WO2025252011A1 - Agent de dégradation contenant un lieur de sulfoximine, intermédiaire de celui-ci et son utilisation - Google Patents

Agent de dégradation contenant un lieur de sulfoximine, intermédiaire de celui-ci et son utilisation

Info

Publication number
WO2025252011A1
WO2025252011A1 PCT/CN2025/098244 CN2025098244W WO2025252011A1 WO 2025252011 A1 WO2025252011 A1 WO 2025252011A1 CN 2025098244 W CN2025098244 W CN 2025098244W WO 2025252011 A1 WO2025252011 A1 WO 2025252011A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
reaction
room temperature
alkyl group
int
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/098244
Other languages
English (en)
Chinese (zh)
Inventor
陈宇锋
柴金华
杨帅
张强
杨刚
杨瑞
周禾
向少云
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Polymed Biopharmaceuticals Inc
Original Assignee
Hangzhou Polymed Biopharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Polymed Biopharmaceuticals Inc filed Critical Hangzhou Polymed Biopharmaceuticals Inc
Publication of WO2025252011A1 publication Critical patent/WO2025252011A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • This invention relates to a degradation agent containing a Sulfoximine linker, its intermediates, and its applications.
  • PROTAC Proteinolysis Targeting Chimera
  • PROTAC is a hybrid bifunctional small molecule compound. Its structure contains two different ligands: an E3 ubiquitin ligase ligand and a target protein-binding ligand, linked by a linker arm.
  • PROTAC brings the target protein and the intracellular ubiquitin ligase E3 closer together, forming a target protein-PROTAC-E3 ternary complex. This complex recruits the E3 ligase to a specific unwanted protein and tags it with a ubiquitinated protein label. Subsequently, it activates the cell's powerful ubiquitination-proteasome system, specifically degrading the target protein and thus inhibiting the corresponding protein signaling pathway.
  • PROTACs exhibit unique advantages: 1. PROTACs do not require prolonged and high-intensity binding to target proteins, and the degradation process is similar to a catalytic reaction, allowing for cyclical binding and degradation of the target protein, thereby reducing systemic drug exposure and minimizing toxic side effects; 2. Degraded target proteins require resynthesis to restore function, therefore, degradation exhibits more efficient and durable anti-tumor effects than inhibition, and is less prone to drug resistance due to target protein mutations; 3. PROTACs also show therapeutic potential for targets currently considered untreatable, such as transcription factors, scaffold proteins, and regulatory proteins. Introducing ligands that bind to different target proteins into PROTAC molecules makes it possible to apply PROTAC technology to the treatment of various diseases. Developing highly effective PROTAC drugs for the treatment of target protein-related diseases is of great significance.
  • This invention provides a degrading agent containing a Sulfoximine linker, its intermediates, and applications, which are completely different from existing technologies.
  • the Sulfoximine linker of this invention exhibits good activity in degrading target proteins and has excellent efficacy.
  • This invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:
  • R1 is a C1-6 alkyl or C3-6 cycloalkyl
  • R2 is a C1-6 alkylene or a C3-6 cycloalkylene
  • R1 and R2 together with the sulfur atom they are attached to form ring A, wherein ring A is a 4-11 member heterocyclic alkyl group; wherein the heteroatom in the 4-11 member heterocyclic alkyl group is independently one or more of N, S and O, and the number is 1, 2 or 3 (containing at least 1 S).
  • D is the target protein binding ligand
  • E is the ligand for E3 ubiquitin ligase.
  • the alkyl group of C 1-6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, for example methyl, ethyl, or isobutyl, e.g., methyl.
  • the C 3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl or cyclobutyl.
  • the C1-6 alkylene group is methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, or tert-butylene, and may also be...
  • the C3-6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the 4-11 member heterocyclic alkyl group in ring A is a 4, 5, or 6 member monocyclic heterocyclic alkyl group, or a 9, 10, or 11 member bicyclic heterospirocyclic alkyl group, with heteroatoms being N and/or S, and the number being 1 or 2. It may also be tetrahydro-2H-thiopyranyl, thiomorpholinyl, 2-thia-7-azaspiro[3.5]nonyl, 2-thiaspiro[3.5]nonyl, 3-thia-9-azaspiro[5.5]undecyl or 3-thiaspiro[5.5]undecyl.
