,2H),1.44-1.36(m,2H),1.47–1.17(m,6H).HRMS(ESI)calculated for C28H34FN5O5S2([M+H]+)m/z:604.2064,found 604.2057. Add intermediate 1-C (100mg), potassium acetate (36.1mg), intermediate 2-B (26.0mg), BrettPhos Pd G3 (25.0mg) and tetrahydrofuran (4mL) in sequence to the microwave tube, and microwave under nitrogen protection. React at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was separated through a silica gel column (dichloromethane: methanol = 98:2) and a C 18 column (acetonitrile: water = 50:50). Purification gave compound 12 (65 mg). 1 H NMR (500MHz, MeOD) δ8.11(d,J＝2.5Hz,1H),7.38(dd,J＝80,10Hz,1H),7.31(d,J＝10Hz,1H),6.48(dd, J＝17.5,11.2Hz,1H),5.98(s,1H),4.85–4.70(m,1H),4.71-4.65(m,4H),4.48–4.36(m,1H),3.75(s,3H) ,3.47-3.43(m,1H),3.1-2.97(m,1H),2.3-2.21(m,2H),2.08-2.05(m,2H),1.72-1.64(m,2H),1.44-1.36( m,2H),1.47–1.17(m,6H).HRMS(ESI)calculated for C 28 H 34 FN 5 O 5 S 2 ([M+H] + )m/z:604.2064,found 604.2057.
实施例13
Example 13
将中间体1-C(150.00mg)、中间体2-C(44.80mg)、1,4-二氧六环(5mL)、乙酸钾(81.00mg)和BrettPhos Pd G3(37.50mg)的混合物在氮气氛围下，通过微波加热至100℃反应3小时。反应液真空浓缩，残留物经硅胶柱层析分离纯化(二氯甲烷:甲醇＝96.3:3.7)，得到化合物13(49.00mg)。1H NMR(500MHz,DMSO-d6)δ9.33(s,1H),8.05(d,J＝2.5Hz,1H),7.79–7.69(m,1H),7.63(s,1H),7.36(d,J＝8.5Hz,1H),7.02(d,J＝7.8Hz,1H),5.93(s,1H),5.44(t,J＝2.4Hz,1H),5.13(d,J＝2.1Hz,1H),4.79–4.69(m,1H),4.68–4.58(m,2H),4.56–4.46(m,3H),4.18(t,J＝6.6Hz,2H),3.31(d,J＝16.6Hz,1H),3.23–3.13(m,2H),2.97–2.87(m,1H),2.17–2.10(m,2H),1.97–1.87(m,2H),1.62–1.52(m,2H),1.40–1.28(m,2H),1.17(d,J＝6.2Hz,6H).HRMS(ESI)calculated for C29H35N5O5S2([M+H]+)m/z:598.2158,found:598.2159.A mixture of Intermediate 1-C (150.00mg), Intermediate 2-C (44.80mg), 1,4-dioxane (5mL), potassium acetate (81.00mg) and BrettPhos Pd G3 (37.50mg) was dissolved in Under a nitrogen atmosphere, the reaction was heated to 100°C by microwave for 3 hours. The reaction solution was concentrated in vacuo, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol=96.3:3.7) to obtain compound 13 (49.00 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ9.33 (s, 1H), 8.05 (d, J = 2.5Hz, 1H), 7.79–7.69 (m, 1H), 7.63 (s, 1H), 7.36 ( d,J＝8.5Hz,1H),7.02(d,J＝7.8Hz,1H),5.93(s,1H),5.44(t,J＝2.4Hz,1H),5.13(d,J＝2.1Hz, 1H),4.79–4.69(m,1H),4.68–4.58(m,2H),4.56–4.46(m,3H),4.18(t,J＝6.6Hz,2H),3.31(d,J＝16.6Hz ,1H),3.23–3.13(m,2H),2.97–2.87(m,1H),2.17–2.10(m,2H),1.97–1.87(m,2H),1.62–1.52(m,2H),1.40 –1.28(m,2H),1.17(d,J＝6.2Hz,6H).HRMS(ESI)calculated for C 29 H 35 N 5 O 5 S 2 ([M+H] + )m/z:598.2158, found:598.2159.
实施例14
Example 14
向单口瓶中，依次加入中间体1-D(140mg)，中间体2-A(40.9mg)，醋酸钾(81mg)，BrettPhos Pd G3(25.06mg,0.028mmol)和1,4-二氧六环(10mL)，氮气氛围下，100℃反应3小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1)得到化合物14(80mg)。1H NMR(500MHz,DMSO-d6)δ8.22(s,1H),7.73(s,1H),7.66(s,1H),7.59-7.52(m,1H),7.42(d,J＝8.0Hz,2H),7.27-7.18(m,1H),7.01(d,J＝7.5Hz,1H),6.97-6.88(m,1H),6.10-5.95(m,1H),5.25-5.19(m,1H),5.18-5.09(m,1H),4.80-4.71(m,3H),3.32-3.26(m,1H),2.93-2.82(m,1H),2.22-2.16(m,1H),2.16-2.06(m,2H),1.96-1.87(m,2H),1.61-1.51(m,2H),1.36-1.29(m,2H),1.16(d,J＝6.1Hz,6H),0.49-0.39(m,2H),0.35-0.27(m,2H).HRMS(ESI)calculated for C28H37N6O4S2([M+H]+)m/z:585.2312,found:585.2318.To the single-neck bottle, add Intermediate 1-D (140mg), Intermediate 2-A (40.9mg), potassium acetate (81mg), BrettPhos Pd G3 (25.06mg, 0.028mmol) and 1,4-dioxane in sequence. Ring (10 mL), react at 100°C for 3 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain compound 14 (80 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ8.22 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.59-7.52 (m, 1H), 7.42 (d, J = 8.0 Hz,2H),7.27-7.18(m,1H),7.01(d,J＝7.5Hz,1H),6.97-6.88(m,1H),6.10-5.95(m,1H),5.25-5.19(m, 1H),5.18-5.09(m,1H),4.80-4.71(m,3H),3.32-3.26(m,1H),2.93-2.82(m,1H),2.22-2.16(m,1H),2.16- 2.06(m,2H),1.96-1.87(m,2H),1.61-1.51(m,2H),1.36-1.29(m,2H),1.16(d,J＝6.1Hz,6H),0.49-0.39( m,2H),0.35-0.27(m,2H).HRMS(ESI)calculated for C 28 H 37 N 6 O 4 S 2 ([M+H]+)m/z:585.2312,found:585.2318.
