WO2024251040A1 - Irak4降解剂及其用途 - Google Patents

Irak4降解剂及其用途 Download PDF

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Publication number
WO2024251040A1
WO2024251040A1 PCT/CN2024/096649 CN2024096649W WO2024251040A1 WO 2024251040 A1 WO2024251040 A1 WO 2024251040A1 CN 2024096649 W CN2024096649 W CN 2024096649W WO 2024251040 A1 WO2024251040 A1 WO 2024251040A1
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mmol
added
deuterium
halogen
independently
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English (en)
French (fr)
Inventor
巫锡伟
余天柱
刘希乐
司徒嘉俊
杨文谦
陈海杰
王慧
陈昭民
李捍雄
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Apichope Bio Pharmaceutical Co Ltd
Guangzhou Runlin Pharmaceutical Technology Co Ltd
Guangzhou Unirise Pharmaceutical Co Ltd
Guangzhou Apichope Pharmaceutical Co Ltd
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Apichope Bio Pharmaceutical Co Ltd
Guangzhou Runlin Pharmaceutical Technology Co Ltd
Guangzhou Unirise Pharmaceutical Co Ltd
Guangzhou Apichope Pharmaceutical Co Ltd
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Application filed by Apichope Bio Pharmaceutical Co Ltd, Guangzhou Runlin Pharmaceutical Technology Co Ltd, Guangzhou Unirise Pharmaceutical Co Ltd, Guangzhou Apichope Pharmaceutical Co Ltd filed Critical Apichope Bio Pharmaceutical Co Ltd
Priority to EP24818572.0A priority Critical patent/EP4725946A1/en
Priority to CN202480039376.5A priority patent/CN121399129A/zh
Publication of WO2024251040A1 publication Critical patent/WO2024251040A1/zh
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular, provides bifunctional compounds for proteolytic degradation of interleukin-1 receptor associated kinase 4 (IRAK4) and methods for treating diseases regulated by IRAK4.
  • IRAK4 interleukin-1 receptor associated kinase 4
  • Interleukin 1 receptor kinase 4 is a threonine/serine protein kinase composed of 460 amino acids, containing a kinase domain and a death domain. Typically, the N-terminal lobe and the C-terminal lobe can be found in the kinase domain, which converge to form an ATP binding site. The death domain exists to bind and interact with MyD88 during protein recruitment. In addition, there are three phosphorylation sites on the protein that participate in trans-phosphorylation.
  • IRAK4 is considered to be a key protein kinase for early activation of IL-1 receptors and TLRs downstream, initiating signal transduction by rapidly activating IRAK1 and IRAK2, leading to an innate immune response.
  • other interleukins such as IL-18 and IL-33, rely on IRAK4 for signal transduction.
  • Clinical pathological studies have shown that individuals with IRAK4 mutations are protected against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal, and individuals can survive to adulthood, and the risk of infection decreases with age. A lot of evidence shows that inhibiting IRAK4-mediated signal transduction will be a promising treatment method. IRAK4 has become an important therapeutic target and attracted widespread research and development interest.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • E3 ubiquitin ligases Such compounds can be recognized by the proteasome of the cell, causing the degradation of the targeted protein, and can effectively reduce the content of the targeted protein in the cell.
  • PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years.
  • Specific degradation of IRAK4 can be achieved by using heterobifunctional small molecules to recruit IRAK4 to ubiquitin ligases and thereby promote ubiquitination and proteasomal degradation of IRAK4, thereby providing therapeutic opportunities in IRAK4-related diseases such as autoimmune diseases, inflammatory diseases, and tumors.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an IRAK4 degrading agent.
  • the present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a drug, wherein the drug targets and degrades IRAK4 by the compound. Treating diseases and/or conditions.
  • the present invention relates to a compound, which is a compound as shown in formula (I), or an isomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in formula (I),
  • Ring A is an 8-13 membered spiro ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
  • Ring B is phenyl, naphthyl, 5-6 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl;
  • R 1 , R 2 and R 3 are each independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, -(C 0-3 alkylene)-C 3-6 cycloalkyl or -(C 0-3 alkylene)-3-8 membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy , -(C 0-3 alkylene)-C 3-6 cycloalkyl and -(C 0-3 alkylene)-3-8 membered heterocyclyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl and C 1-3 hal
  • each R 4 is independently C 1-6 alkyl, C 2-6 alkenyl, phenyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl ring, said R 4 being independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, CN, OH, NO 2 , NH 2 , oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 haloalkyl;
  • each R c is independently hydrogen, deuterium, C 1-6 alkyl, phenyl, C 4-7 cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, and the C 1-6 alkyl, phenyl, C 4-7 cycloalkyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl may be independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 haloalkyl; or two R c groups on the same atom are optionally combined with their middle atom to form a C 4-7 cycloalkyl, a 4-11 membered bridged bicyclic or spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the C The 4-7- membere
  • n and n are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • L is C 1-20 alkylene, wherein 1, 2, 3, 4 or 5 methylene groups may be independently optionally replaced by a unit selected from -CR d ⁇ CR d -, -C ⁇ C-, -C(R d ) 2 -, -Cy-, -O-, -C( ⁇ O)- and -N(R d )-;
  • each -Cy- is independently C 4-7 cycloalkyl, 4-11 membered heterocyclyl, 5-11 membered spirocyclyl, 5-11 membered bridged bicyclyl, phenyl, 5-6 membered heteroaryl, and each -Cy- may be independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, CN, OH, NO 2 , NH 2 , oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and -C 1-3 haloalkyl;
  • each R d is independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 or C 1-3 alkyl;
  • VHL Von Hippel-Lindau
  • CRBN cereblon
  • IAPs inhibitor of apoptosis proteins
  • the human IAP family includes 8 members, and many other organisms contain IAP homologs.
  • IAPs contain an E3 ligase specificity domain and a baculovirus IAP repeat (BIR) domain, which recognizes substrates and promotes their ubiquitination.
  • the DIM of the compound of formula (I) targets VHL, CRBN or IAP of the E3 ligase, which is utilized by the bifunctional compound to induce ubiquitination of IRAK4 and subsequent proteasomal degradation.
  • Ring A is:
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently CH 2 , —C( ⁇ O)—, NH, O, or S;
  • a and c are each independently 1 or 2;
  • each Ra is independently hydrogen, deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , -CF 3 or C 1-6 alkyl; or two Ra groups on the same atom form a C 3-4 cycloalkyl.
  • each Ra is independently hydrogen, deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , -CF 3 , methyl, ethyl, n-propyl or isopropyl; or two Ra groups on the same atom form a cyclopropyl or cyclobutyl.
  • Ring B is:
  • each R b is independently hydrogen, deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , -COOH, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, or 7-8 membered bridged bicyclic ring; the C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, and 7-8 membered bridged bicyclic ring may be independently optionally substituted with 1, 2, or 3 substituents selected from deuterium, halogen, OH, CN, oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-3 haloalkyl.
  • each R b is independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl or The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and It may be optionally substituted independently with 1, 2 or 3 substituents selected from hydrogen, deuterium,
  • Parts are:
  • R b1 and R b4 are each independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , CH 3 , CH 2 CH 3 , -CF 2 or -CF 3 ;
  • R b2 and R b3 are each independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, Piperidinyl, piperazinyl, morpholinyl or The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and It may be optionally substituted independently with 1, 2 or 3 substituents selected from hydrogen
  • Parts are:
  • R b1 and R b4 are each independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , CH 3 , CH 2 CH 3 , -CF 2 or -CF 3 ;
  • R b2 and R b3 are each independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyridine or The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyridine and It may be optionally substituted independently with 1, 2
  • R 1 is hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl
  • R 2 is hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.
  • R 1 is hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , methyl, ethyl, n-propyl, isopropyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 2 is hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , methyl, ethyl, n-propyl, isopropyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 3 is hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 5-6 membered heterocyclyl
  • the C 1-6 alkyl, C 1-4 alkoxy, C 5-6 cycloalkyl and 5-6 membered heterocyclyl may be independently optionally substituted by 1, 2 or 3 deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , C 1-3 alkyl, C 1-3 alkoxy, The group may be substituted with a C 1-3 haloalkoxy group, a C 1-3 hydroxyalkyl group, or a C 1-3 haloalkyl group.
  • R 3 is hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl and morpholinyl groups may be independently optionally substituted with 1 , 2 or 3 substituents selected from deuterium, halogen, oxo, CN, OH, NO 2 , NH 2 , methyl, methoxy, -CH 2 OH, -CHF 2 , -CF 3 , -CHFCH
  • the DIM part is preferably:
  • each R d is independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , methyl, ethyl, n-propyl or isopropyl.
  • L is wherein L is C 1-9 alkylene
  • 1, 2, 3 or 4 methylene groups may be independently optionally selected from -CR d ⁇ CR d -, -C ⁇ C-, -C(R d ) 2 -, -O-, -C( ⁇ O)-, -NH-
  • the unit is replaced by may be independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, halogen, CN, OH, NO2 , NH2 , oxo, methyl , ethyl, isopropyl, methoxy, isopropoxy, -CHF2 , -CF3 , -CHFCH2F , -CF2CHF2 , -CH2CF3 , -OCHF2 and -OCF3 ;
  • Each R d is independently hydrogen, deuterium, halogen, CN, OH, NO 2 , NH 2 , methyl, ethyl, n-propyl or isopropyl.
  • L can be specifically selected as:
  • the compound has a structure represented by formula (II), formula (III), formula (IV), formula (V) or formula (VI):
  • Z2 is CH or N
  • p and q are each independently 1 or 2.
  • the DIM, ring B, R1, R2, R3, Ra, Rb, L, m and n have the meanings as defined in the present invention.
  • the compound is a compound having one of the following structures or an isomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:
  • the present invention relates to a pharmaceutical composition, which comprises a compound of formula (I) of the present invention, or its isomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
  • the present invention relates to the use of the aforementioned compound or its pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a disease associated with IRAK4 in a patient.
  • the disease is selected from inflammatory diseases, infections such as viral, bacterial, fungal and parasitic infections, HIV-1 infection, sepsis, autoimmune disorders or diseases such as rheumatoid arthritis and multiple sclerosis, gout, juvenile idiopathic arthritis, Muckle-Wells disease, familial Mediterranean fever, Behcet's disease, adult Still's disease, proliferative diseases such as cancer, hyperplasia, restenosis, cardiac hypertrophy, leukemia, intravascular coagulation, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, fibrotic and allergic diseases, asthma, atopic dermatitis, hidradenitis suppurativa, Alzheimer's disease, hormone-related diseases, trauma, hemodialysis, ischemic diseases, non-infectious hepatitis, ultraviolet radiation, closed head injury, pancreatitis, periodontitis, graft-versus-host disease and/or transplant rejection.
  • infections such as viral, bacterial, fungal and parasitic infections, HIV
  • the invention obtains a series of compounds with high activity, low toxicity, good metabolic stability and excellent drug properties.
  • the structural formulae and compounds described herein include all isomeric forms, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, the compounds of the present invention are also within the scope of the present invention in their individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs.
  • the structural formulae of the compounds described herein include one or more different isotopically enriched atoms.
  • the "isomers" of the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, geometric isomers or conformational isomers are all within the scope of the present invention.
  • nitrogen oxide used in the present invention means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • the "hydrate” of the present invention refers to an association formed when the solvent molecule is water.
  • solvate refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • Metal refers to a product obtained by metabolism in vivo of a specific compound described in the present invention or a pharmaceutically acceptable salt, analog or derivative thereof, which exhibits similar activity in vivo or in vitro to the compound of formula (I).
  • the metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present invention.
  • Such a product can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage.
  • the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
  • prodrug used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compound of the present invention can be an ester.
  • the esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • 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 tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include variants of deuterium and hydrogen, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical achievable. When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • Cycloalkyl or “cycloalkane” means a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic carbon ring system containing 3-12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but never an aromatic ring.
  • the cycloalkyl contains 3-10 carbon atoms; in another embodiment, the cycloalkyl contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3-6 carbon atoms.
  • Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.
  • Heterocyclyl and “heterocycle” are used interchangeably herein and both refer to saturated or partially unsaturated monocyclic, bicyclic or tricyclic rings containing 3-12 ring atoms, never aromatic rings, wherein at least one ring atom is a heteroatom.
  • heterocyclyl or “heterocycle” contains 3-10 ring atoms; in one embodiment, “heterocyclyl” or “heterocycle” contains 3-8 ring atoms; in another embodiment, “heterocyclyl” or “heterocycle” contains 5-8 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 3-6 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 5-6 ring atoms; in yet another embodiment, “heterocyclyl” or “heterocycle” contains 4-6 ring atoms; unless otherwise specified, heterocyclyl may be carbon or nitrogen radical, and heteroatoms have the meanings as described herein.
  • heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxe
  • heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described herein.
  • Aryl refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring contains 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups can include phenyl, naphthyl and anthracene. The aryl groups can be independently optionally substituted with one or more substituents described herein.
  • Heteroaryl means monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 atoms and has one or more points of attachment to the rest of the molecule.
  • the term “heteroaryl” can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • the 5-10 atom heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.
  • heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl), 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (
  • Spiro means a 5 to 20-membered polycyclic group in which saturated or partially unsaturated monocyclic rings share a carbon atom (called a spiro atom), and may contain 0 to 5 heteroatoms. Preferably, it is 6 to 14 members, more preferably 8 to 13 members, and more preferably 8 to 10 members. Unless otherwise specified, the spiro group is optionally substituted by one or more substituents as described in the present invention. Non-limiting examples include: etc.
  • Bridged bicyclic means a saturated or partially unsaturated bicyclic system with at least one bridge, which may contain 0 to 5 heteroatoms.
  • “Bridge” is an atom that is not branched or connects two bridgeheads or a valence bond, wherein “bridgehead” is any skeleton atom of a ring system bonded to three or more skeleton atoms (except hydrogen).
  • the bridged bicyclic group has 5-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. This type of bridged bicyclic group is well known in the art, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • the bridged bicyclic group is optionally substituted by one or more substituents as described in the present invention. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Its non-limiting examples include: etc.
  • Heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen; a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).
  • Halogen refers to F, Cl, Br or I.
  • Alkyl refers to a straight or branched chain saturated hydrocarbon group consisting of several carbon atoms.
  • Alkenyl refers to a straight or branched hydrocarbon group consisting of multiple carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group.
  • Alkylene means a saturated divalent hydrocarbon radical derived from a straight or branched chain saturated hydrocarbon by eliminating two hydrogen atoms.
  • Alkoxy means a linear or branched monovalent residue of the formula -OR, wherein R is an alkyl group as defined above.
  • Haloalkyl or haloalkoxy means an alkyl or alkoxy group substituted with one or more halogen atoms.
  • Hydroalkyl means an alkyl group substituted with one or more hydroxy groups.
  • a substituent is connected to a ring by a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring.
  • formula (a) means that the substituent R can be substituted mono- or poly-substituted at any substitutable position on the pyridine ring.
  • a wavy line intersecting a bond in a chemical structure represents the point in the chemical structure at which the atom to which the wavy bond is attached is attached to the rest of the molecule or to the rest of a fragment of a molecule.
  • a ring system formed by a linker attached to a ring represents that the linker can be attached to the rest of the molecule at any available position on the ring system.
  • Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.
  • the compounds of the present invention 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 equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.
  • the present invention uses the following abbreviations: mg milligram mmol millimole DIEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate min minute wt% mass percentage DCM Dichloromethane ACN, MeCN Acetonitrile PE Petroleum ether EA Ethyl acetate MeOH Methanol Pd/C Palladium on carbon THF Tetrahydrofuran TBSCl tert-Butyldimethylsilyl chloride TFA Trifluoroacetic acid MsCl Methanesulfonyl chloride ppm per million TMS Tetramethylsilane DMSO Dimethyl sulfoxide TPSA p-Toluenesulfonic acid LDA Lithium diisopropylamide (Boc) 2 O Di
  • MS mass spectrometry
  • M1-1 preparation process refers to the preparation method of Example 142 of WO2017108723A2 (58 mg, 0.16 mmol) was placed in a 50 mL single-mouth bottle, and 4-hydroxymethylpiperidine (37 mg, 0.33 mmol), potassium carbonate (57 mg, 0.41 mmol), and ACN (1 mL) were added respectively, and heated to an external temperature of 60°C for 1 h.
  • M24-1 (5.14 g, 30.00 mmol), M24-2 (3.85 g, 30.00 mmol), p-toluenesulfonic acid (0.86 g, 4.50 mmol) were placed in a 100 mL single-mouth bottle, toluene (80 mL) was added, a water separator was added, the temperature was raised to an external temperature of 135°C, and the mixture was refluxed for 20 h. The mixture was concentrated under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with EA (80 mL ⁇ 2), the organic phases were combined, and dried over anhydrous sodium sulfate.
  • EA 80 mL ⁇ 2
  • M24-7 (440 mg, 0.98 mmol) was placed in a 50 mL single-mouth bottle, methanol (10 mL) was added, and then 10% palladium carbon (100 mg) was added.
  • the hydrogen balloon was replaced three times and then kept the hydrogen balloon, and the reaction was heated to an external temperature of 35°C for 2 hours until the yellow color completely faded.
  • the reaction solution was filtered through diatomaceous earth, and the filter residue was washed with methanol until the filtrate was colorless.
  • the filtrates were combined and concentrated under reduced pressure to obtain 400 mg of compound M24-8 as a gray-dark green foamy solid with a yield of 97.4%, which was directly used in the next step.
  • M26-3 (200 g, 48.34 mmol, 1.00 eq) was dissolved in a mixed solution of DMA (140 mL) and water (14.0 mL), and TEA (26.9 mL, 193 mmol, 4.00 eq) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (3.54 g, 4.83 mmol, 0.10 eq) were added. After replacing the nitrogen, the mixture was heated to 130°C for 12 h. Water (150 mL) was added to the reaction solution, and solids were precipitated.
  • M26-4 (14.0 g, 41.69 mmol, 1.00 eq) was placed in a 100 mL single-mouth bottle, DCM (9 mL) was added, and then dioxane hydrochloride solution (20.0 mL, 4 M) was added, and the reaction solution was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure and purified by HPLC. M26-5 (2.15 g, 8.97 mmol) was obtained as a light yellow solid. Yield: 21.5%.
  • M26-5 (1.00 g, 4.24 mmol, 1.00 eq) was placed in a 100 mL single-mouth bottle, and DCM (7.0 mL) was added. Fuming nitric acid (10 mL, 220.61 mmol, 53 eq) was slowly added dropwise at 0°C. After the addition was complete, the reaction solution was stirred at 0°C for 10 min, then heated to 45°C and continued to stir for 12 h. The reaction solution was concentrated under reduced pressure to obtain M26-6 (1.30 g, 4.63 mmol) as an orange solid.
  • Boc anhydride (4.5 mL, 21.03 mmol, 3.00 eq) was directly added to the reaction solution of the previous step, and stirred at 25°C for 12 h.
  • Two-step yield 44.1%.
  • M27-1 (0.76 g, 2.49 mmol) (preparation process refers to the synthesis process on pages 309-310 of patent WO2019183367A1) and DCM (6 mL) were placed in a 50 mL single-mouth bottle, TFA (1 mL) was added dropwise, and the reaction was stirred at 25 °C for 1 h.
  • M27-2 was obtained by concentration under reduced pressure, 1.0 g of light yellow solid, and the yield was 181%.
  • M27-4 (2700 mg, 5.85 mol), Pd/C (600 mg) and methanol (100 mL) were placed in a 250 mL single-mouth bottle, hydrogen was replaced, and stirred at room temperature for 5 hours. Filtered and concentrated under reduced pressure to obtain M27-5, 2524 mg of white solid, yield: 100%.
  • the preparation process refers to the synthesis of B32-2 on page 573 of patent WO2020206424 A1.
  • the preparation process refers to the synthesis of intermediate APT on page 90 of patent WO2021247899A1.
  • the preparation process refers to the preparation method of intermediate WW on page 195 of patent WO2021158634A1.
  • M33-1 (30.0 g, 174 mmol) was placed in a 1L three-necked flask and tetrahydrofuran (300 mL) was added. The reaction solution was cooled to 0°C, and a tetrahydrofuran solution of lithium aluminum hydride (105 mL, 261 mmol, 2.5 M) was slowly added dropwise at 0°C. After the addition was complete, the reaction was stirred at 25°C overnight. The reaction solution was cooled to 0°C, and sodium sulfate decahydrate was slowly added under an ice bath for quenching. The quenching process lasted for half an hour. After sufficient quenching, the reaction solution was filtered, and the mother liquor obtained by filtration was concentrated under reduced pressure. M33-2 (22.0 g, 169 mmol) was obtained as a white solid. Yield: 97.0%.
  • M33-4 (40.6 g, 143.72 mmol) was placed in a 1 L single-necked bottle, THF (400 mL) was added, the temperature was lowered to 0°C, TBAF (287.4 mL, 287.43 mmol) was added, and the mixture was stirred at room temperature overnight.
  • Ethyl acrylate (184.1 mL, 1691.88 mmol, 7.5 eq) and M35-1 (51.0 g, 225.58 mmol, 1 eq) were placed in a 1 L round-bottom flask, and an equimolar mixture of lactic acid (16.9 mL, 225.58 mmol) and DBU (33.7 mL, 225.58 mmol) was added, and stirred at 80°C for 120 h. Water (500 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (500 mL ⁇ 3).
  • M35-3 (5.00 g, 13.54 mmol, 1.0 eq) was placed in a 100 ml round bottom flask and added to an acetonitrile (25.0 mL) solution, then benzyltrimethylammonium hydroxide (3.7 mL, 20.31 mmol, 1.5 eq, 40 wt.% methanol solution) was added dropwise to the above mixed reaction solution, and the reaction was stirred at 25 ° C for 45 minutes.
  • M35-5 (130 mg, 0.27 mmol, 1.0 eq) was placed in a 50 mL round-bottom flask, and DCM (6.00 mL) was added. After the reaction solution was cooled to 0°C, a hydrochloric acid solution of dioxane (2.00 mL) was slowly added dropwise, and stirred at 25°C for 12 h. The reaction solution was concentrated under reduced pressure to obtain M35 (100 mg, 0.26 mmol) as a brown solid. Yield: 97.1%.
  • M36-1 (100 mg, 0.36 mmol) was placed in a 50 mL single-mouth bottle, dichloromethane (10.0 mL) was added, and manganese dioxide (626 mg, 7.20 mmol, 20 eq) was added to the above reaction solution. After the addition was completed, it was stirred at 25°C for 12 h. The reaction solution was filtered, the filter cake was washed with dichloromethane (20.0 mL) for 5 times, and the filtrate was concentrated under reduced pressure. M36 (99 mg, 0.36 mmol, yield 99.7%) was obtained as a yellow solid.
  • THF 50 mL
  • methyl formate (2.73 g, 45.3
  • 3-Aminopyrazole-4-carboxylic acid (607 mg, 4.78 mmol, 1.0 eq) was placed in a 40 mL single-necked bottle, acetic acid (5.5 mL, 95.56 mmol, 20 eq) was added, and the mixture was stirred at 10 °C for 0.1 h.
  • M37-2 1000 mg, 4.78 mmol, 1.0 eq was dissolved in EtOH (16 mL) and added dropwise to the above reaction solution. The mixture was heated to 80 °C and stirred for 2 h. A white solid was precipitated. The solid was collected by filtration and concentrated under reduced pressure to obtain M37 (520 mg, 2.76 mmol, yield 57.8%) as a white solid.
  • 2-Bromomalonaldehyde (5.86 g, 38.8 mmol, 1.0 eq) was placed in a 100 mL single-necked bottle, EtOH (60 mL) was added, the temperature was raised to 70 ° C, ethyl 5-amino-1H-pyrazole-4-carboxylate (6.02 g, 38.8 mmol, 1.0 eq) and AcOH (28.9 mL, 504 mmol, 13 eq) were added, and the system was stirred at 70 ° C for 0.5 h. The reaction system was placed in an ice bath, and a brown solid gradually precipitated. After filtration, the filter cake was concentrated under reduced pressure to obtain M38-1 (5.80 g, 21.4 mmol, yield: 55.3%) as a brown solid.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • Embodiment 33 is a diagrammatic representation of Embodiment 33.
  • Example 33 a light yellow solid product of 3 mg, with a yield of 3.0%.
  • Embodiment 34 is a diagrammatic representation of Embodiment 34.
  • Embodiment 59 is a diagrammatic representation of Embodiment 59.
  • Example 59-3 50 mg, 0.14 mmol
  • 19-1 73 mg, 0.14 mmol
  • sodium bicarbonate 17.1 mg
  • Embodiment 60 is a diagrammatic representation of Embodiment 60.
  • 2-Fluoro-5-formylbenzoic acid (6.00 g, 35.69 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (60 mL), HATU (14.93 g, 39.26 mmol, 1.1 eq) and DIEA (14.7 mL, 89.22 mmol, 2.5 eq) were added to activate for 1 h, and then 3-aminohexahydropyridine-2,6-dione (4.57 g, 35.69 mmol, 1.0 eq) was added and stirred at room temperature for 4 h.
  • Embodiment 62
  • Embodiment 63
  • 5-Bromo-2-fluorobenzoic acid (7.00 g, 31.9 mmol) was placed in a 100 mL three-necked flask, DCM (70 mL) and DMF (0.2 mL, 3.20 mmol) were added, and oxalyl chloride (2.70 mL, 31.9 mmol, 1 eq) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at 0°C for 10 min and the mixture was resumed. Stir at room temperature for 2h. Concentrate under reduced pressure to remove DCM to obtain 5-bromo-2-fluorobenzoyl chloride (7.00g, 29.5mmol) as a yellow oil.
  • 63-3 35 mg, 0.09 mmol was placed in a 40 mL single-mouth bottle, DMF (2 mL) was added, and then 63-4 (40 mg, 0.08 mmol), NaHCO 3 (13 mg, 0.15 mmol) and TEA (15 mg, 0.15 mmol) and potassium iodide (4 mg, 0.02 mmol) were added to the reaction solution, and the reaction solution was stirred at 60° C. for 10 h. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography to obtain Example 63 (2.2 mg, yield 3.3%) as a white solid.
  • Embodiment 64 is a diagrammatic representation of Embodiment 64.
  • Example 64-2 (105 mg, 0.36 mmol), 1-3 (190 mg, 0.28 mmol), K 2 CO 3 (114.37 mg, 0.83 mmol) and TEA (0.2 mL, 1.66 mmol) were added to acetonitrile (5 mL) and DMF (1 mL), and stirred at 50° C. for 12 h. After the reaction was completed, the reaction solution was filtered to remove inorganic salts, and purified by preparative liquid chromatography to obtain Example 64 as a light yellow solid (26 mg), with a yield of 11.4%.
  • Embodiment 65 is a diagrammatic representation of Embodiment 65.
  • Example 65 As a light yellow solid (20 mg) with a yield of 22%.
  • Embodiment 66
  • M33-5 (511 mg, 3.04 mmol, 2.0 eq) was placed in a 40 mL single-mouth bottle, and DMF (5 mL), 63-1 (500 mg, 1.52 mmol), cesium carbonate (990 mg, 3.04 mmol) and bistriphenylphosphine palladium dichloride (118 mg, 0.15 mmol, 0.1 eq) were added.
  • the reaction solution was reacted at 100 ° C for 2 h under nitrogen protection.
  • 66-1 (220 mg, 0.53 mmol) was placed in a 100 mL single-mouth bottle and added with DCM (5 mL), and DMP (336 mg, 0.79 mmol, 1.5 eq) was added at 0°C, and the reaction solution was stirred at room temperature overnight.
  • Embodiment 67 is a diagrammatic representation of Embodiment 67.
  • Example 67-4 (166.16 mg, 0.24 mmol), M33 (100 mg, 0.24 mmol), potassium acetate (70 mg, 0.72 mmol), sodium triacetoxyborohydride (99 mg, 0.47 mmol) and DMF (1 mL) were added to a 50 mL single-mouth bottle and stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure and separated by HPLC to obtain Example 67 as a yellow solid (10 mg). Yield: 5.1%.
  • Embodiment 68
  • M33-5 (520 mg, 3.09 mmol, 2.0 eq) was placed in a 40 mL single-mouth bottle, and DMF (5.0 mL), M35-4 (500 mg, 1.55 mmol, 1.0 eq) and Cs 2 CO 3 (1.08 g, 3.09 mmol, 2.0 eq) were added to the reaction solution, and stirred at 100° C. for 2 h under nitrogen protection.
  • the reaction solution was concentrated under reduced pressure, THF (300 mL) was added, stirred for 1 h, and then filtered.
  • Example 68-2 (40.0 mg, 0.07 mmol, 1.0 eq) was placed in a 40.0 mL single-mouth bottle, and DMA (2.0 mL), 1-1 (32.7 mg, 0.07 mmol, 1.0 eq), NaI (31.8 mg, 0.21 mmol, 3.0 eq), and DIEA (54.9 mg, 0.43 mmol, 6.0 eq) were added, and the reaction solution was stirred at 50° C. for 16 h. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography to obtain Example 68 (32.9 mg, 0.04 mmol, yield 54.3%) as a yellow solid.
  • Embodiment 69
  • 1-tert-Butyloxycarbonylpiperazine (1g, 5.37mmol) was placed in a 50mL single-mouth bottle, acetonitrile (10mL) was added, sodium carbonate (1.71g, 16.11mmol) was added, and the mixture was stirred at room temperature for 20min, 3-bromopropyne (0.7mL, 8.05mmol) was added, and the mixture was transferred to a 50°C oil bath and stirred for 4h.
  • 69-2 (65 mg, 0.13 mmol) was placed in a 50 mL single-mouth bottle, DCM (3 mL) was added to dissolve, 4.0 M hydrochloric acid dioxane solution (0.7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove the solvent and hydrogen chloride to obtain 69-3 as a brown solid (72 mg), with a yield of 142.1%.
  • 69-4 (35 mg, 0.07 mmol) was placed in a 50 mL single-mouth bottle, DCM (2 mL) was added to dissolve, 4.0 M TFA (196 ⁇ L, 2.55 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure to obtain 69-5 as a black solid (42 mg), with a yield of 135.3%.
  • Example 69-5 (30 mg, 0.07 mmol), 1-1 (32 mg, 0.04 mmol), HATU (39 mg, 0.10 mmol), DIEA (54 mg, 0.42 mmol) were placed in a 25 mL single-mouth bottle, DCM (5 mL) was added, and the mixture was stirred at 25°C for overnight reaction. DCM (10 mL) was added to the reaction solution, and saturated ammonium chloride solution (10 mL) was added for washing. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain Example 69 as a brown solid (29 mg). Yield: 46.9%. Purity: 97.23%.
  • Embodiment 70 is a diagrammatic representation of Embodiment 70.
  • 70-1 (235 mg, 0.53 mmol) was placed in a 40 mL single-necked bottle, a mixed solution of TFA (1 mL) and DCM (9 mL) was added, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 70-2 (180 mg, 0.52 mmol, 98.9%) as a brown oil.
  • 70-3 (466 mg, 0.81 mmol) was placed in a 40 mL single-necked bottle, and DCM (1 mL) and HCl (5 mL) in dioxane were added, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain 70-4 (400 mg, 0.77 mmol, 95.1%) as a yellow solid.
  • Example 70-4 (341 mg, 0.52 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, and DMF (4 mL) was added.
  • 70-2 180 mg, 0.52 mmol, 1.0 eq
  • DIEA 203 mg, 1.57 mmol, 3.0 eq
  • HATU 219 mg, 0.58 mmol, 1.1 eq
  • the reaction solution was stirred at room temperature for 1 h. After the reaction solution was filtered, the filtrate was separated and purified by high performance liquid chromatography to obtain Example 70 (173 mg, 0.19 mmol, yield 36.6%) as a yellow solid.
  • Embodiment 71
  • 71-1 160 mg, 0.34 mmol was placed in a 40 mL single-necked bottle, and DCM (1 mL) was added, followed by a dioxane solution of HCl (4 mL, 16.00 mmol), and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure to obtain 71-2 (160 mg, 0.38 mmol) as a gray solid.
  • Embodiment 72 is a diagrammatic representation of Embodiment 72.
  • Embodiment 73
  • 2-Methylpropane-2-ylpiperidinium-4-carboxylate (208 mg, 1.12 mmol) was placed in a 40 mL single-mouth bottle, dichloromethane (3 mL) was added, M1-1 (330 mg, 0.94 mmol, 1.0 eq) was added, and stirred at 25 ° C for 12 h.
  • 73-1 250 mg, 0.48 mmol was placed in a 40 mL single-mouth bottle, ethanol (2 mL) was added, ammonium chloride (129 mg, 2.41 mmol, 5.0 eq) and water (0.40 mL) were added, the system was heated to 60 ° C, iron powder (134 mg, 2.41 mmol, 5.0 eq) was added, and the reaction solution was stirred at 60 ° C for 4 h. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 73-2 (180 mg, 0.37 mmol, yield: 76.4%) as a yellow solid.
  • 73-3 (100 mg, 0.16 mmol) was placed in a 40 mL single-necked bottle, dichloromethane (1 mL) was added, and dioxane hydrochloride solution (1 mL, 4 M) was added, and stirred at 25°C for 2 h.
  • the reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8 with saturated sodium bicarbonate to precipitate a white solid, which was filtered and the filter cake was collected to obtain 73-4 (50 mg, 0.10 mmol, yield: 66.4%) as a yellow solid.
  • 73-4 (20 mg, 0.04 mmol) was placed in a 40 mL single-mouth bottle, tetrahydrofuran (1 mL) and N, N-dimethylformamide (1 mL) were added, M33 (17 mg, 0.04 mmol, 1 eq) and sodium triacetoxyborohydride (10 mg, 0.05 mmol, 1.2 eq) and potassium acetate (8 mg, 0.08 mmol, 2 eq) were added, and stirred at 25 ° C for 12 h. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography. Example 73 (19 mg, 0.02 mmol, yield 52.6%) was obtained as a white solid.
  • Embodiment 74
  • Chromium trioxide (4.75 g, 47.55 mmol, 4.00 eq) was placed in a 500 mL single-mouth bottle, and concentrated sulfuric acid (10.49 g, 106.99 mmol, 9.00 eq) was added while the temperature was controlled at 0°C.
  • a toluene (60 mL) solution of M33-5 (2.00 g, 11.89 mmol, 1.00 eq) was added, and the system was stirred at 25°C for 2 h.
  • the reaction solution was slowly poured into ice water, and ethyl acetate (100 mL ⁇ 3) was added for extraction.
  • the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 74-1 (1.20 g, 6.59 mmol, yield: 55.4%) as a green solid.
  • Example 74-2 (45 mg, 0.10 mmol, 1.0 eq) was placed in a 40 ml single-mouth bottle, DMF (2 mL) was added, and then 1-1 (47 mg, 0.10 mmol, 1.1 eq), DIEA (39 mg, 0.31 mmol, 3.0 eq) and HATU (42 mg, 0.11 mmol, 1.1 eq) were added, and the reaction solution was stirred at 25 ° C for 2 h. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography. Example 74 (20 mg, 0.02 mmol, yield: 22.8%) was obtained as a yellow solid.
  • Embodiment 75 is a diagrammatic representation of Embodiment 75.
  • Embodiment 76
  • Example 76 as a light yellow solid (212 mg), with a yield of 60.5%.
  • Embodiment 77
  • 77-2 (4 g, 16.39 mmol) was placed in a 100 mL single-mouth bottle, HCl (30 mL, 2M) was added, acrylic acid (1.54 g, 21.31 mmol, 1.3 eq) was added to the reaction solution, and the reaction solution was stirred at 100 ° C overnight. Saturated sodium bicarbonate aqueous solution was added to the reaction solution until the pH was 7-8, and then acetic acid was added to adjust the pH to 5-6, solid precipitated, filtered, and the filter cake was collected to obtain 77-3 (4.68 g, 14.80 mmol, yield 90.3%) as a gray solid.
  • 77-3 (4.58 g, 14.49 mmol) was placed in a 100 mL single-mouth bottle, acetic acid (45 mL) and potassium cyanate (2.35 g, 28.98 mmol, 2.0 eq) were added, and stirred at 60 ° C for 3 h.
  • HCl 45 mL, 2N was added to the reaction solution and continued to stir at 60 ° C overnight.
  • the reaction solution was cooled and filtered, and the filter cake was washed twice with water. The filter cake was collected to obtain 77-4 (3 g, 8.79 mmol, yield 60.7%) as a white solid.
  • ESI-MS (m/z): Br, 340.9, 342.9 [M+1, M+3] + .
  • 77-4 (300 mg, 0.88 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, and dioxane (5 mL), tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (378 mg, 1.76 mmol, 2.0 eq), Cs 2 CO 3 (859 mg, 2.64 mmol, 3.0 eq), and palladium catalyst (CAS No.: 1814936-54-3) (85 mg, 0.09 mmol, 0.1 eq) were added to the reaction solution and stirred at 100°C for 2 h.
  • 77-5 (270 mg, 0.57 mmol, 1.0 eq) was placed in a 50 mL single-necked bottle, DCM (6 mL) was added, and a hydrochloric acid dioxane solution (4 mL) was added and stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure to obtain 77-6 (238 mg, 0.57 mmol) as a white solid.
  • Example 77-6 (238 mg, 0.57 mmol, 1.0 eq) was placed in a 50 mL single-necked bottle and DMF (6 mL), 1-1 (262.48 mg, 0.57 mmol, 1.0 eq), DIEA (0.3 mL, 1.70 mmol, 3.0 eq), and HATU (237 mg, 0.62 mmol, 3.0 eq) were added to the reaction solution and stirred at room temperature for 1 h. After the reaction solution was filtered, it was separated and purified by HPLC to obtain Example 77 (176 mg, 0.20 mmol, 36.0%) as a yellow solid.
  • Embodiment 78
  • 78-1 (100 mg, 0.24 mmol, 1.0 eq) was placed in a 10 mL single-necked bottle, formic acid (2 mL) was added, and the system was stirred at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain 78-2 (80 mg, 0.22 mmol, yield 89.9%) as a yellow oil.
  • Example 78-2 (70 mg, 0.19 mmol, 1.0 eq) was placed in a 10 mL single-necked bottle, DMA (2 mL) was added, and then 1-1 (87 mg, 0.19 mmol, 1.0eq), potassium acetate (47mg, 0.23mmol, 3.0eq) and sodium acetate borohydride (55mg, 0.57mmol, 1.2eq), stirred at 25°C for 12h. The reaction solution was concentrated under reduced pressure and separated and purified by high performance liquid chromatography to obtain Example 78 (53mg, 0.07mmol, yield 34.5%) as a yellow solid.
  • Embodiment 79
  • 79-1 (6.00 g, 24.2 mmol, 1.0 eq) was placed in a 100 mL single-mouth bottle, methanol (60 mL) and boron trifluoride ether (2.06 g, 0.6 eq) were added, and the reaction was stirred at 25 ° C for 2 h.
  • 79-4 (20 mg, 0.05 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, and DCM (1 mL) and DMP (31 mg, 0.07 mmol, 1.5 eq) were added, and the reaction solution was stirred at 25 ° C for 2 h.
  • the reaction solution was quenched by adding saturated sodium bicarbonate solution, and ethyl acetate (10 mL ⁇ 3) was added for extraction.
  • the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 79-5 (20 mg, 0.05 mmol) crude product, which was directly used in the next step.
  • Example 79-5 (25 mg, 0.06 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, DMA (1 mL) was added, and then 1-1 (28 mg, 0.06 mmol, 1.0 eq), acetic acid (37 mg, 0.01 mmol, 0.1 eq) and sodium acetate borohydride (13 mg, 0.06 mmol, 1.0 eq) were added, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was filtered and purified by high performance liquid chromatography to obtain Example 79 (4.93 mg, 0.01 mmol, yield: 9.3%) as a yellow solid.
  • Embodiment 80 is a diagrammatic representation of Embodiment 80.
  • reaction solution was cooled to 0°C, 0.62 mL H 2 O, 0.62 mL 15% NaOH solution, and 1.24 mL H 2 O were added dropwise, and THF (30 mL) was added, stirred for 10 min, filtered, and the filtrate was concentrated under reduced pressure to obtain 80-2 (2.58 g, 15.63 mmol) as a colorless liquid.
  • NiCl2.dtbbpy (0.06 g, 0.15 mmol, 0.05 eq) and [Ir(df(CF3)ppy)2(dtbbpy)]PF6 (CAS No.: 870987-63-6) (0.03 g, 0.03 mmol, 0.01 eq) were added under nitrogen protection, and nitrogen was replaced for 10 min.
  • 80-5 (80 mg, 0.23 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, and DCM (3 mL) and DMP (148 mg, 0.35 mmol, 1.5 eq) were added to the reaction solution, and the reaction solution was stirred at room temperature for 5 h. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and dichloromethane (10 mL ⁇ 2) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 80-6 (50 mg, 0.15 mmol, yield 62.9%) as a light yellow solid.
  • Example 80-6 (50 mg, 0.15 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, DMA (2 mL), 1-1 (68 mg, 0.15 mmol, 1.0 eq), AcOH (18 mg, 0.29 mmol, 2.0 eq), sodium acetate borohydride (37 mg, 0.18 mmol, 1.2 eq) were added to the reaction solution, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was filtered and separated and purified by high performance liquid chromatography to obtain Example 80 (22.29 mg, 0.03 mmol, yield 19.3%) as a light yellow solid.
  • Embodiment 81
  • Embodiment 82
  • Example 82-3 (100 mg, 0.27 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, DMA (2 mL), 1-1 (124 mg, 0.27 mmol, 1.0 eq), potassium acetate (79 mg, 0.81 mmol, 3.0 eq), sodium triacetoxyborohydride (57 mg, 0.27 mmol, 1.0 eq) were added to the reaction solution, and stirred at 25 ° C for 1 h. The reaction solution was separated and purified by high performance liquid chromatography to obtain Example 82 (83.64 mg, 0.10 mmol, yield: 37.9%) as a yellow solid.
  • Embodiment 83
  • Example 78-2 (53 mg, 0.14 mmol) was placed in a 40 mL single-mouth bottle, DMA (2 mL) was added, 61-2 (66 mg, 0.14 mmol, 1.0 eq), potassium acetate (28 mg, 0.29 mmol, 2.0 eq), sodium acetate borohydride (36 mg, 0.17 mmol, 1.2 eq) were added, and the reaction solution was stirred at room temperature for 2 h. After the reaction solution was filtered, the filtrate was collected and purified by high performance liquid chromatography to obtain Example 83 (34.8 mg, 0.04 mmol, yield 29.8%) as a white solid.
  • Embodiment 84 and Embodiment 85 are identical to Embodiment 84 and Embodiment 85:
  • 84-3 (80 mg, 0.23 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, DMA (2 mL), 1-1 (104 mg, 0.23 mmol, 1.0 eq), potassium acetate (44 mg, 0.45 mmol, 2.0 eq), sodium acetate borohydride (47 mg, 0.23 mmol, 1.0 eq) were added to the reaction solution, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was filtered, and the filtrate was sent to high performance liquid chromatography for separation and purification to obtain 84-4 (40 mg, 0.05 mmol, yield 22.2%) as a yellow solid, which was directly used for SFC separation.
  • Example 84-4 (40 mg, 0.05 mmol) was separated by SFC to obtain Example 84 and Example 85.
  • Example 84 or Example 85 (15.15 mg, 0.02 mmol, yield 37.6%) is a yellow solid. Purity: 99.18%, 100% ee.
  • Example 34 A similar synthesis method as in Example 34 was used to synthesize the corresponding intermediates.
  • the structural characterization data are shown in the following table:
  • Embodiment 91 is a diagrammatic representation of Embodiment 91.
  • M1-1 (900 mg, 2.55 mmol, 1.0 eq) was placed in a 100 mL single-mouth bottle, and a 30% methanol solution of sodium methoxide (2.29 g, 12.7 mmol, 5.0 eq) was added, and stirred at 40°C for 4 h.
  • Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL ⁇ 3).
  • the organic phases were combined and backwashed once with saturated brine (20 mL), and the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 91-1 (900 mg, 2.47 mmol, yield 96.7%) as a yellow solid.
  • 91-3 (500 mg, 0.99 mmol, 1.0 eq) was placed in a 50 mL single-necked bottle, DCM (5 mL) was added, and dioxane hydrochloride solution (5 mL) was added, and stirred at 15 ° C for 2 h.
  • Embodiment 92
  • Methyl 1-methoxy-4-oxyylidenecyclohexane-1-carboxylate (25.0 g, 134 mmol, 1.0 eq) was placed in a 250 mL three-necked flask, and MeOH (175 mL) was added.
  • NaBH 4 (10.2 g, 268 mmol, 2.0 eq) was slowly added at 0°C, and stirred in an ice bath for 1.5 h.
  • Saturated aqueous ammonium chloride solution 200 mL was added to the reaction solution, and water (100 mL) was added to dissolve the salt.
  • Example 92-5 (80 mg, 0.18 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, DMA (3 mL), 1-1 (82 mg, 0.18 mmol, 1.0 eq), AcOH (21.19 mg, 0.35 mmol, 2.0 eq), sodium cyanoborohydride (22 mg, 0.35 mmol, 1.0 eq) were added to the reaction solution, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was filtered and separated and purified by high performance liquid chromatography to obtain Example 92 (40.79 mg, 0.05 mmol, yield 25.7%) as a yellow solid.
  • Embodiment 93 is a diagrammatic representation of Embodiment 93.
  • 93-1 (35.0 g, 85.2 mmol, 1.0 eq) was placed in a 1L three-necked flask and THF (150 mL) was added.
  • LDA (51.1 mL, 102 mmol, 1.2 eq) was added dropwise at -65 °C under nitrogen protection. After the addition, it was stirred at -65 °C for 1 h.
  • NFSI (22.3 mL, 102 mmol, 1.2 eq) was dissolved in THF (150 mL) and then added dropwise at -65 °C to the above reaction solution. The reaction solution was stirred at room temperature overnight.
  • 93-4 (3.00 g, 148 mmol, 1.0 eq) was placed in a 100 mL three-necked flask, and DCM (15 mL), TEA (2.25 g, 22.27 mmol, 1.1 eq) and DMAP (20 mg, 0.20 mmol, 0.01 eq) were added. The temperature was lowered to 0 °C and a solution of TBSCl (3.36 g, 22.27 mmol, 1.1 eq) in DCM (15 mL) was added dropwise. The reaction solution was stirred at room temperature overnight.
  • Embodiment 94
  • 94-3 (1.30 g, 4.33 mmol, 1.0 eq) was placed in a 100 mL single-mouth bottle, THF (10 mL) and TBAF solution (8.70 mL, 8.65 mmol, 1 M, 2.0 eq) were added to the reaction solution, and the reaction solution was stirred at room temperature overnight.
  • Embodiment 95 is a diagrammatic representation of Embodiment 95:
  • Embodiment 96
  • Embodiment 97
  • Embodiment 98
  • the synthesis process of compound 98-1 refers to the synthesis method of P735 of WO2022147465A1 specification.
  • Embodiment 99 is a diagrammatic representation of Embodiment 99:
  • 99-1 (5.00 g, 20.4 mmol, 1.0 eq) was placed in a 100 mL single-necked bottle, AcOH (35 mL) and urea (2.46 g, 40.9 mmol, 2.0 eq) were added, and stirred at 120°C for 12 h. Water (100 mL) was added to the reaction solution to precipitate a white solid, which was filtered, and the filter cake was collected and concentrated under reduced pressure to obtain 99-2 (2.5 g, 9.29 mmol, yield 45.4%).
  • Embodiment 100 is a diagrammatic representation of Embodiment 100.
  • Example 100 was obtained by a similar synthesis method to Example 78 as a white solid.
  • Embodiment 101 is a diagrammatic representation of Embodiment 101.
  • Embodiment 102
  • 3-(4-bromophenyl)piperidine-2,6-dione 500 mg, 1.86 mmol, 1.0 eq
  • was placed in a 50 mL single-mouth bottle, and dioxane (5 mL), 4-(dimethoxymethyl)piperidine (890 mg, 5.59 mmol, 3.0 eq), Cs 2 CO 3 (1.82 g, 5.59 mmol, 3.0 eq), 1814936-54-3 (181 mg, 0.19 mmol, 0.1 eq) were added to the reaction solution, and stirred at 100°C for 2 h under nitrogen protection.
  • Embodiment 103
  • Example 77-6 (300 mg, 0.72 mmol, 1.0 eq) was placed in a 40 mL single-mouth bottle, DMF (5 mL), 61-2 (330 mg, 0.72 mmol, 1.0 eq), DIEA (185 mg, 1.43 mmol, 2.0 eq) were added to the reaction solution, and finally HATU (299 mg, 0.79 mmol, 1.1 eq) was added and stirred at room temperature for 2 h. After the reaction solution was filtered, the filtrate was separated and purified by high performance liquid chromatography to obtain Example 103 (357.08 mg, 0.40 mmol, yield 55.6%) as a white solid.
  • THP-1 cells were inoculated in a 6-well cell culture plate, and the cell plate was placed in a 5% carbon dioxide incubator at 37°C for overnight culture. Then, a dimethyl sulfoxide solution of the compound to be tested was added, and the final concentration of the compound was in the range of 0.0128 to 1000 nM. After continuing to culture for 24 hours, the culture medium was removed, and the cells were collected into a 1.5 mL centrifuge tube. After adding lysis buffer and grinding thoroughly, the cells were placed on ice for 30 minutes, centrifuged at 15000xg and 4°C for 20 minutes, and the supernatant was taken to detect the IRAK4 protein level by Western Blot. The experimental results are shown in Table 1:
  • mice Six male mice weighing 20-30 g were divided into two groups. One group was intravenously injected with 2 mg/kg, and the other group was gavaged with 10 mg/kg. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration. After pretreatment, plasma samples were detected by LC/MS/MS in MRM mode, and appropriate standard curves were established to quantify the target compounds in plasma samples to obtain the drug concentration-time curve in plasma. WinNonlin software was used to calculate pharmacokinetic parameters using a non-compartmental model.
  • mice show that the compound of the present invention has good pharmacokinetic properties in mice.