  • ring A when ring A also contains N, ring A is connected to D through N atoms.
  • n1, n2, n3, n4, n5, and n6 are independently 1, 2, or 3; X1 and X2 are independently -CH- or N.
  • D is the EGFR target protein binding ligand.
  • the EGFR target protein binding ligand has the structure shown in Formula D1:
  • L1 and L2 are either absent or C1-6 alkylene groups
  • Ring B is absent or a 4-6 membered heterocyclic alkyl group; the heteroatom in the 4-6 membered heterocyclic alkyl group is one or more of N, S and O, and the number is 1, 2 or 3;
  • the ring C is a 4-12 member heterocyclic alkyl or a 4-12 member heterocyclic alkyl substituted with one or more Ra ; the heteroatoms in the 4-12 member heterocyclic alkyl and the 4-12 member heterocyclic alkyl substituted with one or more Ra are one or more of N, S and O, and the number is 1, 2, 3 or 4.
  • R3 is an alkyl group of -OC 1-6 or an alkyl group of -OC 1-6 substituted by one or more R 3a .
  • R 3a is independently a halogen or deuterium;
  • R 4 is a C 1-6 alkyl, a C 3-6 cycloalkyl, a C 1-6 alkyl substituted with one or more R 4a-1 , a C 3-6 cycloalkyl substituted with one or more R 4a-2 , a 5-6 member heteroaryl substituted with one or more R 4a-3 , wherein the heteroatom in the 5-6 member heteroaryl substituted with one or more R 4a-4 is one or more of N, S and O, and the number is 1, 2 or 3;
  • Each R 4a-1 , each R 4a-2 , each R 4a-3 and each R 4a-4 is independently a halogen, deuterium or a C1-6 alkyl group;
  • R5 is a halogen, a C1-6 alkyl group, or a C1-6 alkyl group substituted with one or more halogens;
  • R7 and R8 are independently H, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkyl substituted with one or more halogens, or C3-6 cycloalkyl substituted with one or more halogens; or, R7 and R8 together with the atoms attached to them form a 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group substituted with one or more Ra atoms ; wherein the heteroatom in the 5-6 membered heteroaryl group is independently one or more of N, S, and O, and the number is 1, 2, or 3.
  • Each Ra is independently a halogen, a C1-6 alkyl group, or an -OC1-6 alkyl group.
  • the C1-6 alkylene group may be methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, or tert-butylene, and may also be methylene,
  • the 4-6 membered heterocyclic alkyl group can be a 4, 5, or 6 membered monocyclic heterocyclic alkyl group, with the heteroatom being N, and the number being 1 or 2. It can also be an nitrogen-containing heterocyclic butyl group, pyrrolidinyl group, piperidinyl group, or piperazine group, for example... Bit 1 is connected to L1 , and bit 2 is connected to L2 .
  • the 4-12 membered heterocyclic alkyl group and the 4-12 membered heterocyclic alkyl group substituted with one or more Ra can be 4-6 membered monocyclic heterocyclic alkyl groups or 6-12 membered bicyclic spirocyclic heterocyclic alkyl groups, the heteroatoms being N and/or O, and the number being 1 or 2, and can also be piperidinyl, piperazine, tetrahydrofuranyl or 3,9-diazaspiro[5.5]undecyl, for example
  • the 1st position is connected to L2
  • the 2nd position is connected to the phenyl group.
  • the halogen is preferably F, Cl, Br or I, for example Cl or Br.
  • the C1-6 alkyl group substituted by one or more R4a-1 may be any C1-6 alkyl group substituted by one or more R4a-1.
  • the 5-6 member heteroaryl group and the 5-6 member heteroaryl group substituted with one or more Ra atoms are preferably 6 member heteroaryl groups, the heteroatom is N, and the number is 1 or 2. They are also preferably pyridyl, pyrimidinyl, or pyrazinyl groups, for example... This indicates that a cyclic ring is formed here with the benzene ring.
  • the 3-12 membered heterocyclic alkyl group substituted with one or more Ra can be a 4-6 membered monocyclic heterocyclic alkyl group substituted with halogen, or it can be...
  • the 1st position is connected to L2
  • the 2nd position is connected to the phenyl group.
  • Position 1 is connected to R2 , and position 2 is connected to the phenyl group.