实施例15
Example 15
向微波管中，依次加入中间体1-B(100mg)，1,4-二氧六环(6mL)，乙酸钾(37.2mg)和BrettPhos Pd G3(17.19mg)和中间体2-J(38.5mg)，混合物在氮气氛围下，加热至100℃反应3小时。反应结束，将反应液减压浓缩，所得粗品用硅胶柱层析分离纯化，得到化合物15(70mg)。1H-NMR(500MHz,DMSO-d6)δ9.13(s,1H),7.89(d,J＝2.5Hz,1H),7.66(s,1H),7.51-7.47(m,1H),7.38-7.37(m,1H),7.00(d,J＝7.5Hz,1H),5.57-5.52(m,1H),4.78-4.71(m,1H),4.44-4.40(m,2H),3.76(s,3H),3.31-3.27(m,1H),2.96-2.87(m,1H),2.50-2.43(m,1H),2.17-2.10(m,2H),1.95-1.88(m,2H),1.62-1.51(m,2H),1.38-1.28(m,2H),1.16(d,J＝6.5Hz,6H),1.00-0.94(m,2H),0.91-0.85(m,2H).HRMS(ESI)m/z:616.2063([M+H]+).To the microwave tube, add intermediate 1-B (100mg), 1,4-dioxane (6mL), potassium acetate (37.2mg) and BrettPhos Pd G3 (17.19mg) and intermediate 2-J (38.5 mg), the mixture was heated to 100°C for 3 hours in a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain compound 15 (70 mg). 1 H-NMR (500MHz, DMSO-d 6 ) δ9.13 (s, 1H), 7.89 (d, J = 2.5Hz, 1H), 7.66 (s, 1H), 7.51-7.47 (m, 1H), 7.38 -7.37(m,1H),7.00(d,J＝7.5Hz,1H),5.57-5.52(m,1H),4.78-4.71(m,1H),4.44-4.40(m,2H),3.76(s ,3H),3.31-3.27(m,1H),2.96-2.87(m,1H),2.50-2.43(m,1H),2.17-2.10(m,2H),1.95-1.88(m,2H),1.62 -1.51(m,2H),1.38-1.28(m,2H),1.16(d,J＝6.5Hz,6H),1.00-0.94(m,2H),0.91-0.85(m,2H).HRMS(ESI )m/z:616.2063([M+H] + ).
实施例16
Example 16
向单口瓶中，依次加入中间体1-B(100mg)，中间体2-K(94mg)，1,4-二氧六环(3mL)、乙酸钾(37.2mg)和BrettPhos Pd G3(17.19mg)，加毕通入氮气置换后，加热至100℃反应2小时。反应结束，将反应液直接减压浓缩，残留物以硅胶柱分离纯化，得到化合物16(51mg)。1H NMR(500MHz,DMSO-d6)δ8.65(s,1H),7.95(d,J＝2.5Hz,1H),7.66(s,2H),7.35(d,J＝8.4Hz,1H),7.02(d,J＝7.8Hz,1H),5.47(t,J＝6.0Hz,1H),4.79–4.69(m,1H),4.40(d,J＝6.0Hz,2H),3.76(s,3H),3.30(t,J＝5.8Hz,1H),2.97–2.87(m,1H),2.44–2.34(m,1H),2.17–2.11(m,2H),1.99(s,3H),1.96–1.86(m,2H),1.62–1.52(m,2H),1.38–1.30(m,2H),1.16(d,J＝6.2Hz,6H),1.01–0.91(m,2H),0.93–0.83(m,2H).MS(ESI)m/z：612.23[M+H]+.To the single-neck bottle, add Intermediate 1-B (100mg), Intermediate 2-K (94mg), 1,4-dioxane (3mL), potassium acetate (37.2mg) and BrettPhos Pd G3 (17.19mg) in sequence. ), after adding nitrogen for replacement, heat to 100°C and react for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified on a silica gel column to obtain compound 16 (51 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ8.65 (s, 1H), 7.95 (d, J = 2.5Hz, 1H), 7.66 (s, 2H), 7.35 (d, J = 8.4Hz, 1H) ,7.02(d,J＝7.8Hz,1H),5.47(t,J＝6.0Hz,1H),4.79–4.69(m,1H),4.40(d,J＝6.0Hz,2H),3.76(s, 3H),3.30(t,J＝5.8Hz,1H),2.97–2.87(m,1H),2.44–2.34(m,1H),2.17–2.11(m,2H),1.99(s,3H),1.96 –1.86(m,2H),1.62–1.52(m,2H),1.38–1.30(m,2H),1.16(d,J＝6.2Hz,6H),1.01–0.91(m,2H),0.93–0.83 (m,2H).MS(ESI)m/z: 612.23[M+H] + .
实施例17
Example 17
向三口瓶中，依次加入中间体1-B(100mg)、中间体2-L(42.6mg)，1,4-二氧六环(5mL)和醋酸钾(37.2mg)、BrettPhos Pd G3(17.19mg)，混合物在氮气保护下于100℃搅拌反应2小时。反应结束，将反应液直接减压浓缩，残留物分别用硅胶柱、C18(40g)柱分离纯化，得到化合物17(60mg)。1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.09(d,J＝2.4Hz,1H),7.86–7.60(m,3H),7.46(d,J＝8.4Hz,1H),7.02(d,J＝7.7Hz,1H),6.37(s,1H),5.52(t,J＝6.0Hz,1H),4.77-4.72(m,1H),4.39(d,J＝6.0Hz,2H),3.32-3.30(m,1H),2.93(tt,J＝11.8,3.5Hz,1H),2.47–2.41(m,1H),2.15-2.13(m,2H),1.93-1.91(m,2H),1.60-1.53(m,2H),1.38-1.30(m,2H),1.17(d,J＝6.2Hz,6H),1.02–0.96(m,2H),0.93–0.88(m,2H).HRMS(ESI)m/z:634.1973[M+H]+.To the three-necked flask, add Intermediate 1-B (100mg), Intermediate 2-L (42.6mg), 1,4-dioxane (5mL) and potassium acetate (37.2mg), BrettPhos Pd G3 (17.19 mg), the mixture was stirred and reacted at 100°C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified using a silica gel column and a C18 (40g) column to obtain compound 17 (60 mg). 1 H NMR (500MHz, DMSO-d 6 ) δ9.72 (s, 1H), 8.09 (d, J = 2.4Hz, 1H), 7.86–7.60 (m, 3H), 7.46 (d, J = 8.4Hz, 1H),7.02(d,J＝7.7Hz,1H),6.37(s,1H),5.52(t,J＝6.0Hz,1H),4.77-4.72(m,1H),4.39(d,J＝6.0 Hz,2H),3.32-3.30(m,1H),2.93(tt,J＝11.8,3.5Hz,1H),2.47–2.41(m,1H),2.15-2.13(m,2H),1.93-1.91( m,2H),1.60-1.53(m,2H),1.38-1.30(m,2H),1.17(d,J＝6.2Hz,6H),1.02–0.96(m,2H),0.93–0.88(m, 2H).HRMS(ESI)m/z:634.1973[M+H] + .