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Abstract

本发明涉及一类白细胞介素-1受体相关激酶4(IRAK4)降解剂及其在制备治疗与IRAK4相关疾病的药物中的用途。具体涉及式(I)所示化合物、及其异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。

Description

IRAK4降解剂及其用途
本申请主张以下优先权：
CN202310688429.3，申请日：2023年6月9日；CN202410025235.X，申请日：2024年1月5日；CN202410437935.X，申请日：2024年4月11日。
技术领域
本发明涉及药物化学领域，具体地，本发明提供了用于蛋白水解降解白细胞介素-1受体相关激酶4(IRAK4)的双功能化合物和用于治疗由IRAK4调节的疾病的方法。
背景技术
白细胞介素1受体激酶4(IRAK4)是由460个氨基酸组成的苏氨酸/丝氨酸蛋白激酶，包含激酶结构域和死亡结构域，通常，在激酶结构域中可以找到N末端叶(lobe)和C末端叶，它们会聚在一起形成ATP结合位点，死亡结构域的存在是为了在蛋白质募集过程中结合MyD88并与之相互作用，此外，蛋白质上存在三个参与反式磷酸化的磷酸化位点。IRAK4被认为是IL-1受体和TLR下游的早期激活的关键蛋白激酶，通过快速激活IRAK1和IRAK2启动信号传导，导致先天免疫反应。此外，其他白细胞介素，如IL-18和IL-33，依赖IRAK4进行信号传导。临床病理学研究表明，具有IRAK4突变的个体对慢性肺病、炎症性肠病有防护作用。IRAK4缺陷本身无致死性，个体能够存活至成年，且随年龄增长受感染风险降低。诸多证据表明抑制IRAK4介导的信号传导将是一种有希望的治疗方法，IRAK4成为了一类重要治疗靶点，吸引了广泛的研发兴趣。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物，此类化合物能够被细胞的蛋白酶体识别，引起靶向蛋白的降解，能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体，使PROTAC技术应用于各种疾病的治疗成为可能，该技术近年来同时得到了广泛的关注。
IRAK4的特异性降解可以通过使用异双官能小分子将IRAK4募集至泛素连接酶并因此促进IRAK4的泛素化和蛋白酶体降解来实现，从而在IRAK4相关的疾病如自身免疫性疾病、炎性疾病和肿瘤中提供治疗机会。
发明内容
本发明提供一种化合物，或其药物组合物，其可作为IRAK4降解剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过所述化合物靶向降解IRAK4来 治疗疾病和/或病症。
具体的：
一方面，本发明涉及一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
其中：
环A为具有0-3个独立地选自氮、氧和硫的杂原子的8-13元螺环；
环B为苯基、萘基、5-6元单环杂芳基或9-10元双环杂芳基；
R1、R2和R3各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C2-6烯基、C1-6烷氧基、-(C0-3亚烷基)-C3-6环烷基或-(C0-3亚烷基)-3-8元杂环基，其中，所述C1-6烷基、C2-6烯基、C1-6烷氧基、-(C0-3亚烷基)-C3-6环烷基和-(C0-3亚烷基)-3-8元杂环基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟基烷基和C1-3卤代烷基的取代基所取代；
各Ra和Rb独立地为氢、氘、卤素、氧代、CN、NO2、-R4、-ORc、-SRc、-N(Rc)2、-C(Rc)3、-S(＝O)2Rc、-S(＝O)2N(Rc)2、-S(＝O)Rc、-S(＝O)(NRc)Rc、-P(＝O)(ORc)2、-P(＝O)(N(Rc)2)2、-CF(Rc)2、-CF2(Rc)、-CF3、-C(Rc)2-ORc、-C(Rc)2-N(Rc)2、-C(＝O)Rc、-C(＝O)ORc或-C(＝O)N(Rc)2；或相同原子上的两个Ra基团任选地与其中间原子结合在一起形成C3-4环烷基或3-4元杂环基；
各R4独立地为C1-6烷基、C2-6烯基、苯基、C3-7环烷基、3-7元杂环基或5-6元杂芳基环，所述R4可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代；
各Rc独立地为氢、氘、C1-6烷基、苯基、C4-7环烷基、4-7元杂环基或5-6元杂芳基，所述C1-6烷基、苯基、C4-7环烷基、4-7元杂环基和5-6元杂芳基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代；或相同原子上的两个Rc基团任选地与其中间原子结合在一起形成C4-7环烷基、具有0-3个独立地选自氮、氧和硫的杂原子的4-11元的桥接双环或螺环，所述C4-7环烷基和具有0-3个独立地选自氮、氧和硫的杂原子的4-11元的桥接双环或螺环可进一步任 选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代；
m和n各自独立为0、1、2、3、4、5、6、7或8；
L为C1-20亚烷基，其中1、2、3、4或5个亚甲基可独立任选地被选自-CRd＝CRd-、-C≡C-、-C(Rd)2-、-Cy-、-O-、-C(＝O)-和-N(Rd)-的单元所置换；
其中各-Cy-独立地为C4-7环烷基、4-11元杂环基、5-11元螺环基、5-11元桥接双环基、苯基、5-6元杂芳基，所述各-Cy-可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和-C1-3卤代烷基的取代基所取代；
各Rd独立地为氢、氘、卤素、CN、OH、NO2、NH2或C1-3烷基；
以及DIM为E3泛素连接酶结合部分。Von Hippel-Lindau(VHL)和cereblon(CRBN)蛋白是两种普遍表达和生物学上重要的Cullin RING E3泛素连接酶复合物的底物识别亚基，此外，凋亡抑制蛋白(IAP)是涉及抑制细胞凋亡的蛋白家族。人类IAP家族包括8个成员，并且许多其它生物体含有IAP同源物。IAP含有E3连接酶特异性结构域和杆状病毒IAP重复(BIR)结构域，其识别底物并促进它们的泛素化。式(I)化合物的DIM靶向E3连接酶的VHL、CRBN或IAP，其被双功能化合物利用以诱导IRAK4的泛素化和随后的蛋白酶体降解。
在一些实施方案中，环A为：
其中：
X1、X2、X3、X4、X5各自独立地为CH2、-C(＝O)-、NH、O或S；
a和c各自独立地为1或2；
b和d各自独立地为0、1或2，其中，b和d不同时为0且b和d之和为2、3或4。在一些实施方案中，各Ra独立地为氢、氘、卤素、氧代、CN、OH、NO2、NH2、-CF3或C1-6烷基；或相同原子上的两个Ra基团形成C3-4环烷基。优选各Ra独立地为氢、氘、卤素、氧代、CN、OH、NO2、NH2、-CF3、甲基、乙基、正丙基或异丙基；或相同原子上的两个Ra基团形成环丙基或环丁基。
在一些实施方案中，环B为：
在一些实施方案中，其中各Rb独立地为氢、氘、卤素、氧代、CN、OH、NO2、NH2、-COOH、C1-6烷基、C3-6环烷基、4-6元杂环基或7-8元桥接双环；所述C1-6烷基、C3-6环烷基、4-6元杂环基和7-8元桥接双环可独立任选地被1、2或3个选自氘、卤素、OH、CN、氧代、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代。优选各Rb独立地为氢、氘、卤素、CN、OH、NO2、NH2、-COOH、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基或所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基和可独立任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、甲基、乙基、甲氧基、乙氧基、-CHF2、-CF3、-OCHF2和-OCF3的取代基所取代。
在一些实施方案中，其中部分为：
其中：
Rb1和Rb4各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、CH3、CH2CH3、-CF2或-CF3；
Rb2和Rb3各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、-COOH、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、 哌啶基、哌嗪基、吗啉基或所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基和可独立任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、甲基、乙基、甲氧基、乙氧基、-CHF2、-CF3、-OCHF2和-OCF3的取代基所取代。
或其中部分为：
其中：
Rb1和Rb4各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、CH3、CH2CH3、-CF2或-CF3；
Rb2和Rb3各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、-COOH、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、吡啶或所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、吡啶和可独立任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、甲基、乙基、甲氧基、乙氧基、-CHF2、-CF3、-OCHF2和-OCF3的取代基所取代。
一些实施方案中，其中R1为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C1-6烷氧基或C3-6环烷基；R2为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C1-6烷氧基或C3-6环烷基。优选R1为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基、异丙基、甲氧基、环丙基、环丁基、环戊基或环己基；R2为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基、异丙基、甲氧基、环丙基、环丁基、环戊基或环己基。
一些实施方案中，其中R3为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C1-4烷氧基、C3-6环烷基或5-6元杂环基，所述C1-6烷基、C1-4烷氧基、C5-6环烷基和5-6元杂环基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、 C1-3卤代烷氧基、C1-3羟基烷基和C1-3卤代烷基的取代基所取代。优选R3为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、哌啶基、哌嗪基或吗啉基，所述甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、哌啶基、哌嗪基和吗啉基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、甲基、甲氧基、-CH2OH、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-OCHF2、-OCF3和-CH2CHF2和-C(CH3)2OH的取代基所取代。
在一些实施方案中，DIM部分为其中：X为CH或N；Y为键、-CH2-、-NH-、-O-、-C(＝O)-或-C(＝O)NH-；环C为苯基、5-6元单环杂芳基或9-10元双环杂芳基，所述环C可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代。
DIM部分优选为：

在一些实施方案中，其中L为C3-12亚烷基，其中1、2、3、4或5个亚甲基可独立任选地被选自-CRd＝CRd-、、-C(Rd)2-、-Cy-、-O-、-C(＝O)-、-N(Rd)-的单元所置换。优选L为C3-9亚烷基，其中1、2或3个亚甲基可独立任选地被选自-CRd＝CRd-、-C(Rd)2-、-O-、-C(＝O)-、-NH-、 的单元所置换，所述 可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、甲基、乙基、异丙基、甲氧基、异丙氧基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-OCHF2和-OCF3的取代基所取代；各Rd独立地为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基或异丙基。
在一些实施方案中，其中L为其中L为C1-9亚烷基，其中1、2、3或4个亚甲基可独立任选地被选自-CRd＝CRd-、-C≡C-、-C(Rd)2-、-O-、-C(＝O)-、-NH-、 的单元所置换，所述 可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、甲基、乙基、异丙基、甲氧基、异丙氧基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-OCHF2和-OCF3的取代基所取代；
各Rd独立地为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基或异丙基。
L可具体选为：

本发明还有一些方案是由上述各变量任意组合而来。
一些实施方案中，所述化合物，其具有式(II)、式(III)、式(IV)、式(V)或式(VI)所示结构：

其中：
Z1、Z3和Z4各自独立地为CH2、-C(＝O)-、NH、O或S；
Z2为CH或N；
p和q各自独立地为1或2。
所述DIM、环B、R1、R2、R3、Ra、Rb、L、m和n具有本发明所述的含义。
在一些实施方案中，所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：