  • Position 1 is connected to ring C, and position 2 is connected to -NH-.
  • Position 1 is connected to R2
  • position 2 is connected to the phenyl group
  • any of the following structures is preferred:
  • E is a CRBN-type ubiquitin ligase ligand.
  • the CRBN-type ubiquitin ligase ligand is preferably the structure shown in Formula E1:
  • X e1 is N or CR e2 ;
  • Re1 and Re2 are independently hydrogen, C1-6 alkyl groups, or halogens
  • the ring E is a C 6-10 aryl, a 5-14 heteroaryl, a C 6-10 aryl substituted with one or more Re3 atoms, or a 5-14 heteroaryl substituted with one or more Re3 atoms; the heteroatoms in the 5-14 heteroaryl and the 5-14 heteroaryl substituted with one or more Re3 atoms are independently one or more of N, S, or O, and the number is 1, 2, 3, or 4;
  • Each Re3 is independently a halogen, oxo group, cyano group, C1-6 alkyl group, C1-6 alkyl group substituted with one or more halogens, -OC1-6 alkyl group, or C3-6 cycloalkyl group;
  • Re3 atoms attached to the same atom can form -( CH2 ) n7- , where n7 is 1, 2, 3, or 4.
  • the halogen and the halogen in the C1-6 alkyl group substituted with one or more halogens are independently preferably F, Cl, Br or I, for example F.
  • the C1-6 alkyl group, the C1-6 alkyl group substituted with one or more halogens, and the C1-6 alkyl group of the -OC1-6 alkyl group are independently preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, e.g., methyl.
  • the C3-6 cycloalkyl group is preferably cyclopropane, cyclobutane, cyclopentane, or cyclohexane.
  • the C6-10 aryl group and the C6-10 aryl group substituted with one or more Re3 groups are independently preferably phenyl or naphthyl.
  • the 5-14 member heteroaryl group and the 5-14 member heteroaryl group substituted with one or more Re3 are preferably 5-6 member monocyclic heteroaryl groups or 9-10 member bicyclic fused heteroaryl groups (5-6 member heterocyclic benzophenyl, 5-6 member heteroenylbenzophenyl, 5-6 member heteroaryl benzo-6 member heteroaryl, such as pyridine or pyrimidine), the heteroatom is N and/or O, and the number is 1, 2 or 3, more preferably N and/or O. Position 1 is connected to Y, and position 2 is connected to N (N in the Sulfoximine group).
  • E1 is E1-1, E1-2, E1-3, or E1-4:
  • Xe2 is either C or N
  • Z1 , Z2 , Z3 , Z4 and Z5 are independently N, CH or CRe3 , and Z1 , Z2 , Z3 , Z4 and Z5 are not simultaneously N;
  • Xe1 , Y, Re1 and Re3 are defined as described above;
  • Z6 , Z7 , Z8 , and Z9 are independently N, CH, or CRe3 , and Z6 , Z7 , Z8 , and Z9 are not simultaneously N;
  • Xe1 , Y, Re1 , and Re3 are defined as described above;
  • X e3 is N or C
  • Z12 is CH2 , CRe3Re3 , CRe3 , O, NH, or NRe3 ;
  • Z13 is C or N ;
  • Z6 , Z7 , Z8 , and Z9 are independently N, CH, or CRe3 , and Z6 , Z7 , Z8 , and Z9 are not simultaneously N;
  • Xe1 , Y, Re1 , and Re3 are defined as described above;
  • Z14 is N or C;
  • Z15 is CH or CR e3 ;
  • Z6 , Z7 , Z8 and Z9 are independently N, CH or CR e3 , and Z6 , Z7 , Z8 and Z9 are not simultaneously N;
  • X e1 , Re1 and Re3 are not simultaneously N;
  • Each Re3 is independently a halogen, a C1-6 alkyl group, or a -OC1-6 alkyl group, with Xe1 attached at position 1 and N attached at position 2.
  • Each Re3 is independently a halogen, a C1-6 alkyl group, or a -OC1-6 alkyl group, with Xe1 attached at position 1 and N attached at position 2.
  • Each Re3 is independently a C1-6 alkyl group, with Xe1 attached at position 1 and N attached at position 2.