试验例1.体外细胞增殖抑制活性Test Example 1. In vitro cell proliferation inhibitory activity
1.1 Daudi细胞增殖抑制活性测定1.1 Determination of Daudi cell proliferation inhibitory activity
取处于生长状态良好的Daudi细胞，收集至离心管，调整细胞密度至5×104个/mL，接种于96孔板上(100μL/孔)，同时使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-4.57nM，2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入检测试剂CCK-8(厂家：北京同仁化学，10μL/孔)，细胞培养箱中孵育4小时后，PerkinElmer Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。试验结果见表1。Take Daudi cells that are in good growth status and collect them into centrifuge tubes. Adjust the cell density to 5×10 4 cells/mL and inoculate them on a 96-well plate (100 μL/well). At the same time, use a nanoliter sampler to add compounds. Make the final concentration of the compound 10000nM-4.57nM, 2 duplicate wells, and set controls at the same time. After continuing to culture in the cell culture incubator for 72 hours, add the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well). After incubating in the cell culture incubator for 4 hours, detect the absorbance value at 450 nm with a PerkinElmer Envision microplate reader. Parameter analysis, dose-response curve fitting, and IC 50 calculation. The test results are shown in Table 1.
1.2 WI38-VA13细胞增殖抑制活性测定1.2 Determination of WI38-VA13 cell proliferation inhibitory activity
取处于生长状态良好的WI38-VA13细胞，收集至离心管，调整细胞密度至4×104个/mL，接种于96孔板上(100μL/孔)，同时使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-4.57nM，2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入检测试剂CCK-8(厂家：北京同仁化学，10μL/孔)，细胞培养箱中孵育2小时后，PerkinElmer Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。试验结果见表1。Take WI38-VA13 cells that are in good growth status, collect them in centrifuge tubes, adjust the cell density to 4×10 4 cells/mL, inoculate them on a 96-well plate (100 μL/well), and use a nanoliter sampler to add compounds. In the same way, the final concentration of the compound is 10000nM-4.57nM, 2 duplicate wells, and controls are set at the same time. After continuing to culture in the cell culture incubator for 72 hours, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well). After incubating in the cell culture incubator for 2 hours, detect the absorbance value at 450 nm with a PerkinElmer Envision microplate reader. Parameter analysis, dose-response curve fitting, and IC 50 calculation. The test results are shown in Table 1.
对于Daudi细胞，A表示IC50＜0.1μM；对于WI38-VA13细胞，+表示＞2μM。For Daudi cells, A indicates IC50 <0.1 μM; for WI38-VA13 cells, + indicates >2 μM.
表1化合物细胞增殖抑制活性结果

Table 1 Compound cell proliferation inhibitory activity results

本公开的化合物具有改善的或优异的Daudi细胞抑制活性；且相较于WI38-VA13细胞，对Daudi细胞具有选择性抑制活性。The compounds of the present disclosure have improved or excellent inhibitory activity on Daudi cells; and compared with WI38-VA13 cells, they have selective inhibitory activity on Daudi cells.
试验例2.体外肝微粒体代谢稳定性Test Example 2. Metabolic stability of liver microsomes in vitro
肝微粒体温孵样本(人、猴、犬、大鼠及小鼠)制备为混合PBS缓冲液(pH＝7.4)，肝微粒体溶液(0.5mg/mL)，受试化合物及NADPH+MgCl2溶液于37℃及300rpm孵育1小时。0小时样本制备为混合PBS缓冲液(pH＝7.4)，肝微粒体溶液(0.5mg/mL)，受试化合物。样本加入含内标的乙腈溶液经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定。Liver microsome body temperature incubation samples (human, monkey, dog, rat and mouse) were prepared as a mixture of PBS buffer (pH=7.4), liver microsome solution (0.5mg/mL), test compound and NADPH+ MgCl2 solution Incubate at 37°C and 300rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH=7.4), liver microsome solution (0.5 mg/mL), and test compound. The sample was added to an acetonitrile solution containing an internal standard and subjected to protein precipitation to prepare a supernatant, which was diluted and used for LC/MS/MS measurement.
试验结果表明，本公开测试化合物体外代谢稳定(例如60min剩余量较多)，人和/或小鼠肝微粒代谢中60min剩余量超过50％。The test results show that the test compound of the present disclosure has stable metabolism in vitro (for example, the remaining amount is relatively large in 60 minutes), and the remaining amount in 60 minutes in the metabolism of human and/or mouse liver microparticles exceeds 50%.
试验例3.小鼠药代动力学Test Example 3. Mouse pharmacokinetics
ICR小鼠，体重18～22g，适应3～5天后，随机分组，每组9只，按10mg/kg剂量灌胃受试化合物溶液。ICR mice, weighing 18 to 22 g, were randomly divided into groups of 9 after adapting for 3 to 5 days, and the test compound solution was orally administered at a dose of 10 mg/kg.
采血时间点15min、0.5h、1h、2h、3h、4h、6h、8h、10h、24h，于眼眶取血制备待测血浆样品。Blood collection time points are 15min, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, and 24h. Blood is collected from the orbit to prepare plasma samples to be tested.
吸取30μL待测血浆样品和标曲样品，加入含内标的乙腈溶液经蛋白沉淀得到上清液，稀释后用于LC/MS/MS测定。Take 30 μL of the plasma sample to be tested and the standard sample, add acetonitrile solution containing the internal standard, undergo protein precipitation to obtain the supernatant, and dilute it for LC/MS/MS measurement.
采用非房室模型拟合药代参数。Noncompartmental models were used to fit pharmacokinetic parameters.
表2化合物小鼠药代动力学试验结果
Table 2 Compound mouse pharmacokinetic test results
试验结果表明，本公开的化合物在药代动力学试验中显示出良好的性质，包括但不限于生物利用度、AUC、Cmax、t1/2、Tmax等方面的优势。 The test results show that the compounds of the present disclosure show good properties in pharmacokinetic tests, including but not limited to advantages in bioavailability, AUC, C max , t 1/2 , T max and other aspects.