一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)所述的化合物，或其异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的赋形剂、载体、辅剂或它们的任意组合。
另一方面，本发明涉及前述的化合物或其药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻患者与IRAK4相关的疾病。
在一些实施方案中，所述疾病选自炎症性疾病、感染如病毒、细菌、真菌和寄生虫感染、HIV-1感染、败血症、自身免疫性病症或疾病如类风湿性关节炎和多发性硬化症、痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病、增殖性疾病如癌症、增生、再狭窄、心脏肥大、白血病、血管内凝血、骨病、代谢疾病、神经和神经退行性疾病、心血管疾病、纤维化和过敏性疾病、哮喘、特应性皮炎、化脓性汗腺炎、阿尔茨海默病、激素相关疾病、外伤、血液透析、缺血性疾病、非感染性肝炎、紫外线辐射、闭合性头部损伤、胰腺炎、牙周炎、移植物抗宿主病和/或移植排斥。
本发明得到一系列活性高、毒性低、代谢稳定性好、成药性质优的化合物。
相关定义：
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短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，而应该按照普通的含义去理解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。
除非其他方面表明，本发明所描述的结构式和所述的化合物包括所有的异构形式、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐和前药。因此，本发明的化合物的单个立体化学异构体、对映异构体、非对映异构体、几何异构体、构象异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐和前药的化合物也属于本发明的范围。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
除非其他方面表明，本发明的“异构体”包括所有的同分异构形式(如对映异构，非对映异构，几何异构或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体、几何异构体或构象异构体的混合物都属于本发明的范围。
除非其他方面表明，本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。
除非其他方面表明，本发明的“水合物”是指溶剂分子是水所形成的缔合物。
除非其他方面表明，本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于：水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。
“代谢产物”是指本发明所述的具体的化合物或其药学上可接受的盐、类似物或衍生物在体内通过代谢作用所得到的产物，其在体内或体外表现出与式(I)化合物类似的活性。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用、或酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类、脂肪族(C1-24)酯类、酰氧基甲基酯类、碳酸酯、氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。
本发明所采用的术语“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。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，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(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。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0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
“环烷基”或“环烷烃”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环碳环体系，为饱和环或含一个或多个不饱和键的环，但绝不包含芳香环。在一实施方案中，环烷基包含3-10个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。这样的实例包括，但并不限于环丙基、环丁基、环戊基和环己基等。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环，绝不包含芳香环，其中至少一个环原子为杂原子。在一实施方案中，“杂环基”或“杂环”包含3-10个环原子；在一实施方案中，“杂环基”或“杂环”包含3-8个环原子；在另一实施方案中，“杂环基”或“杂环”包含5-8个环原子；在又一实施方案中，“杂环基”或“杂环”包含3-6个环原子；还在一实施方案中，“杂环基”或“杂环”包含5-6个环原子；再在一实施方案中，“杂环基”或“杂环”包含4-6个环原子；除非另外说明，杂环基可以是碳基或氮基，杂原子具有如本发明所述的含义。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、2-吡咯啉基、3-吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基和2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH2-基团被-C(＝O)-取代的实例包括，但不限于：2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于环丁砜基和1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环是芳香族的，其中每一个环包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香环，且至少一个环体系包含一个或多个杂原子，其中每一个环包含5-7个原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基包含1、2、3或4个独立选自O，S和N的杂原子，其中氮原子可以被进一步氧化。
杂芳基基团的实例包括，但并不限于：呋喃基、咪唑基(如N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、异噁唑基、恶唑基(如2-噁唑基、4-噁唑基、5-噁唑基)、吡咯基(如N-吡咯 基、2-吡咯基、3-吡咯基)、吡啶基、嘧啶基(如2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基、噻唑基(如2-噻唑基、4-噻唑基、5-噻唑基)、四唑基(如5-四唑基)、三唑基、噻吩基(如2-噻吩基、3-噻吩基)、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、吲哚啉基、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基和[1,2,4]三唑并[1,5-a]吡啶基，等等。
“螺环”表示饱和或部分不饱和的单环之间共用一个碳原子(称螺原子)的5至20元多环基团，可以含有0至5个的杂原子。优选为6至14元，进一步优选为8至13元，更优选8至10元，除非另外说明，否则螺环基团任选地被一或多个如本发明所描述的取代基取代。其非限定性实例包括： 等等。
“桥接双环”表示具有至少一个桥的饱和或部分不饱和的双环系统，可以含有0至5个的杂原子。“桥”为原子的未分支或连接两个桥头的原子或价键，其中“桥头”为与三个或更多个骨架原子(除氢以外)键合的环系统的任何骨架原子。在一些实施例中，桥接双环基团具有5-12个环成员和0-4个独立地选自氮、氧或硫的杂原子。这类桥接双环基团为所属领域中熟知的，其中每一个基团在任何可取代碳或氮原子处与分子的其余部分连接。除非另外说明，否则桥接双环基团任选地被一或多个如本发明所描述的取代基取代。另外或替代地，桥接双环基团的任何可取代氮任选地被取代。其非限定性实例包括： 等等。
“杂原子”表示氧、硫、氮、磷或硅中的一或多种(包含氮、硫、磷或硅的任何氧化形式；任何碱性氮的季铵化形式；杂环的可取代氮，例如N(如3，4-二氢-2H-吡咯基中)、NH(如吡咯烷基中)或NR+(如N取代的吡咯烷基中)。
“卤素”是指F、Cl、Br或I。
“氘”表示重氢，D。
“烷基”表示直链或支链的数个碳原子组成的饱和碳氢基团。
“烯基”表示直链或支链的包含至少一个碳-碳双键的由多个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。
“亚烷基”表示从直链或支链的饱和碳氢化物消去两个氢原子得到的饱和二价烃基。
“烷氧基”表示由式-OR表示的直链或支链的单价残基，其中R是上文所定义的烷基。
“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代。
“羟基烷基”表示烷基基团被一个或多个羟基所取代。
如本文所用，取代基画一个键连接到环上形成的环体系代表取代基在该环上任何可取代的位置都可以取代。例如，式(a)代表取代基R可以在吡啶环上任何可能被取代的位置上单取代或多取代。
如本文所用，与化学结构中的键相交的波浪线表示在化学结构中波状键与其连接的原子与分子的其余部分或与分子的片段的其余部分连接的点。
如本文所用，一个连接键连接到环上形成的环体系(如式b所示)代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。式b代表八氢环戊烯并[c]吡咯环上任何可能连接的位置均可与分子其余部分相连。
除非化学上或结构上需要，否则化学基团的书写或命名顺序不指示或暗示方向性。
如果结构与名称之间存在差异，则以结构为准。
一般合成过程
本发明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发明的实施例。
本发明采用下述缩略词：
mg      毫克                          mmol  毫摩
DIEA    N,N-二异丙基乙胺              DMF   N,N-二甲基甲酰胺
HATU    2-(7-氮杂苯并三氮             h     小时
唑)-N,N,N',N'-四甲基脲六氟磷酸酯
min     分钟                          wt％   质量百分比
DCM     二氯甲烷                      ACN、MeCN  乙腈
PE      石油醚                        EA    乙酸乙酯
MeOH    甲醇                          Pd/C  钯炭
THF     四氢呋喃                      TBSCl 叔丁基二甲基氯硅烷
TFA     三氟乙酸                      MsCl  甲磺酰氯
ppm     每百万单位                    TMS   四甲基甲硅烷
DMSO    二甲基亚砜                    TPSA  对甲苯磺酸
LDA     二异丙基氨基锂                (Boc)2O  二碳酸二叔丁酯
TEA     三乙胺                        LAH   氢化铝锂
DMAP    4-二甲氨基吡啶                TBAF  四丁基氟化铵
Pd(PPh3)2Cl  双三苯基磷二氯化钯        EtOH  乙醇
t-BuOK  叔丁醇钾                      AcOH  醋酸
t-BuONa  叔丁醇钠
下例实施例中所使用的原料、试剂等，如无特殊说明，均来源于市售或已知文献的合成路线。
设备及检测条件描述如下：1H NMR谱使用Bruker 500MHz核磁共振谱仪记录。1H NMR谱以CDCl3、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26 ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、q(quartet，四重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽的单峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数J，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent G6125C四级杆HPLC-MS(色谱柱型号：XBridge BEH C18,4.6 x 50mm,2.5微米,6min,流速为1mL/min。流动相：0％-95％(ACN)在(含0.1％甲酸的H2O:ACN＝90:10)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用DAD检测。
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。
具体实施方式
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，以下实施例仅用于说明本发明而不是对本发明的限制。
中间体的合成
中间体1(M1)：
步骤一：
将M1-1(制备过程参照WO2017108723A2实施例142的制备方法)(58mg,0.16mmol)置于50mL单口瓶中，分别加入4-羟甲基哌啶(37mg,0.33mmol)、碳酸钾(57mg,0.41mmol)、ACN(1mL)，加热至外温60℃反应1h。反应液过滤得到滤液，滤渣溶于水(5mL)，加入EA(5mL×2)萃取，合并有机相，无水硫酸钠干燥，柱层析纯化，PE:EA＝92:8～60:40，得橙色固体M1-2(54mg，产率：76.0％)。
ESI-MS(m/z):448.4[M+H]+.
1H NMR(500MHz,DMSO-d6)δ7.81(s,1H),6.61(s,1H),4.45(t,J＝5.1Hz,1H),3.57–3.48(m, 2H),3.41–3.32(m,2H),3.14(d,J＝12.0Hz,2H),3.01(s,2H),2.74(t,J＝11.5Hz,2H),1.83–1.65(m,7H),1.53–1.44(m,1H),1.41(s,9H),1.32–1.20(m,3H).
步骤二：
将M1-2(54mg,0.12mmol)、Pd/C(10wt％)(15mg)置于50mL单口瓶中，加入甲醇(10mL)，使用氢气球置换氢气3次并保持氢气氛围，外温35℃反应2h。反应液用硅藻土过滤除去Pd/C，用MeOH(20mL)洗至滤饼无色，合并有机相，减压蒸馏除去MeOH，得灰色固体M1-3(45mg，产率：89.6％)。
ESI-MS(m/z):418.5[M+H]+.
1H NMR(500MHz,CDCl3)δ6.63(s,1H),6.56(s,1H),3.73(s,2H),3.60(d,J＝6.2Hz,2H),3.42(t,J＝10.7Hz,2H),3.21(d,J＝11.3Hz,2H),2.92(s,2H),1.96–1.82(m,5H),1.75–1.60(m,4H),1.57–1.50(m,2H),1.50(s,9H).
步骤三：
将M1-3(320mg,0.82mmol)、吡唑[1,5-a]嘧啶-3-羧酸(134mg,0.82mmol)、HATU(375mg,0.99mmol)、DIEA(531mg,4.11mmol)置于50mL单口瓶中，加入DCM(18mL)，室温搅拌反应2h。反应液加入DCM(20mL)和水(15mL)，充分搅拌后静置分液，有机相无水硫酸钠干燥，旋干，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～98:2，得到棕黄色浆状物M1(417mg，产率：95.0％)。
ESI-MS(m/z):563.3[M+H]+.
1H NMR(400MHz,CDCl3)δ10.51(s,1H)8.75-8.87(m,3H)8.33-8.43(m,1H)7.03(dd,J＝6.97,4.16Hz,1H)6.71(s,1H)3.68-3.82(m,2H)3.64(d,J＝5.13Hz,2H)3.42(br t,J＝10.33Hz,2H)3.16(br d,J＝6.60Hz,2H)3.02(s,2H)2.73(br s,2H)1.92(br d,J＝13.33Hz,2H)1.70-1.86(m,7H)1.49(s,9H).
中间体2(M2)：
依次将M1-3(1.43g,3.43mmol)、呋喃[3,2-b]吡啶-3-羧酸(0.61g,3.77mmol)、DIEA(1.7mL, 10.27mmol)、HATU(1.56g,4.11mmol)置于100m L单口瓶中，加入无水DMF(10mL)，氮气置换，室温搅拌反应3h。向反应液中慢慢滴加水(80mL)，加完后搅拌30min。倒出水相，水相用EA(100mL)萃取，分液，EA相倒入反应瓶中剩余的发粘产物团，搅拌至完全溶解澄清，后用饱和食盐水(20mL×3)洗涤。有机相无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～95:5，得到棕黄色固体M2(1.34g，产率：69.8％)。
ESI-MS(m/z):563.2[M+H]+
1H NMR(400MHz,CDCl3)δ10.97(s,1H),8.68-8.75(m,1H),8.64(s,1H),8.33(s,1H),7.86-7.94(m,1H),7.33-7.41(m,1H),6.71-6.79(m,1H),3.69-3.82(m,2H),3.63(d,J＝5.88Hz,2H),3.36-3.49(m,2H),3.14-3.26(m,2H),3.02(s,2H),2.76(t,J＝10.07Hz,2H),1.92(d,J＝13.76Hz,2H),1.69-1.87(m,7H),1.49(s,9H).
采用上述中间体M1和中间体M2相似的方法分别制备以下中间体：



中间体24(M24)：
步骤一：
将M24-1(5.14g,30.00mmol)、M24-2(3.85g,30.00mmol)、对甲苯磺酸(0.86g,4.50mmol)置于100mL单口瓶中，加入甲苯(80mL)，加分水器，升温至外温135℃回流反应20h。减压浓缩，剩余物加入水(40mL)，用EA(80mL×2)萃取，合并有机相，无水硫酸钠干燥。减压浓缩，柱层析分离，洗脱剂为：PE:EA＝100:0～92:8，得到化合物M24-3，白色结晶性固体5.05g，产率：59.8％。
ESI-MS(m/z):282.1[M+H]+.
1H NMR(500MHz,CDCl3)δ6.67(dd,J＝8.5,4.5Hz,1H),6.56(dd,J＝8.2,2.4Hz,1H),6.50(td,J＝9.6,2.5Hz,1H),4.19(q,J＝7.1Hz,2H),3.77–3.61(m,4H),2.00(t,J＝5.4Hz,4H),1.30(t,J＝7.1Hz,3H).
步骤二：
将M24-3(4.57g,16.25mmol)置于100mL单口瓶中，加入乙醇(64mL)，冰浴冷却，慢慢加入NaOH(2.60g,64.99mmol)的水(8mL)溶液，加完后升温至外温80℃回流反应过夜。减压浓缩，剩余物加入DCM(100mL)和水(40mL)，充分搅拌后静置分液，上层水相用DCM(50mL)萃取一次，合并有机相，无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物M24-4，类白色固体3.38g，收率：99.5％。
ESI-MS(m/z):210.0[M+H]+.
1H NMR(500MHz,CDCl3)δ6.66(dd,J＝8.5,4.5Hz,1H),6.55(dd,J＝8.3,2.5Hz,1H),6.48(td,J＝9.6,2.5Hz,1H),3.12–3.04(m,4H),2.07(s,2H),2.04–1.98(m,4H).
步骤三：
将M24-4(3.00g,14.34mmol)置于100mL单口瓶中，加入DCM(30mL)，冰浴冷却，慢慢滴加发烟硝酸(3mL)，加完后保持冰浴反应2h。反应完全后减压浓缩除去DCM，后升温到水浴温度60℃继续浓缩除去过量的发烟硝酸。浓缩完毕，得到化合物M24-5黄色固体，直接投入下一步反应。
ESI-MS(m/z):255.1[M+H]+.
步骤四：
将步骤三得到的黄色固体M24-5置于100mL单口瓶中，加入DCM(50mL)混合，冰浴冷却，加入二碳酸二叔丁酯(4.69g,21.51mmol)，慢慢滴加三乙胺(4.35mg,43.01mmol)，加完后自然升温反应过夜。反应液加入水(30mL)，充分萃取后静置分液，上层水相再用DCM(30mL)萃取一次，合并有机相，无水硫酸钠干燥，浓缩。柱层析分离，PE：EA＝100:0～85:15，得到化合物M24-6类白色固体4.59g，产率：85.3％。
ESI-MS(m/z):299.0[M-55]+.
1H NMR(500MHz,CDCl3)δ7.50(d,J＝6.4Hz,1H),6.70(d,J＝10.3Hz,1H),3.73–3.59(m,4H),2.03(t,J＝5.6Hz,4H),1.51(s,9H).
步骤五：
将M24-6(354mg,1.00mmol)置于50mL单口瓶中，依次加入碳酸钾(414mg,3.00mmol)、4-羟甲基哌啶(230mg,2.00mmol)、乙腈(10mL)，加热至外温60℃反应1h。反应液加入饱和食盐水(15mL)，用EA(30mL)萃取，有机相无水硫酸钠干燥，浓缩，柱层析分离，洗脱剂为：PE:EA＝100:0～50:50，得到化合物M24-7橙黄色固体449mg，产率：100％。
ESI-MS(m/z):450.2[M+H]+.
1H NMR(500MHz,CDCl3)δ7.41(s,1H),6.69(s,1H),3.68-3.62(m,4H),3.59(d,J＝6.3Hz,2H),3.27(d,J＝11.6Hz,2H),2.83(t,J＝11.4Hz,2H),2.00(t,J＝5.3Hz,4H),1.84(d,J＝12.4Hz,2H),1.72-1.64(m,2H),1.55(td,J＝12.2,2.8Hz,2H),1.51(s,9H).
步骤六：
将M24-7(440mg,0.98mmol)置于50mL单口瓶中，加入甲醇(10mL)，再加入10％钯炭(100mg)，氢气球置换三次后保持氢气球，加热至外温35℃反应2h至黄色全部褪去。反应液硅藻土过滤，滤渣用甲醇洗涤至滤液无色，合并滤液，减压浓缩，得到化合物M24-8灰墨绿色泡沫状固体400mg，产率：97.4％，直接用于下一步反应。
ESI-MS(m/z):420.3[M+H]+.
步骤七：
将M24-8(400mg,0.95mmol)、吡唑[1,5-a]嘧啶-3-羧酸(156mg,0.95mmol)、HATU(435mg,1.14mmol)、DIEA(616mg,4.77mmol)置于50mL单口瓶中，加入DCM(10mL)，室温搅拌反应2h。反应液加入DCM(30mL)和水(15mL)，充分搅拌后静置分液，水相用DCM(20mL)萃取依次，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～98:2，得到化合物M24黄色固体471mg，产率：87.5％。
ESI-MS(m/z):565.3[M+H]+.
1H NMR(500MHz,CDCl3)δ10.67(s,1H),8.81(d,J＝4.5Hz,3H),8.13(s,1H),7.04(dd,J＝6.2,4.8Hz,1H),6.80(s,1H),3.72–3.58(m,6H),3.20-3.05(m,2H),2.85-2.70(m,2H),2.05-1.92(m,4H),1.90-1.76(m,4H),1.75-1.55(m,4H),1.51(s,9H).
中间体25(M25):
用中间体24(M24)相似的方法合成中间体25(M25)。
ESI-MS(m/z):565.3[M+H]+.
1H NMR(500MHz,CDCl3)δ11.12(s,1H),8.72(d,J＝4.6Hz,1H),8.63(s,1H),8.12(s,1H),7.90(d,J＝8.3Hz,1H),7.38(dd,J＝8.3,4.8Hz,1H),6.83(s,1H),3.70-3.60(m,6H),3.14(d,J＝10.5Hz,2H),2.84-2.71(m,2H),2.05-1.95(m,4H),1.90–1.75(m,4H),1.76–1.63(m,2H),1.51(s,9H).
中间体26(M26):
步骤一：
在-72℃下将LDA(2.46mL,18.6mmol，5.29eq)滴入到THF(7mL)和M26-2(0.61g,2.92mmol,0.83eq)的混合物中。滴加完反应液在-72℃搅拌1h后开始滴加M26-1(1.00g,3.52mmol,1.00eq),滴加完后室温搅拌16h。将反应液缓慢倒入水(10mL)中,乙酸乙酯(10mL×3)萃取,有机相用盐水(10mL)洗涤，无水硫酸钠干燥,柱层析法纯化(SiO2，石油醚/乙酸乙酯＝100:1～10:1)。 得到M26-3(920mg,2.22mmol,收率63.2％)为淡黄色粘稠油状物。
ESI-MS(m/z):313.0[M-100+1]+.
1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.58Hz,1H),7.48(d,J＝2.50Hz,1H),7.17(dd,J＝8.58,2.50Hz,1H),4.12-4.29(m,2H),3.10(s,2H),3.01(br s,2H),1.89(br d,J＝12.99Hz,2H),1.67(td,J＝13.11,4.29Hz,2H),1.47(s,9H).
步骤二：
将M26-3(20 0g,48.34mmol,1.00eq)溶于DMA(140mL)与水(14.0mL)的混合溶液中,加入TEA(26.9mL,193mmol,4.00eq)和1,1-双(二苯基磷)二茂铁氯化钯(3.54g,4.83mmol,0.10eq),置换氮气后加热到130℃反应12h。将水(150mL)加入到反应液中,有固体析出,滤出固体后,滤液用乙酸乙酯(150mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥后减压浓缩,柱层析纯化(SiO2，石油醚/乙酸乙酯＝100:1～10:1)。得到M26-4(13.00g,31.97mmol)为淡黄色固体状。
收率：66.2％.
ESI-MS(m/z):280.1[M-55]+.
步骤三：
将M26-4(14.0g,41.69mmol,1.00eq)置于100mL单口瓶中,加入DCM(9mL)后再加入盐酸二氧六环溶液(20.0mL,4M),反应液室温搅拌12h。反应液减压浓缩,高效液相色谱分离纯化。得到M26-5(2.15g,8.97mmol)为淡黄色固体。收率：21.5％.
ESI-MS(m/z):236.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.13Hz,1H)7.46(d,J＝0.63Hz,1H),7.36(dt,J＝8.19,0.78Hz,1H),3.18(dt,J＝13.01,3.63Hz,2H),3.07(s,2H),2.80(td,J＝12.41,2.69Hz,2H),1.85-1.93(m,2H),1.30-1.43(m,2H).
步骤四：
将M26-5(1.00g,4.24mmol,1.00eq)置于100mL单口瓶中加入DCM(7.0mL),0℃下缓慢滴加发烟硝酸(10mL,220.61mmol,53eq),滴加完反应液0℃下搅拌10min后升温至45℃继续搅拌12h。反应液减压浓缩,得到M26-6(1.30g,4.63mmol)为橙色固体。
ESI-MS(m/z):281.0[M+1]+.
步骤五：
将六氢吡啶-4-基甲酚(4.1mL,35.09mmol,5.00eq)溶于DCM(14mL)中,加入M26-6(1.97g,7.02mmol,1.00eq),25℃下搅拌2h。得到M26-7(2.52g,7.01mmol)的反应液直接用于下一步 反应。
ESI-MS(m/z):360.2[M+1]+.
步骤六：
在上一步的反应液中直接加入Boc酸酐(4.5mL,21.03mmol,3.00eq),25℃下搅拌12h。反应液减压浓缩，柱层析纯化(SiO2，石油醚/乙酸乙酯＝5:1～0:1),得到M26-8(1.58g,3.09mmol)为黄色固体。两步收率：44.1％。
ESI-MS(m/z):460.2[M+1]+.
步骤七：
在250mL单口瓶中加入THF(20mL),氩气保护下加入湿钯碳(1.1g,10.34mmol，3.01eq),M26-8(1.58g,3.44mmol,1.00eq)溶于THF(20mL)加入到上述反应液中，反应液在氢气(15psi)压力下室温搅拌3h。将反应液过滤，滤液减压浓缩，得到M26-9(1.50g,3.32mmol,收率96.5％)为类白色固体。
ESI-MS(m/z):430.3[M+1]+.
步骤八：
将M26-9(1.50g,3.32mmol,1.0eq)、呋喃并[3,2-b]吡啶-3-羧酸(569mg,3.49mmol,1.0eq)加入到100mL单口瓶中加入DMF(10mL),DIEA(1.2mL,6.98mmol,2.0eq),HATU(1.46g,3.84mmol,1.10eq),反应液25℃下搅拌2h。反应液减压浓缩，柱层析纯化(石油醚：乙酸乙酯＝3:1-1:2),得到M26(1.90g,2.24mmol,收率64.2％)为白色固体。
ESI-MS(m/z):575.3[M+1]+.
1H NMR(400MHz,CDCl3)δ10.92(s,1H),8.84(s,1H),8.68(dd,J＝4.77,1.19Hz,1H),8.63(s,1H),7.90(dd,J＝8.40,1.13Hz,1H),7.38(dd,J＝8.40,4.83Hz,1H),7.21(s,1H),4.14(br d,J＝1.55Hz,2H),3.63(d,J＝5.36Hz,2H),3.30(br d,J＝11.80Hz,2H),3.01(s,4H),2.72-2.80(m,2H),1.85-1.98(m,3H),1.35-1.55(m,13H),0.99(t,J＝7.27Hz,2H).
中间体27(M27)：
步骤一：
将M27-1(0.76g,2.49mmol)(制备过程参照专利WO2019183367A1第309-310页合成过程)、DCM(6mL)置于50mL单口瓶中，滴加TFA(1mL)，25℃搅拌反应1h。减压浓缩，得M27-2，淡黄色固体1.0g，产率：181％.
ESI-MS(m/z):222.0[M+H]+.
步骤二：
将M27-2(1.0g,2.49mmol)置于50mL单口瓶中，加入DCM(12.5mL)溶解，冰浴冷却，滴加发烟硝酸(25mL)，0℃下搅拌10min，室温搅拌1h。硝化完成后，减压浓缩，加入DCM(8mL)溶解，降温至0℃，加入二碳酸二叔丁酯(0.81g,3.72mmol)，滴加三乙胺(0.75g,7.44mmol)，0℃下搅拌10min，后室温搅拌2h。在0℃下，缓慢加入饱和氯化铵溶液(10mL)和饱和氯化钠溶液(10mL)，用EA(10mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝100:0～85:15，得M27-3，白色固体0.4g，产率：44.0％。
ESI-MS(m/z-100):267.0[M+H]+.
1H NMR(500MHz,CDCl3)δ8.52(d,J＝7.7Hz,1H),7.04(d,J＝10.6Hz,1H),4.15(d,J＝7.2Hz,2H),3.26(s,2H),2.97(s,1H),2.90(s,1H),2.03–1.97(m,2H),1.51(s,9H).
步骤三：
将M27-3(400mg,1.09mmol)、4-(羟甲基)哌啶-1-甲酸叔丁酯(252mg,2.18mmol)、碳酸钾(377mg,2.73mmol)、乙腈(4mL)置于10mL单口瓶中，外温60℃下搅拌16小时。减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝100:0～60:40，得到M27-4，黄色固体300mg，产率：59.5％。
ESI-MS(m/z):462.2[M+H]+.
1H NMR(500MHz,CDCl3)δ8.21(s,1H),6.60(s,1H),4.15(s,2H),3.60(d,J＝6.2Hz,2H),3.47 (d,J＝12.8Hz,2H),3.22(s,2H),3.05(t,J＝11.8Hz,2H),2.00–1.94(m,2H),1.88(d,J＝12.8Hz,2H),1.84–1.76(m,1H),1.64–1.58(m,4H),1.51(s,9H).
步骤四：
将M27-4(2700mg,5.85mol)、Pd/C(600mg)和甲醇(100mL)置于250mL单口瓶中，置换氢气，室温搅拌5小时。过滤，减压浓缩得到M27-5，白色固体2524mg，产率：100％。
ESI-MS(m/z):432.3[M+H]+.
步骤五：
将M27-5(1100mg,2.55mmol)、吡唑并[1,5-a]嘧啶-3-羧酸(830mg,5.1mmol)、HATU(1450mg,3.82mmol)、DIEA(1290mg,12.75mmol)和DCM(10mL)置于50mL单口瓶中，室温搅拌16h。加入饱和氯化钠溶液(120mL)，用EA(120mL×3)萃取，减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝100:0～50:50，得到M27，黄色固体500mg，产率：34.0％。
ESI-MS(m/z):577.3[M+H]+.
中间体28(M28)：
将M27-5(1400mg,3.24mmol)、呋喃并[3,2-b]吡啶-3-羧酸(528mg,3.24mmol)、HATU(1850mg,4.87mmol)、DIEA(1310mg,12.98mmol)和DCM(20mL)置于50mL单口瓶中，室温搅拌16小时。加入饱和氯化钠溶液(120mL)，用EA(120mL×3)萃取，减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝100:0～50:50，得到M28，黄色固体900mg，产率：95.3％。
ESI-MS(m/z):577.2[M+H]+.
1H NMR(500MHz,CDCl3)δ10.59(s,1H),8.59(s,1H),8.55(d,J＝4.7Hz,1H),8.50(s,1H),7.78(d,J＝8.4Hz,1H),7.26(dd,J＝8.3,4.8Hz,1H),6.74(s,1H),4.10–3.99(m,2H),3.48(d,J＝5.0Hz,2H),3.25(d,J＝11.6Hz,2H),3.10–3.04(m,2H),2.63(t,J＝10.8Hz,2H),1.89–1.86(m,1H),1.83(dd,J＝12.9,4.1Hz,2H),1.71(d,J＝10.0Hz,2H),1.60(d,J＝7.4Hz,2H),1.48(s,2H),1.38(s,9H).
中间体29(M29)：
制备过程参照专利WO2021247897A1第[00443]段Intermediate HP的合成。
中间体30(M30)：
制备过程参照专利WO2020206424 A1第573页B32-2的合成。
中间体31(M31)：
及其盐型
制备过程参照专利WO2021247899A1第90页中间体APT的合成。
中间体32(M32)：
制备过程参照专利WO2021158634A1第195页中间体WW制备方法。
中间体33(M33)：
步骤一：
将M33-1(30.0g,174mmol)置于1L的三口瓶中加入四氢呋喃(300mL)，将反应液降温至0℃，在0℃缓慢滴加氢化铝锂的四氢呋喃溶液(105mL,261mmol,2.5M)，滴加完毕后反应在25℃下搅拌过夜。将反应液降温至0℃，冰浴下缓慢加入十水硫酸钠进行淬灭，淬灭过程半小时，充分淬灭后将反应液进行过滤，然后将过滤得到的母液减压浓缩。得到M33-2(22.0g,169mmol)为白色固体。收率：97.0％。
ESI-MS(m/z):没有MS响应。
1H NMR(400MHz,CD3OD)δ3.64-3.42(m,1H),3.36-3.34(m,2H),2.03-1.90(m,2H),1.87-1.76(m,2H),1.45-1.33(m,1H),1.30-1.16(m,2H),1.06-0.92(m,2H).
步骤二：
将M33-2(43.5g,334.13mmol)溶于DCM(400mL)溶液中，将氯二甲基(2-甲基丙-2-基)硅烷(57.9mL,334.13mmol,1.00eq)，TEA(35.5g,350.83mmol,1.05eq)和DMAP(0.41g,3.34mmol,0.01eq)加入到反应液中，反应液在25℃下搅拌12h。反应液中加入水(400mL)，水相用DCM(400mL×3)萃取后将合并的有机相用无水硫酸钠干燥，减压浓缩，柱层析纯化(PE/EA＝10:1-1:1)。得到M33-3(63.0g,257.72mmol,收率77.1％)为淡黄色油状物。
ESI-MS(m/z):没有MS响应。
步骤三：
将M33-3(15.25g,62.38mmol)溶于THF(150mL)溶液中，反应液降温至0℃，在氮气保护下，缓慢加入NaH(3.74g,93.58mmol,1.5eq)，加完后反应液在0℃下搅拌30min，然后将溴丙炔(8.1mL,74.86mmol,1.2eq)加入到上述混合反应液，反应液25℃下搅拌12h。将反应液降温至0℃，向反应液中缓慢加入水淬灭NaH。淬灭完毕向用乙酸乙酯(200mL×3)萃取，有机相用饱和食盐水(300mL)反洗一次后用无水硫酸钠干燥，减压浓缩，柱层析纯化(PE/EA＝10:1-5:1).得到M33-4(5.33g,18.87mmol,30.2％)为黄色油状物。
ESI-MS(m/z):没有MS响应。
步骤四：
将M33-4(40.6g,143.72mmol)置于1L单口瓶中加入THF(400mL),降温至0℃加入TBAF(287.4mL,287.43mmol),室温搅拌过夜,反应液减压浓缩后柱层析纯化(PE/EA＝10/1-2/1),得到M33-5(25g,148.60mmol)为棕色油状物。
ESI-MS(m/z):没有MS响应。
1H NMR(400MHz,DMSO-d6)δ4.17(d,J＝2.38Hz,2H),3.34-3.39(m,2H),3.24(br t,J＝5.57Hz,2H),2.54(br s,1H),1.97-2.07(m,3H),1.72-1.85(m,2H),1.27-1.42(m,1H),1.06-1.18(m,2H),0.84-1.00(m,2H).
步骤五：
将M33-5(6g,35.66mmol,2.0eq)置于100mL单口瓶中加入DMF(60mL)和M29(6.03g,17.83mmol),碳酸铯(11.62g,35.66mmol,2.0eq)和双三苯基磷二氯化钯(1.39g,1.78mmol,0.1eq)加入到反应液中,反应液在氮气保护下100℃搅拌2h。反应液中加入四氢呋喃(150mL),搅拌1h后过滤,滤饼用THF(50mL×2)冲洗,滤液减压浓缩,柱层析纯化(石油醚:四氢呋喃＝3:1-1:2),得到M33-6(2.37g,5.57mmol,收率31.2％)为黄色固体。
ESI-MS(m/z):426.3[M+1]+.
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),7.18(d,J＝7.8Hz,1H),7.12(d,J＝7.7Hz,1H),7.04(t,J＝7.8Hz,1H),5.41(dd,J＝12.6,5.3Hz,1H),4.47(s,2H),4.41(t,J＝5.3Hz,1H),3.65(s,3H),3.43(td,J＝10.7,5.3Hz,1H),3.21(t,J＝5.7Hz,2H),2.97–2.82(m,1H),2.71(ddd,J＝35.6,22.0,10.6Hz,2H),2.05(d,J＝11.3Hz,3H),1.76(d,J＝12.2Hz,2H),1.36–1.25(m,1H),1.20–1.09(m,2H),0.92(q,J＝11.0Hz,2H).
步骤六：
将M33-6(0.70g,1.65mmol)溶于DCM(10.0mL)中，反应液降温至0℃，将Dess-Martin(1.05g, 2.47mmol,1.50eq)加入到上述反应液中，加料完毕后反应室温搅拌12h。向反应液中加入饱和碳酸氢钠水溶液进行淬灭Dess-Martin氧化剂，硅藻土过滤，滤液用DCM(20.0mL×3)萃取，合并的有机相用饱和食盐水反洗(30mL)后用无水硫酸钠干燥，减压浓缩旋，柱层析纯化(PE/EA＝1:1-1:5)，得到M33(340mg,0.80mmol,收率48.8％)为淡黄色固体。
ESI-MS(m/z):424.1[M+1]+.
1H NMR(400MHz,CDCl3)δ9.59(s,1H),8.08(s,1H),7.10(d,J＝7.9Hz,1H),6.92(t,J＝7.9Hz,1H),6.69(d,J＝7.9Hz,1H),5.13(dd,J＝12.5,5.3Hz,1H),4.39(s,2H),3.71(s,3H),3.51–3.41(m,1H),2.91-2.60(m,3H),2.24–2.12(m,2H),2.11–1.98(m,4H),1.40–1.26(m,4H).
中间体34(M34)：
采用(1s,4s)-乙基4-羟基环己甲酸基酯为起始物料，采用跟中间体33(M33)相同的合成方法合成中间体34(M34)。
ESI-MS(m/z):424.2[M+1]+.
1H NMR(400MHz,CDCl3)δ9.65(s,1H),8.12(br s,1H),7.17(d,J＝7.88Hz,1H),6.94-7.04(m,1H),6.73-6.82(m,1H),5.20(dd,J＝12.57,5.32Hz,1H),4.39-4.45(m,2H),3.75-3.82(m,4H),2.67-2.96(m,3H),2.15-2.35(m,2H),1.87-2.09(m,4H),1.62-1.76(m,4H).
中间体35(M35)：
步骤一：
将3-溴-2-氟苯甲腈(100g,500mmol)置于2L的三口圆底烧瓶中加入乙醇(700mL)，将甲基肼(267.8mL,1999.90mmol,4eq,40％水溶液)缓慢滴加到上述反应液中，滴加完毕后反应升温至80℃搅拌过夜。将反应液进行真空浓缩，加入水(500mL)，用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，柱层析分离，洗脱剂为：PE:EA＝5:1～1:1。得到M35-1(51.0g,225.58mmol)的黄色固体。收率：45.1％。
ESI-MS(m/z):226.0[M+1]+.
1H NMR(400MHz,DMSO-d6)δ7.72(dd,J＝0.8,7.9Hz,1H),7.48(dd,J＝0.8,7.4Hz,1H),6.82(t,J＝7.7Hz,1H),5.59(s,2H),4.01(s,3H).
步骤二：
将DBU(33.7mL,225.58mmol)和乳酸(16.9mL,225.58mmol)等摩尔混合在100mL的圆底烧瓶中，反应在25℃下搅拌过夜。将丙烯酸乙酯(184.1mL,1691.88mmol,7.5eq)和M35-1(51.0g,225.58mmol,1eq)置于1L圆底烧瓶中，加入乳酸(16.9mL,225.58mmol)和DBU(33.7mL,225.58mmol)等摩尔混合物，80℃下搅拌120h。向反应体系加入水(500mL)，用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，柱层析分离，洗脱剂为： PE:EA＝10:1～3:1。得到M35-2(30.0g,91.97mmol)的棕色油状物,收率：40.8％。
ESI-MS(m/z):326.0[M+1]+.
步骤三：
将M35-2(30.0g,91.97mmol,1eq)置于500mL圆底烧瓶中加入冰乙酸(120mL)，然后将氰酸钾(10.9mL,275.91mmol,3eq)加入到上述反应液，加料完毕后，反应在25℃下搅拌过夜。将反应液减压浓缩除去AcOH，向反应体系倒入水(100mL)，乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝30:1～20:1。得到M35-3(14.0g,37.92mmol)棕色固体。收率：41.2％。
ESI-MS(m/z):369.0[M+1]+.
步骤四：
将M35-3(5.00g,13.54mmol,1.0eq)置于100ml圆底烧瓶加入乙腈(25.0mL)溶液中，然后将苄基三甲基氢氧化铵(3.7mL,20.31mmol,1.5eq,40wt.％甲醇溶液)滴加到上述混合反应液中，反应在25℃下搅拌45分钟。向反应体系倒入水(50mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，柱层析分离，洗脱剂为：PE:EA＝5:1～1:1。得到M35-4(2.00g,6.19mmol)的淡黄色固体。收率：45.7％。
ESI-MS(m/z):323.0[M+1]+.
步骤五：
将M35-4(1.00g,3.09mmol,1.0eq)置于100ml圆底烧瓶加入DMF(10mL)，然后依次加入叔-丁基4-(丙-2-炔-1-氧基)哌啶-1-甲酸基酯(0.89g,3.71mmol,1.2eq)、碳酸铯(2.02g,6.19mmol,2.0eq)，加料完毕氮气置换3次后将二氯双(三苯基膦)钯(II)(0.24g,0.31mmol，0.1eq)加入到上述反应液，加料完毕后反应在氮气保护下80℃搅拌2小时。将反应液真空浓缩除去DMF后，向反应体系倒入水(50mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，柱层析分离，洗脱剂为：PE:EA＝5:1～1:1。得到M35-5(130mg,0.27mmol)的棕色油状物。收率：8.7％。
ESI-MS(m/z):426.3[M-55]-
步骤六：
将M35-5(130mg,0.27mmol,1.0eq)置于50mL圆底烧瓶，加入DCM(6.00mL)，反应液降温至0℃后缓慢滴加盐酸二氧六环溶液(2.00mL)，在25℃下搅拌12h。反应液减压浓缩，得到M35(100mg,0.26mmol)的棕色固体。收率：97.1％。
ESI-MS(m/z):382.2[M+1]+.
中间体36(M36)：
步骤一：
将M35-4(1.00g,3.09mmol)置于50mL单口瓶,加入二氧六环(10.0mL)，将三丁基-λ4-锡烷基甲醇(1.49g,4.64mmol,1.5eq)加入到上述反应液，氮气置换3次，四三苯基磷钯(0.18g,0.15mmol)加入到上述反应液中，反应在90℃下搅拌12h。向反应体系倒入水(30.0mL)中，用乙酸乙酯(30.0mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩。柱层析分离，洗脱剂为：EA:MeOH＝20:1～9:1。得到M36-1(0.1g,0.36mmol,收率11.8％)为淡黄色油状物。ESI-MS(m/z):275.2[M+1]+.
步骤二：
将M36-1(100mg,0.36mmol)置于50mL单口瓶中,加入二氯甲烷(10.0mL)，将二氧化锰(626mg,7.20mmol,20eq)加入到上述反应液中，加料完毕后25℃下搅拌12h。反应液过滤，滤饼用二氯甲烷(20.0mL)洗涤5次，滤液减压浓缩。得到M36(99mg,0.36mmol,收率99.7％)为黄色固体。
ESI-MS(m/z):273.2[M+1]+.
1H NMR(400MHz,DMSO-d6)δ10.77-10.45(m,1H),10.28(s,1H),8.05(br dd,J＝7.8,11.9Hz,2H),7.35(t,J＝7.6Hz,1H),4.29(s,3H),3.94(br t,J＝6.4Hz,2H),2.78(br t,J＝6.4Hz,2H).
中间体37(M37)：
步骤一：
将M37-1(5.00g,34.9mmol,1.0eq)置于250mL单口瓶中,加入THF(50mL)和甲酸甲酯(2.73g,45.3mmol,1.3eq),0℃下缓慢加入叔丁醇钾的四氢呋喃溶液(38.4mL,38.4mmol,1M,1.1 eq),搅拌2h后加入正己烷(40mL),将体系升温到10℃继续搅拌0.1h,反应液静置析出白色固体,过滤并用(THF:Hexane＝1:1)的混合溶剂冲洗滤饼,收集固体减压浓缩,得到M37-2(900mg,4.30mmol,收率12.3％)为白色固体。
1H NMR(400MHz,CD3OD)δ5.14-5.37(m,1H),4.74(s,1H),3.63(q,J＝7.11Hz,4H),1.12-1.28(m,6H).
步骤二：
将3-氨基吡唑-4-甲酸(607mg,4.78mmol,1.0eq)置于40mL单口瓶,加入醋酸(5.5mL,95.56mmol,20eq),在10℃下搅拌0.1h,将M37-2(1000mg,4.78mmol,1.0eq)溶于EtOH(16mL)滴入到上述反应液中,升温至80℃搅拌2h,析出白色固体,过滤收集固体减压浓缩,得到M37(520mg,2.76mmol,收率57.8％)为白色固体。
1H NMR(400MHz,DMSO-d6)δ10.05(d,J＝2.03Hz,1H),8.96(d,J＝2.03Hz,1H),8.69(s,1H)
中间体38(M38)：
步骤一：
将2-溴丙二醛(5.86g,38.8mmol,1.0eq)置于100mL单口瓶中加入EtOH(60mL),升温至70℃后加入乙基5-氨基-1H-吡唑-4-甲酸基酯(6.02g,38.8mmol,1.0eq)与AcOH(28.9mL,504mmol,13eq),体系在70℃搅拌0.5h,将反应体系置于冰浴中,逐渐析出棕色固体,过滤后滤饼减压浓缩得到M38-1(5.80g,21.4mmol,收率:55.3％)为棕色固体。
ESI-MS(m/z):270.0,272.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.76(d,J＝2.13Hz,1H),8.91(d,J＝2.13Hz,1H),8.61(s,1H),4.30(q,J＝7.05Hz,2H),1.31(t,J＝7.07Hz,3H)
步骤二：
将M38-1(1.00g,3.70mmol,1.0eq)置于100mL单口瓶中加入二氧六环(9mL)和水(1mL),乙酸甲基三氟硼酸钾盐(870mg,0.14mmol,1.3eq),Pd(dba)2(320mg,0.56mmol,0.15eq),RuPhos(0.52g,1.11mmol,0.3eq)与碳酸钠(0.59g,5.55mmol,1.5eq)加入到反应液中,110℃搅拌10h。反应液减压浓缩后加入水(30mL),乙酸乙酯(80mL×3)萃取,合并有机相加入无水硫 酸钠干燥,柱层析分离纯化(石油醚:乙酸乙酯＝2:1-0:1),得到M38-2(450mg,2.03mmol,收率:54.9％)为淡黄色固体。
ESI-MS(m/z):222.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.83(d,J＝1.91Hz,1H),8.59(s,1H),5.57(br s,1H),4.63(s,2H),4.30(q,J＝7.15Hz,2H),1.31(t,J＝7.09Hz,4H).
步骤三：
将M38-2(370mg,1.67mmol,1.0eq)置于100mL单口瓶中加入EtOH(5mL),加入NaOH(100mg,2.51mmol,1.5eq)的水(5mL)溶液,50℃下搅拌2h。向反应液中滴入盐酸(1M)至pH＝6,将混合液减压浓缩,得到M38(323mg,1.67mmol)为淡黄色固体直接用于下一步反应。
ESI-MS(m/z):194.0[M+H]+.
实施例
实施例1：
步骤一：
将M1(3g,5.33mmol)置于250mL单口瓶中加入DCM(15mL),HCl的二氧六环溶液(15mL,60.00mmol)，反应室温搅2h。反应液减压浓缩后加入饱和碳酸氢钠水溶液(30mL)，搅拌30min后过滤，滤饼用水洗两次，收集滤饼加入乙酸乙酯(15mL)，搅拌2h后过滤，收集滤饼，得到化合物1-1(1.8g,3.89mmol,73.0％)为黄色固体。
ESI-MS(m/z):463.2[M+H]+.
步骤二：
将KOAc(196mg,2.00mmol)、1-1(232mg,0.50mmol)、4-(2-氧代乙基)哌啶-1-羧酸叔丁酯(114mg,0.50mmol)置于25mL单口瓶中，氮气置换，加入无水DMF(1.5mL)，室温搅拌反应30min， 后加入三乙酰氧基硼氢化钠(212mg,1.00mmol)，继续室温搅拌反应2h。反应液滤膜过滤并用少量DMF洗涤，滤液送制备色谱纯化，得到化合物1-2，灰色固体199mg，产率：59.1％。ESI-MS(m/z):674.7[M+H]+.
步骤三：
将1-2(199mg,0.30mmol)置于50mL单口瓶中，加入DCM(10mL)搅拌溶解，慢慢加入4.0M的盐酸二氧六环溶液(6mL)，室温搅拌反应2h。反应液直接减压浓缩，得到化合物1-3，棕黄色固体，直接用于下一步反应。
步骤四：
将M30(92mg,0.25mmol)、1-3(172mg,0.30mmol)、碳酸钾(103.82mg,0.75mmol)、三乙胺(152mg,1.50mmol)置于25mL单口瓶中，加入无水乙腈(5mL)和无水DMF(3mL)，氮气置换后加热至外温70℃反应过夜。反应液过滤，滤液旋蒸除去乙腈等低沸点溶剂，剩余DMF溶液送制备色谱纯化，得到实施例1，淡黄色固体50mg，产率：23.6％。
ESI-MS(m/z):845.8[M+H]+.
1H NMR(500MHz,CDCl3)δ10.49(s,1H),8.87–8.76(m,3H),8.47(s,2H),8.25(br s,1H),7.04(dd,J＝6.9,4.2Hz,1H),6.98(t,J＝7.8Hz,1H),6.91(d,J＝7.6Hz,1H),6.77(d,J＝7.7Hz,1H),6.67(s,1H),5.23(dd,J＝12.2,5.1Hz,1H),3.81(s,3H),3.71–3.58(m,4H),3.41–3.29(m,2H),3.17–3.02(m,6H),3.02–2.62(m,10H),3.38–2.21(m,3H),2.11(d,J＝14.0Hz,2H),2.01(t,J＝11.3Hz,2H),1.88–1.62(m,9H),1.50–1.34(m,2H).
实施例2：
步骤一：
将M3(1300mg,2.43mmol)置于100mL单口瓶中，加入DCM(30mL)溶解，慢慢加入4.0M 的盐酸二氧六环溶液(5mL)，保持室温搅拌反应3h。反应液直接减压浓缩，得到化合物2-1，棕黄色固体，直接用于下一步反应。
步骤二：
于25mL单口瓶中，将KOAc(197mg,2.01mmol)、2-1(232mg,0.50mmol)、4-(2-氧代乙基)哌啶-1-羧酸叔丁酯(114mg,0.50mmol)混合于无水DMF(3mL)中，室温搅拌反应30min，加入三乙酰氧基硼氢化钠(212mg,1.00mmol)，继续室温搅拌反应2h。反应液加入水(20mL)，用EA(40mL×2)萃取，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩。柱层析分离，洗脱剂为：DCM:MeOH＝100:0～90:10，得到化合物2-2，淡黄色固体324mg，产率：100％。
ESI-MS(m/z):646.8[M+H]+.
1H NMR(500MHz,CDCl3)δ10.37(s,1H),8.76(d,J＝6.3Hz,1H),8.72-8.67(m,2H),8.38(s,1H),7.00(dd,J＝6.6,4.2Hz,1H),6.59(s,1H),4.10-3.95(m,2H),3.91-3.85(m,4H),3.35-2.84(m,12H),2.69-2.57(m,2H),2.28-2.02(m,4H),1.75-1.55(m,4H),1.53-1.43(m,1H),1.38(s,9H),1.10(dd,J＝20.9,11.6Hz,2H).
步骤三：
将2-2(315mg,0.49mmol)置于50mL单口瓶中，加入DCM(10mL)溶解，慢慢加入4.0M的盐酸二氧六环溶液(2mL)，保持室温搅拌反应3h。反应液直接减压浓缩，得到化合物2-3，棕黄色固体，直接用于下一步反应。
步骤四：
依次将M30(73mg,0.20mmol)、2-3(108mg,0.20mmol)、碳酸钾(82mg,0.60mmol)、三乙胺(121mg,1.19mmol)置于25mL单口瓶中，加入DMF(1mL)和乙腈(5mL)，加热至外温50℃搅拌反应过夜。反应液加入水(15mL)，用DCM(40mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～95:5，得到实施例2，淡黄色固体79mg，产率：84.5％。
ESI-MS(m/z):817.7[M+H]+.
1H NMR(500MHz,CDCl3)δ10.37(s,1H),8.76(dd,J＝6.9,1.3Hz,1H),8.73-8.67(m,2H),8.36(s,1H),8.19(br s,1H),6.98(dd,J＝6.9,4.1Hz,1H),6.88(t,J＝7.7Hz,1H),6.82(d,J＝7.5Hz,1H),6.67(d,J＝7.6Hz,1H),6.59(s,1H),5.14(dd,J＝12.1,5.2Hz,1H),3.95-3.85(m,4H),3.73(s,3H),3.61–3.46(m,2H),2.97(s,2H),2.90–2.50(m,12H),2.20–1.87(m,4H),1.67–1.48(m,4H),1.36–1.08(m,8H).
用与实施例1和实施例2相似的方法合成以下实施例：