  • Preferred Bit 1 is connected to X e1 , and bit 2 is connected to N.
  • E1 is preferably any of the following structures:
  • the compound represented by Formula I is any of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as shown in Formula I as described above, or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.
  • the present invention also provides the use of the above-described compound as shown in Formula I, its pharmaceutically acceptable salt, or the above-described pharmaceutical composition in the preparation of a medicament for the prevention or treatment of cancer (e.g., lung cancer).
  • cancer e.g., lung cancer
  • the lung cancer mentioned is preferably non-small cell lung cancer or lung adenocarcinoma.
  • the present invention also provides the use of the above-described compound as shown in Formula I, its pharmaceutically acceptable salt, or the above-described pharmaceutical composition in the preparation of a medicament for the prevention or treatment of EGFR-related diseases.
  • the EGFR-related diseases mentioned are preferably diseases caused by mutations in the EGFR protein.
  • the EGFR protein mutations are preferably selected from the following mutation sites: Del19-T790M-C797S mutation, L858R-T790M-C797S mutation, Del19-C797S mutation, L858R-C797S mutation, L858R-T790M mutation, Del19 mutation, and L858R mutation.
  • the present invention also provides a method for treating or preventing a disease comprising administering to a patient an effective amount of the compound shown in Formula I, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, wherein the disease is the EGFR-related disease described above or the lung cancer described above.
  • the present invention also provides a compound as shown in Formula II or III, or a salt thereof (e.g., to prepare a compound as shown in Formula I):
  • the compound represented by Formula II is preferably any one of the following compounds:
  • the salts of the compounds represented by Formula II are preferably hydrochloride or trifluoroacetate.
  • the compound represented by Formula III is preferably any one of the following compounds:
  • alkyl refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-6 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.
  • alkylene refers to a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "alkyl”.
  • (monocyclic)cycloalkyl refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-6 ), which is monocyclic.
  • (Monocyclic)cycloalkyl groups include, but are not limited to: wait.
  • cycloalkylene refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term “cycloalkylene”.
  • heterocyclic alkyl refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 4 to 14), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S), and is either monocyclic or polycyclic (2-ring) spirocyclic.
  • Heterocyclic alkyl groups are attached to the rest of the molecule via carbon atoms or heteroatoms.
  • Heterocyclic alkyl groups include, but are not limited to: wait.
  • aryl refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C6 to C10 ), which can be monocyclic or polycyclic (e.g., two or three). In polycyclic cases, the monocyclic rings share two atoms and one bond, and (at least one ring/each ring) is aromatic. The aryl group is attached to the rest of the molecule via an aromatic or non-aromatic ring.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, and others. wait.
  • heteroaryl refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5 to 14), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic (2 or 3 rings), sharing two atoms and one bond between the monocyclic rings, and (at least one ring/each ring) is aromatic.
  • Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they can be attached to the rest of the molecule via rings with or without heteroatoms; they can be attached to the rest of the molecule via aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to: wait.
  • therapeutic effective dose refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.
  • pharmaceutical excipients refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives.
  • excipients and additives please refer to the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *Handbook of Pharmaceutical Excipients* (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).
  • treatment refers to eliminating the cause of an illness or relieving symptoms.
  • prevention refers to reducing the risk of developing a disease.
  • patient refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.
  • the reagents and raw materials used in this invention are all commercially available.
  • the Sulfoximine-type degrading agent of this invention has good protein degradation activity and excellent efficacy.
  • Room temperature refers to 20-30°C; unless otherwise specified in the reaction examples, all reactions are carried out under a nitrogen atmosphere.
  • a nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon of approximately 1L.
  • Hydrogenation reactions are typically carried out under vacuum, filled with hydrogen gas, and repeated three times.
  • a hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon of approximately 1L.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Rapid column chromatography was performed using an Agilent (FS-9200T) automated column press, and pre-packed silica gel columns were used with Sante. Pre-packed column.
  • Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The thickness used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.
  • Reversed-phase preparative chromatography was performed using a Waters-3767 reversed-phase preparative chromatograph.
  • Preparation column Waters SunFire, 250*19mm, 5mm or Xbridge Prep C18 or Gemini C18 21.2*250 5um; Mobile phase: A: 0.05% ammonia-water solution; B: acetonitrile; Detection wavelength: 254nm &214nm; Flow rate: 20ml/min.