Claims (21)

  1. 式I化合物、其立体异构体或其药学上可接受的盐，
    A compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof,
    其中，in,
    R1选自3-10元杂环烷基、5-6元杂芳基、8-15元杂环基、苯基、3-10元环烷基、C2-10烯基或C2-10炔基；R 1 is selected from 3-10 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-15 membered heterocyclyl, phenyl, 3-10 membered cycloalkyl, C 2-10 alkenyl or C 2- 10 alkynyl;
    所述3-10元杂环烷基或5-6元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 3-10-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
    所述8-15元杂环基、苯基或3-10元环烷基任选地被一个或多个Rc取代；The 8-15-membered heterocyclyl, phenyl or 3-10-membered cycloalkyl is optionally substituted by one or more R c ;
    所述C2-10烯基或C2-10炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；The C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogens, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
    Ra选自氘代C1-6烷基、C2-10烯基、C2-10炔基、-C1-3烷基-CON(C1-6烷基)2，所述氘代C1-6烷基、C2-10烯基、C2-10炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R a is selected from deuterated C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, -C 1-3 alkyl-CON(C 1-6 alkyl) 2 , the deuterated C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl are optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1- 3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
    Rb选自卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)、-N(C1-3烷基)2、C1-6烷基、C3-6环烷基或者卤代C1-6烷基；R b is selected from halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl or halo C 1-6 alkyl;
    Rc选自C1-6烷基、C2-10烯基、C2-10炔基、氧代、卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2，所述C2-10烯基或C2-10炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R c is selected from C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, oxo, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH (C 1-3 alkyl) Or -N(C 1-3 alkyl) 2 , the C 2-10 alkenyl or C 2-10 alkynyl group is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2. -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 substitution;
    Rd及Re分别独立地选自H、卤素、CN或C1-6烷基；R d and R e are independently selected from H, halogen, CN or C 1-6 alkyl;
    L选自键或NRf；L is selected from bond or NR f ;
    R2选自C1-6烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、C3-6环烷基或3-6元杂环烷基任选地被一个或多个OH、OC1-3烷基、卤素、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R 2 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
    X1及X2分别独立地选自NRg或O；X 1 and X 2 are independently selected from NR g or O;
    Y选自CH2、N或O；Y is selected from CH 2 , N or O;
    Rf及Rg分别独立地选自H或C1-3烷基；R f and R g are independently selected from H or C 1-3 alkyl;
    R3选自C1-6烷基、C3-6环烷基或3-6元杂环烷基，所述C1-6烷基、C3-6环烷基或3-6元杂环烷基任选地被一个或多个OH、OC1-3烷基、卤素、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代；R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl Cycloalkyl is optionally substituted with one or more OH, OC 1-3 alkyl, halogen, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
    R4及R5分别独立地选自H、OH、卤素、CN、NH2、C1-6烷基或C1-6烷氧基取代。R 4 and R 5 are each independently selected from H, OH, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substitution.
  2. 如权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐，所述R1选自3-8元杂环烷基、5-6元杂芳基、8-13元杂环基、苯基、3-8元环烷基、C2-8烯基或C2-8炔基；The compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said R1 is selected from the group consisting of 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, 8- 13-membered heterocyclyl, phenyl, 3-8-membered cycloalkyl, C 2-8 alkenyl or C 2-8 alkynyl;
    所述3-8元杂环烷基或5-6元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 3-8-membered heterocycloalkyl or 5-6-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
    所述8-13元杂环基、苯基或3-8元环烷基任选地被一个或多个Rc取代；The 8-13-membered heterocyclyl, phenyl or 3-8-membered cycloalkyl is optionally substituted by one or more R c ;
    所述C2-8烯基或C2-8炔基任选地被一个或多个卤素或OH取代；The C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens or OH;
    或者，所述R1选自4-6元杂环烷基、5-6元杂芳基、8-11元杂环基、苯基、4-6元环烷基、C3-6烯基或C3-6炔基；Or, the R 1 is selected from 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-11 membered heterocyclyl, phenyl, 4-6 membered cycloalkyl, C 3-6 alkenyl or C 3-6 alkynyl;
    所述4-6元杂环烷基或5-6元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
    所述8-11元杂环基、苯基或4-6元环烷基任选地被一个或多个Rc取代；The 8-11 membered heterocyclyl, phenyl or 4-6 membered cycloalkyl is optionally substituted by one or more R c ;
    或者，所述R1选自5元杂芳基、8元杂环基、10元杂环基、11元杂环基或C4-5炔基； Alternatively, the R 1 is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl, 11-membered heterocyclyl or C 4-5 alkynyl;
    所述5元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
    所述8元杂环基、10元杂环基或11元杂环基任选地被一个或多个Rc取代；The 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c ;
    或者，所述R1选自5元杂芳基、含有稠合环的8元杂环基、含有稠合环及螺环的10元杂环基、含有稠合环及螺环的11元杂环基或C4-5炔基；Alternatively, the R 1 is selected from a 5-membered heteroaryl group, an 8-membered heterocyclic group containing a fused ring, a 10-membered heterocyclic group containing a fused ring and a spiro ring, an 11-membered heterocyclic group containing a fused ring and a spiro ring. Cyclic group or C 4-5 alkynyl group;
    所述5元杂芳基被一个或多个Ra取代，任选地被一个或多个Rb取代；The 5-membered heteroaryl is substituted by one or more R a , optionally substituted by one or more R b ;
    所述8元杂环基、10元杂环基或11元杂环基任选地被一个或多个Rc取代；The 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl is optionally substituted by one or more R c ;
    或者，所述R1选自吡唑基、咪唑基、***基、5,6-二氢-4H-吡咯并[1,2-b]吡唑基、6,7-二氢-5H-吡咯并[1,2-b][1,2,4]***基、5',6'-二氢螺环[环丙烷-1,4'-吡咯并[1,2-b]吡唑]基、6',7'-二氢螺[环丙烷-1,4'-吡唑并[5,1-c][1,4]噁嗪]基、4'H,6'H-螺[环丙烷-1,5'-吡咯并[1,2-b]吡唑]基、戊-3-炔-2-基或丁-2-炔-1-基，Or, the R 1 is selected from pyrazolyl, imidazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H- Pyrro[1,2-b][1,2,4]triazolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-b]pyrazole ] group, 6',7'-dihydrospiro[cyclopropane-1,4'-pyrazolo[5,1-c][1,4]oxazine] group, 4'H,6'H-spiro [Cyclopropan-1,5'-pyrrolo[1,2-b]pyrazol]yl, pent-3-yn-2-yl or but-2-yn-1-yl,