实施例18：
步骤一：
将2-1(218mg,0.50mmol)置于25mL单口瓶中，加入无水DMF(6mL)，室温搅拌溶解，再加入碳酸钾(208mg,1.51mmol)和(2-溴乙氧基)-叔丁基二甲基硅烷(480mg,2.01mmol)，加热至外温60℃搅拌反应过夜。反应液加入DCM(50mL)，用水(15mL)洗涤，分液，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～90:10，得到化合物18-1，淡黄色固体244mg，产率：82.0％。
ESI-MS(m/z):593.6[M+H]+.
1H NMR(500MHz,CDCl3)δ10.36(s,1H),8.74(dd,J＝7.0,1.4Hz,1H),8.70(s,1H),8.68(dd,J＝3.9,1.4Hz,1H),8.35(s,1H),6.97(dd,J＝6.9,4.1Hz,1H),6.60(s,1H),3.95–3.81(m,4H),3.78-3.71(m,2H),2.93(s,2H),2.82(dd,J＝12.3,8.0Hz,4H),2.75-2.50(m,6H),1.95-1.85(m,4H),0.83(s,9H),-0.00(s,6H).
步骤二：
将18-1(235mg,0.40mmol)置于50mL单口瓶中，加入THF(8mL)，室温搅拌溶解，冰浴冷却，慢慢加入1.0M TBAF(0.5mL,0.48mmol)，加完后撤去冰浴，30℃下反应4h。反应液直接减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～90:10，得到化合物18-2，黄色固体165mg，产率：87.0％。
ESI-MS(m/z):479.5[M+H]+.
1H NMR(500MHz,CDCl3)δ10.38(s,1H),8.76(dd,J＝7.0,1.4Hz,1H),8.73-8.67(m,2H),8.37(s,1H),6.99(dd,J＝6.9,4.1Hz,1H),6.61(s,1H),3.94–3.81(m,4H),3.63(t,J＝4.9Hz,2H), 2.96(s,2H),2.89–2.79(m,4H),2.76-2.58(m,6H),2.00–1.80(m,4H).
步骤三：
将18-2(161mg,0.34mmol)置于25mL单口瓶中，加入三乙胺(170mg,1.68mmol)和DCM(8mL)，室温搅拌至溶解，冰浴冷却，慢慢加入MsCl(58mg,0.50mmol)，加完后撤去冰浴，室温反应3h。反应液加入水(15mL)，用DCM(30mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到化合物18-3，淡黄色固体164mg，产率：87.6％，直接用于下一步反应。ESI-MS(m/z):497.4[M+H]+.
步骤四：
于25mL单口瓶中，将M31(67mg,0.17mmol)混合于乙腈(3mL)中，加入18-3(82mg,0.15mmol)和碳酸钾(61mg,0.44mmol)，再加入DMF(1mL)，加热至外温60℃搅拌反应过夜。反应液滤膜过滤，滤液制备色谱纯化，冻干得到实施例18，类白色固体74mg，产率：58.6％。ESI-MS(m/z):857.7[M+H]+.
实施例19：
步骤一：
将化合物1-1(600mg,1.30mmol)，三乙胺(0.4mL,2.59mmol)，加入DMF(8mL)中，搅拌10分钟后，加入1-溴-2-氯乙烷(923mg,6.50mmol)和碳酸氢钠(218mg,2.59mmol)，溶液于室温下反应过夜，减压浓缩，加水(20mL)，用二氯甲烷(20mL×3)萃取，无水硫酸钠干燥，减压浓缩，硅胶柱层析(DCM/MeOH＝20:1)得到化合物19-1，黄色固体产物450mg,产率66.1％。ESI-MS(m/z):525.2[M+H]+.
步骤二：
将M31(40mg,0.10mmol)，三乙胺(20mg,0.20mmol)加入DMF(5mL)中，搅拌10分钟，再加入19-1(50mg,0.10mmol)和碳酸氢钠(17mg,0.20mmol)，溶液于50℃下反应5h，冷却至室温，减压浓缩，制备液相分离纯化，冻干得到实施例19，淡黄色固体产物6.5mg,产率7.7％。
ESI-MS(m/z):885.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.48(s,1H),9.36(dd,J＝7.0,1.6Hz,1H),8.91–8.87(m,1H),8.67(s,1H),8.33(s,1H),7.36–7.30(m,1H),7.18(d,J＝7.8Hz,1H),7.14–7.10(m,1H),7.03(t,J＝8.0Hz,1H),6.72(s,1H),5.40(dd,J＝12.6,5.4Hz,1H),4.47(s,2H),3.64(s,3H), 3.61–3.52(m,2H),3.44–3.37(m,4H),3.01–2.88(m,5H),2.82–2.56(m,8H),2.46(s,4H),2.22–2.11(m,2H),2.08–1.99(m,1H),1.93–1.68(m,8H),1.64–1.44(m,5H).
用与实施例18和实施例19相似的方法合成以下实施例：


实施例31：
步骤一：
依次将18-3(82mg,0.15mmol)、2-叔丁氧羰基-2,7-二氮杂螺[3.5]壬烷(50mg,0.22mmol)、碳酸钾(61mg,0.44mmol)置于25mL单口烧瓶中，加入乙腈(2mL)，加热至外温60℃反应过夜。反应液加入DCM(50mL)，用水(20mL)洗涤一次，分液，有机相无水硫酸钠干燥。减压浓缩，柱层析分离，洗脱剂为：DCM:MeOH＝100:0～90:10，得到化合物31-1，黄色固体85mg，产率：84.0％。
ESI-MS(m/z):687.6[M+H]+.
1H NMR(500MHz,CDCl3)δ10.37(s,1H),8.75(dd,J＝7.0,1.5Hz,1H),8.73–8.64(m,2H),8.36(s,1H),6.98(dd,J＝6.9,4.1Hz,1H),6.60(s,1H),3.92–3.82(m,4H),3.54(s,4H),2.94(s,2H),2.87–2.80(m,4H),2.71–2.47(m,6H),2.43–2.11(m,6H),1.98-1.78(m,4H),1.75-1.65(m,4H),1.37(s,9H).
步骤二：
将31-1(80mg,0.12mmol)置于25mL单口瓶中，加入DCM(5mL)溶解，室温下慢慢滴加盐酸二氧六环溶液(1.5mL)，加完后保持室温搅拌反应2h。反应液直接减压浓缩，得到化合物31-2，淡粉黄色固体，直接用于下一步反应。
ESI-MS(m/z):587.6[M+H]+.
步骤三：
依次将M30(46.84mg,0.13mmol)、31-2(68mg,0.12mmol)、三乙胺(70mg,0.70mmol)、碳酸钾(64mg,0.46mmol)置于25mL单口烧瓶中，再加入无水乙腈(3mL)和无水DMF(1mL)，加热至外温60℃搅拌反应过夜。反应液加入DCM(50mL)，用水(15mL)洗涤一次，静置分液，有机相无水硫酸钠干燥，减压浓缩后制备薄层色谱纯化，得到淡黄色固体再送制备液相纯化，得到实施例31，淡黄色固体15mg，产率：14.6％。
ESI-MS(m/z):858.7[M+H]+.
1H NMR(500MHz,CDCl3)δ10.47(s,1H),8.85(dd,J＝7.0,1.4Hz,1H),8.81(s,1H),8.79–8.76(m,1H),8.45(s,1H),8.28(br s,1H),7.08(dd,J＝6.9,4.2Hz,1H),6.96(dt,J＝15.2,7.5Hz,2H),6.75(d,J＝7.5Hz,1H),6.69(s,1H),5.22(dd,J＝12.3,5.2Hz,1H),4.03–3.90(m,4H),3.87–3.72(m,5H),3.04-2.96(m,6H),2.96-2.91(m,4H),2.89–2.38(m,12H),2.27–1.96(m,4H),1.92-1.75(m,8H).
实施例32：
步骤一：
将化合物19-1(60mg,0.11mmol)，2-甲基丙-2-基2,7-二氮杂螺(3,5)壬烷-7-羧酸盐(26mg,0.11mmol)，三乙胺(23mg,0.23mmol)，碳酸钾(24mg,0.17mmol)分别加入DMF(6mL)中,溶液于50℃下反应过夜，冷却至室温，减压浓缩，硅胶大板纯化(DCM/MeOH＝20:1)得到化合物32-1，黄色固体产物50mg,产率61.2％。
ESI-MS(m/z):715.4[M+H]+.
步骤二：
将化合物32-1(50mg,0.07mmol)加入到二氯甲烷(5mL)中，往溶液中加入三氟乙酸(1mL,13.46mmol)，溶液于室温下反应2小时，减压浓缩得到化合物32-2，油状粗品45mg，直接进 行下一步反应。
ESI-MS(m/z):615.4[M+H]+.
步骤三：
将32-2(45mg,0.07mmol)溶于无水DMF(6mL)中，再加入三乙胺(15mg,0.15mmol)，溶液搅拌5分钟后，继续加入冰乙酸(41mg,0.22mmol)，M32(21mg,0.07mmol)，室温搅拌30分钟，再加入三乙酰氧基硼氢化钠(6mg,0.16mmol)，溶液于室温下反应过夜，减压浓缩，制备纯化(ACN/H2O＝1:1)冻干得到实施例32，淡黄色固体产物8.0mg,产率12.3％。
ESI-MS(m/z):886.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.48(s,1H),9.38–9.33(m,1H),8.92–8.87(m,1H),8.67(s,1H),8.33(s,1H),7.36–7.31(m,1H),7.06(d,J＝8.0Hz,1H),6.95(t,J＝7.6Hz,1H),6.86(d,J＝7.6Hz,1H),6.72(s,1H),5.37(dd,J＝12.6,5.4Hz,1H),4.55(t,J＝5.4Hz,1H),3.66(s,3H),3.58(s,2H),3.46–3.37(m,2H),3.04–2.83(m,9H),2.78–2.54(m,6H),2.48–2.36(m,4H),2.36–2.21(m,5H),2.07–2.07-1.97(m,1H),1.86–1.64(m,7H),1.65–1.45(m,7H).
实施例33：
步骤一：
将2-甲基丙-2-基2,7-二氮杂螺(3,5)壬烷-7-羧酸盐(24mg,0.11mmol)，三乙胺(21mg,0.21mmol)加入到DMF(5mL)中，溶液于室温下搅拌5分钟后，再加入醋酸(0.1mL,0.31mmol)，M32(30mg,0.10mmol)，溶液继续搅拌30分钟，再加入三乙酰氧基硼氢化钠(8mg,0.21mmol)，溶液于室温下反应过夜，减压浓缩，反相制备色谱纯化(ACN/H2O＝1:1)，冻干得到化合物33-1，白色固体产物40mg,产率77.0％。
ESI-MS(m/z):498.3[M+H]+.
步骤二：
将33-1(40mg,0.08mmol)加入到二氯甲烷(5mL)中，再加入三氟乙酸(1mL,13.46mmol)，溶液于室温下反应2小时，减压浓缩，得到化合物33-2，油状液体45mg，直接进行下一步反应。ESI-MS(m/z):398.2[M+H]+.
步骤三：
将33-2(45mg,0.11mmol)，三乙胺(23mg,0.23mmol)加入DMF(5mL)中，溶液于室温下搅拌10分钟，再加入碳酸氢钠(29mg,0.35mmol)，19-1(60mg,0.11mmol)，溶液于50℃下反应过夜。减压浓缩，制备液相分离纯化(ACN/H2O＝1:1)，冻干得到实施例33，淡黄色固体产物3mg,产率3.0％。
ESI-MS(m/z):886.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.48(s,1H),9.38–9.33(m,1H),8.91–8.87(m,1H),8.67(s,1H),8.32(s,1H),7.67–7.49(m,1H),7.35–7.31(m,1H),7.04(d,J＝6.8Hz,1H),6.94–6.91(m,1H),6.72(s,1H),5.37(dd,J＝12.4,5.4Hz,1H),4.55(t,J＝5.4Hz,1H),3.81–3.77(m,2H),3.65(s,3H),3.39(t,J＝5.4Hz,2H),3.02–2.83(m,9H),2.78–2.54(m,6H),2.47–2.38(s,4H),2.36–2.25(m,5H),2.07–1.96(m,1H),1.84–1.65(m,7H),1.65–1.43(m,7H).
实施例34：
将M33(1.3g,3.07mmol,1.0eq)置于100mL单口瓶中加入DMA(15mL),1-1(1.42g,3.07mmol,1.0eq),乙酸钾(0.60g,6.14mmol,2.0eq),三乙酰氧基硼氢化钠(0.78g,3.68mmol,1.2eq)加入到反应液中,反应液室温搅拌2h。反应液过滤后高效液相色谱分离纯化,得到实施例34(1.34g,1.53mmol,收率49.7％)为黄色固体。
ESI-MS(m/z):870.5[M+1]+.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.49(s,1H),9.36(dd,J＝7.00,1.50Hz,1H),8.90(dd,J＝4.13,1.50Hz,1H),8.68(s,1H),8.34(s,1H),7.31-7.38(m,1H),7.18(d,J＝7.75Hz,1H),7.10-7.15(m,1H),6.99-7.09(m,1H),6.73(s,1H),5.41(dd,J＝12.57,5.32Hz,1H),4.55(t,J＝5.32Hz,1H),4.47(s,2H),3.65(s,3H),3.37-3.51(m,3H),2.84-3.03(m,5H),2.53-2.78(m,5H),2.32-2.48(m,3H),2.01-2.15(m,5H),1.68-1.87(m,8H),1.42-1.65(m,4H),1.12-1.27(m, 2H),0.84-0.98(m,2H).
用与实施例34相似的方法合成下表中的实施例：