  • LCMS was performed using a Waters ARC HPLC-QDA instrument.
  • Chromatographic column ACQUITY UPLC BEH C18 3.5um 3.0*50mm; Ion source: ESI; Mobile phase: A: 0.05% ammonia-water solution; B: 0.05% ammonia-acetonitrile solution; Detection wavelength: 254nm &214nm; Run time: 1.5ml/min/3.5min.
  • HPLC was performed using a Waters W2489 Instrument instrument.
  • Chromatographic column Xbridge C18, 4.6*50mm; Mobile phase: A: 0.1% ammonia-water solution; B: acetonitrile; Detection wavelength: 254nm &214nm; Run time: 9.0min.
  • Step A Int-1a (3.0 g, 10.07 mmol), dimethylphosphine oxide (0.86 g, 11.08 mmol), potassium phosphate (6.4 g, 30.21 mmol), palladium acetate (0.23 g, 1.01 mmol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (1.75 g, 0.3 mmol) were added to 1,4-dioxane (50 mL) and stirred at 100 °C for 4 hours under nitrogen protection.
  • Step B Int-1b (1.1 g, 4.43 mmol), cyclopropylboronic acid (0.76 g, 8.86 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.33 g, 0.44 mmol), and potassium carbonate (2.82 g, 19.93 mmol) were added to 1,4-dioxane (15 mL) and water (1.5 mL). The mixture was stirred at 100 °C for 4 hours under nitrogen protection.
  • Step A Int-2a (20.4 g, 193 mmol) was dissolved in dichloromethane (200 mL), and triethylamine (39.2 g, 387 mmol, 54.0 mL) was added. Di-tert-butyl dicarbonate (46.5 g, 213 mmol, 48.9 mL) was added dropwise at 0 °C, and the mixture was stirred overnight at room temperature. The reaction solution was washed successively with saturated ammonium chloride aqueous solution and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure to a white solid, and dried under vacuum to obtain solid Int-2b (21.8 g, yield 55.57%).
  • 1H NMR 400 MHz, DMSO- d6 ) ⁇ 3.62–3.52 (m, 4H), 2.55–2.47 (m, 6H), 1.40 (s, 9H).
  • Step C Int-2c (8.5 g, 36.2 mmol) and Int-2d (10.1 g, 30.2 mmol) were dissolved in dioxane (170 mL).
  • t-BuXPhos-Pd- G3 (2.40 g, 3.02 mmol)
  • t-BuXPhos (1.28 g, 3.02 mmol) were added to the reaction solution.
  • the mixture was purged with nitrogen three times and reacted at 100 °C for 3 hours. LC/MS showed the reaction was complete.
  • Step D At room temperature, Int-2e (2 g, 4.08 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C in an ice bath, and hydrochloric acid/dioxane solution (4.0 M, 10 mL) was added. The reaction was allowed to proceed at room temperature for approximately 2 hours. LC/MS showed that the starting material had completely reacted. The reaction solution was concentrated under reduced pressure to obtain Int-2 (2.2 g, crude product). It was an off-white solid. No further purification was required. ESI-MS (m/z): 391.2 (M+H) + .
  • Step A Int-3a (22.5 g, 95.3 mmol) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (26.3 g, 190.6 mmol) and methyl iodoforme (20.3 g, 143 mmol) were added to the reaction solution. The mixture was stirred at 45 °C for 2 hours, and TLC showed that the reaction was complete. After cooling to room temperature, the reaction solution was poured into water (300 mL), and a solid precipitated. The solid was collected by filtration, washed with water, and dried under vacuum to obtain solid Int-3b (22 g, yield 92.29%).
  • Step B Int-3b (22 g, 88 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoborane-2-yl)-1H-pyrazole (22 g, 105.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.2 g, 4.4 mmol), and potassium carbonate (30.4 g, 220 mmol) were added to a mixed solvent of 1,4-dioxane (200 mL) and water (20 mL). The mixture was stirred overnight at 90 °C under a nitrogen atmosphere, and the reaction was confirmed to be complete by LC/MS.