    所述吡唑基、咪唑基或***基被一个或多个Ra取代，任选地被一个或多个Rb取代；The pyrazolyl, imidazolyl or triazolyl group is substituted by one or more R a , optionally substituted by one or more R b ;
    所述5,6-二氢-4H-吡咯并[1,2-b]吡唑基、6,7-二氢-5H-吡咯并[1,2-b][1,2,4]***基、5',6'-二氢螺环[环丙烷-1,4'-吡咯并[1,2-b]吡唑]基、6',7'-二氢螺[环丙烷-1,4'-吡唑并[5,1-c][1,4]噁嗪]基、4'H,6'H-螺[环丙烷-1,5'-吡咯并[1,2-b]吡唑]基任选地被一个或多个Rc取代；The 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]tri Azolyl, 5',6'-dihydrospiro[cyclopropane-1,4'-pyrrolo[1,2-b]pyrazol]yl, 6',7'-dihydrospiro[cyclopropane-1 ,4'-pyrazolo[5,1-c][1,4]oxazin]yl, 4'H,6'H-spiro[cyclopropane-1,5'-pyrrolo[1,2-b ]pyrazol] group is optionally substituted by one or more R c ;
    或者，所述R1选自 Alternatively, the R 1 is selected from
    所述被一个或多个Ra取代，任选地被一个或多个Rb取代；described Substituted by one or more Ra , optionally substituted by one or more Rb ;
    所述任选地被一个或多个Rc取代；described optionally substituted by one or more Rc ;
    或者，所述R1选自 Alternatively, the R 1 is selected from
    所述被一个或多个Ra取代，任选地被一个或多个Rb取代；described Substituted by one or more Ra , optionally substituted by one or more Rb ;
    所述任选地被一个或多个Rc取代；described optionally substituted by one or more Rc ;
    任选地，上述杂环烷基、杂芳基或杂环基的杂原子选自氮、氧或硫；Optionally, the heteroatom of the above-mentioned heterocycloalkyl, heteroaryl or heterocyclic group is selected from nitrogen, oxygen or sulfur;
    或者，所述杂环基的杂原子选自氮或氧； Alternatively, the heteroatom of the heterocyclyl group is selected from nitrogen or oxygen;
    任选地，所述杂原子的个数可以选自1、2、3、4、5或6个；Optionally, the number of heteroatoms can be selected from 1, 2, 3, 4, 5 or 6;
    或者，杂原子的个数选自2、3或4个，或者杂原子的个数选自2或3个；Alternatively, the number of heteroatoms is selected from 2, 3 or 4, or the number of heteroatoms is selected from 2 or 3;
    或者，所述杂环基至少包含2个杂原子，选自氮或氧；Alternatively, the heterocyclyl group contains at least 2 heteroatoms selected from nitrogen or oxygen;
    或者，所述杂环基的杂原子为2个氮原子、或者3个氮原子、或者2个氮原子及其1个氧原子；Alternatively, the heteroatoms of the heterocyclic group are 2 nitrogen atoms, or 3 nitrogen atoms, or 2 nitrogen atoms and 1 oxygen atom;
    任选地，所述杂环基可以是单环、双环或三环；Optionally, the heterocyclyl group may be monocyclic, bicyclic or tricyclic;
    或者，所述杂环基选自双环或三环；Alternatively, the heterocyclyl group is selected from bicyclic or tricyclic rings;
    或者，所述双环或三环之间可以通过稠合环、桥环或螺环形式连接；Alternatively, the bicyclic or tricyclic rings can be connected through fused rings, bridged rings or spiro rings;
    或者，所述杂环基选自双环或三环，所述双环通过稠合环方式连接，所述三环通过螺环和稠合环方式连接；或者，所述杂环基选自双环或三环，所述双环或三环中有一个环选自杂芳环或芳香环；Alternatively, the heterocyclyl group is selected from a bicyclic ring or a tricyclic ring, the bicyclic ring is connected through a fused ring, and the tricyclic ring is connected through a spiro ring and a fused ring mode; or the heterocyclyl group is selected from a bicyclic ring or a tricyclic ring. Ring, one of the bicyclic or tricyclic rings is selected from a heteroaromatic ring or an aromatic ring;
    任选地，所述杂环基选自双环或三环，其中与NH部位直接连接的环是芳香环或杂芳环；Optionally, the heterocyclyl group is selected from bicyclic or tricyclic rings, in which the ring directly connected to the NH site is an aromatic ring or a heteroaromatic ring;
    或者，其中杂环基选自5元环稠合5元环、3元环螺6元环稠合5元环、或3元环螺5元环稠合5元环；Alternatively, the heterocyclyl group is selected from a 5-membered ring fused to a 5-membered ring, a 3-membered spiro 6-membered ring fused to a 5-membered ring, or a 3-membered spiro 5-membered ring fused to a 5-membered ring;
    或者，所述R1选自 Alternatively, the R 1 is selected from
    或者，所述R1选自 Alternatively, the R 1 is selected from
  3. 如权利要求1或2所述的式I化合物、其立体异构体或其药学上可接受的盐，所述Ra选自氘代C1-4烷基、C2-8烯基、C2-8炔基、-C1-3烷基-CON(C1-3烷基)2，所述氘代C1-4烷基、C2-8烯基、C2-8炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt as claimed in claim 1 or 2, wherein the R a is selected from the group consisting of deuterated C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, -C 1-3 alkyl-CON(C 1-3 alkyl) 2 , the deuterated C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl is optional Optionally substituted by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 ;
    或者，Ra选自氘代C1-3烷基、C2-6烯基、C2-6炔基、-C1-2烷基-CON(C1-3烷基)2，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-2烷基、CN、NH2、-NH(C1-2烷基)或-N(C1-2烷基)2取代；Alternatively, R a is selected from deuterated C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-2 alkyl-CON(C 1-3 alkyl) 2 , said C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogens, OH, OC 1-2 alkyl, CN, NH 2 , -NH (C 1-2 alkyl) or -N (C 1-2 alkyl) 2 substitution;
    或者，Ra选自氘代C1-3烷基、C2-4烯基、C2-4炔基、-CH2CON(C1-2烷基)2，所述C2-4烯基或C2-4炔基任选地被一个或多个氟、氯、溴或OH取代；Alternatively, R a is selected from deuterated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CH 2 CON (C 1-2 alkyl) 2 , the C 2-4 alkyl The base or C 2-4 alkynyl group is optionally substituted by one or more fluorine, chlorine, bromine or OH;
    或者，Ra选自氘代甲基、乙烯基、丙烯基、乙炔基、丙炔基、-CH2CON(CH3)2，所述乙烯基、丙烯基、乙炔基或丙炔基任选地被一个或多个氟或OH取代；Alternatively, R a is selected from deuterated methyl, vinyl, propenyl, ethynyl, propynyl, -CH 2 CON (CH 3 ) 2 , the vinyl, propenyl, ethynyl or propynyl optionally Ground is replaced by one or more fluorine or OH;
    或者，Ra选自任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2取代的 Alternatively, R a is selected from optionally modified by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl ) 2 replaced
    或者，Ra选自氘代甲基、 Alternatively, R a is selected from deuterated methyl,
  4. 如权利要求1-3任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，Rb选自卤素、OH、CN、NH2、C1-3烷基、C3-4环烷基或者卤代C1-3烷基；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-3, R b is selected from halogen, OH, CN, NH 2 , C 1-3 alkyl, C 3-4 cycloalkyl or halo C 1-3 alkyl;
    或者，Rb选自氟、氯、溴、C1-3烷基、C3-4环烷基或者卤代C1-3烷基；Alternatively, R b is selected from fluorine, chlorine, bromine, C 1-3 alkyl, C 3-4 cycloalkyl or halo C 1-3 alkyl;
    或者，Rb选自氟、氯、甲基、环丙基或-CHF2。Alternatively, R b is selected from fluorine, chlorine, methyl, cyclopropyl or -CHF 2 .