实施例59：
步骤一：
将(2-羟乙基)氨基甲酸叔丁酯(5g,31.11mmol)和3-溴丙-1-炔(11g,93.16mmol)溶于四氢呋喃(75mL)中，加入四丁基碘化铵(1.14g,3.11mmol)，碘化钠(465mg,3.11mmol)，氢氧化钾(5.22g,93.33mmol)，室温下搅拌过夜，反应完毕，加水淬灭，用乙酸乙酯(50mL×3)萃取，有机相减压浓缩，粗产物柱层析分离，洗脱剂：DCM/MeOH(v/v)＝15/1，得到化合物59-1，无色油状液体4.6g，产率：74.19％。
ESI-MS(m/z):200.2[M+H]+.
步骤二：
将59-1(710mg,3.56mmol)和碘化亚铜(2.68g,0.356mmol)，碳酸铯(3.471g,10.68mmol)，双三苯基膦二氯化钯(125mg,0.18mmol)，加入DMF(30mL)中溶解，在氮气保护下，85℃下搅拌过夜，反应完毕，加入少量水淬灭，乙酸乙酯(50ml×3)萃取，减压下浓缩有机相，旋干拌样过柱分离，洗脱剂:DCM/MeOH(v/v)＝15/1，得到化合物59-2，淡黄色油状产物400mg，产率：24.69％。
ESI-MS(m/z):457.1[M+H]+.
步骤三：
将59-2(200mg,0.44mmol)溶于二氯甲烷(20mL),加入盐酸-1,4-二氧六环溶液(4mL)，室温下反应过夜。反应完毕，减压浓缩，后加入二氯甲烷(20mL×3)萃取,有机相旋干得到化合物59-3，黄色油状产物120mg，产率76.69％。
ESI-MS(m/z):357.1[M+H]+.
步骤四：
将59-3(50mg,0.14mmol)和19-1(73mg,0.14mmol)溶于DMF(20mL)中，加入碳酸氢钠(17mg,1.4mmol)，在室温下，氮气保护反应过夜，反应完毕，减压浓缩后，制备色谱分离，洗脱剂ACN:H2O＝1:1，冻干得到实施例59，白色固体2.4mg，产率：2％。
ESI-MS(m/z):845.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.48(s,1H),9.35(d,J＝7.2Hz,1H),8.90(d,J＝4.2Hz,1H),8.67(s,1H),8.31(s,1H),7.33–7.31(m,4.2Hz,1H),7.16–7.14(m,2H),7.04–6.97(m,1H),6.72(s,1H),5.40–5.38(m,1H),4.57–4.55(m,1H),4.47(s,2H),3.66(s,3H),3.64–3.60(m,3H),2.91(d,J＝10.0Hz,6H),2.76(s,2H),2.69–2.60(m,6H),2.48–2.37(m,6H),2.10–1.87(m,2H),1.81–1.66(m,6H),1.62–1.48(m,3H).
实施例60：
步骤一：
将59-2(200mg,0.43mmol)溶于甲醇(40ml)中，加入Pd/C(60mg)，Pd(OH)2(60mg)，在氢气球下搅拌过夜，反应完毕，抽滤后减压浓缩，得到化合物60-1，无色油状产物200mg，产率：99.0％。
ESI-MS(m/z):461.1[M+H]+.
步骤二：
将60-1(200mg,0.44mmol)溶于二氯甲烷(20ml)，加入三氟乙酸(4ml)，室温下反应2h，反应完毕，旋干萃取分离，得到化合物60-2，无色油状产物120mg，产率：76.9％。
ESI-MS(m/z):361.1[M+H]+.
步骤三：
将19-1(50mg,0.14mmol)和60-2(73mg,0.14mmol)溶于DMF(20mL)中，加入碳酸氢钠(17mg,1.4mmol)，在室温下，氮气保护反应过夜，反应完毕，减压浓缩，得粗品60mg，送制备，洗脱剂ACN:H2O＝1:1，冻干后得到实施例60，白色固体产物2.0mg，产率1.79％。
ESI-MS(m/z):849.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.48(s,1H),9.36(d,J＝11.0Hz,1H),8.89(d,J＝4.2Hz,1H),8.67(d,J＝5.2Hz,1H),8.31(s,1H),7.33(d,J＝11.4Hz,1H),7.06–6.82(m,3H),6.71(s,1H),5.47–5.30(m,1H),4.56(d,J＝13.2Hz,1H),3.58(s,3H),3.49–3.45(m,4H),3.01–2.85(m,9H),2.76–2.58(m,10H),2.33(s,2H),2.03–1.42(m,15H).
实施例61：
步骤一：
将2-氟-5-甲酰基苯甲酸(6.00g,35.69mmol,1.0eq)溶于N,N-二甲基甲酰胺(60mL)中，加入HATU(14.93g,39.26mmol,1.1eq)和DIEA(14.7mL,89.22mmol,2.5eq)活化1h后，加入3-氨基六氢吡啶-2,6-二酮(4.57g,35.69mmol,1.0eq),室温搅拌4h。反应结束后，将反应体系缓慢倒入冰水中，边倒边搅拌，用乙酸乙酯萃取两次，合并有机相用盐水反洗一次，硫酸镁干燥过滤后合并滤液浓缩,浓缩后有固体析出，用乙酸乙酯打浆得绿色固体，滤液柱层析纯化。合并得到化合物61-1(3.68g，收率37.1％)为绿色固体。
ESI-MS(m/z):279.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.04(s,1H),8.83(br d,J＝8.3Hz,1H),8.21(dd,J＝2.0,6.9Hz,1H),8.11(ddd,J＝2.1,5.0,8.3Hz,1H),7.57(dd,J＝8.7,9.9Hz,1H),4.94-4.69(m,1H),2.92-2.56(m,2H),2.21-1.94(m,2H).
步骤二：
将M2(1.00g,1.78mmol)中加入二氯甲烷(3mL)，全部溶清后慢慢滴加4.0M的盐酸二氧六环溶液(7mL,28.00mmol)，反应液在25℃下搅拌反应2h。反应液减压浓缩，得到化合物61-2(900mg,1.80mmol)为浅黄色固体。
ESI-MS(m/z):463.3[M+H]+
步骤三：
将61-2(200mg,0.43mmol)中加入甲醇(3mL)，DIEA(0.1mL,0.86mmol,2.0eq)加入到反应液中，4-(2-氧代乙基)哌啶-1-羧酸叔丁酯(98mg,0.43mmol,1.0eq)加入到反应中，加入醋酸调节pH为5-6左右，加入氰基硼氢化钠(40mg,0.64mmol,1.5eq)，反应液在25℃下搅拌反应2h。反应液减压浓缩，得到的油状物中加入水(15mL)，乙酸乙酯(20mL×2)萃取后合并有机相用饱和食盐水(10mL)洗涤，有机相干燥后减压浓缩，薄层色谱分离纯化(乙酸乙酯：甲醇＝10:1)，得到化合物61-3(197mg,0.26mmol)为白色固体。收率：60.3％.
ESI-MS(m/z):674.4[M+H]+
步骤四：
将61-3(176mg,0.26mmol)中加入二氯甲烷(4mL)，盐酸二氧六环溶液(4mL,16.0mmol)加入到反应液中，反应液在25℃下搅拌反应1h。反应液减压浓缩，得到化合物61-4(200mg,0.35mmol)为黄色的固体。
ESI-MS(m/z):574.4[M+H]+
步骤五：
将61-4(103mg,0.18mmol,1.0eq)溶于甲醇(2mL)，DIEA(0.1mL,0.36mmol,2.0eq)加入到反应液中，61-1(50mg,0.18mmol,1.0eq)加入到反应液中，加入冰乙酸调节pH＝5-6，后加入氰基硼氢化钠(17mg,0.27mmol,1.5eq)，反应液在50℃下搅拌反应2h。反应液减压浓缩除去甲醇，高效液相色谱分离纯化(甲酸条件分离)。得到实施例61(35mg,0.04mmol,收率21.9％)为浅黄色固体。
ESI-MS(m/z):836.5[M+H]+
1H NMR(400MHz,CD3OD)δ8.78(dd,J＝4.75,1.13Hz,1H),8.73(s,1H),8.43(br d,J＝5.50Hz,2H),8.30(s,1H),8.10(dd,J＝8.44,1.06Hz,1H),7.89(dd,J＝6.88,1.75Hz,1H),7.60-7.67 (m,1H),7.53(dd,J＝8.44,4.82Hz,1H),7.31(dd,J＝10.44,8.57Hz,1H),6.78(s,1H),3.93(s,2H),3.52(d,J＝5.88Hz,2H),3.37-3.46(m,2H),3.27-3.30(m,1H),3.06-3.22(m,8H),2.68-2.91(m,4H),2.46-2.57(m,2H),2.01-2.38(m,7H),1.41-1.96(m,13H).
实施例62：
将61-4(84.29mg,0.15mmol,1.0eq)置于40mL的单口瓶中，加入MeOH(2mL)，DIEA(38mg,0.29mmol,2.0eq)，加入M36(40mg,0.15mmol,1.0eq)，加入冰乙酸调节pH＝5-6，加入三乙酰氧基硼氢化钠(11.08mg,0.18mmol,1.2eq)，反应液在45℃下搅拌16h。反应液减压浓缩后高效液相色谱分离纯化，得到实施例62(5.78mg,0.01mmol,收率4.7％)为白色固体。
ESI-MS(m/z):830.5[M+1]+.
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.41-10.63(m,1H),8.96(s,1H),8.74(d,J＝4.89Hz,1H),8.31(s,1H),8.25(d,J＝8.53Hz,1H),7.52-7.60(m,2H),7.17(d,J＝6.40Hz,1H),7.02(t,J＝7.40Hz,1H),6.73(s,1H),4.30(s,3H),3.89(br t,J＝6.65Hz,2H),3.74(s,2H)2.98(br s,2H),2.94(br d,J＝11.54Hz,3H),2.81-2.84(m,2H),2.77(br t,J＝6.59Hz,2H),2.64(br t,J＝11.17Hz,3H),2.29-2.38(m,4H),1.99(br t,J＝10.16Hz,2H),1.49-1.87(m,14H),1.30-1.40(m,3H),1.10(br d,J＝9.66Hz,1H).
实施例63：
步骤一：
将5-溴-2-氟苯甲酸(7.00g,31.9mmol)置于100mL三口瓶中，加入DCM(70mL)和DMF(0.2mL,3.20mmol)，0℃下滴加草酰氯(2.70mL,31.9mmol,1eq)，滴加完后0℃搅拌10min，恢复 室温搅拌2h。减压浓缩除去DCM，得到5-溴-2-氟苯甲酰氯(7.00g,29.5mmol)为黄色油状物。将3-氨基六氢吡啶-2,6-二酮(3.02g,23.6mmol)溶于DCM(30mL)中，加入DIEA(12.2mL,73.7mmol,3eq),降温至0℃，滴加5-溴-2-氟苯甲酰氯(7.00g,29.48mmol,1.25eq)的DCM(40mL)溶液，恢复室温继续搅拌4h。反应结束后，反应液直接过滤，滤饼用二氯甲烷淋洗，收集滤饼，得到化合物63-1(5.02g,15.2mmol,收率51.7％)为黄色固体。
ESI-MS(m/z):329.9,331.9[M+1]+.
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.75(br d,J＝8.2Hz,1H),7.79-7.70(m,2H),7.37-7.28(m,1H),4.85-4.65(m,1H),2.86-2.68(m,1H),2.59-2.52(m,1H),2.18-1.95(m,2H).
步骤二：
将63-1(1.00g,3.04mmol)溶于DMF(10mL)中，加入2-甲基丙烷-2-基4-(丙-2-炔氧基)六氢吡啶-1-甲酸基酯(1.09g,4.56mmol,1.5eq)和碳酸铯(3.96g,12.15mmol,4eq)以及CuI(60mg,0.30mmol,0.1eq)，加入分子筛,氮气置换后加入Pd(PPh3)Cl2(60mg)，氮气置换三次后80℃反应2h.将反应体系倒入水(50mL)，用乙酸乙酯萃取(100mL×2)，合并有机相，用饱和食盐水反洗一次，硫酸钠干燥，过滤,减压浓缩后柱层析纯化(PE:EA＝20:1-0:1)。得到化合物63-2(902mg,1.85mmol,收率60.9％)为棕色固体。
ESI-MS(m/z):488.3[M+1]+.
步骤三：
将63-2(900mg,1.64mmol)溶于DCM(8mL)中，加入HCl/dioxane(2mL),室温搅拌4h。将反应液直接过滤，滤饼用二氯甲烷淋洗，收集滤饼，得到化合物63-3(455mg,1.17mmol，收率71.6％).
ESI-MS(m/z):388.2[M+1]+.
步骤四：
将61-2(300mg,0.65mmol)置于40mL单口瓶中，加入MeOH(3mL)，加入DIEA(0.3mL,1.95mmol,3eq)和2-氯乙醛(0.2mL,1.30mmol,2eq)后加入冰醋酸调节pH为5-6，加入氰基硼氢化钠(81.5mg,1.30mmol,2eq)，室温搅拌反应2h。反应液直接过滤，滤饼用乙酸乙酯(5mL)洗涤，收集滤饼得到化合物63-4(80mg,0.15mmol,收率23.5％)为白色固体。
ESI-MS(m/z):525.3[M+1]+.
1H NMR(400MHz,CD3OD)δ8.78(dd,J＝4.75,1.13Hz,1H),8.73(s,1H),8.29(s,1H),8.09(dd,J＝8.44,1.06Hz,1H),7.52(dd,J＝8.38,4.75Hz,1H),6.78(s,1H),3.97(br t,J＝6.25Hz,2H), 3.37-3.57(m,6H),3.15(s,2H),3.08(br d,J＝11.01Hz,2H),2.66-2.78(m,2H),1.99-2.28(m,4H),1.55-1.88(m,5H).
步骤五：
将63-3(35mg,0.09mmol)置于40mL单口瓶中，加入DMF(2mL)，再加入63-4(40mg,0.08mmol)，NaHCO3(13mg,0.15mmol)和TEA(15mg,0.15mmol)和碘化钾(4mg,0.02mmol)加入到反应液中，反应液在60℃下搅拌10h.反应液减压浓缩后高效液相色谱纯化，得到实施例63(2.2mg,收率3.3％)为白色固体。
ESI-MS(m/z):875.7[M+1]+.
1H NMR(400MHz,DMSO-d6)δ10.81-10.95(m,2H),8.95(s,1H),8.66-8.80(m,2H),8.22-8.34(m,3H),7.50-7.71(m,3H),7.29-7.39(m,1H),6.73(s,1H),4.70-4.83(m,1H),4.46-4.58(m,1H),4.40(s,2H),2.89-3.01(m,6H),2.53-2.77(m,11H),1.97-2.17(m,5H),1.68-1.92(m,9H),1.41-1.64(m,6H).
实施例64：
步骤一：
将64-1(1g,3.09mmol)和Pd(PPh3)4(0.36g,0.31mmol)溶于ACN(20mL)，置换氮气，滴加(三丁基锡)甲醇(1.99g,6.19mmol)，加热至外温90℃反应48h。反应完毕后，减压浓缩，加入乙酸乙酯(20mL)，搅拌，过滤，将滤饼减压浓缩得到3-(4-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(400mg,1.46mmol)。将3-(4-(羟甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(400mg,1.46mmol)置于100mL单口瓶中，加入DCM(10mL)和TEA(0.4mL)，室温下缓慢滴加MsCl(0.3mL,3.65mmol)，室温下搅拌反应2h。反应完毕后，加入DCM(50mL)和水(50mL)，充分搅拌后静置分液，有机相用无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂为：DCM:MeOH＝1:0～10:1，得到化合物64-2，白色固体(180mg)，产率：21％。
ESI-MS(m/z):293.1[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.13(d,J＝10.5Hz,1H),7.96(d,J＝4.0Hz,2H),5.69(s,1H),5.16(dd,J＝12.9,5.4Hz,1H),3.32(s,2H),2.92(d,J＝17.6Hz,1H),2.66–2.53(m,2H),2.29(s, 1H),2.11–2.04(m,1H),1.24(s,1H).
步骤二：
将64-2(105mg,0.36mmol)，1-3(190mg,0.28mmol)，K2CO3(114.37mg,0.83mmol)和TEA(0.2mL,1.66mmol)加入到乙腈(5mL)和DMF(1mL)中，50℃搅拌反应12h。反应完毕后，反应液过滤除去无机盐，经制备液相色谱纯化，得到实施例64，淡黄色固体26mg，产率：11.4％。
ESI-MS(m/z):830.3[M+H]+.
1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.47(s,1H),9.34(d,J＝7.0Hz,1H),8.89(d,J＝2.7Hz,1H),8.66(s,1H),8.32(s,1H),7.62(d,J＝7.3Hz,1H),7.53(d,J＝7.4Hz,1H),7.47(t,J＝7.5Hz,1H),7.32(dd,J＝6.9,4.2Hz,1H),6.71(s,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.53–4.47(m,2H),4.39(d,J＝17.5Hz,1H),3.55(t,J＝9.0Hz,2H),3.39(t,J＝5.2Hz,2H),3.25(s,1H),2.97(s,2H),2.92(d,J＝10.5Hz,2H),2.75(s,2H),2.64(d,J＝11.1Hz,2H),2.45(d,J＝4.5Hz,1H),2.43–2.37(m,2H),2.32(d,J＝7.2Hz,2H),2.05–2.00(m,1H),1.94(t,J＝11.9Hz,2H),1.79(s,2H),1.72(d,J＝11.3Hz,4H),1.63(d,J＝12.4Hz,2H),1.61–1.54(m,2H),1.51(s,1H),1.37(d,J＝6.6Hz,2H),1.30(s,1H),1.25(d,J＝11.3Hz,2H),1.14(d,J＝11.9Hz,2H).
实施例65：
步骤一：
将65-1(1.0g,3.09mmol)和Pd(PPh3)4(0.36g,0.31mmol)溶于1,4-二氧六环(20mL)，置换氮气，滴加三丁基锡甲醇(1.99g,6.19mmol)，加热至外温90℃反应48h。反应完毕后，减压浓缩，加入乙酸乙酯(20mL)，搅拌，过滤，将滤饼减压浓缩得到2-(2,6-二氧橙皮苷-3-基)-4-(羟甲基)异吲哚啉-1,3-二酮(400mg,1.46mmol)。将2-(2,6-二氧橙皮苷-3-基)-4-(羟甲基)异吲哚啉-1,3-二酮(400mg,1.46mmol)置于100mL单口瓶中，加入DCM(10mL)和TEA(0.4mL)，室温下滴加MsCl(0.3mL,3.65mmol)，室温下搅拌反应2h。反应完毕后，加入DCM(50mL)和水(50mL)，充分搅拌后静置分液，有机相用无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂为：DCM:MeOH＝1:0-10:1，得到65-2，白色固体180mg，产率21％。
ESI-MS(m/z):384.1[M+18].
步骤二：
将65-2(50mg,0.14mmol)，1-3(72.31mg,0.10mmol)，K2CO3(43.53mg,0.31mmol)，TEA(63mg,0.63mmol)，乙腈(5mL)和DMF(1mL)中加入50mL单口瓶，50℃搅拌反应16h。反应完毕后，过滤，经制备液相色谱纯化，得到实施例65，淡黄色固体20mg，产率：22％。
ESI-MS(m/z):844.3[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.49(s,1H),9.35(d,J＝7.0Hz,1H),8.90(d,J＝2.7Hz,1H),8.67(s,1H),8.37(s,1H),7.88(d,J＝29.9Hz,3H),7.34(dd,J＝6.9,4.2Hz,1H),6.72(s,1H),5.13(d,J＝7.3Hz,1H),4.55(d,J＝5.1Hz,1H),3.94(s,1H),3.46(d,J＝20.4Hz,2H),3.40(t,J＝5.1Hz,2H),3.13(s,2H),3.08(d,J＝7.0Hz,4H),2.93(d,J＝8.4Hz,2H),2.87(d,J＝4.8Hz,2H),2.63(s,2H),2.31(s,4H),2.07(s,4H),1.68(dd,J＝38.1,13.3Hz,6H),1.53(s,2H),1.19(t,J＝7.3Hz,6H).
实施例66：
步骤一：
将M33-5(511mg,3.04mmol,2.0eq)置于40mL单口瓶中,加入DMF(5mL),63-1(500mg,1.52mmol),碳酸铯(990mg,3.04mmol)和双三苯基磷二氯化钯(118mg,0.15mmol,0.1eq),反应液在氮气保护下100℃反应2h。反应液减压浓缩后加入THF(10mL),搅拌10min后过滤,滤液减压浓缩，薄层色谱分离纯化(石油醚:四氢呋喃＝1:2),得到66-1(220mg,0.53mmol,收率34.8％)为无色油。
ESI-MS(m/z):417.3[M+1]+.
步骤二：
将66-1(220mg,0.53mmol)置于100mL单口瓶中加入DCM(5mL),0℃下加入DMP(336mg,0.79mmol,1.5eq)，反应液室温搅拌过夜。反应液加入饱和碳酸氢钠水溶液(10mL)搅拌10min，二氯甲烷(15mL×2)萃取,合并有机相，无水硫酸钠干燥后减压浓缩,薄层色谱分离纯化(石油醚：THF＝1:1),得到66-2(115mg,0.25mmol,收率46.5％)为白色固体。
ESI-MS(m/z):415.2[M+1]+.
1H NMR(400MHz,CDCl3)δ9.66(d,J＝0.86Hz,1H),8.17(dd,J＝7.34,2.20Hz,1H),8.09(br s,1H),7.13(dd,J＝11.49,8.56Hz,1H),4.75-4.85(m,1H),4.42(s,2H),3.49-3.57(m,1H),2.70-2.94(m,3H),2.00-2.26(m,6H),1.33-1.43(m,4H).
步骤三：
将66-2(40mg,0.10mmol)置于40mL单口瓶中,加入DMF(1mL)和THF(1mL),加入1-1(89mg,0.19mmol,2.0eq),0℃加入KOAc(19mg,0.19mmol,2.0eq),室温搅拌反应0.5h,0℃下加入三乙酰氧基硼氢化钠(24mg,0.12mmol,1.2eq),反应液0℃反应2h。反应液减压浓缩后高效液相色谱分离纯化,得到实施例66(28.03mg,0.03mmol,收率30.5％)为黄色固体。
ESI-MS(m/z):861.3[M+1]+.
1H NMR(400MHz,DMSO-d6)δ10.64-11.06(m,1H),10.49(s,1H),9.35(dd,J＝7.00,1.50Hz,1H),8.87-8.93(m,1H),8.73(br d,J＝8.38Hz,1H),8.66-8.70(m,1H),8.33(s,1H),7.56-7.79(m,2H),7.29-7.41(m,2H),6.73(s,1H),4.73-4.81(m,1H),4.54-4.63(m,1H),4.38-4.44(m,2H),2.87-3.05(m,5H),2.75-2.86(m,2H),2.64(br t,J＝11.07Hz,3H),2.37(br s,2H),1.98-2.22(m,7H),1.69-1.85(m,8H),1.40-1.64(m,5H),1.10-1.23(m,2H),0.83-0.97(m,2H).
实施例67：
步骤一：
将M1-1(1000mg,2.84mmol)、NaOH(283.80mg,7.10mmol)、水(5mL)和DMSO(10mL)加入到50mL单口瓶中，70℃下搅拌2h。反应完毕后，向反应体系内加入乙酸乙酯(100mL)，水(100mL)，萃取，减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝1:0～1:1，得到化合物67-1，黄色固体700mg。产率：70.49％。
ESI-MS(m/z):295.1[M-55]+.
1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),6.48(s,1H),3.50(dd,J＝11.8,6.7Hz,2H),3.37(s,2H),3.02(s,2H),1.82–1.72(m,4H),1.44(s,1H),1.41(s,9H).
步骤二：
将67-1(650mg,1.86mmol)、2-氯-2,2-二氟乙酸钠(850mg,5.58mmol)，K2CO3(897mg,6.49mmol)和DMSO(6.5mL)加入50mL单口瓶中，95℃下搅拌2h。反应完毕后，加入水(65mL)，用乙酸乙酯萃取(65mL×2)，减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝1:0～1:1，得到化合物67-2，黄色固体650mg。产率：87.60％。
ESI-MS(m/z):无响应
1H NMR(500MHz,DMSO-d6)δ8.01(s,1H),7.43 -7.14(m,1H),6.90(s,1H),3.57–3.53(m,2H),3.36(s,2H),3.12(s,2H),1.84–1.76(m,4H),1.42(s,9H).
步骤三：
将67-2(650mg,1.62mmol)加入到甲醇(10mL)中，加入钯炭(130mg,0.162mmol)，室温搅拌反应1h。反应完毕后，过滤，减压浓缩，得到黑色固体(601mg,1.62mmol)。依次将黑色固体(601mg,1.62mmol)、吡唑[1,5-a]嘧啶-3-羧酸(264mg,1.62mmol)、N-甲基咪唑(465mg,5.67mmol)、TCFH(545mg,1.94mmol)和乙腈(10mL)置于100mL单口瓶中，室温搅拌反应2h。反应完毕后，减压浓缩，柱层析纯化，洗脱剂为：PE:EA＝1:0～1:1，得到化合物67-3，黄色固体650mg。产率：59.88％。
ESI-MS(m/z):516.2[M+H]+.
1H NMR(500MHz,DMSO-d6)δ10.22(s,1H),9.37(dd,J＝7.0,1.4Hz,1H),8.85(dd,J＝4.1,1.4Hz,1H),8.69(s,1H),8.29(s,1H),7.33(dd,J＝6.9,4.2Hz,1H),7.43-7.14(t,J,1H),6.78(s,1H),3.54(dd,＝11.7,6.5Hz,2H),3.38(s,2H),3.08(s,2H),1.80(d,J＝13.8Hz,2H),1.76–1.70(m,2H),1.42(s,9H).
步骤四：
将67-3(500mg,0.97mmol)溶于DCM(10mL)，滴加盐酸二氧六环溶液(2mL)，室温搅拌1h。 减压浓缩，直接用于下一步。得到化合物67-4，白色固体650mg。产率：124.1％。
ESI-MS(m/z):416.0[M+H]+.
步骤五：
将67-4(166.16mg,0.24mmol)、M33(100mg,0.24mmol)、乙酸钾(70mg,0.72mmol)、三乙酰氧基硼氢化钠(99mg,0.47mmol)和DMF(1mL)加入50mL单口瓶，室温搅拌2h。反应完毕后，减压浓缩，HPLC制备分离得到实施例67，黄色固体10mg。产率：5.1％。
ESI-MS(m/z):823.3[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),10.20(s,1H),9.37(d,J＝6.9Hz,1H),8.84(d,J＝2.5Hz,1H),8.68(s,1H),8.26(s,1H),7.42-7.28(m,2H),7.17(d,J＝7.5Hz,1H),7.12(d,J＝7.4Hz,1H),7.03(t,J＝7.8Hz,1H),6.76(s,1H),5.39(dd,J＝12.3,5.0Hz,1H),4.47(s,2H),3.65(s,3H),3.03(s,2H),2.93–2.87(m,1H),2.70(d,J＝12.5Hz,1H),2.64(d,J＝17.3Hz,2H),2.12(d,J＝6.9Hz,2H),2.05(d,J＝17.6Hz,4H),1.87–1.75(m,6H),1.47(s,2H),1.24(s,2H),1.18(d,J＝11.1Hz,2H),0.90(dd,J＝24.0,11.6Hz,2H).
实施例68：
步骤一：
将M33-5(520mg,3.09mmol,2.0eq)置于40mL单口瓶中加入DMF(5.0mL),M35-4(500mg,1.55mmol,1.0eq)和Cs2CO3(1.08g,3.09mmol,2.0eq),二氯双三苯基磷钯(120mg,0.15mmol,0.10eq)加入到反应液中,氮气保护下100℃下搅拌2h。反应液减压浓缩后加入THF(300mL)搅拌1h后过滤，滤液减压浓缩，柱层析纯化(石油醚：乙酸乙酯＝2:1-1:2),得到68-1(200mg,0.49mmol,收率31.5％)为淡黄色固体。
ESI-MS(m/z):411.1[M+1]+.
1H NMR(400MHz,CDCl3)δ7.56-7.62(m,2H),7.41-7.46(m,1H),7.02(dd,J＝8.11,7.27Hz,1H),4.43(s,2H),4.28(s,3H),3.99-4.06(m,2H),3.38-3.43(m,2H),2.82(t,J＝6.74Hz,2H),2.05-2.14(m,2H),1.73-1.88(m,3H),1.36(s,1H),1.20-1.30(m,2H),0.91-1.02(m,2H).
步骤二：
将68-1(200mg,0.49mmol,1.0eq)置于40mL单口瓶中,加入DCM(5.0mL)和TEA(148mg,1.46mmol,3.0eq),反应液在0℃下加入TsCl(186mg,0.97mmol,2.0eq),室温搅拌过夜。反应液中加入水(10.0mL),二氯甲烷(10.0mL×2)萃取,合并有机相无水硫酸钠干燥后减压浓缩,薄层色谱分离纯化(石油醚:THF＝1:1),得到68-2(150mg,0.19mmol,收率38.9％)为灰白色泡沫状固体。
ESI-MS(m/z):565.2[M+1]+.
步骤三：
将68-2(40.0mg,0.07mmol，1.0eq)置于40.0mL单口瓶中，加入DMA(2.0mL),1-1(32.7mg,0.07mmol,1.0eq),NaI(31.8mg,0.21mmol,3.0eq),DIEA(54.9mg,0.43mmol,6.0eq),反应液在50℃搅拌反应16h。反应液减压浓缩后高效液相色谱分离纯化,得到实施例68(32.9mg,0.04mmol,收率54.3％)为黄色固体。
ESI-MS(m/z):855.5[M+1]+.
1H NMR(400MHz,DMSO-d6)δ10.59(br s,1H),10.48(br s,1H),9.34(br d,J＝6.38Hz,1H),8.88(br s,1H),8.67(s,1H),8.32(br s,1H),7.69(br d,J＝7.88Hz,1H),7.52(br d,J＝6.75Hz,1H),7.32(br s,1H),7.11(br t,J＝7.32Hz,1H),6.71(br s,1H),4.56(br s,1H),4.52(br s,2H),4.28(br s,3H),3.91(br d,J＝5.50Hz,3H),2.86-3.02(m,5H),2.59-2.79(m,5H),2.37(br d,J＝1.63Hz,3H),1.99-2.20(m,5H),1.67-1.86(m,8H),1.42-1.61(m,4H),1.13-1.24(m,2H),0.83-0.97(m,2H).
实施例69：
步骤一：
将1-叔丁氧羰基哌嗪(1g,5.37mmol)置于50mL单口瓶中，加入乙腈(10mL)，加入碳酸钠(1.71g,16.11mmol)室温下搅拌20min，添加3-溴丙炔(0.7mL,8.05mmol)，转移至50℃油浴中搅拌4h。反应液中加入EA(10mL)，加入饱和氯化铵溶液(10mL×2)洗涤，无水硫酸钠干燥，柱层析纯化，洗脱剂为：PE:EA＝95:5～75:25，得到69-1，淡黄色油状液体672mg，产率：56.0％。
ESI-MS(m/z):225.0[M+H]+.
1H NMR(500MHz,DMSO-d6)δ3.34–3.31(m,4H),3.28(d,J＝2.2Hz,2H),3.14(s,1H),2.41–2.35(m,4H),1.42–1.37(m,9H).
步骤二：
于50mL单口瓶中，将M29(452mg,1.34mmol)溶于DMF(4mL)，加入69-1(300mg,1.34mmol)，三乙胺(406mg,4.01mmol)，双三苯基磷二氯化钯(104mg,0.13mmol)，CuI(50mg,0.27mmol)到上述混合反应液，氮气置换3次后，反应在80℃下搅拌过夜。反应液中加入DCM(15mL)，加入饱和氯化铵溶液(15mL×2)洗涤，有机相用无水硫酸钠干燥，柱层析纯化，洗脱剂为：DCM:MeOH＝100:0～95:5，得到69-2，棕色泡沫状固体176mg，产率：25.9％。
ESI-MS(m/z):482.4[M+H]+.
1H NMR(500MHz,CDCl3)δ8.38(s,1H),7.16(d,J＝7.8Hz,1H),6.98(t,J＝7.9Hz,1H),6.76(d, J＝7.8Hz,1H),5.19(dd,J＝12.6,5.3Hz,1H),3.76(s,3H),3.66(s,2H),3.56(s,4H),2.93(d,J＝17.2Hz,1H),2.86–2.63(m,6H),2.26–2.17(m,1H),1.46(s,9H).
步骤三：
将69-2(65mg,0.13mmol)置于50mL单口瓶中，加入DCM(3mL)溶解，缓慢滴加4.0M的盐酸二氧六环溶液(0.7mL)，保持室温搅拌反应1h。反应液减压浓缩除去溶剂及氯化氢，得到69-3，棕色固体72mg，产率：142.1％。
ESI-MS(m/z):382.3[M+H]+.
步骤四：
于50mL单口瓶中，加入69-3(49mg,0.13mmol)、溴乙酸叔丁酯(38mg,0.20mmol)、DIEA(168mg,1.30mmol)混合于乙腈(2mL)，室温搅拌反应5h。反应液中加入DCM(15mL)，加入饱和氯化铵溶液(15mL)洗涤，无水硫酸钠干燥，柱层析纯化，洗脱剂为：DCM:MeOH＝100:0～95:5，得到69-4，棕色固体38mg，产率：59.0％。
ESI-MS(m/z):496.5[M+H]+.
1H NMR(500MHz,CDCl3)δ8.02(s,1H),7.08(t,J＝10.3Hz,1H),6.94–6.84(m,1H),6.66(d,J＝7.8Hz,1H),5.11(dd,J＝12.5,5.2Hz,1H),3.70(s,3H),3.49(s,2H),3.06(s,2H),2.87(d,J＝17.4Hz,1H),2.79–2.54(m,7H),2.15(dd,J＝13.7,6.2Hz,1H),1.39(s,9H),1.22(s,2H).
步骤五：
将69-4(35mg,0.07mmol)置于50mL单口瓶中，加入DCM(2mL)溶解，缓慢滴加4.0M的TFA(196μL,2.55mmol)，保持室温搅拌反应2h。减压浓缩除去溶剂及三氟乙酸，得到69-5，黑色固体42mg，产率：135.3％。
ESI-MS(m/z):440.4[M+H]+.
步骤六：
将69-5(30mg,0.07mmol)、1-1(32mg,0.04mmol)、HATU(39mg,0.10mmol)、DIEA(54mg,0.42mmol)置于25mL单口瓶中，加DCM(5mL)，25℃搅拌反应过夜。反应液中加入DCM(10mL)，加入饱和氯化铵溶液(10mL)洗涤，有机相用无水硫酸钠干燥，柱层析纯化，得到实施例69，棕色固体29mg，产率：46.9％。纯度：97.23％。
ESI-MS(m/z):884.6[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),10.49(s,1H),9.34(d,J＝6.9Hz,1H),8.90(d,J＝2.7Hz,1H),8.66(s,1H),8.36(s,1H),7.33(dd,J＝6.9,4.2Hz,1H),7.15(dd,J＝15.8,7.7Hz,2H),7.02(t,J＝7.9Hz,1H),6.73(s,1H),5.40(dd,J＝12.8,5.2Hz,1H),4.53(s,1H),4.07(s,6H),3.84 (s,1H),3.68(s,5H),3.52(s,2H),3.41(s,3H),3.04(s,3H),2.94(d,J＝10.6Hz,3H),2.63(d,J＝11.4Hz,4H),2.08–1.79(m,5H),1.78–1.41(m,8H).
实施例70：
步骤一：
将M29(1.00g,2.96mmol,1.0eq)置于100mL单口瓶中加入DMF(10mL),N-Boc哌嗪(0.83g,4.44mmol,1.5eq),叔丁醇钠(0.85g,8.87mmol,3.0eq)和钯催化剂(CAS:1814936-54-3)(29mg,0.03mmol,0.1eq)加入到反应液中，反应液氮气保护下100℃搅拌2h。反应液中加入水(100mL),二氯甲烷(80mL×2)萃取,合并有机相用无水氯化钠反洗一次(50mL),分出有机相用无水硫酸钠干燥后减压浓缩。柱层析分离(石油醚:乙酸乙酯＝2:1-0:1),得到的样品加入乙酸乙酯(10mL)搅拌1h后过滤,收集滤饼,得到70-1(220mg,0.50mmol,收率16.8％)为白色固体。
ESI-MS(m/z):444.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.23(s,1H),6.98-7.07(m,1H),6.93(d,J＝8.03Hz,1H),6.63(d,J＝7.78Hz,1H),5.24(br dd,J＝11.61,4.83Hz,1H),4.03-4.25(m,2H),3.79(s,3H),2.72-3.17(m,9H),2.18-2.29(m,1H),1.51(s,9H).
步骤二：
将70-1(235mg,0.53mmol)置于40mL单口瓶中,加入TFA(1mL)和DCM(9mL)的混合溶液,反应液室温搅拌1h。反应液减压浓缩,得到70-2(180mg,0.52mmol,98.9％)为棕色油状物。
ESI-MS(m/z):344.1[M+H]+.
步骤三：
将1-1(500mg,1.08mmol,1.0eq)置于100mL单口瓶中加入乙腈(5mL),加入溴乙酸叔丁酯(316mg,1.62mmol,1.5eq)和DIEA(1.39g,10.8mmol,10eq),反应液室温搅拌过夜。反应液过滤,滤饼用乙腈洗涤一次(5mL),收集滤饼,得到70-3(466mg,0.81mmol,收率74.8％)为黄色固体。
ESI-MS(m/z):577.5[M+H]+.
步骤四：
将70-3(466mg,0.81mmol)置于40mL单口瓶中加入DCM(1mL)和HCl(5mL)的二氧六环溶液,反应液室温搅拌2h。反应液减压浓缩,得到70-4(400mg,0.77mmol,95.1％)为黄色固体。
ESI-MS(m/z):521.4[M+H]+.
步骤五：
将70-4(341mg,0.52mmol,1.0eq)置于40mL单口瓶中加入DMF(4mL),70-2(180mg,0.52mmol,1.0eq),DIEA(203mg,1.57mmol,3.0eq)加入到反应液中,加入HATU(219mg,0.58mmol,1.1eq),反应液室温搅拌1h。反应液过滤后,滤液高效液相色谱分离纯化,得到实施例70(173mg,0.19mmol,收率36.6％)为黄色固体。
ESI-MS(m/z):846.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.10(br s,1H),10.50(s,1H),9.36(dd,J＝6.94,1.56Hz,1H),8.90(dd,J＝4.06,1.56Hz,1H),8.68(s,1H),8.35(s,1H),7.34(dd,J＝6.94,4.19Hz,1H),6.97-7.04(m,1H),6.90-6.97(m,2H),6.74(s,1H),5.37(br dd,J＝12.51,5.25Hz,1H),4.56(br s,1H),4.37-4.50(m,1H),4.16-4.33(m,1H),3.67(s,3H),3.40(br s,3H),3.06-3.21(m,3H),3.01(br s,2H),2.79-2.96(m,5H),2.55-2.75(m,9H),1.97-2.06(m,1H),1.66-1.96(m,7H),1.46-1.65(m,3H).
实施例71：
步骤一：
将2-(2,6-二氧亚基哌啶-3-基)-5,6-二氟异二氢吲哚-1,3-二酮(200mg,0.68mmol,1.0eq)置于40mL单口瓶中加入DMSO(2mL),叔-丁基2-(哌嗪-1-基)醋酸盐(136mg,0.68mmol,1.0eq)和DIEA(263mg,2.04mmol,3.0eq)加入到反应液中,反应液140℃搅拌1h。反应液中加入水(10mL),过滤,滤饼用水洗两次(10mL×2),收集滤饼,得到71-1(200mg,0.40mmol,收率59.4％)为土黄色固体。
ESI-MS(m/z):475.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.74(d,J＝11.38Hz,1H),7.47(d,J＝7.38Hz,1H),5.11(dd,J＝12.82,5.44Hz,1H),3.22-3.29(m,4H),3.20(s,2H),2.84-2.95(m,1H),2.66-2.72(m,4H),2.55(s,2H),1.98-2.12(m,1H),1.43(s,9H).
步骤二：
将71-1(160mg,0.34mmol)置于40mL单口瓶中加入DCM(1mL),加入HCl的二氧六环溶液(4mL,16.00mmol),反应液室温搅拌6h。反应液减压浓缩，得到71-2(160mg,0.38mmol)为灰色固体。
ESI-MS(m/z):419.2[M+H]+
步骤三：
将71-2(70mg,0.17mmol,1.0eq)置于40mL单口瓶中加入DMF(2mL),DIEA(65mg,0.50mmol,3.0eq),1-1(77mg,0.17mmol,1.0eq)加入到反应液中,最后加入HATU(70mg,0.18mmol,1.1eq),反应液室温搅拌过夜。反应液减压浓缩后高效液相色谱分离纯化,得到实施例71(53.45mg,0.06mmol,收率35.3％)为黄色固体。
ESI-MS(m/z):863.4[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.50(s,1H),9.37(dd,J＝7.00,1.50Hz,1H),8.90(dd,J＝4.19,1.56Hz,1H),8.68(s,1H),8.37(s,1H),7.74(d,J＝11.38Hz,1H),7.49(d,J＝7.38Hz,1H),7.34(dd,J＝6.94,4.19Hz,1H),6.76(s,1H),5.12(dd,J＝12.88,5.38Hz,1H),4.56(t,J＝5.25Hz,1H),3.56-3.85(m,3H),3.36-3.49(m,4H),3.21-3.30(m,5H),3.07(s,2H),2.83-2.98(m,3H),2.55-2.73(m,8H),1.99-2.11(m,1H),1.67-1.94(m,6H),1.45-1.65(m,3H).
实施例72：
将1-3(70mg,0.12mmol)置于40mL单口瓶中加入DMSO(2mL),2-(2,6-二氧亚基哌啶-3-基)-5,6-二氟异二氢吲哚-1,3-二酮(36mg,0.12mmol,1.0eq),DIEA(32mg,0.24mmol,2.0eq)加入到反应液中,90℃搅拌1h。反应液过滤,滤液高效液相色谱分离,得到实施例72(38mg,0.04mmol,36.4％)为黄色固体。