  • Step C Int-3c (6.2 g, 24.7 mmol) was dissolved in dimethyl sulfoxide (60 mL), and Int-3d (5.6 g, 37 mmol) and potassium carbonate (10.2 g, 74.1 mmol) were added. The mixture was stirred overnight at 120 °C, and the reaction was complete according to LC/MS. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step A Iodine (87.4 g, 34.44 mmol) in acetic acid (500 mL) was added dropwise to a solution of Int-4a (25.0 g, 17.22 mmol) in acetic acid (500 mL), and the mixture was stirred at 60 °C for 16 hours.
  • LC-MS showed that the reaction was complete.
  • Step B Int-4b (20.0 g, 7.38 mmol), dimethylphosphine oxide (8.6 g, 11.07 mmol), potassium phosphate (31.3 g, 14.76 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (4.3 g, 0.74 mmol), and palladium acetate (1.65 g, 0.74 mmol) were added to 1,4-dioxane (250 mL) and stirred at 100 °C for 16 hours under nitrogen protection.
  • Step C A solution of Int-4c (5.0 g, 22.6 mmol) in N,N-dimethylformamide (35 mL) was added dropwise to a suspension of sodium hydride (3.62 g, 90.4 mmol, 60%) in tetrahydrofuran (25 mL) under ice bath conditions, and the mixture was stirred at 0 °C for 40 min. A solution of 5-bromo-2,4-dichloropyrimidine (10.3 g) in tetrahydrofuran (25 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 25 °C for 4 h. LC-MS showed the reaction was complete. The reaction mixture was poured into ice water, and a solid precipitated.
  • Step A Under nitrogen atmosphere, pinacol diborate (3.14 g, 12.38 mmol), Int-5a (2 g, 6.19 mmol), potassium acetate (1.82 g, 18.57 mmol), and DPPF palladium dichloride (226.43 mg, 0.309 mmol) were dissolved in 1,4-dioxane (25 mL) and reacted at 100 °C with stirring for 16 hours. LC/MS showed that the reaction was complete. The reaction solution was cooled, and 30 mL of petroleum ether was added and stirred for 10 minutes. A solid was formed, filtered, and dried to give Int-5b (1.6 g, yield 69.83%), ESI-MS (m/z): 371.2 [M+H] + .
  • Step B Ammonium acetate (3.33 g, 43.22 mmol), sodium periodate (924.41 mg, 4.32 mmol), and Int-5b (1.6 g, 4.32 mmol) were dissolved in a mixed solvent of acetonitrile (20 mL) and water (10 mL). The mixture was stirred at 50 °C for 16 hours, and LC/MS showed that the reaction was complete. A large amount of solid was produced. The reaction solution was filtered, washed with water, and dried to give a white solid Int-5c (1.1 g, yield 88.35%). ESI-MS (m/z): 290.1 [M+H] + .
  • Step C Int-5c (500 mg, 1.74 mmol), Int-2c (406.71 mg, 1.74 mmol), triethylamine (1.05 g, 10.41 mmol, 1.45 mL), and copper acetate (690.82 mg, 3.47 mmol) were dissolved in N,N-dimethylformamide (6 mL). The mixture was stirred at 40 °C for 16 hours, and LC/MS showed that the reaction was complete.
  • Step D Dissolve Int-5d (340 mg, 0.713 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. Concentrate the reaction solution to obtain Int-5 (0.26 g, crude product), which requires no further purification.
  • Step B At 0°C, Int-7b (40 g, 245.17 mmol) was dissolved in concentrated sulfuric acid (80 mL, 98%), and concentrated nitric acid (28 g, 65%) was added. The resulting mixture was stirred at 0°C for 1 hour. LC/MS showed that the reaction was complete. The reaction mixture was poured into ice water (1000 mL) and stirred for 10 minutes. A large amount of solid was produced, which was filtered, washed with water, and dried under vacuum to give Int-7c (54 g, crude product). ESI-MS (m/z): 208.92 (M+H) + .
  • Step D Int-7d (10 g, 44.13 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (20 g, 158.87 mmol), DPPF palladium dichloride (4 g, 5.29 mmol), and potassium phosphate (23 g, 110.32 mmol) were dissolved in 1,2-dichloroethane (250 mL) and water (50 mL), and stirred overnight at 80 °C under a nitrogen atmosphere. LC/MS showed that the reaction was complete.