  5. 如权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，Rc选自C1-4烷基、C2-8烯基、C2-8炔基、卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2，所述C2-8烯基或C2-8炔基任选地被一个或多个卤素、OH、CN或NH2取代；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-4, R c is selected from C 1-4 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-8 alkenyl or C 2-8 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 ;
    或者，Rc选自C1-3烷基、C2-6烯基、C2-6炔基、卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、CN或NH2取代；Alternatively, R c is selected from C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl) or N (C 1-3 alkyl) 2 , the C 2-6 alkenyl or C 2-6 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 ;
    或者，Rc选自C1-3烷基、C2-4烯基、C2-4炔基、卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3 烷基)或N(C1-3烷基)2，所述C2-4烯基或C2-4炔基任选地被一个或多个卤素、OH、CN或NH2取代；Alternatively, R c is selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 Alkyl) or N(C 1-3 alkyl) 2 , the C 2-4 alkenyl or C 2-4 alkynyl group is optionally substituted by one or more halogens, OH, CN or NH 2 ;
    或者，Rc选自C2-4烯基、C2-4炔基、卤素、OH、CN或NH2，所述C2-4烯基、C2-4炔基任选地被一个或多个卤素、OH、CN或NH2取代；Alternatively, R c is selected from C 2-4 alkenyl, C 2-4 alkynyl, halogen, OH, CN or NH 2 , the C 2-4 alkenyl, C 2-4 alkynyl is optionally replaced by one or more halogen, OH, CN or NH 2 substitution;
    或者，Rc选自卤素、OH、CN或NH2；Alternatively, R c is selected from Halogen, OH, CN or NH 2 ;
    或者，Rc选自氟、氯或溴；Alternatively, R c is selected from Fluorine, chlorine or bromine;
    或者，Rc选自或氟。Alternatively, R c is selected from Or fluorine.
  6. 如权利要求1-5任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，Rd及Re分别独立地选自氢、卤素、CN或C1-3烷基；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-5, Rd and Re are independently selected from hydrogen, halogen, CN or C 1-3 alkyl;
    或者，Rd及Re分别独立地选自氢、氟、氯、CN或甲基；Alternatively, R d and R e are each independently selected from hydrogen, fluorine, chlorine, CN or methyl;
    或者，Rd及Re为氢。Alternatively, R d and Re are hydrogen.
  7. 如权利要求1-6任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，L选自键或NH；或者，L选自键。The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 6, L is selected from a bond or NH; alternatively, L is selected from a bond.
  8. 如权利要求1-7任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，R2选自C1-3烷基、C3-5环烷基或3-5元杂环烷基，所述C1-3烷基、C3-5环烷基或3-5元杂环烷基任选地被一个或多个OH、卤素、CN、NH2或C1-3烷氧基取代；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-7, R2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl or 3 -5-membered heterocycloalkyl, the C 1-3 alkyl, C 3-5 cycloalkyl or 3-5-membered heterocycloalkyl is optionally replaced by one or more OH, halogen, CN, NH 2 or C 1-3 alkoxy substitution;
    或者，R2选自C1-3烷基、C3-5环烷基或4元杂环烷基，所述C1-3烷基、C3-5环烷基或4元杂环烷基任选地被一个或多个OH、卤素、CN或NH2取代；Alternatively, R 2 is selected from C 1-3 alkyl, C 3-5 cycloalkyl or 4-membered heterocycloalkyl, said C 1-3 alkyl, C 3-5 cycloalkyl or 4-membered heterocycloalkyl The radical is optionally substituted by one or more OH, halogen, CN or NH;
    或者，R2选自乙基、环丙基、双环戊基或4元杂环烷基，所述乙基、环丙基、双环戊基或4元杂环烷基任选地被一个或多个氟、氯或溴取代；Alternatively, R 2 is selected from ethyl, cyclopropyl, dicyclopentyl or 4-membered heterocycloalkyl, which is optionally replaced by one or more A fluorine, chlorine or bromine substitution;
    或者，R2选自乙基、环丙基、双环戊基或含有1个选自N或O的杂原子的4元杂环烷基，所述乙基、环丙基、双环戊基或杂环烷基任选地被一个或多个氟、氯或溴取代；Alternatively, R 2 is selected from ethyl, cyclopropyl, dicyclopentyl or a 4-membered heterocycloalkyl containing 1 heteroatom selected from N or O. The ethyl, cyclopropyl, dicyclopentyl or hetero Cycloalkyl is optionally substituted with one or more fluorine, chlorine or bromine;
    或者，R2选自乙基、双环戊基、氧杂环丁基或任选地被一个或多个氟取代的环丙基；Alternatively, R 2 is selected from ethyl, dicyclopentyl, oxetanyl or cyclopropyl optionally substituted by one or more fluorine;
    或者，R2选自乙基、 Alternatively, R 2 is selected from ethyl,
  9. 如权利要求1-8任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，X1及X2分别独立地选自NH或O；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 8, X 1 and X 2 are independently selected from NH or O;
    或者，X1选自NH，X2选自O。Alternatively, X 1 is selected from NH and X 2 is selected from O.
  10. 如权利要求1-9任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，Y选自CH2或O；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 9, Y is selected from CH 2 or O;
    或者，Y选自CH2。Alternatively, Y is selected from CH2 .
  11. 如权利要求1-10任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，Rf及Rg分别独立地选自H或甲基；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 10, R f and R g are independently selected from H or methyl;
    或者，Rf及Rg为H。Alternatively, R f and R g are H.
  12. 如权利要求1-11任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，R3选自C1-4烷基、C3-5环烷基或3-5元杂环烷基，所述C1-4烷基、C3-5环烷基或3-5元杂环烷基任选地被一个或多个OH、卤素、CN、NH2或C1-3烷氧基取代；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-11, R 3 is selected from C 1-4 alkyl, C 3-5 cycloalkyl or 3 -5-membered heterocycloalkyl, the C 1-4 alkyl, C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl is optionally replaced by one or more OH, halogen, CN, NH 2 or C 1-3 alkoxy substitution;
    或者，R3选自C1-4烷基、C3-4环烷基或3-4元杂环烷基，所述C1-4烷基、C3-4环烷基或3-4元杂环烷基 任选地被一个或多个OH、卤素、CN或NH2取代；Alternatively, R 3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl, said C 1-4 alkyl, C 3-4 cycloalkyl or 3-4 1-membered heterocycloalkyl optionally substituted by one or more OH, halogen, CN or NH ;
    或者，R3选自C1-4烷基、C3-4环烷基或3-4元杂环烷基；Alternatively, R 3 is selected from C 1-4 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl;
    或者，R3选自C1-4烷基；Alternatively, R 3 is selected from C 1-4 alkyl;
    或者，R3选自C3-4烷基；Alternatively, R 3 is selected from C 3-4 alkyl;
    或者，R3选自异丙基。Alternatively, R3 is selected from isopropyl.