ESI-MS(m/z):848.5[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.49(s,1H),9.36(dd,J＝7.03,1.55Hz,1H),8.90(dd,J＝4.17,1.55Hz,1H),8.68(s,1H),8.34(s,1H),7.71(d,J＝11.44Hz,1H),7.45(d,J＝7.63Hz,1H),7.34(dd,J＝6.97,4.23Hz,1H),6.73(s,1H),5.11(dd,J＝12.81,5.42Hz,1H),4.55(t,J＝5.25Hz,1H),3.60(br d,J＝11.32Hz,2H),3.40(t,J＝5.25Hz,2H),2.82-3.04(m,8H),2.60-2.69(m,4H),2.36-2.42(m,2H),1.67-2.10(m,11H),1.41-1.65(m,7H),1.26-1.39(m,2H).
实施例73：
步骤一：
将2-甲基丙烷-2-基六氢吡啶-4-甲酸基酯(208mg,1.12mmol)置于40mL单口瓶中加入二氯甲烷(3mL),加入M1-1(330mg,0.94mmol,1.0eq),25℃搅拌12h。反应液减压浓缩,薄层色谱纯化(石油醚:乙酸乙酯＝3:1),得到73-1(400mg,0.77mmol,收率82.5％)为无色油。
ESI-MS(m/z):518.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),6.68(s,1H),3.54-3.66(m,2H),3.13-3.24(m,2H),3.07(s,2H),2.85(t,J＝10.6Hz,2H),2.34-2.45(m,1H),2.05(s,1H),1.59-1.94(m,9H),1.47(s,18H).
步骤二：
将73-1(250mg,0.48mmol)置于40mL单口瓶中加入乙醇(2mL),加入氯化铵(129mg,2.41mmol,5.0eq)和水(0.40mL),将体系升温到60℃后加入铁粉(134mg,2.41mmol,5.0eq),反应液在60℃下搅拌4h。反应液过滤,滤液收集后减压浓缩得到73-2(180mg,0.37mmol,收率:76.4％)为黄色固体。
ESI-MS(m/z):488.2[M+H]+
步骤三：
将吡唑并[1,5-a]嘧啶-3-羧酸(50mg,0.31mmol)置于40mL单口瓶中加入乙腈(2mL),加入73-2(150mg,0.31mmol,1.0eq),1-甲基咪唑(75mg,0.06mmol,3.0eq)和N,N,N,N-四甲基氯甲脒六氟磷酸盐(8mg,0.02mmol,1.2eq),25℃下反应12h。反应液减压浓缩,薄层色谱分离纯化(石油醚:乙酸乙酯＝3:1),得到73-3(100mg,0.16mmol,收率51.4％)为黄色固体。
ESI-MS(m/z):633.4[M+H]+
步骤四：
将73-3(100mg,0.16mmol)置于40mL单口瓶中加入二氯甲烷(1mL),加入盐酸二氧六环溶液(1mL,4M),25℃下搅拌2h。反应液减压浓缩,饱和碳酸氢钠调节pH到8,析出白色固体,过滤,收集滤饼得到73-4(50mg,0.10mmol,收率:66.4％)为黄色固体。
ESI-MS(m/z):477.3[M+H]+
步骤五：
将73-4(20mg,0.04mmol)置于40mL单口瓶中加入四氢呋喃(1mL)和N,N二甲基甲酰胺(1mL),加入M33(17mg,0.04mmol,1eq)和三乙酰氧基硼氢化钠(10mg,0.05mmol,1.2eq)和乙酸钾(8mg,0.08mmol,2eq),25℃下搅拌12h。反应液过滤，滤液通过高效液相色谱法进行纯化。得到实施例73(19mg,0.02mmol,收率52.6％)为白色固体。
ESI-MS(m/z):884.5[M+H]+
1H NMR(400MHz,DMSO-d6)δppm 11.12(s,1H),10.54(s,1H),9.36(d,J＝7.00Hz,1H),8.89(br d,J＝3.00Hz,1H),8.68(s,1H),8.37(s,1H),8.17(s,1H),7.34(dd,J＝6.94,4.19Hz,1H),7.17(d,J＝7.75Hz,1H),7.09-7.13(m,1H),6.99-7.06(m,1H),6.72(s,1H),5.40(br dd,J＝12.51,5.25Hz,1H),4.46(s,2H),3.64(s,3H),3.42-3.46(m,2H),2.98(s,2H),2.84-2.92(m,3H),2.59-2.77(m,5H),2.32-2.43(m,3H),2.13(br d,J＝6.88Hz,2H),1.98-2.08(m,5H),1.73-1.92(m,8H),1.47(br s,1H),1.12-1.23(m,2H),0.84-0.96(m,2H).
实施例74：
步骤一：
将三氧化铬(4.75g,47.55mmol,4.00eq)置于500mL单口瓶中,将温度控制在0℃加入浓硫酸(10.49g,106.99mmol,9.00eq),将体系降温到0℃后加入M33-5(2.00g,11.89mmol,1.00eq)的甲苯(60mL)溶液,再将体系在25℃下搅拌2h。将反应液慢慢倒入冰水中,加入加入乙酸乙酯(100mL×3)萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥后减压浓缩,得到74-1(1.20g,6.59mmol,收率:55.4％)为绿色的固体。
步骤二：
将M29(100mg,0.30mmol,1.00eq)置于40mL单口瓶中,加入DMF(1mL),74-1(107mg,0.59mmol,2.00eq)和碳酸铯(192mg,0.59mmol,2.00eq),加入二(三苯基磷)二氯化钯(46mg,0.06mmol,0.2eq),氮气保护下100℃搅拌2h。反应液过滤,滤液通过高效液相色谱法进行纯化,得到74-2(40mg,0.09mmol,收率:30.8％)为黄色的固体。
ESI-MS(m/z):440.1[M+H]+
步骤三：
将74-2(45mg,0.10mmol,1.0eq)置于40ml单口瓶,加入DMF(2mL)后加入1-1(47mg,0.10mmol,1.1eq),DIEA(39mg,0.31mmol,3.0eq)和HATU(42mg,0.11mmol,1.1eq),反应液在25℃搅拌2h。将反应液过滤，滤液用高效液相色谱法进行纯化。得到实施例74(20mg,0.02mmol,收率:22.8％)为黄色的固体。
ESI-MS(m/z):884.4[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.10(br s,1H),10.50(s,1H),9.36(dd,J＝7.00,1.38Hz,1H),8.90(dd,J＝4.00,1.25Hz,1H),8.68(s,1H),8.36(s,1H),7.34(dd,J＝7.00,4.25Hz,1H),7.18(d,J＝7.75Hz,1H),7.13(d,J＝7.75Hz,1H),7.01-7.06(m,1H),6.76(s,1H),5.41(dd,J＝12.63,5.25Hz,1H),4.55(br t,J＝5.13Hz,1H),4.48(s,2H),3.75-3.85(m,1H),3.66(s,4H),3.46-3.58 (m,2H),3.37-3.43(m,3H),3.01-3.08(m,2H),2.83-2.97(m,3H),2.60-2.77(m,5H),2.00-2.13(m,3H),1.51-1.92(m,11H),1.37-1.49(m,2H),1.21-1.34(m,2H).
实施例75：
步骤一：
于50mL单口瓶中，加入M31(158mg,0.4mmol)、溴乙酸叔丁酯(117mg,0.60mmol)、DIEA(516mg,4.00mmol)混合于乙腈(4mL)，室温搅拌反应过夜。反应液中加入DCM(15mL)，加入饱和氯化铵溶液(15mL)洗涤，无水硫酸钠干燥，柱层析纯化，洗脱剂为：DCM:MeOH＝100:0～95:5，得到75-1，棕色固体127mg，产率：62.2％。
ESI-MS(m/z):511.6[M+H]+.
1H NMR(500MHz,CDCl3)δ8.72(s,1H),7.08(d,J＝7.8Hz,1H),6.89(t,J＝7.9Hz,1H),6.70(d,J＝7.8Hz,1H),5.14(dd,J＝12.7,5.3Hz,1H),4.36(s,2H),3.69(s,3H),3.63–3.53(m,1H),3.08(s,2H),2.86–2.58(m,5H),2.38(t,J＝8.9Hz,2H),2.17–2.08(m,1H),1.91(d,J＝10.1Hz,2H),1.68(dt,J＝16.7,6.1Hz,2H),1.39(s,9H).
步骤二：
将75-1(127mg,0.25mmol)置于50mL单口瓶中，加入DCM(3mL)溶解，缓慢加入TFA(1020mg,8.95mmol)，保持室温搅拌反应1.5h。反应液减压浓缩，得到75-2，棕色粘稠状固体148.3mg，产率：131.2％。
ESI-MS(m/z):455.4[M+H]+.
步骤三：
将75-2(113mg,0.25mmol)、1-1(191mg,0.25mmol)、HATU(142mg,0.38mmol)、DIEA(193mg,1.50mmol)置于25mL单口瓶中，加DCM(7mL)，25℃搅拌反应过夜。反应液中加入DCM(20mL)，加入饱和氯化铵溶液(20mL)洗涤，有机相用无水硫酸钠干燥，柱层析纯化，洗脱剂 为：DCM:MeOH＝100:0～93:7，得到实施例75，淡黄色固体170mg，产率：75.6％。
ESI-MS(m/z):899.7[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.50(s,1H),9.35(d,J＝6.0Hz,1H),8.90(d,J＝2.7Hz,1H),8.68(s,1H),8.37(s,1H),7.34(dd,J＝6.8,4.2Hz,1H),7.19(d,J＝7.7Hz,1H),7.13(d,J＝7.6Hz,1H),7.05(t,J＝7.9Hz,1H),6.75(s,1H),5.40(dd,J＝12.8,5.2Hz,1H),4.59–4.44(m,3H),3.83(s,1H),3.66(s,3H),3.61–3.35(m,5H),3.26(d,J＝14.8Hz,3H),3.14–2.84(m,7H),2.77–2.58(m,4H),2.11–1.42(m,15H).
实施例76：
将70-4(203mg,0.39mmol)、M31(154mg,0.39mmol)、HATU(222mg,0.58mmol)、DIEA(302mg,2.34mmol)置于25mL单口瓶中，加DCM(7mL)，25℃搅拌反应过夜。反应液中加入DCM(15mL)，加入饱和氯化铵溶液(15mL)洗涤，无水硫酸钠干燥，柱层析纯化，洗脱剂为：DCM:MeOH＝100:0～95:5，得到实施例76，淡黄色固体212mg，产率：60.5％。
ESI-MS(m/z):899.7[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.48(s,1H),9.34(d,J＝6.6Hz,1H),8.89(d,J＝2.7Hz,1H),8.67(s,1H),8.33(s,1H),7.33(dd,J＝6.7,4.3Hz,1H),7.18(d,J＝7.7Hz,1H),7.14(d,J＝7.7Hz,1H),7.04(t,J＝7.8Hz,1H),6.72(s,1H),5.40(dd,J＝12.7,5.2Hz,1H),4.57–4.49(m,3H),3.92–3.78(m,3H),3.66(s,3H),3.43–3.39(m,2H),3.18–3.03(m,2H),3.02–2.84(m,5H),2.77–2.44(m,11H),2.08–2.00(m,1H),1.98–1.92(m,1H),1.84(d,J＝13.1Hz,3H),1.74(dd,J＝19.6,10.9Hz,4H),1.64–1.46(m,4H).
实施例77：
步骤一：
将4-溴-2,5-二氟苯甲腈(10.0g,45.87mmol,1.0eq)置于250mL单口瓶中加入EtOH(70mL),甲基肼硫酸盐(19.8g,137.61mmol,3.0eq),三乙胺(25.5mL,183.49mmol,4.0eq),反应液80℃搅拌6h。反应液减压浓缩除去乙醇后加入水(150mL)有固体析出,过滤,收集滤饼,滤饼中加入DCM(20mL)搅拌30min后过滤,收集滤饼,得到77-2(4g,16.39mmol,收率35.7％)为白色固体。
ESI-MS(m/z):Br,244.0,246.0[M+1,M+3]+.
1H NMR(400MHz,CDCl3)δ7.44(d,J＝5.25Hz,1H),7.24(d,J＝8.13Hz,1H),3.98(s,2H),3.82(s,3H).
步骤二：
将77-2(4g,16.39mmol)置于100mL单口瓶中加入HCl(30mL,2M),丙烯酸(1.54g,21.31mmol,1.3eq)加入到反应液中,反应液100℃搅拌过夜。反应液中加入饱和碳酸氢钠水溶液至pH为7-8,再加入醋酸调pH为5-6,有固体析出,过滤,收集滤饼,得到77-3(4.68g,14.80mmol,收率90.3％)为灰色固体。
ESI-MS(m/z):Br,316.0,318.0[M+1,M+3]+.
1H NMR(400MHz,DMSO-d6)δ7.84(d,J＝5.50Hz,1H),7.67(d,J＝9.01Hz,1H),3.77(s,3H),3.45(br t,J＝6.75Hz,2H),2.59(br t,J＝6.82Hz,2H).
步骤三：
将77-3(4.58g,14.49mmol)置于100mL单口瓶中加入乙酸(45mL)和氰酸钾(2.35g,28.98mmol,2.0eq)，60℃搅拌3h。反应液中加入HCl(45mL,2N)后继续60℃搅拌过夜。反应液冷却后过滤,滤饼用水洗涤两次,收集滤饼,得到77-4(3g,8.79mmol,收率60.7％)为白色固体。ESI-MS(m/z):Br,340.9,342.9[M+1,M+3]+.
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.17(d,J＝5.63Hz,1H),7.63(d,J＝9.13Hz,1H),4.01(s,3H),3.93(t,J＝6.69Hz,2H),2.76(t,J＝6.69Hz,2H).
步骤四：
将77-4(300mg,0.88mmol,1.0eq)置于40mL单口瓶中加入二氧六环(5mL),2-(4-羟基哌啶-4-基)乙酸叔丁酯(378mg,1.76mmol,2.0eq),Cs2CO3(859mg,2.64mmol,3.0eq),钯催化剂(CAS号：1814936-54-3)(85mg,0.09mmol,0.1eq)加入到反应液中,100℃下搅拌2h。将反应液加入DCM(30mL),过滤,滤液减压浓缩,柱层析分离纯化(PE:EA＝5:1～0:1),得到77-5(300mg,0.63mmol,收率71.7％)为淡黄色固体。
ESI-MS(m/z):476.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δppm 10.53(s,1H),7.33(d,J＝12.87Hz,1H),7.12(d,J＝7.15Hz,1H),4.58(s,1H),3.94(s,3H),3.90(t,J＝6.68Hz,2H),3.12-3.22(m,2H),3.01-3.10(m,2H),2.74(t,J＝6.68Hz,2H),2.40(s,2H),1.81-1.91(m,2H),1.70-1.79(m,2H),1.43(s,9H).
步骤五：
将77-5(270mg,0.57mmol,1.0eq)置于50mL单口瓶中加入DCM(6mL),加入盐酸二氧六环溶液(4mL)室温搅拌12h,将反应液减压浓缩,得到77-6(238mg,0.57mmol)为白色固体。ESI-MS(m/z):420.1[M+H]+.
步骤六：
将77-6(238mg,0.57mmol,1.0eq)置于50mL单口瓶中并加入DMF(6mL),1-1(262.48mg,0.57mmol,1.0eq),DIEA(0.3mL,1.70mmol,3.0eq),HATU(237mg,0.62mmol,3.0eq)加入到反应液中,室温搅拌1h,反应液过滤后,高效液相色谱分离纯化,得到实施例77(176mg,0.20mmol,36.0％)为黄色固体。
ESI-MS(m/z):864.6[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.47-10.54(m,2H),9.36(d,J＝7.00Hz,1H),8.90(d,J＝2.88Hz,1H),8.68(s,1H),8.36(s,1H),7.30-7.38(m,2H),7.13(d,J＝7.00Hz,1H),6.76(s,1H),5.01(s,1H),4.55(t,J＝5.07Hz,1H),3.95(s,3H),3.89(t,J＝6.63Hz,3H),3.71-3.79(m,1H),3.55- 3.65(m,1H),3.38-3.48(m,3H),3.18(m,2H),3.03-3.12(m,4H),2.93(m,2H),2.74(t,J＝6.63Hz,2H),2.59-2.68(m,4H),1.78-1.90(m,5H),1.68-1.77(m,5H),1.46-1.65(m,3H).
实施例78：
步骤一：
将M29(500mg,1.48mmol,1.0eq)置于100mL单口瓶中加入DMA(5mL),4-(二甲氧基甲基)哌啶(941mg,5.91mmol,4.0eq),叔丁醇钠(426mg,4.44mmol,3.0eq),钯催化剂(CAS号：1814936-54-3)(143mg,0.15mmol,0.1eq)加入到反应液中,反应液100℃下搅拌2h。反应液减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝20:1～1:1),得到产物加入乙酸乙酯(10mL)搅拌1h后过滤，收集滤饼,得到78-1(100mg,0.24mmol,收率16.2％)为白色固体。
ESI-MS(m/z):417.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),6.94-7.04(m,1H),6.86-6.93(m,2H),5.37(br dd,J＝12.41,5.32Hz,1H),4.15(br d,J＝5.75Hz,1H),3.63(s,3H),3.31(s,6H),3.13(br d,J＝11.49Hz,2H),2.86-2.95(m,1H),2.61-2.77(m,4H),1.97-2.06(m,1H),1.67-1.81(m,3H),1.41-1.57(m,2H).
步骤二：
将78-1(100mg,0.24mmol,1.0eq)置于10mL单口瓶,加入甲酸(2mL),将体系在25℃下搅拌1h。反应液减压浓缩,得到78-2(80mg,0.22mmol,收率89.9％)为黄色油。
ESI-MS(m/z):371.2[M+H]+.
步骤三：
将78-2(70mg,0.19mmol,1.0eq)置于10mL单口瓶,加入DMA(2mL)，后加入1-1(87mg,0.19 mmol,1.0eq)、醋酸钾(47mg,0.23mmol,3.0eq)和醋酸硼氢化钠(55mg,0.57mmol,1.2eq)，25℃下搅拌12h。反应液减压浓缩,高效液相色谱分离纯化,得到实施例78(53mg,0.07mmol,收率34.5％)为黄色固体。
ESI-MS(m/z):817.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.36(dd,J＝7.00,1.38Hz,1H),8.90(dd,J＝4.06,1.31Hz,1H),8.68(s,1H),8.34(s,1H),7.34(dd,J＝6.94,4.19Hz,1H),6.95-7.01(m,1H),6.88(dd,J＝12.07,8.07Hz,2H),6.74(s,1H),5.36(dd,J＝12.63,5.38Hz,1H),4.57(t,J＝5.25Hz,1H),3.64(s,3H),3.39-3.42(m,3H),3.12(m,2H),3.00(s,2H),2.93(m,3H),2.60-2.76(m,8H),2.44(m,2H),2.26(m,2H),1.97-2.04(m,1H),1.68-1.88(m,9H),1.51-1.63(m,3H),1.27-1.41(m,2H).
实施例79：
步骤一：
将79-1(6.00g,24.2mmol,1.0eq)置于100mL单口瓶,加入甲醇(60mL)和三氟化硼乙醚(2.06g,0.6eq),反应在25℃下搅拌2h。反应液减压浓缩,柱层析法(石油醚:乙酸乙酯＝20:1～5:1)纯化,得到79-2(3.40g,12.1mmol,收率:50.2％)为黄色的油。
ESI-MS(m/z):280.3[M+H]+.
1H NMR(400MHz,CDCl3)δ7.30-7.42(m,5H),5.14(s,2H),3.87(d,J＝12.96Hz,2H),3.53(s,2H),3.17-3.28(m,5H),1.83(d,J＝13.57Hz,2H),1.37-1.51(m,2H).
步骤二：
将10％湿钯碳(500mg,4.70mmol,1.4eq)置于100mL单口瓶,加入乙醇(20mL)后加入79-2(900mg,3.22mmol,1.0eq),氢气置换三次后反应液在15Psi,25℃下搅拌12h。反应液过滤,滤 液减压浓缩,得到79-3(500mg,3.44mmol,收率:96.9％)为黄色固体。
ESI-MS(m/z):146.2[M+H]+.
1H NMR(400MHz,CDCl3)δ3.69(q,J＝7.00Hz,1H),3.50(s,2H),3.16-3.28(s,3H),2.72-2.99(m,4H),1.76(d,J＝13.63Hz,2H),1.45(ddd,J＝13.70,9.94,4.25Hz,2H).
步骤三：
将M29(200mg,0.59mmol,1.0eq)置于100mL单口瓶,加入二氧六环(2mL)后加入79-3(128mg,0.89mmol,1.5eq)和碳酸铯(578mg,1.77mmol,3.0eq),加入催化剂(CAS号:1612891-29-8)(49mg,0.06mmol,0.1eq),反应液在氮气保护下100℃搅拌2h。反应液减压浓缩,加入水(10mL),乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水洗涤后无水硫酸钠干燥,减压浓缩,薄层色谱法(二氯甲烷:甲醇＝15:1)纯化,得到79-4(50mg,0.12mmol,收率:21.0％)为黄色固体。
ESI-MS(m/z):403.4[M+H]+.
1H NMR(400MHz,CDCl3)δ9.69(s,1H),8.28(dd,J＝7.70,1.22Hz,1H),7.90-7.98(m,1H),7.73(t,J＝7.27Hz,1H),5.22(dd,J＝12.29,5.20Hz,1H),3.76(s,3H),3.39(s,2H),3.02-3.11(s,3H),2.70-2.94(m,3H),2.18-2.27(m,1H),1.85-2.05(m,4H),1.43-1.48(m,2H),1.22-1.28(m,2H).
步骤四：
将79-4(20mg,0.05mmol,1.0eq)置于40mL单口瓶,加入DCM(1mL)和DMP(31mg,0.07mmol,1.5eq),将反应液在25℃下搅拌2h。反应液加入饱和碳酸氢钠溶液淬灭,加入乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水洗涤后无水硫酸钠干燥,减压浓缩得到79-5(20mg,0.05mmol)粗品直接用于下一步。
ESI-MS(m/z):401.4[M+H]+.
步骤五：
将79-5(25mg,0.06mmol,1.0eq)置于40mL单口瓶,加入DMA(1mL)后加入1-1(28mg,0.06mmol,1.0eq),醋酸(37mg,0.01mmol,0.1eq)和醋酸硼氢化钠(13mg,0.06mmol,1.0eq),反应液室温搅拌2h。反应液过滤后高效液相色谱分离纯化,得到实施例79(4.93mg,0.01mmol,收率:9.3％)为黄色固体。
ESI-MS(m/z):847.9[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.49(s,1H),9.36(dd,J＝7.07,1.56Hz,1H),8.90(dd,J＝4.19,1.56Hz,1H),8.68(s,1H),8.34(s,1H),7.29-7.39(m,1H),6.91-7.01(m,2H),6.87(d,J＝8.00Hz,1H),6.73(s,1H),5.36(dd,J＝12.69,5.32Hz,1H),4.55(t,J＝5.32Hz,1H),3.65 (s,3H),3.40(t,J＝5.13Hz,3H),3.19(s,3H),3.00(s,2H),2.85-2.96(m,7H),2.61-2.75(m,8H),1.91-2.03(m,3H),1.69-1.85(m,8H),1.47-1.65(m,4H).
实施例80：
步骤一：
将80-1(3.00g,15.5mmol,1.0eq)置于100mL三口瓶中加入THF(30mL),0℃下滴加四氢铝锂(6.50mL,16.3mmol,2.5M,1.05eq)的四氢呋喃溶液,滴完后室温搅拌过夜。反应液降温至0℃,滴加0.62mL H2O,0.62mL15％NaOH溶液,1.24mL H2O,补加THF(30mL)后搅拌10min过滤,滤液减压浓缩,得到80-2(2.58g,15.63mmol)为无色液体。
1H NMR(400MHz,CDCl3)δ4.57(quin,J＝7.05Hz,1H),3.67(d,J＝6.43Hz,2H),2.71-2.83(m,1H),2.50-2.65(m,4H).
步骤二：
将80-2(2.50g,15.1mmol,1.0eq)置于100mL单口瓶中加入二氯甲烷(25mL)和咪唑(2.06g,30.3mmol,2.0eq)，TBSCl(3.42g,22.7mmol,1.5eq)加入到反应液中,反应液室温搅拌过夜。反应液中加入水(80mL)和二氯甲烷(100mL),分出有机相用饱和食盐水反洗一次(80mL),有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝10:1-1:1),得到80-3(4.00g,14.3mmol,收率94.5％)为无色油。
1H NMR(400MHz,CDCl3)δ4.57(quin,J＝7.16Hz,1H),3.60(d,J＝5.25Hz,2H),2.66-2.78(m,1H),2.52-2.62(m,4H),0.91(s,9H),0.06(s,6H).
步骤三：
将M29(1.00g,2.96mmol,1.0eq)溶于DME(25mL)中,加入80-3(1.24g,4.44mmol,1.5eq),TTMSS(1.10g,4.44mmol,1.5eq),碳酸钠(0.63g,5.91mmol,2.0eq),置换氮气10min,在氮气保护下加入NiCl2.dtbbpy(0.06g,0.15mmol,0.05eq),[Ir(df(CF3)ppy)2(dtbbpy)]PF6(CAS号：870987-63-6)(0.03g,0.03mmol,0.01eq),置换氮气10min,较准流速S1＝0.17mL/min,50℃, 保留时间60min,冲洗管路,开启光源(hv＝395nm,24w)和泵,60min后，收集反应液。反应液中加入水(100mL),乙酸乙酯(100mL×2)萃取,合并有机相用饱和氯化钠水溶液反洗一次(80mL),分出有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝5:1-1:2),得到80-4(560mg,1.22mmol,收率41.4％)为黄色固体。
ESI-MS(m/z):458.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.02(br s,1H),7.15-7.24(m,1H),7.08(q,J＝7.96Hz,1H),6.65-6.70(m,1H),5.18-5.24(m,1H),3.74-3.76(m,2H),3.64-3.72(m,3H),3.61(d,J＝5.13Hz,1H),2.92-3.02(m,2H),2.73-2.88(m,2H),2.12-2.38(m,5H),0.93(d,J＝8.38Hz,9H),0.09(d,J＝12.01Hz,6H).
步骤四：
将80-4(560mg,1.22mmol,,1.0eq)置于40mL单口瓶中加入THF(5mL),TBAF的四氢呋喃溶液(2.40mL,2.45mmol,1M,2.0eq)加入到反应液中,反应液室温搅拌过夜。反应液中加入水(30mL),乙酸乙酯(50mL×2)萃取,合并有机相用无水硫酸钠干燥后减压浓缩,柱层析分离纯化(石油醚:乙酸乙酯＝2:1-0:1),得到的油状物加入乙酸乙酯(10mL)搅拌30min后过滤,收集滤饼得到80-5(110mg,0.32mmol,收率26.2％)为白色固体。
ESI-MS(m/z):344.1[M+H]+.
1H NMR(400MHz,CDCl3)δ8.10(br s,1H),7.12-7.25(m,1H),7.08(q,J＝8.13Hz,1H),6.69(dd,J＝7.44,5.44Hz,1H),5.22(dd,J＝12.01,5.13Hz,1H),4.09-4.19(m,1H),3.82(d,J＝6.75Hz,1H),3.62-3.72(m,4H),2.92-2.99(m,1H),2.70-2.89(m,2H),2.59(m,1H),2.40-2.50(m,2H),2.19-2.32(m,2H),2.06-2.15(m,1H).
步骤五：
将80-5(80mg,0.23mmol,1.0eq)置于40mL单口瓶中加入DCM(3mL),DMP(148mg,0.35mmol,1.5eq)加入到反应液中,反应液室温搅拌5h。反应液中加入饱和碳酸氢钠水溶液(10mL),二氯甲烷(10mL×2)萃取,合并有机相用无水硫酸钠干燥后减压浓缩,得到80-6(50mg,0.15mmol,收率62.9％)为浅黄色固体。
ESI-MS(m/z):342.1[M+H]+.
1H NMR(400MHz,CDCl3)δ9.75-10.10(m,1H),8.10(br s,1H),7.11-7.25(m,2H),6.75(d,J＝7.70Hz,1H),5.20-5.30(m,1H),4.17-4.21(m,1H),3.66-3.77(m,3H),3.26-3.36(m,1H),2.95-3.04(m,1H),2.74-2.92(m,3H),2.45-2.66(m,3H),2.24-2.30(m,1H).
步骤六：
将80-6(50mg,0.15mmol,1.0eq)置于40mL单口瓶中加入DMA(2mL),1-1(68mg,0.15mmol,1.0eq),AcOH(18mg,0.29mmol,2.0eq),醋酸硼氢化钠(37mg,0.18mmol,1.2eq)加入到反应液中,反应液室温搅拌2h。反应液过滤后高效液相色谱分离纯化,得到实施例80(22.29mg,0.03mmol,收率19.3％)为浅黄色固体。
ESI-MS(m/z):788.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.49(s,1H),9.36(dd,J＝7.00,1.50Hz,1H),8.90(dd,J＝4.25,1.50Hz,1H),8.68(s,1H),8.34(s,1H),7.34(dd,J＝7.07,4.19Hz,1H),6.97-7.22(m,3H),6.74(s,1H),5.33-5.40(m,1H),4.55(t,J＝5.44Hz,1H),3.93-4.21(m,1H),3.51-3.62(m,3H),3.40(br t,J＝5.00Hz,2H),2.84-3.03(m,5H),2.56-2.74(m,6H),2.32-2.46(m,6H),2.12-2.23(m,1H),1.69-2.05(m,9H),1.48-1.65(m,3H).
实施例81：
步骤一：
将M29(300mg,0.89mmol,1.0eq)置于40mL单口瓶,加入1,4-二氧六环(3mL)后加入2-(4-羟基哌啶-4-基)乙酸叔丁酯(287mg,1.33mmol,1.5eq)和碳酸铯(869mg,2.67mmol,3.0eq),最后加入钯催化剂(CAS号:1612891-29-8)(74mg,0.09mmol,0.1eq),反应液在100℃下搅拌2h。反应液减压浓缩,加入水(30mL)，乙酸乙酯(30mL×3)萃取,有机相用饱和氯化钠洗涤，后用薄层色谱法(二氯甲烷:甲醇＝15:1)纯化,得到81-2(120mg,0.25mmol,收率:28.6％)为黄色固体。
ESI-MS(m/z):473.5[M+H]+.
1H NMR(400MHz,CDCl3)δ8.21(s,1H),7.01(br d,J＝4.82Hz,2H),6.53-6.62(m,1H),5.21 (dd,J＝12.37,5.20Hz,1H),3.77(s,3H),3.16-3.28(m,2H),2.89-2.99(m,3H),2.67-2.87(m,3H),2.46(s,2H),2.17-2.27(m,1H),1.73-1.91(m,4H),1.50(s,9H).
步骤二：
将81-2(110mg,0.23mmol,1.0eq)置于40mL单口瓶,加入DCM(1mL)后加入盐酸二氧六环溶液(1mL),反应在25℃下搅拌2h。反应液减压浓缩,得到81-3(90mg,0.22mmol,收率:92.8％)为黄色固体。
ESI-MS(m/z):417.4[M+H]+.
步骤三：
将1-1(99mg,0.22mmol,1.0eq)置于40mL单口瓶,加入81-3(90mg,0.22mmol,1.0eq)后加入DIEA(83mg,0.65mmol,3.0eq),最后加入HATU(90mg,0.24mmol,1.1eq),反应在25℃下搅拌2h。反应液通过高效液相色谱法进行纯化,得到实施例81(89.26mg,0.10mmol,收率:48.0％)为黄色固体。
ESI-MS(m/z):861.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.50(s,1H),9.36(dd,J＝7.03,1.53Hz,1H),8.90(dd,J＝4.16,1.47Hz,1H),8.68(s,1H),8.36(s,1H),7.33(dd,J＝6.97,4.16Hz,1H),6.90-7.01(m,2H),6.86(d,J＝7.95Hz,1H),6.76(s,1H),5.35(dd,J＝12.59,5.26Hz,1H),4.96(br s,1H),4.56(t,J＝4.83Hz,1H),3.70-3.93(m,2H),3.55-3.67(m,4H),3.37-3.49(m,3H),3.00-3.11(m,4H),2.82-2.97(m,5H),2.58-2.76(m,6H),1.95-2.04(m,1H),1.68-1.90(m,10H),1.46-1.65(m,3H).
实施例82：
步骤一：
将82-1(2.00g,7.24mmol,1.0eq)置于100mL单口瓶中加入NMP(40mL),加入哌啶-4-基甲醇(830mg,7.24mmol,1.0eq)和DIEA(2.81g,21.72mmol,3.0eq),90℃搅拌12h。反应液中加入H2O(50mL),乙酸乙酯(80mL×2)萃取,合并有机相用无水硫酸钠干燥后减压浓缩,柱层析(石油醚:乙酸乙酯＝0:1)纯化,得到82-2(1.60g,4.31mmol,收率:59.5％)为黄色的油。
ESI-MS(m/z):372.1[M+H]+.
1H NMR(400MHz,CDCl3)δ8.11(br s,1H),7.62-7.71(m,1H),7.29(d,J＝2.38Hz,1H),7.06(dd,J＝8.58,2.38Hz,1H),4.94(dd,J＝12.28,5.25Hz,1H),3.99(d,J＝12.99Hz,2H),3.51-3.58(m,2H),3.36-3.42(m,2H),3.00(m,2H),2.34-2.41(m,2H),2.08-2.17(m,1H),1.88(m,2H),1.31-1.43(m,2H).
步骤二：
将82-2(500mg,1.35mmol,1.0eq)置于100mL单口瓶中加入DCM(5mL),降温到0℃加入DMP(599mg,1.41mmol,1.05eq)，25℃下搅拌2h。反应液中加入饱和碳酸氢钠溶液淬灭并调节pH＝7～8后加入二氯甲烷(10mL×3)萃取,有机相用饱和氯化钠洗涤后无水硫酸钠干燥,减压浓缩,柱层析法(石油醚:乙酸乙酯＝1:1)纯化,得到82-3(140mg,0.38mmol,收率:28.2％)为白色固体。
ESI-MS(m/z):370.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),9.68(s,1H),7.72(d,J＝8.50Hz,1H),7.40(s,1H),7.32(dd,J＝8.57,1.94Hz,1H),5.13(dd,J＝12.88,5.25Hz,1H),4.00(br d,J＝13.26Hz,2H),3.18-3.29(m,2H),2.87-3.03(m,1H),2.58-2.80(m,4H),1.95-2.03(m,2H),1.57-1.69(m,2H).
步骤三：
将82-3(100mg,0.27mmol,1.0eq)置于40mL单口瓶中加入DMA(2mL)、1-1(124mg,0.27mmol,1.0eq),醋酸钾(79mg,0.81mmol,3.0eq),三乙酰氧基硼氢化钠(57mg,0.27mmol,1.0eq)加入到反应液中,25℃下搅拌1h。反应液通过高效液相色谱法分离纯化,得到实施例82(83.64mg,0.10mmol,收率:37.9％)为黄色固体。
ESI-MS(m/z):816.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.51(s,1H),9.37(dd,J＝6.97,1.47Hz,1H),8.91(dd,J＝4.03,1.34Hz,1H),8.69(s,1H),8.35(s,1H),7.67(d,J＝8.56Hz,1H),7.30-7.38(m,2H),7.20-7.28(m,1H),6.75(s,1H),5.08(dd,J＝12.96,5.26Hz,1H),4.60(t,J＝5.13Hz,1H),4.07(br d,J＝12.71Hz,2H),3.41-3.43(m,3H),2.91-3.03(m,6H),2.55-2.72(m,5H),2.34-2.48(m, 2H),2.20(br d,J＝6.97Hz,2H),1.98-2.08(m,1H),1.71-1.89(m,9H),1.50-1.66(m,3H),1.08-1.24(m,2H).
实施例83：
将78-2(53mg,0.14mmol)置于40mL单口瓶中加入DMA(2mL),加入61-2(66mg,0.14mmol,1.0eq),乙酸钾(28mg,0.29mmol,2.0eq),醋酸硼氢化钠(36mg,0.17mmol,1.2eq),反应液室温搅拌2h。反应液过滤后收集滤液进行高效液相色谱分离纯化,得到实施例83(34.8mg,0.04mmol,收率29.8％)为白色固体。
ESI-MS(m/z):817.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.09(br s,1H),10.93(s,1H),8.97(s,1H),8.75(br d,J＝4.41Hz,1H),8.33(s,1H),8.25(br d,J＝8.58Hz,1H),7.57(dd,J＝8.34,4.77Hz,1H),6.94-7.01(m,1H),6.85-6.92(m,2H),6.75(s,1H),5.36(dd,J＝12.40,5.01Hz,1H),4.54(t,J＝5.13Hz,1H),3.63(s,3H),3.38(t,J＝5.13Hz,2H),3.11(m,2H),2.84-3.04(m,5H),2.56-2.76(m,7H),2.42(m,2H),2.25(m,2H),1.96-2.05(m,1H),1.67-1.91(m,9H),1.45-1.67(m,4H),1.32(m,2H).
实施例84和实施例85：
步骤一：
将84-1(200mg,0.62mmol)置于40mL单口瓶中加入二氧六环(4mL),哌啶-4-基甲醇(107mg,0.93mmol,1.5eq),碳酸铯(403mg,1.24mmol,2.0eq),催化剂(CAS号：1612891-29-8)(60mg,0.06mmol,0.1eq)加入到反应液中,反应液100℃搅拌2h。反应液中加入二氯甲烷(20mL),过滤,滤液减压浓缩后柱层析纯化(二氯甲烷:甲醇＝15:1-10:1),得到84-2(120mg,0.34mmol,收率54.2％)为白色固体。
ESI-MS(m/z):358.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.50(br d,J＝8.50Hz,1H),6.98-7.20(m,2H),5.05(dd,J＝13.32,5.07Hz,1H),4.49(t,J＝5.25Hz,1H),4.27-4.37(m,1H),4.16-4.25(m,1H),3.90(br d,J＝12.76Hz,2H),3.28(br t,J＝5.69Hz,2H),2.77-2.97(m,3H),2.37(br dd,J＝13.01,4.38Hz,1H),1.92-2.02(m,1H),1.58-1.80(m,4H),1.15-1.30(m,2H).
步骤二：
将84-2(100mg,0.28mmol,1.0eq)置于40mL单口瓶中加入DCM(3mL)，DMP(125mg,0.29mmol,0.1eq)加入到反应液中,反应液室温搅拌1h。反应液中加入饱和碳酸氢钠水溶液(10mL),二氯甲烷萃取(10mL×2),合并有机相用无水硫酸钠干燥后减压浓缩,薄层色谱分离纯化(二氯甲烷:甲醇＝10:1),得到84-3(80mg,0.23mmol,收率80.5％)为黄色油。
ESI-MS(m/z):356.1[M+H]+.
步骤三：
将84-3(80mg,0.23mmol,1.0eq)置于40mL单口瓶中加入DMA(2mL),1-1(104mg,0.23mmol,1.0eq),乙酸钾(44mg,0.45mmol,2.0eq),醋酸硼氢化钠(47mg,0.23mmol,1.0eq)加入到反应液中,反应液室温搅拌2h。反应液过滤,滤液送高效液相色谱分离纯化,得到84-4(40mg,0.05mmol,收率22.2％)为黄色固体，直接用于SFC拆分。
步骤四：
将84-4(40mg，0.05mmol)进行SFC分离,得到实施例84和实施例85。
实施例84或实施例85(15.15mg,0.02mmol,收率37.6％)为黄色固体。纯度：99.18％,100％ee.
ESI-MS(m/z):802.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.50(s,1H),9.36(d,J＝7.05Hz,1H),8.90(d,J＝2.60Hz,1H),8.68(s,1H),8.35(s,1H),7.51(d,J＝8.04Hz,1H),7.34(dd,J＝6.80,4.45Hz,1H),7.02-7.11(m,2H),6.74(s,1H),5.05(dd,J＝13.42,4.64Hz,1H),4.58(t,J＝5.44Hz,1H),4.16-4.37(m,2H),3.89(d,J＝11.75Hz,2H),3.41(m,2H),2.79-3.03(m,7H),2.55-2.70(m,5H),2.32-2.45(m,3H),2.21(m,2H),1.93-2.02(m,1H),1.68-1.90(m,9H),1.48-1.66(m,3H),1.14- 1.27(m,2H).
另一(15.98mg,0.02mmol,收率39.6％)为黄色固体。
ESI-MS(m/z):802.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.50(s,1H),9.37(d,J＝6.31Hz,1H),8.91(d,J＝3.22Hz,1H),8.69(s,1H),8.35(s,1H),7.51(d,J＝8.41Hz,1H),7.35(dd,J＝6.99,4.14Hz,1H),6.99-7.13(m,2H),6.74(s,1H),5.05(dd,J＝13.36,4.95Hz,1H),4.57(t,J＝5.32Hz,1H),4.16-4.39(m,2H),3.83-3.96(m,2H),3.39-3.43(m,2H),2.79-3.05(m,7H),2.54-2.71(m,5H),2.33-2.46(m,3H),2.16-2.26(m,2H),1.94-2.02(m,1H),1.69-1.89(m,9H),1.48-1.65(m,3H),1.14-1.27(m,2H).
采用实施例34的相似的合成方法，采用相应的中间体合成，结构表征数据如下表：