  13. 如权利要求1-12任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，R4及R5分别独立地选自氢、OH、卤素、CN、NH2、C1-3烷基或C1-3烷氧基取代；The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 12, R 4 and R 5 are independently selected from hydrogen, OH, halogen, CN, NH 2 , C 1-3 alkyl or C 1-3 alkoxy substituted;
    或者，R4及R5分别独立地选自氢、卤素、C1-3烷基或C1-3烷氧基取代；Alternatively, R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy substitution;
    或者，R4及R5分别独立地选自氢。Alternatively, R 4 and R 5 are each independently selected from hydrogen.
  14. 如权利要求1-13任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，结构片段选自 The compound of formula I according to any one of claims 1 to 13, its stereoisomer or its pharmaceutically acceptable salt, structural fragment Selected from
    或者，结构片段选自 Or, structure fragment Selected from
    或者，结构片段选自 Or, structure fragment Selected from
    或者，结构片段选自 Or, structure fragment Selected from
    任选地，结构片段选自 Optionally, structural fragments Selected from
    或者，结构片段选自 Or, structure fragment Selected from
  15. 如权利要求1-14任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，所述杂芳基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6烯基、C2-6炔基或氘代C1-3烷基，当其被两个Ra取代，其中一个Ra选自C2-6烯基或C2-6炔基，另一个Ra选自氘代C1-3 烷基，所述C2-6烯基或C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代；The compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein the heteroaryl group is substituted by one or two R a , optionally by one or Multiple R b is substituted, when it is substituted by one R a , said R a is selected from C 2-6 alkenyl, C 2-6 alkynyl or deuterated C 1-3 alkyl, when it is substituted by two R a Substituted, one R a is selected from C 2-6 alkenyl or C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 Alkyl, the C 2-6 alkenyl or C 2-6 alkynyl is optionally replaced by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH (C 1-3 alkyl ) or N(C 1-3 alkyl) 2 substitution;
    或者，上述杂芳基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6炔基，当其被两个Ra取代，其中一个Ra选自C2-6炔基，另一个Ra选自氘代C1-3烷基，所述C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代；Alternatively, the above-mentioned heteroaryl is substituted by one or two R a , optionally substituted by one or more R b , when it is substituted by one R a , said R a is selected from C 2-6 alkynyl, when it is Substituted by two R a , one R a is selected from C 2-6 alkynyl group, the other R a is selected from deuterated C 1-3 alkyl group, the C 2-6 alkynyl group is optionally substituted by one or more Each halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 substituted;
    或者，所述吡唑基、咪唑基或***基被一个或两个Ra取代，任选地被一个或多个Rb取代，当其被一个Ra取代，所述Ra选自C2-6炔基，当其被两个Ra取代，其中一个Ra选自C2-6炔基，另一个Ra选自氘代C1-3烷基，所述C2-6炔基任选地被一个或多个卤素、OH、OC1-3烷基、CN、NH2、NH(C1-3烷基)或N(C1-3烷基)2取代；Alternatively, the pyrazolyl, imidazolyl or triazolyl group is substituted by one or two R a , optionally substituted by one or more R b , when it is substituted by one R a , the R a is selected from C 2-6 alkynyl, when it is substituted by two R a , one R a is selected from C 2-6 alkynyl, and the other R a is selected from deuterated C 1-3 alkyl, the C 2-6 alkyne The radical is optionally substituted by one or more halogen, OH, OC 1-3 alkyl, CN, NH 2 , NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 ;
    或者，所述杂环基任选被一个或两个Rc取代，当被一个Rc取代，Rc选自C2-4烯基、或C2-4炔基；当被两个Rc取代，其中一个Rc选自C2-4烯基、或C2-4炔基，另一个Rc选自卤素、OH、CN或NH2；所述C2-4烯基或C2-4炔基任选地被一个或多个选自卤素、OH、CN或NH2取代；Alternatively, the heterocyclyl group is optionally substituted by one or two R c , and when substituted by one R c , R c is selected from C 2-4 alkenyl, or C 2-4 alkynyl; when substituted by two R c , one R c is selected from C 2-4 alkenyl or C 2-4 alkynyl, the other R c is selected from halogen, OH, CN or NH 2 ; the C 2-4 alkenyl or C 2-4 alkynyl is optionally replaced by a or multiple substitutions selected from halogen, OH, CN or NH 2 ;
    或者，所述杂环基任选被一个或两个Rc取代，当被一个Rc取代，Rc选自当被两个Rc取代，其中一个Rc选自另一个Rc选自卤素。Alternatively, the heterocyclyl group is optionally substituted by one or two R c , and when substituted by one R c , R c is selected from When replaced by two R c , one of which is selected from The other R c is selected from halogen.
  16. 如权利要求1-15任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中式I化合物选自式I-A、式I-A’、式II、式II-A、式III、式III-A、式IV、式IV-A、式V、或式V-A化合物，

    The compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the compound of formula I is selected from formula IA, formula I-A', formula II, formula II -A, a compound of formula III, formula III-A, formula IV, formula IV-A, formula V, or formula VA,

    其中，in,
    R’选自氢、卤素、OH、OC1-3烷基、CN、NH2、-NH(C1-3烷基)或-N(C1-3烷基)2；R' is selected from hydrogen, halogen, OH, OC 1-3 alkyl, CN, NH 2 , -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
    R6各自独立地选自C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、卤素、OH、CN、NH2、C3-6环烷基、OC1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2；R 6 is each independently selected from C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, halogen, OH, CN, NH 2 , C 3-6 cycloalkyl, OC 1-3 alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
    环A选自5-6元杂芳基或8-15元杂环基；Ring A is selected from 5-6 membered heteroaryl or 8-15 membered heterocyclyl;
    m选自0、1、2、3或4；m is selected from 0, 1, 2, 3 or 4;
    环B选自不存在、C3-4环烷基或3-4元杂环烷基；Ring B is selected from absence, C 3-4 cycloalkyl or 3-4 membered heterocycloalkyl;
    环C选自5-6元杂环烷基；Ring C is selected from 5-6 membered heterocycloalkyl;
    环D选自5-6元杂芳基；Ring D is selected from 5-6 membered heteroaryl;
    n选自0、1、2、3或4；或者，n选自0、1、2或3。n is selected from 0, 1, 2, 3 or 4; alternatively, n is selected from 0, 1, 2 or 3.
  17. 如权利要求16所述的化合物、其立体异构体或其药学上可接受的盐，所述R’选自氢、卤素、OH、OC1-2烷基、CN、NH2、-NH(C1-2烷基)或-N(C1-2烷基)2；The compound according to claim 16, its stereoisomer or its pharmaceutically acceptable salt, said R' is selected from hydrogen, halogen, OH, OC 1-2 alkyl, CN, NH 2 , -NH ( C 1-2 alkyl) or -N (C 1-2 alkyl) 2 ;
    或者，R’选自选自氢、氟、氯、溴或OH；Alternatively, R' is selected from hydrogen, fluorine, chlorine, bromine or OH;
    或者，R’选自选自氢、氟、溴或OH；Alternatively, R' is selected from hydrogen, fluorine, bromine or OH;
    或者，R’选自选自氢、氟或OH；和/或，Alternatively, R' is selected from hydrogen, fluorine or OH; and/or,
    任选地，所述R6各自独立地选自C1-3烷基、氘代C1-3烷基、卤代C1-3烷基、卤素、OH、CN、NH2、C3-4环烷基、OC1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2；Optionally, each of the R 6 is independently selected from C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, halogen, OH, CN, NH 2 , C 3- 4 -cycloalkyl, OC 1-3 alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 ;
    或者，R6各自独立地选自C1-3烷基、氘代C1-3烷基、卤代C1-3烷基、卤素或C3-4环烷基；Alternatively, each R 6 is independently selected from C 1-3 alkyl, deuterated C 1-3 alkyl, halo-substituted C 1-3 alkyl, halogen or C 3-4 cycloalkyl;
    或者，R6各自独立地选自甲基、氘代甲基、卤代甲基、氟、氯、溴或环丙基；Alternatively, R 6 is each independently selected from methyl, deuterated methyl, halomethyl, fluorine, chlorine, bromine or cyclopropyl;
    或者，R6各自独立地选自甲基、-CD3、-CHF2、氟、氯或环丙基；和/或，Alternatively, R 6 is each independently selected from methyl, -CD 3 , -CHF 2 , fluorine, chlorine or cyclopropyl; and/or,
    任选地，m选自0、1、2或3；Optionally, m is selected from 0, 1, 2 or 3;
    或者，m选自0或1；和/或，Alternatively, m is selected from 0 or 1; and/or,
    任选地，所述环A选自5元杂芳基、8元杂环基、10元杂环基或11元杂环基；Optionally, the ring A is selected from 5-membered heteroaryl, 8-membered heterocyclyl, 10-membered heterocyclyl or 11-membered heterocyclyl;
    或者，环A选自5元杂芳基、含有稠合环的8元杂环基、含有稠合环及螺环的10元杂环基、含有稠合环及螺环的11元杂环基；Alternatively, Ring A is selected from the group consisting of a 5-membered heteroaryl group, an 8-membered heterocyclyl group containing a fused ring, a 10-membered heterocyclyl group containing a fused ring and a spiro ring, and an 11-membered heterocyclyl group containing a fused ring and a spiro ring. ;
    或者，环A选自5元杂芳基；Alternatively, Ring A is selected from 5-membered heteroaryl;
    或者，环A选自五元含氮杂芳基；Alternatively, Ring A is selected from five-membered nitrogen-containing heteroaryl;
    或者，环A选自吡唑基、咪唑基或***基；Alternatively, Ring A is selected from pyrazolyl, imidazolyl or triazolyl;
    或者，环A选自吡唑；和/或，Alternatively, Ring A is selected from pyrazole; and/or,
    任选地，所述环B选自不存在或C3-4环烷基；Optionally, the ring B is selected from absent or C 3-4 cycloalkyl;
    或者环B选自不存在或环丙基；和/或，Or Ring B is selected from absent or cyclopropyl; and/or,
    任选地，所述环C选自吡咯烷基或吗啉基；和/或，Optionally, the ring C is selected from pyrrolidinyl or morpholinyl; and/or,
    任选地，环D选自5元杂芳基；Optionally, Ring D is selected from 5-membered heteroaryl;
    或者，环D选自吡唑基或***基；和/或， Alternatively, Ring D is selected from pyrazolyl or triazolyl; and/or,
    或者，所述环B为不存在，环C为吡咯烷基，环D选自吡唑基或***基；Alternatively, the ring B does not exist, the ring C is a pyrrolidinyl group, and the ring D is selected from a pyrazolyl group or a triazolyl group;
    或者，所述环B为环丙基、环C选自吡咯烷基或吗啉基，环D为吡唑基；Alternatively, the ring B is cyclopropyl, ring C is selected from pyrrolidinyl or morpholinyl, and ring D is pyrazolyl;
    任选地，结构片段选自 Optionally, structural fragments Selected from
  18. 以下化合物、其立体异构体或其药学上可接受的盐，


    The following compounds, their stereoisomers or their pharmaceutically acceptable salts,


  19. 药物组合物，其包含权利要求1-18任一项所述化合物、其立体异构体或其药学上可接受的盐。A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof.
  20. 权利要求1-18任一项所述化合物、其立体异构体或其药学上可接受的盐、或权利要求19所述药物组合物在制备预防或者治疗相关疾病的药物中的用途；The use of the compound according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of medicines for preventing or treating related diseases;
    任选地，所述相关疾病选自癌症、自身免疫疾病、免疫缺陷或神经退行性疾病；Optionally, the associated disease is selected from cancer, autoimmune disease, immunodeficiency or neurodegenerative disease;
    任选地，所述癌症选自淋巴瘤、白血病或实体瘤。Optionally, the cancer is selected from lymphoma, leukemia or solid tumor.
  21. 权利要求1-18任一项所述的化合物、其药学上可接受的盐、或其立体异构体、或权利要求19所述的药物组合物在治疗相关疾病中的用途；The use of the compound according to any one of claims 1 to 18, its pharmaceutically acceptable salt, or its stereoisomer, or the pharmaceutical composition according to claim 19 in the treatment of related diseases;
    任选地，所述相关疾病选自癌症、自身免疫疾病、免疫缺陷或神经退行性疾病；Optionally, the associated disease is selected from cancer, autoimmune disease, immunodeficiency or neurodegenerative disease;
    任选地，所述癌症选自淋巴瘤、白血病或实体瘤。 Optionally, the cancer is selected from lymphoma, leukemia or solid tumor.
PCT/CN2023/084374 2022-03-29 2023-03-28 Compound containing thiazole ring WO2023185831A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021164746A1 (en) * 2020-02-19 2021-08-26 江苏先声药业有限公司 Substituted aryl compound
CN114072390A (en) * 2019-03-12 2022-02-18 赛泰尔治疗公司 RAD51 inhibitors
CN115677684A (en) * 2021-07-21 2023-02-03 先声药业有限公司 Substituted aryl or heteroaryl compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114072390A (en) * 2019-03-12 2022-02-18 赛泰尔治疗公司 RAD51 inhibitors
WO2021164746A1 (en) * 2020-02-19 2021-08-26 江苏先声药业有限公司 Substituted aryl compound
CN115677684A (en) * 2021-07-21 2023-02-03 先声药业有限公司 Substituted aryl or heteroaryl compounds

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