实施例91：
步骤一：
将M1-1(900mg,2.55mmol,1.0eq)置于100mL单口瓶中加入甲醇钠30％甲醇溶液(2.29g,12.7mmol,5.0eq),40℃下搅拌4h。向反应液中加入水(20mL),用乙酸乙酯(20mL×3)萃取,有机相合并后用饱和食盐水(20mL)反洗一次,有机相用无水硫酸钠干燥,减压浓缩后得到91-1(900mg,2.47mmol,收率96.7％)为黄色固体。
ESI-MS(m/z):365.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.85(s,1H),6.47(s,1H),3.93(s,3H),3.75(m,2H),3.34-3.43(m,2H),2.98(s,2H),1.92(m,2H),1.69-1.79(m,2H),1.48(s,9H).
步骤二：
向75mL氢化瓶中加入Pd/C 10％(900mg),加入THF(7mL),将91-1(900mg,2.47mmol,1.0 eq)的THF溶液(10mL)加入到反应瓶中,25℃,50psi压力下搅拌12h。反应液过滤,滤液减压浓缩,得到91-2(800mg,2.39mmol,收率96.9％)为黄色固体。
ESI-MS(m/z):335.2[M+H]+.
1H NMR(400MHz,CDCl3)δ6.57(s,1H),6.37(s,1H),3.81(s,3H),3.75(br t,J＝6.50Hz,2H),3.35-3.45(m,2H),2.89(s,2H),1.83-1.93(m,2H),1.63-1.72(m,2H),1.48(s,9H).
步骤三：
将91-2(700mg,2.09mmol,1.0eq)置于100mL单口瓶中加入乙腈(7mL),6-(三氟甲基)吡啶-2-羧酸(400mg,2.09mmol,1.0eq),NMI(0.8mL,10.4mmol,5.0eq)与TCFH(704mg,2.51mmol,1.2eq)加入到反应液中,室温搅拌12h。将析出固体过滤,滤饼减压浓缩,得到91-3(1.00g,1.97mmol,收率94.1％)为白色固体。
ESI-MS(m/z):508.2[M+H]+.
1H NMR(400MHz,CDCl3)δ10.31(s,1H),8.47(d,J＝7.75Hz,1H),8.33(s,1H),8.10(t,J＝7.81Hz,1H),7.84(d,J＝7.75Hz,1H),6.47(s,1H),3.92(s,3H),3.74(m,2H),3.37-3.47(m,2H),3.00(s,2H),1.92(m,2H),1.68-1.77(m,2H),1.49(s,9H).
步骤四：
将91-3(500mg,0.99mmol,1.0eq)置于50mL单口瓶中加入DCM(5mL),加入盐酸二氧六环溶液(5mL),15℃下搅拌2h,将反应液减压浓缩后加入饱和碳酸氢钠水溶液至pH＝7-8,过滤,滤饼用水冲洗后减压浓缩,得到91-4(400mg,0.98mmol,收率99.7％)为黄色固体。
ESI-MS(m/z):408.0[M+H]+.
步骤五：
将91-4(200mg,0.49mmol,1.0eq)置于50mL单口瓶中加入DMA(3.5mL),M33(207.89mg,0.49mmol,1.0eq),KOAc(144mg,1.47mmol,3.0eq),醋酸硼氢化钠(103mg,0.49mmol,1.0eq)加入到反应液中,室温搅拌1h。反应液进行高效液相色谱法纯化,得到实施例91(161mg,0.20mmol,收率40.2％)为黄色固体。
ESI-MS(m/z):815.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.12(s,1H),8.33-8.45(m,2H),8.11-8.23(m,2H),7.18(d,J＝7.75Hz,1H),7.10-7.14(m,1H),7.00-7.06(m,1H),6.68(s,1H),5.41(br dd,J＝12.69,5.32Hz,1H),4.47(s,2H),3.86(s,3H),3.65(s,3H),3.41-3.51(m,2H),2.97(s,2H),2.84-2.94(m,1H),2.59-2.78(m,2H),2.38(m,3H),2.11(br d,J＝7.13Hz,2H),1.97-2.07(m,3H),1.68-1.88(m,6H),,1.38-1.52(m,1H),1.11-1.23(m,2H),0.82-0.96(m,2H).
实施例92：
步骤一：
将甲基1-甲氧基-4-氧亚基环己烷-1-甲酸基酯(25.0g,134mmol,1.0eq)置于250mL三口瓶中加入MeOH(175mL),0℃下缓慢加入NaBH4(10.2g,268mmol,2.0eq),冰浴搅拌1.5h,将饱和氯化铵水溶液(200mL)加入到反应液中,再加入水(100mL)使盐溶解,乙酸乙酯(200mL×3)萃取,合并有机相用无水硫酸钠干燥,减压浓缩后柱层析纯化(石油醚:乙酸乙酯＝5:1-1:1),得到92-1(14.0g,74.38mmol,收率55.4％)为透明无色油状物。
ESI-MS(m/z):189.1[M+H]+.
1H NMR(400MHz,CDCl3)δ3.72(s,3H),3.59-3.68(m,1H),3.23(s,3H),1.98-2.07(m,2H),1.78-1.86(m,2H),1.67-1.75(m,2H),1.51-1.62(m,2H).
步骤二：
将92-1(5.00g,26.5mmol,1.0eq)置于100mL的三口瓶中加入DMA(35mL),0℃下慢慢加入NaH(1.59g,39.8mmol,1.5eq),0℃搅拌反应5h,3-溴丙炔(5.93g,39.8mmol,1.5eq)在0℃下滴加到反应液中,室温搅拌12h。将反应液缓慢倒入饱和氯化铵水溶液(100mL)中,乙酸乙酯(150mL×3)萃取,分出有机相用饱和食盐水(100mL)反洗一次,有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝10:1-2:1),得到92-2(220mg,0.97mmol,收率18.3％) 为黄色油状物。
1H NMR(400MHz,CDCl3)δ4.13(d,J＝2.38Hz,2H),3.68(s,3H),3.41-3.53(m,1H),3.17(s,3H),2.34(t,J＝2.32Hz,1H),1.98(m,2H),1.76-1.84(m,2H),1.63-1.73(m,2H),1.49-1.59(m,2H).
步骤三：
将92-2(1.50g,6.63mmol,1.0eq)置于100mL三口瓶中加入THF(15mL),0℃下滴加LiAlH4的四氢呋喃溶液(8.0mL,19.9mmol,3.0eq,2.5M),室温搅拌2h。冰浴下加入水(1mL),15％NaOH水溶液(1mL),水(3mL)淬灭反应，加入乙酸乙酯(40mL)搅拌10min后过滤,滤液减压浓缩,得到92-3(1.13g,5.70mmol,收率86.0％)为黄色油状物。
1H NMR(400MHz,CDCl3)δ4.20(s,2H),3.49-3.56(m,1H),3.46(br s,2H),3.20(s,3H),2.41(br s,1H),1.94(m,2H),1.74-1.87(m,3H),1.53-1.63(m,2H),1.18-1.33(m,2H).
步骤四：
将M29(800mg,2.37mmol)置于100mL单口瓶中加入DMF(10mL),92-3(703mg,3.55mmol,1.5eq)和Cs2CO3(3.00g,9.46mmol,4.0eq),双三苯基磷二氯化钯(184mg,0.24mmol,0.1eq)加入到反应液中,100℃下搅拌2h。反应液中加入THF(50mL)后过滤,收集滤液减压浓缩,柱层析纯化(石油醚:THF＝2:1-1:2),得到的固体中加入乙酸乙酯(10mL)搅拌10min后过滤,收集滤饼,得到92-4(0.17g,0.37mmol,收率15.8％)为白色固体。
ESI-MS(m/z):478.2[M+23]+.
1H NMR(400MHz,DMSO-d6)δppm 11.12(s,1H),7.18(d,J＝7.75Hz,1H),7.10-7.15(m,1H),7.00-7.07(m,1H),5.40(dd,J＝12.69,5.32Hz,1H),4.47(s,2H),4.44-4.46(m,1H),3.65(s,3H),3.44-3.54(m,1H),3.29(d,J＝5.63Hz,2H),3.11(s,3H),2.83-2.96(m,1H),2.63-2.79(m,2H),1.99-2.09(m,1H),1.70-1.82(m,4H),1.32-1.45(m,2H),1.19-1.31(m,2H).
步骤五：
将92-4(130mg,0.29mmol,1.0eq)置于40mL单口瓶中加入DCM(3mL),DMP(145mg,0.34mmol,1.2eq)加入到反应液中,反应液室温搅拌2h。反应液中加入饱和碳酸氢钠水溶液(10mL),二氯甲烷(10mL×2)萃取,有机相用饱和食盐水反洗一次(8mL),分出有机相用无水硫酸钠干燥后减压浓缩,得到92-5(80mg,0.18mmol,收率61.8％)为白色固体。
ESI-MS(m/z):454.2[M+1]+.
1H NMR(400MHz,DMSO-d6)δ11.15(br s,1H),9.56(s,1H),7.20(d,J＝7.82Hz,1H),7.15(d,J＝7.34Hz,1H),7.03-7.09(m,1H),5.43(dd,J＝12.71,5.38Hz,1H),4.51(s,2H),3.67(s,3H), 3.54-3.64(m,1H),3.22(s,3H),2.86-2.98(m,1H),2.65-2.80(m,2H),2.01-2.10(m,1H),1.78-1.93(m,4H),1.39-1.61(m,4H).
步骤六：
将92-5(80mg,0.18mmol,1.0eq)置于40mL单口瓶中加入DMA(3mL),1-1(82mg,0.18mmol,1.0eq),AcOH(21.19mg,0.35mmol,2.0eq),氰基硼氢化钠(22mg,0.35mmol,1.0eq)加入到反应液中,反应液室温搅拌2h。反应液过滤后高效液相色谱分离纯化,得到实施例92(40.79mg,0.05mmol,收率25.7％)为黄色固体。
ESI-MS(m/z):900.5[M+1]+.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.49(s,1H),9.36(dd,J＝7.00,1.38Hz,1H),8.90(dd,J＝4.13,1.50Hz,1H),8.68(s,1H),8.33(s,1H),7.34(dd,J＝6.94,4.19Hz,1H),7.18(d,J＝7.88Hz,1H),7.11-7.16(m,1H),7.01-7.07(m,1H),6.72(s,1H),5.41(dd,J＝12.63,5.25Hz,1H),4.55(t,J＝5.32Hz,1H),4.48(s,2H),3.66(s,3H),3.47-3.56(m,1H),3.40(br t,J＝5.19Hz,2H),3.10(s,3H),2.85-3.00(m,5H),2.60-2.76(m,6H),2.52-2.58(m,2H),2.33(br s,2H),2.00-2.11(m,1H),1.68-1.90(m,10H),1.48-1.64(m,3H),1.26-1.45(m,4H).
实施例93：
步骤一：
将(1r,4r)-乙基4-羟基环己甲酸基酯(20.0g,116mmol,1.0eq)置于1L三口瓶中加入DMF(140mL)和咪唑(8.70g,127mmol,1.1eq),二苯基叔丁基氯硅烷(33.5g,122mmol,1.05eq)在室温滴加到反应液中,反应液室温搅拌过夜。反应液中加入水(200mL)和乙酸乙酯(500mL),分出有机相用水洗一次(100mL),饱和氯化钠洗一次(80mL),有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝30:1-1:1),得到93-1(40.5g,98.63mmol,收率84.9％)为无色油。
1H NMR(400MHz,CDCl3)δ7.67(dd,J＝7.94,1.44Hz,4H),7.35-7.46(m,6H),4.07(q,J＝7.13Hz,2H),3.55-3.66(m,1H),2.21(tt,J＝11.15,3.42Hz,1H),1.81-1.95(m,4H),1.27-1.47(m,4H),1.21(t,J＝7.07Hz,3H),1.06(s,9H).
步骤二：
将93-1(35.0g,85.2mmol,1.0eq)置于1L三口瓶中加入THF(150mL),反应液在氮气保护下-65℃滴加LDA(51.1mL,102mmol,1.2eq),滴加完后-65℃搅拌1h,NFSI(22.3mL,102mmol,1.2eq)溶于THF(150mL)后-65℃滴加到上述反应液中,反应液室温搅拌过夜。反应液倒入饱和 氯化铵水溶液中(300mL),乙酸乙酯(150mL×2)萃取,合并有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝100:1-10:1),得到93-2(36g,83.99mmol,收率98.5％)的为黄色油。
ESI-MS(m/z):429.3[M+H]+.
1H NMR(400MHz,CDCl3)δ7.65-7.69(m,4H),7.36-7.45(m,6H),4.27(q,J＝7.13Hz,2H),4.09-4.14(m,1H),2.32-2.53(m,2H),1.76-1.85(m,2H),1.58-1.69(m,4H),1.35(t,J＝7.13Hz,3H),1.10(s,8H).
步骤三：
将93-2(36.0g,83.9mmol,1.0eq)置于1L单口瓶中加入THF(300mL),TBAF溶液(168.0mL,167.98mmol,1M,2.0eq)加入到反应液中,反应液室温搅拌过夜。反应液减压浓缩后柱层析纯化(石油醚:乙酸乙酯＝10:1-1:1)。得到93-3(4.20g,22.08mmol,收率26.3％)为浅黄色油。1H NMR(400MHz,CDCl3)δ4.25(q,J＝7.13Hz,2H),4.10-4.16(m,1H),2.17-2.37(m,2H),1.79-1.98(m,4H),1.69-1.78(m,2H),1.32(t,J＝7.13Hz,3H).
二维鉴定结论：NOESY:H-9与H-8相关.质子:H-7a(2.3ppm,J＝36Hz)
结论:H-9e,F-13a.
步骤四：
将93-3(5.00g,26.3mmol,1.0eq)置于100mL三口瓶中加入THF(50mL),0℃下滴加LiAlH4(15.8mL,39.4mmol,2.5M,1.5eq)的四氢呋喃溶液,反应液室温搅拌过夜。反应液在0℃下慢慢加入十水硫酸钠固体(5.0g),搅拌1h补加THF(100mL),过滤,收集滤液减压浓缩,得到93-4(3.00g,20.3mmol,收率77.0％)为浅黄色油。
1H NMR(400MHz,CD3OD)δ3.92(dt,J＝4.97,2.45Hz,1H),3.53(s,1H),3.48(s,1H),1.72-1.86(m,4H),1.53-1.68(m,4H).
步骤五：
将93-4(3.00g,148mmol,1.0eq)置于100mL的三口瓶中加入DCM(15mL),TEA(2.25g,22.27mmol,1.1eq)和DMAP(20mg,0.20mmol,0.01eq),降温至0℃滴加TBSCl(3.36g,22.27mmol,1.1eq)的DCM(15mL)溶液,反应液室温搅拌过夜。反应液中加入水(80mL)和二氯甲烷(100mL),分出有机相用饱和食盐水洗一次(80mL),有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝100:1-10:1),得到93-5(3.30g,12.6mmol,收率62.1％)为无色油状物。
1H NMR(400MHz,CDCl3)δ4.08(br d,J＝2.00Hz,1H),3.61(d,J＝19.76Hz,2H),1.77-1.95 (m,4H),1.60-1.72(m,4H),0.91(s,9H),0.08(s,6H).
步骤六：
将93-5(5.50g,20.9mmol,1.0eq)置于100mL三口瓶中加入THF(50mL),0℃下加入NaH(1.26g,31.44mmol,1.5eq),0℃搅拌3h,溴丙炔(2.99g,25.2mmol,1.2eq)在0℃下滴加到反应液中,反应液室温搅拌过夜。反应液倒入饱和氯化铵水溶液中(80mL),乙酸乙酯(100mL×2)萃取,分出有机相用饱和食盐水反洗一次(50mL),有机相用无水硫酸钠干燥后减压浓缩,柱层析分离纯化(石油醚:乙酸乙酯＝10:1-1:1),得到93-6(3.50g,11.6mmol,收率55.6％)为黄色油。
1H NMR(400MHz,CDCl3)δ4.15(d,J＝2.25Hz,2H),3.80-3.87(m,1H),3.59(d,J＝19.76Hz,2H),2.40(t,J＝2.31Hz,1H),1.75-1.84(m,5H),1.65-1.73(m,3H),0.91(s,9H),0.07(s,6H).
步骤七：
将93-6(3.50g,11.7mmol,1.0eq)置于100mL单口瓶中加入THF(35mL),TBAF(23.3mL,23.3mmol,1M,2.0eq)加入到反应液中,反应液室温搅拌过夜。反应液减压浓缩后柱层析纯化(石油醚:乙酸乙酯＝10:1-1:1),得到93-7(2.00g,10.7mmol,收率92.2％)为浅黄色油。
1H NMR(400MHz,CDCl3)δ4.16(d,J＝2.25Hz,2H),3.84(m,1H),3.55-3.66(m,2H),2.41(t,J＝2.38Hz,1H),1.72-1.83(m,8H).
步骤八：
将93-7(1.00g,5.37mmol,2.0eq)置于100mL单口瓶中加入DMF(10mL),M29(0.91g,2.68mmol,1.0eq),碳酸铯(1.75g,5.37mmol,2.0eq)和双三苯基磷二氯化钯(0.21g,0.27mmol,0.1eq)加入到反应液中,反应液100℃搅拌2h。反应液中加入THF(150mL),搅拌30min后过滤,收集滤液减压浓缩,柱层析分离纯化(石油醚:四氢呋喃＝2:1-1:2),得到的产物中加入乙酸乙酯(8mL)搅拌10min后过滤,收集滤饼,得到93-8(350mg,0.79mmol,收率29.4％)为白色固体。
ESI-MS(m/z):444.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.18(d,J＝7.88Hz,1H),7.10-7.14(m,1H),7.00-7.07(m,1H),5.40(dd,J＝12.63,5.38Hz,1H),4.90(t,J＝6.00Hz,1H),4.47(s,2H),3.83(br s,1H),3.64(s,3H),3.42(d,J＝6.00Hz,1H),3.35-3.39(m,1H),2.86(m,1H),2.59-2.73(m,2H),2.01-2.09(m,1H),1.53-1.80(m,8H).
步骤九：
将93-8(150mg,0.34mmol,1.0eq)置于40mL单口瓶中加入DCM(4mL),0℃下慢慢加入DMP (288mg,0.68mmol,2.0eq),反应液室温搅拌3h。反应液慢慢倒入饱和碳酸氢钠水溶液中(10mL),二氯甲烷(10mL×2)萃取,合并有机相用无水硫酸钠干燥后减压浓缩,柱层析分离纯化(石油醚:四氢呋喃＝1:2)。得到93-9(100mg,0.23mmol,收率67.0％)为白色固体。
ESI-MS(m/z):442.3[M+H]+.
1H NMR(400MHz,CDCl3)δ9.72(d,J＝5.38Hz,1H),8.18(br s,1H),7.18(d,J＝7.34Hz,1H),6.99-7.02(m,1H),6.77(d,J＝7.34Hz,1H),5.21(dd,J＝12.47,5.26Hz,1H),3.94(br s,1H),3.78(s,3H),2.68-3.01(m,3H),1.67-2.11(m,9H).
步骤十：
将93-9(70mg,0.16mmol,1.0eq)置于40mL单口瓶中加入DMA(2mL),1-1(73mg,0.16mmol,1.0eq),氰基硼氢化钠(20mg,0.32mmol,2.0eq),AcOH(10mg,0.16mmol,1.0eq)],反应液室温搅拌1h。反应液过滤后高效液相色谱分离纯化,得到实施例93(39.69mg,0.04mmol,收率27.9％)为浅黄色固体。
ESI-MS(m/z):888.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.51(s,1H),9.33-9.42(m,1H),8.88-8.97(m,1H),8.70(s,1H),8.36(s,1H),7.36(dd,J＝6.93,4.21Hz,1H),7.20(d,J＝7.92Hz,1H),7.13-7.17(m,1H),7.03-7.09(m,1H),6.76(s,1H),5.43(dd,J＝12.62,5.44Hz,1H),4.59(t,J＝5.26Hz,1H),4.50(s,2H),3.85(br s,1H),3.67(s,3H),3.42(br t,J＝5.01Hz,3H),2.87-3.04(m,5H),2.56-2.79(m,8H),2.01-2.10(m,1H),1.68-1.88(m,14H),1.51-1.66(m,3H).
实施例94：
步骤一：
将93-5(6.80g,25.9mmol)置于250mL三口瓶中加入THF(70mL),对硝基苯甲酸(5.20g,31.1mmol,1.2eq),三苯基磷(8.16g,31.1mmol,1.2eq)加入到反应液中,反应液在0℃下滴加DIAD(6.29g,31.1mmol,1.2eq),室温搅拌2h。反应液中加入水(100mL),乙酸乙酯(80mL×2)萃取,合并有机相用饱和食盐水反洗一次(50mL),分出有机相用无水硫酸钠干燥后减压浓缩,柱层析分离纯化(石油醚:乙酸乙酯＝30:1-10:1),得到94-1(3.50g,8.50mmol,收率32.8％)为白色固体。
1H NMR(400MHz,CDCl3)δ8.18-8.25(m,2H),8.11-8.17(m,2H),7.18(s,1H),4.89-4.98(m,1H),3.52(d,J＝16.63Hz,2H),1.78-1.95(m,5H),1.44-1.69(m,3H),0.83(s,9H),0.00(s,6H).
步骤二：
将94-1(3.50g,8.50mmol)置于100mL单口瓶中加入THF(15mL),氢氧化锂(710mg,17.0mmol,2.0eq)溶于H2O(15mL)加入到反应液中,反应液室温搅拌过夜。反应液中加入水(80mL),乙酸乙酯萃取(100mL×2),合并有机相用无水硫酸钠干燥后减压浓缩,柱层析纯化(石油醚:乙酸乙酯＝10:1-1:1),得到94-2(1.70g,6.48mmol,收率76.2％)为无色油。
1H NMR(400MHz,CDCl3)δ3.60-3.67(m,1H),3.56(d,J＝16.76Hz,2H),1.83-1.97(m,4H),1.58-1.69(m,2H),1.37-1.51(m,2H),0.91(s,9H),0.07(s,6H).
步骤三：
将94-2(1.70g,6.48mmol,1.0eq)置于100mL三口瓶中加入THF(17mL),0℃下加入NaH(0.52g,12.9mmol,2.0eq),0℃搅拌3h,溴丙炔(1.16g,7.77mmol,1.2eq)在0℃滴加到反应液中,反应液室温搅拌过夜。反应液倒入饱和氯化铵水溶液中(80mL),乙酸乙酯(100mL×2)萃取,分出有机相用饱和食盐水反洗一次(50mL),有机相用无水硫酸钠干燥后减压浓缩,柱层析分离纯化(石油醚:乙酸乙酯＝10:1-1:1),得到94-3(1.30g,4.33mmol,收率66.8％)为浅黄色油。
1H NMR(400MHz,CDCl3)δ4.22(d,J＝2.35Hz,2H),3.56(d,J＝16.70Hz,2H),3.46-3.53(m,1H),2.41(t,J＝2.23Hz,1H),1.87-1.98(m,4H),1.59-1.70(m,2H),1.39-1.55(m,2H),0.91(s,9H),0.07(s,6H).
步骤四：
将94-3(1.30g,4.33mmol,1.0eq)置于100mL单口瓶中加入THF(10mL),TBAF溶液(8.70mL,8.65mmol,1M,2.0eq)加入到反应液中,反应液室温搅拌过夜。反应液减压浓缩后柱层析纯化(石油醚:乙酸乙酯＝10:1-1:1),得到94-4(700mg,3.76mmol,收率86.9％)为浅黄色油。
1H NMR(400MHz,CDCl3)δ4.22(d,J＝2.35Hz,2H),3.59(d,J＝19.67Hz,2H),3.50-3.55(m,1H),2.42(t,J＝2.35Hz,1H),2.04-2.10(m,2H),1.88-1.96(m,2H),1.59-1.72(m,2H),1.34-1.52(m,2H).
步骤五：
将94-4(550mg,2.96mmol,2.0eq)置于100mL单口瓶中加入DMF(6mL),M29(500mg,1.48mmol,1.0eq),碳酸铯(963mg,2.96mmol,2.0eq)和双三苯基磷二氯化钯(115mg,0.15mmol,0.1eq)加入到反应液中,反应液100℃搅拌2h。反应液中加入THF(30mL),过滤后滤液减压浓缩,柱层析分离纯化(石油醚:四氢呋喃＝2:1-1:2),得到的油状物中加入乙酸乙酯(5mL),搅拌10min后过滤,收集滤饼,得到94-5(80mg,0.18mmol,收率12.2％)为白色固体。
ESI-MS(m/z):444.2[M+H]+.
1H NMR(400MHz,CDCl3)δ8.03(br s,1H),7.18(d,J＝7.75Hz,1H),7.00(t,J＝7.94Hz,1H),6.77(d,J＝7.38Hz,1H),5.20(dd,J＝12.57,5.32Hz,1H),4.49(s,2H),3.79(s,3H),3.54-3.68(m,3H),2.70-3.02(m,3H),2.21-2.29(m,1H),2.04-2.14(m,2H),1.92-2.01(m,2H),1.65-1.79(m,3H),1.35-1.54(m,2H).
步骤六：
将94-5(80mg,0.18mmol,1.0eq)置于40mL单口瓶中加入DCM(3mL),DMP(114mg,0.27mmol,1.5eq)加入到反应液中,室温搅拌2h。反应液中加入饱和碳酸氢钠水溶液(10mL),乙酸 乙酯(10mL×2)萃取,合并有机相无水硫酸钠干燥后浓缩,薄层色谱分离纯化(石油醚:四氢呋喃＝0:1),得到94-6(70mg,0.16mmol,收率87.9％)为白色固体。
ESI-MS(m/z):442.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.67(d,J＝6.50Hz,1H),7.11-7.21(m,2H),7.01-7.08(m,1H),5.41(dd,J＝12.51,5.13Hz,1H),4.52(s,2H),3.63-3.68(m,4H),2.84-2.97(m,1H),2.59-2.78(m,2H),2.01(m,2H),1.81-1.94(m,3H),1.66-1.76(m,2H),1.40-1.53(m,2H).
步骤七：
将94-6(70mg,0.16mmol,1.0eq)置于40mL单口瓶中加入DMA(2mL),1-1(73mg,0.16mmol,1.0eq),冰乙酸(10mg,0.16mmol,1.0eq),氰基硼氢化钠(15mg,0.24mmol,1.5eq)加入到反应液中,反应液室温搅拌2h。反应液过滤后高效液相色谱分离纯化,得到实施例94(21.05mg,0.02mmol,收率14.8％)为浅黄色固体。
ESI-MS(m/z):888.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.49(s,1H),9.36(d,J＝7.00Hz,1H),8.90(d,J＝3.88Hz,1H),8.68(s,1H),8.33(s,1H),7.34(dd,J＝6.94,4.19Hz,1H),7.18(d,J＝7.75Hz,1H),7.11-7.16(m,1H),7.01-7.08(m,1H),6.73(s,1H),5.41(dd,J＝12.63,5.25Hz,1H),4.55(t,J＝5.19Hz,1H),4.50(s,2H),3.66(s,3H),3.59(br s,1H),3.40(t,J＝5.07Hz,3H),2.86-3.02(m,5H),2.56-2.78(m,7H),2.47(br s,1H),2.00-2.07(m,1H),1.69-1.99(m,10H),1.42-1.63(m,7H).
实施例95：
将19-1(40mg,0.08mmol,1.0eq)置于40mL单口瓶中加入DMF(1.5mL),70-2(31mg,0.09mmol,1.2eq),NaI(11mg,0.08mmol,1.0eq),NaHCO3(27mg,0.32mmol,4.0eq),TEA(32mg,0.32mmol,4.0eq)加入到反应液中,反应液60℃搅拌过夜。反应液过滤后高效液相色谱分离纯化,得到实施例95(15.4mg,0.02mmol,收率22.9％)为浅黄色固体。
ESI-MS(m/z):832.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.51(s,1H),9.38(dd,J＝7.00,1.50Hz,1H),8.91(dd,J＝4.13,1.38Hz,1H),8.69(s,1H),8.35(s,1H),7.35(dd,J＝7.00,4.25Hz,1H),6.86-7.05(m,3H),6.75(s,1H),5.37(dd,J＝12.57,5.19Hz,1H),4.59(t,J＝5.25Hz,1H),3.64(s,3H),3.41(m,3H),2.84-3.04(m,12H),2.56-2.75(m,10H),2.25-2.37(m,2H),1.97-2.05(m,1H),1.69-1.88(m,7H),1.45-1.67(m,4H).
实施例96：
将M29(20mg,0.06mmol,1.0eq)与1-3(33mg,0.06mmol,1.0eq)置于40mL单口瓶中加入DMF(1mL),叔丁醇钠(17mg,0.18mmol,3.0eq)和CAS:1612891-29-8(5mg,0.01mmol,0.1eq),100℃搅拌2小时。将反应液进行高效液相色谱分离纯化,得到实施例96(1.44mg,收率2.9％)为淡黄色固体。
ESI-MS(m/z):831.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.85-11.37(s,1H),10.49(s,1H),9.35(d,J＝7.00Hz,1H),8.89(br d,J＝3.25Hz,1H),8.67(s,1H),8.33(s,1H),7.33(dd,J＝7.00,4.25Hz,1H),6.95-7.02(m,1H),6.89-6.94(m,1H),6.86(br d,J＝8.00Hz,1H),6.70-6.75(m,1H),5.34(br dd,J＝12.63,5.75Hz,1H),4.56(br t,J＝5.13Hz,1H),3.63(s,3H),3.02-3.13(m,3H),2.88-3.01(m,5H),2.59-2.74(m,7H),2.30-2.46(m,5H),1.96-2.06(m,1H),1.66-1.88(m,9H),1.35-1.64(m,8H).
实施例97：
化合物97-1的合成过程参考专利WO2022143856A1说明书P79-P80。
将1-1(83mg,0.18mmol)，97-1(70mg,0.18mmol)，KOAc(35mg,0.36mmol)，三乙酰氧基硼氢化钠(114mg,0.54mmol)和DMA(1mL)加入10mL单口瓶中，室温搅拌1h。反应完毕后， 加入水(1mL)，过滤，柱层析分离。洗脱剂为DCM:MeOH＝1:0～10:1，得到实施例97，黄色固体50mg。纯度95.22％。
ESI-MS(m/z):834.6[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),10.49(s,1H),9.35(dd,J＝6.96,1.44Hz,1H),8.89(dd,J＝4.14,1.38Hz,1H),8.68(s,1H),8.34(s,1H),7.70(d,J＝11.42Hz,1H),7.43(d,J＝7.40Hz,1H),7.27-7.38(m,1H),6.73(s,1H),5.11(dd,J＝12.86,5.33Hz,1H),4.55(t,J＝5.21Hz,1H),3.61(br d,J＝11.54Hz,2H),3.40(br t,J＝4.77Hz,2H),2.83-3.03(m,7H),2.52-2.70(m,6H),2.42(br s,2H),2.22(br d,J＝6.65Hz,2H),2.00-2.09(m,1H),1.66-1.90(m,9H),1.48-1.65(m,3H),1.21-1.36(m,2H).
实施例98：
化合物98-1的合成过程参考WO2022147465A1说明书P735的合成方法。
将98-1(88mg,0.19mmol)，1-1(70mg,0.19mmol)，KOAc(37mg,0.38mmol)，三乙酰氧基硼氢化钠(120mg,0.57mmol)和DMA(1mL)加入100mL单口瓶中，室温搅拌1h。反应完毕后，加入水(1mL)，过滤，柱层析分离。洗脱剂为DCM:MeOH＝1:0～10:1。得到实施例98，黄色固体30mg。
ESI-MS(m/z):816.7[M+H]+.
1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.49(s,1H),9.33-9.40(m,1H),8.90(br d,J＝2.89Hz,1H),8.68(s,1H),8.35(s,1H),7.34(dd,J＝6.84,4.33Hz,1H),6.94-7.09(m,3H),6.74(s,1H),5.38(br dd,J＝12.42,5.40Hz,1H),4.56(t,J＝5.21Hz,1H),3.56-3.61(m,3H),3.40(br t,J＝4.89Hz,2H),3.18-3.30(m,1H),2.84-3.04(m,5H),2.54-2.78(m,6H),2.44(br d,J＝7.28Hz,3H),1.49-2.06(m,20H).
实施例99：
步骤一：
将对溴苯胺(10.0g,58.1mmol,1.0eq)置于100mL单口瓶中加入甲苯(7mL)和丙烯酸(5.03g,69.7mmol,1.2eq),100℃下搅拌8h。向反应液中加入NaOH水溶液(1N,200mL),分出水相加入2M盐酸调pH值为3后用乙酸乙酯(250mL×3)萃取,合并有机相用无水硫酸钠干燥,减压浓缩,柱层析分离(石油醚:乙酸乙酯＝10:1～0:1),得到99-1(10g,40.9mmol,70.5％)为浅棕色固体。
ESI-MS(m/z):Br,244.0[M+1]+,246.0[M+3]+.
1H NMR(400MHz,CDCl3)δ7.22-7.27(m,2H),6.46-6.53(m,2H),3.42(t,J＝6.26Hz,2H),2.65(t,J＝6.26Hz,2H).
步骤二：
将99-1(5.00g,20.4mmol,1.0eq)置于100mL单口瓶中加入AcOH(35mL)和尿素(2.46g,40.9mmol,2.0eq),120℃下搅拌12h。向反应液中加入水(100mL)有白色固体析出,过滤,收集滤饼减压浓缩,得到99-2(2.5g,9.29mmol,收率45.4％)。
ESI-MS(m/z):Br,269.0[M+1]+,271.0[M+3]+.
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),7.52-7.62(m,2H),7.26-7.34(m,2H),3.78(t,J＝6.62Hz,2H),2.70(t,J＝6.68Hz,2H).
步骤三：
将99-2(300mg,1.11mmol,1.0eq)与DMA(3mL)置于50mL单口瓶中,4-(二甲氧基甲基)哌啶(532mg,3.34mmol,3.0eq),Cs2CO3(182mg,0.56mmol,3.0eq),催化剂(CAS号:1814936-54-3)(108mg,0.11mmol,0.1eq)加入到反应液中,氮气保护下100℃搅拌2h。将反应液减压浓缩后加入二氯甲烷,过滤,滤液减压浓缩后柱层析分离纯化(石油醚：乙酸乙酯＝5:1-0:1),得到99-3(120mg,0.35mmol,收率31.0％)为浅黄色固体。
ESI-MS(m/z):348.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.53(br s,1H),7.15(d,J＝9.01Hz,2H),6.94(d,J＝9.01Hz,2H),4.09(d,J＝7.13Hz,1H),3.81(t,J＝6.69Hz,2H),3.71(br d,J＝12.26Hz,2H),3.38(s,6H),2.81(t,J＝6.69Hz,2H),2.70(td,J＝12.26,2.25Hz,2H),1.85(m,2H),1.77(m,1H),1.37-1.54(m,2H).
步骤四：
将99-3(72mg,0.21mmol,1.0eq)置于40mL单口瓶中加入甲酸(3mL),25℃下搅拌2h,将反应液在减压浓缩,得到99-4(62mg,0.21mmol,100.0％)是棕色的油。
ESI-MS(m/z):302.1[M+H]+.
步骤五：
将99-4(62mg,0.21mmol,1.0eq)置于50mL单口瓶中加入DMA(2mL),1-1(95mg,0.21mmol,1.0eq),KOAc(60mg,0.62mmol,3.0eq)，三乙酰氧基硼氢化钠(43mg,0.21mmol,1.0eq)加入到反应液中,室温搅拌1h。反应液过滤后进行高效液相色谱分离纯化,得到实施例99(65.0mg,0.09mmol,收率42.2％)为黄色固体。
ESI-MS(m/z):748.6[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.25(s,1H),9.36(dd,J＝6.88,1.50Hz,1H),8.90(dd,J＝4.13,1.50Hz,1H),8.68(s,1H),8.35(s,1H),7.34(dd,J＝7.00,4.25Hz,1H),7.14(d,J＝9.01Hz,2H),6.93(d,J＝9.01Hz,2H),6.74(s,1H),4.55(t,J＝5.32Hz,1H),3.65-3.73(m,4H),3.40(br t,J＝5.25Hz,2H),3.00(s,2H),2.93(d,J＝10.51Hz,2H),2.62-2.72(m,8H),2.22(d,J＝6.75Hz,2H),1.67-1.90(m,10H),1.45-1.65(m,4H),1.16-1.30(m,2H).
实施例100：
参考实施例78相似的合成方法得到实施例100，为白色固体。
ESI-MS(m/z):817.5[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.09(br s,1H),10.93(s,1H),8.97(s,1H),8.75(br d,J＝4.41 Hz,1H),8.33(s,1H),8.25(br d,J＝8.58Hz,1H),7.57(dd,J＝8.34,4.77Hz,1H),6.94-7.01(m,1H),6.85-6.92(m,2H),6.75(s,1H),5.36(dd,J＝12.40,5.01Hz,1H),4.54(t,J＝5.13Hz,1H),3.63(s,3H),3.38(t,J＝5.13Hz,2H),3.11(m,2H),2.84-3.04(m,5H),2.56-2.76(m,7H),2.42(m,2H),2.25(m,2H),1.96-2.05(m,1H),1.67-1.91(m,9H),1.45-1.67(m,4H),1.32(m,2H).
实施例101：
步骤一：
将(5-溴-2-氟苯基)乙腈(5.00g,23.36mmol,1.0eq)置于100mL单口瓶中加入THF(35mL),加入丙烯酸甲酯(2.21g,25.70mmol,1.1eq),降温至0℃加入甲醇钠(0.13g,2.34mmol,0.1eq),25℃下搅拌2h。反应液减压浓缩,柱层析分离纯化(石油醚：乙酸乙酯＝1:1),得到101-1(670mg,1.43mmol,收率8.1％)为白色固体。
ESI-MS(m/z):Br,300.3[M+1]+,302.0[M+3]+.
1HNMR(400MHz,CDCl3)δ7.59(dd,J＝6.54,2.38Hz,1H),7.46(m,1H),7.01(t,J＝9.17Hz,1H),4.24(t,J＝7.46Hz,1H),3.70(s,3H),2.45-2.61(m,2H),2.16-2.29(m,2H).
步骤二：
将101-1(670mg,2.23mmol,1.0eq)置于40mL单口瓶中加入AcOH(6.7mL)和H2SO4(0.67mL),90℃搅拌2h,向反应液中加入水,析出白色固体,过滤,收集滤饼减压浓缩,得到101-2(500mg,1.75mmol,收率:78.3％)为白色固体。
ESI-MS(m/z):Br,285.9[M+1]+,287.9[M+3]+.
1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.50-7.61(m,2H),7.20(t,J＝9.36Hz,1H),4.08(dd,J＝12.87,4.89Hz,1H),2.67-2.79(m,1H),2.55-2.59(m,1H),2.24(m,1H),1.96-2.04(m,1H).
步骤三：
将101-2(500mg,1.86mmol,1.0eq)置于50mL单口瓶中加入二氧六环(5mL),4-(二甲氧基甲基)哌啶(834mg,5.24mmol,3.0eq),Cs2CO3(1708mg,5.24mmol,3.0eq),催化剂(CAS号:1814936-54-3)(170mg,0.17mmol,0.1eq)加入到反应液中,氮气保护下100℃搅拌2h。反应液中加入二氯甲烷(20mL),过滤,滤液减压浓缩,柱层析分离(石油醚：乙酸乙酯＝5:1-0:1),得到101-3(175mg,0.48mmol,收率:27.5％)为黄色固体,纯度：88.4％。
ESI-MS(m/z):365.1[M+H]+.
1H NMR(400MHz,CDCl3)δ7.89(br s,1H),6.86-6.96(m,1H),6.73-6.83(m,1H),6.59-6.68(m,1H),4.02(d,J＝7.25Hz,1H),3.77(dd,J＝11.26,5.25Hz,1H),3.45-3.52(m,2H),3.30(s,6H),2.67-2.76(m,1H),2.49-2.66(m,3H),2.11-2.30(m,2H),1.74-1.82(m,2H),1.65(m,1H),1.32-1.45(m,2H).
步骤四：
将101-3(160mg,0.44mmol,1.0eq)置于40mL单口瓶中加入甲酸(5mL),25℃下搅拌3h,将反应液减压浓缩,得到101-4(139mg,0.44mmol)为黄色的油。
ESI-MS(m/z):319.1[M+H]+.
步骤五：
将101-4(139mg,0.44mmol,1.0eq)置于50mL单口瓶中加入DMA(4mL),1-1(201mg,0.44mmol,1.0eq),KOAc(128mg,1.31mmol,3.0eq),三乙酰氧基硼氢化钠(92mg,0.44mmol,1.0eq)加入到反应液中,20℃搅拌1h。反应液过滤后滤液进行高效液相色谱分离纯化,得到实施例101(127mg,0.17mmol,收率:38.3％)为黄色固体，纯度：98.2％。
ESI-MS(m/z):765.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.84(br s,1H),10.49(s,1H),9.36(dd,J＝7.03,1.43Hz,1H),8.90(dd,J＝4.05,1.43Hz,1H),8.68(s,1H),8.35(s,1H),7.33(dd,J＝6.97,4.23Hz,1H),7.01(t,J＝9.30Hz,1H),6.80-6.91(m,2H),6.73(s,1H),4.56(t,J＝5.25Hz,1H),3.95(dd,J＝12.58,4.95Hz,1H),3.58(br d,J＝10.97Hz,2H),3.40(br t,J＝5.01Hz,2H),2.99(s,2H),2.93(br d,J＝10.97Hz,2H),2.53-2.81(m,7H),2.33-2.50(m,3H),2.17-2.30(m,3H),1.95-2.05(m,1H),1.69-1.90(m,8H),1.47-1.68(m,4H),1.14-1.28(m,2H).
实施例102：
步骤一：
将3-(4-溴苯基)哌啶-2,6-二酮(500mg,1.86mmol,1.0eq)置于50mL单口瓶中加入二氧六环(5mL),4-(二甲氧基甲基)哌啶(890mg,5.59mmol,3.0eq),Cs2CO3(1.82g,5.59mmol,3.0eq),1814936-54-3(181mg,0.19mmol,0.1eq)加入到反应液中,氮气保护下100℃搅拌2h。反应液中加入DCM(80mL),过滤,滤液减压浓缩后柱层析分离纯化(PE:EA＝3:1～0:1),得到102-1(100mg,0.29mmol,收率15.5％)为黄色固体。
ESI-MS(m/z):347.2[M+H]+.
1H NMR(400MHz,CDCl3)δ7.92(br s,1H),7.08(d,J＝8.63Hz,2H),6.93(d,J＝8.63Hz,2H),4.09(d,J＝7.25Hz,1H),3.67-3.76(m,3H),3.38(s,6H),2.60-2.76(m,4H),2.15-2.33(m,2H),1.85(br d,J＝13.26Hz,2H),1.70-1.78(m,1H),1.45(m,2H).
步骤二：
将102-1(90mg,0.26mmol,1.0eq)置于40mL单口瓶中加入甲酸(4mL),25℃下搅拌1h,将反应液减压浓缩,得到102-2(78.03mg,0.26mmol)为黄色油。
ESI-MS(m/z):300.3[M+H]+.
步骤三：
将102-2(78mg,0.26mmol,1.0eq)置于50mL单口瓶中加入DMA(3mL),1-1(120mg,0.26mmol,1.0eq),KOAc(76mg,0.78mmol,3.0eq),三乙酰氧基硼氢化钠(55mg,0.26mmol,1.0eq)加入到反应液中，室温搅拌1h,反应液过滤后,高效液相色谱分离纯化,得到实施例102(67.41mg,0.09mmol,收率34.8％)为黄色固体,。
ESI-MS(m/z):747.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),10.49(s,1H),9.36(dd,J＝7.03,1.43Hz,1H),8.90(dd,J＝4.17,1.55Hz,1H),8.68(s,1H),8.34(s,1H),7.30-7.37(m,1H),7.04(d,J＝8.70Hz,2H),6.89(d,J＝8.70Hz,2H),6.74(s,1H),4.56(t,J＝5.25Hz,1H),3.63-3.77(m,3H),3.40(br t,J＝5.13Hz,2H),2.99(s,2H),2.93(br d,J＝11.09Hz,2H),2.59-2.70(m,5H),2.35-2.49(m,4H),2.21(br d,J＝7.03Hz,2H),1.98-2.17(m,2H),1.45-1.91(m,13H),1.15-1.28(m,2H).
实施例103：
将77-6(300mg,0.72mmol,1.0eq)置于40mL单口瓶中加入DMF(5mL),61-2(330mg,0.72mmol,1.0eq),DIEA(185mg,1.43mmol,2.0eq)加入到反应液中,最后加入HATU(299mg,0.79mmol,1.1eq),室温搅拌2h。反应液过滤后,滤液进行高效液相色谱分离纯化,得到实施例103(357.08mg,0.40mmol,收率55.6％)为白色固体。
ESI-MS(m/z):864.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.53(s,1H),8.98(s,1H),8.75(d,J＝4.17Hz,1H),8.36(s,1H),8.22-8.30(m,1H),7.51-7.66(m,1H),7.34(d,J＝12.87Hz,1H),7.13(d,J＝7.15Hz,1H),6.78(s,1H),5.02(s,1H),4.54(t,J＝5.13Hz,1H),3.95(s,3H),3.84-3.93(m,3H),3.75(m,1H),3.61(m,1H),3.36-3.50(m,3H),3.15-3.23(m,2H),3.03-3.13(m,4H),2.96(m,2H),2.75(t,J＝6.68Hz,2H),2.59-2.70(m,4H),1.66-1.95(m,10H),1.44-1.65(m,3H).
实验例1对THP-1细胞中IRAK4的降解试验
在6孔细胞培养板中接种适量的THP-1细胞，细胞板置于5％二氧化碳培养箱中37℃培养过夜，然后再加入待测化合物的二甲亚砜溶液，化合物终浓度在0.0128～1000nM范围内，继续培养24小时后，去掉培养基，收集细胞至1.5mL的离心管中，加入裂解液充分研磨后，冰上放置30分钟，15000xg、4℃离心20分钟，取上清液用蛋白免疫印迹法(Western Blot)检测IRAK4蛋白水平。实验结果见表1：
表1本发明化合物对IRAK4蛋白降解活性


实验结果显示，本发明化合物对IRAK4蛋白均有良好的降解作用。
实验例2：小鼠药代动力学试验
1.试验方法：
取20～30g雄性小鼠6只，分为两组，一组2mg/kg静脉注射给药，一组10mg/kg灌胃给药。分别于给药后0.083、0.25、0.5、1、2、4、6、8和24h采血，血浆样本经前处理后，以LC/MS/MS在MRM模式下检测，并建立合适的标准曲线对血浆样品中目标化合物进行定量，以获得血浆中药物浓度-时间曲线。采用WinNonlin软件以非房室模型计算药动学参数。
2.试验结果：
对本发明化合物进行了上述药代动力学试验，结果见表2：
表2本发明化合物的小鼠药代动力学结果
实验结果表明，本发明化合物在小鼠体内具有较好的药代动力学性质。

Claims (30)

  1. 一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    其中：
    环A为具有0-3个独立地选自氮、氧和硫的杂原子的8-13元螺环；
    环B为苯基、萘基、5-6元单环杂芳基或9-10元双环杂芳基；
    R1、R2和R3各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C2-6烯基、C1- 6烷氧基、-(C0-3亚烷基)-C3-6环烷基或-(C0-3亚烷基)-3-8元杂环基，其中，所述C1-6烷基、C2-6烯基、C1-6烷氧基、-(C0-3亚烷基)-C3-6环烷基和-(C0-3亚烷基)-3-8元杂环基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟基烷基和C1-3卤代烷基的取代基所取代；
    各Ra和Rb独立地为氢、氘、卤素、氧代、CN、NO2、-R4、-ORc、-SRc、-N(Rc)2、-C(Rc)3、-S(＝O)2Rc、-S(＝O)2N(Rc)2、-S(＝O)Rc、-S(＝O)(NRc)Rc、-P(＝O)(ORc)2、-P(＝O)(N(Rc)2)2、-CF(Rc)2、-CF2(Rc)、-CF3、-C(Rc)2-ORc、-C(Rc)2-N(Rc)2、-C(＝O)Rc、-C(＝O)ORc或-C(＝O)N(Rc)2；或相同原子上的两个Ra基团任选地与其中间原子结合在一起形成C3-4环烷基或3-4元杂环基；各R4独立地为C1-6烷基、C2-6烯基、苯基、C3-7环烷基、3-7元杂环基或5-6元杂芳基环，所述R4可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代；
    各Rc独立地为氢、氘、C1-6烷基、苯基、C4-7环烷基、4-7元杂环基或5-6元杂芳基，所述C1-6烷基、苯基、C4-7环烷基、4-7元杂环基和5-6元杂芳基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1- 3卤代烷基的取代基所取代；或相同原子上的两个Rc基团任选地与其中间原子结合在一起形成C4-7环烷基、具有0-3个独立地选自氮、氧和硫的杂原子的4-11元的桥接双环或螺环，所述C4-7环烷基和具有0-3个独立地选自氮、氧和硫的杂原子的4-11元的桥接双环或螺环可进一步任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、C1- 3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代；
    m和n各自独立为0、1、2、3、4、5、6、7或8；
    L为C1-20亚烷基，其中1、2、3、4或5个亚甲基可独立任选地被选自-CRd＝CRd-、-C≡C-、-C(Rd)2-、-Cy-、-O-、-C(＝O)-和-N(Rd)-的单元所置换；
    其中各-Cy-独立地为C4-7环烷基、4-11元杂环基、5-11元螺环基、5-11元桥接双环基、苯基、5-6元杂芳基，所述各-Cy-可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和-C1-3卤代烷基的取代基所取代；
    各Rd独立地为氢、氘、卤素、CN、OH、NO2、NH2或C1-3烷基；
    以及DIM为E3泛素连接酶结合部分。
  2. 如权利要求1所述的化合物，其中环A为：
    其中：
    X1、X2、X3、X4、X5各自独立地为CH2、-C(＝O)-、NH、O或S；
    a和c各自独立地为1或2；
    b和d各自独立地为0、1或2，其中，b和d不同时为0且b和d之和为2、3或4。
  3. 如权利要求1或2所述的化合物，其中各Ra独立地为氢、氘、卤素、氧代、CN、OH、NO2、NH2、-CF3或C1-6烷基；或相同原子上的两个Ra基团形成C3-4环烷基。
  4. 如权利要求1-3任一项所示的化合物，其中各Ra独立地为氢、氘、卤素、氧代、CN、OH、NO2、NH2、-CF3、甲基、乙基、正丙基或异丙基；或相同原子上的两个Ra基团形成环丙基或环丁基。
  5. 如权利要求1-4任一项所述的化合物，其中环B为：

  6. 如权利要求1-5任一项所述的化合物，其中各Rb独立地为氢、氘、卤素、氧代、CN、OH、NO2、NH2、-COOH、C1-6烷基、C3-6环烷基、4-6元杂环基或7-8元桥接双环；所述C1-6烷基、C3-6环烷基、4-6元杂环基和7-8元桥接双环可独立任选地被1、2或3个选自氘、卤素、OH、CN、氧代、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代。
  7. 如权利要求1-6任一项所述的化合物，其中，各Rb独立地为氢、氘、卤素、CN、OH、NO2、NH2、-COOH、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基或所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基和可独立任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、甲基、乙基、甲氧基、乙氧基、-CHF2、-CF3、-OCHF2和-OCF3的取代基所取代。
  8. 如权利要求1-7任一项所述的化合物，其中部分为：
    其中：
    Rb1和Rb4各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、CH3、CH2CH3、-CF2或-CF3；
    Rb2和Rb3各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、-COOH、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基或所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基和可独立任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、 NH2、甲基、乙基、甲氧基、乙氧基、-CHF2、-CF3、-OCHF2和-OCF3的取代基所取代。
  9. 如权利要求1-5任一项所述的化合物，其中部分为：
    其中：
    Rb1和Rb4各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、CH3、CH2CH3、-CF2或-CF3；
    Rb2和Rb3各自独立地为氢、氘、卤素、CN、OH、NO2、NH2、-COOH、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、吡啶或所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、二氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、吡啶和可独立任选地被1、2或3个选自氢、氘、卤素、氧代、CN、OH、NO2、NH2、甲基、乙基、甲氧基、乙氧基、-CHF2、-CF3、-OCHF2和-OCF3的取代基所取代。
  10. 如权利要求1-9任一项所述的化合物，其中R1为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C1-6烷氧基或C3-6环烷基；
    R2为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C1-6烷氧基或C3-6环烷基。
  11. 如权利要求1-10任一项所述的化合物，其中R1为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基、异丙基、甲氧基、环丙基、环丁基、环戊基或环己基；
    R2为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基、异丙基、甲氧基、环丙基、环丁基、环戊基或环己基。
  12. 如权利要求1-11任一项所述的化合物，其中R3为氢、氘、卤素、CN、OH、NO2、NH2、C1-6烷基、C1-4烷氧基、C3-6环烷基或5-6元杂环基，所述C1-6烷基、C1-4烷氧基、C3-6环烷基和5-6元杂环基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1- 3烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟基烷基和C1-3卤代烷基的取代基所取代。
  13. 如权利要求1-12任一项所述的化合物，其中R3为氢、氘、卤素、CN、OH、NO2、NH2、 甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、哌啶基、哌嗪基或吗啉基，所述甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、哌啶基、哌嗪基和吗啉基可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、甲基、甲氧基、-CH2OH、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-OCHF2和-OCF3的取代基所取代。
  14. 如权利要求1-12任一项所述的化合物，其中R3为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、哌啶基、哌嗪基或吗啉基，所述甲基、乙基、异丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、哌啶基、哌嗪基和吗啉基可独立任选地被1、2或3个选自-CH2CHF2和-C(CH3)2OH的取代基所取代。
  15. 如权利要求1-14任一项所述的化合物，其中DIM部分为：
    其中：
    X为CH或N；
    Y为键、-CH2-、-NH-、-O-、-C(＝O)-或-C(＝O)NH-；
    环C为苯基、5-6元单环杂芳基或9-10元双环杂芳基，所述环C可独立任选地被1、2或3个选自氘、卤素、氧代、CN、OH、NO2、NH2、C1-3烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3卤代烷基的取代基所取代。
  16. 如权利要求1-15任一项所述的化合物，其中DIM部分为：
  17. 如权利要求1-15任一项所述的化合物，其中DIM部分为：
  18. 如权利要求1-15任一项所述的化合物，其中DIM部分为：
  19. 如权利要求1-15任一项所述的化合物，其中DIM部分为：
  20. 如权利要求1-14任一项所述的化合物，其中DIM部分为：
  21. 如权利要求1-20任一项所述的化合物，其中L为C3-12亚烷基，其中1、2、3、4或5个亚甲基可独立任选地被选自-CRd＝CRd-、-C≡C-、-C(Rd)2-、-Cy-、-O-、-C(＝O)-、-N(Rd)-的单元所置换。
  22. 如权利要求1-21任一项所述的化合物，其中L为C3-9亚烷基，其中1、2或3个亚甲基可独立任选地被选自-CRd＝CRd-、-C≡C-、-C(Rd)2-、-O-、-C(＝O)-、-NH-、 的单元所置换，所述 可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、甲基、乙基、异丙基、甲氧基、异丙氧基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-OCHF2和-OCF3的取代基所取代；
    各Rd独立地为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基或异丙基。
  23. 如权利要求1-22任一项所述的化合物，其中L为：
  24. 如权利要求1-20任一项所述的化合物，其中L为其中L为C1-9亚烷基，其中1、2、3或4个亚甲基可独立任选地被选自-CRd＝CRd-、-C≡C-、-C(Rd)2-、-O-、-C(＝O)-、-NH-、 的单元所置换，所述 可独立任选地被1、2或3个选自氘、卤素、CN、OH、NO2、NH2、氧代、甲基、乙基、异丙基、甲氧基、异丙氧基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-OCHF2和-OCF3的取代基所取代；
    各Rd独立地为氢、氘、卤素、CN、OH、NO2、NH2、甲基、乙基、正丙基或异丙基。
  25. 如权利要求1-20、24任一项所述的化合物，其中L为：
  26. 如权利要求1-25任一项所述的化合物，其具有式(II)、式(III)、式(IV)、式(V)或式(VI)所示结构：
    其中：
    Z1、Z3和Z4各自独立地为CH2、-C(＝O)-、NH、O或S；
    Z2为CH或N；
    p和q各自独立地为1或2。
  27. 一种化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：







  28. 一种药物组合物，包含权利要求1-27任意一项所述的化合物，所述药物组合物任选地进一步包含药学上可接受的赋形剂、载体、辅剂或它们的任意组合。
  29. 权利要求1-27任意一项所述的化合物或者权利要求28所述的药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻患者与IRAK4相关的疾病。
  30. 如权利要求29所述的用途，其中所述疾病选自炎症性疾病、感染如病毒、细菌、真菌和寄 生虫感染、HIV-1感染、败血症、自身免疫性病症或疾病如类风湿性关节炎和多发性硬化症、痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病、增殖性疾病如癌症、增生、再狭窄、心脏肥大、白血病、血管内凝血、骨病、代谢疾病、神经和神经退行性疾病、心血管疾病、纤维化和过敏性疾病、哮喘、特应性皮炎、化脓性汗腺炎、阿尔茨海默病、激素相关疾病、外伤、血液透析、缺血性疾病、非感染性肝炎、紫外线辐射、闭合性头部损伤、胰腺炎、牙周炎、移植物抗宿主病和/或移植排斥。
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