  • Step E At room temperature, Int-7e (6 g, 29.10 mmol) was dissolved in methanol (100 mL). Palladium on carbon (1 g, 10 wt.%) was added to the reaction solution. After purging with a hydrogen balloon, the mixture was stirred at 25 °C for 5 hours. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain Int-7f (3.9 g, yield 76%). ESI-MS (m/z): 176.95 (M+H) + .
  • Step F At room temperature, iodine monochloride (4.7 g, 26.56 mmol) was added to Int-7f (3.9 g, 22.13 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 1 hour. LC/MS showed that the reaction was complete. The pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-7g (5.5 g, 82% yield). ESI-MS (m/z): 302.97 (M+H) + .
  • Step G Potassium phosphate (11.6 g, 54.63 mmol) was added to a solution of Int-7 g (5.5 g, 18.21 mmol) and dimethylphosphine oxide (2.84 g, 36.41 mmol) in 1,4-dioxane (100 mL). Then, palladium acetate (820 mg, 3.64 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (4.2 g, 7.28 mmol) were added to the mixture. After nitrogen purging, the mixture was stirred overnight at 100 °C. The mixture was filtered and concentrated under reduced pressure.
  • Step A At 0°C, Int-7a (50 g, 344.45 mmol) was dissolved in concentrated sulfuric acid (400 mL, 98%), and concentrated nitric acid (39.5 g, 65%) was added. The resulting mixture was stirred at 0°C for 1 hour. LC/MS showed that the reaction was complete. The reaction mixture was poured into ice water (1000 mL) and stirred for 10 minutes. A large amount of solid was produced, which was filtered, washed with water, and dried under vacuum to give Int-8a (57 g, crude product). ESI-MS (m/z): 190.92 (M+H) + .
  • Step C Int-8b (23 g, 110.26 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxane (34 g, 220.52 mmol), DPPF palladium dichloride (4.03 g, 22.05 mmol), and potassium carbonate (53.3 g, 385.91 mmol) were dissolved in 1,4-dioxane (500 mL) and water (50 mL), and stirred overnight at 100 °C under a nitrogen atmosphere.
  • Step D At room temperature, Int-8c (15 g, 74.92 mmol) was dissolved in methanol (200 mL). Palladium on carbon (3 g, 10 wt.%) was added to the reaction solution. After purging with a hydrogen balloon, the mixture was stirred at 25 °C for 16 hours. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain Int-8d (12.0 g, 95% yield). ESI-MS (m/z): 173.1 (M+H) + .
  • Step E At room temperature, iodine monochloride (4.3 g, 26.47 mmol) was added to Int-8d (3.8 g, 22.06 mmol) in acetic acid (40 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-8e (6.3 g, 95% yield).
  • Step F Potassium phosphate (10.5 g, 49.30 mmol) was added to a solution of Int-8e (5.88 g, 19.72 mmol) and dimethylphosphine oxide (3.08 g, 36.44 mmol) in 1,4-dioxane (100 mL). Then, palladium acetate (885 mg, 3.94 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (2.28 g, 3.94 mmol) were added to the mixture. After nitrogen purging, the mixture was stirred overnight at 100 °C. The mixture was filtered and concentrated under reduced pressure.
  • Step C At room temperature, iodine monochloride (900 mg, 5.53 mmol) was added to Int-9c (640 mg, 3.69 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int-9d (900 mg, yield 81%). ESI-MS (m/z): 299.79 (M+H) + .
  • Step D Potassium phosphate (1.6 g, 7.52 mmol) was added to a solution of Int-9d (900 mg, 3.01 mmol) and dimethylphosphine oxide (470 mg, 6.02 mmol) in 1,4-dioxane (20 mL). Then, palladium acetate (135 mg, 0.602 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (348 mg, 0.602 mmol) were added to the mixture. After nitrogen purging, the mixture was stirred overnight at 100 °C. The mixture was filtered and concentrated under reduced pressure.
  • Step A Int-10a (300 mg, 0.99 mmol), Int-2c (231.17 mg, 0.99 mmol), cesium carbonate (707.17 mg, 2.17 mmol), t-BuXPhos (41.83 mg, 0.099 mmol), and t-BuXPhos Pd G3 (78.37 mg, 0.099 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and N,N-dimethylformamide (3 mL). The mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. LC/MS showed that the reaction was complete.
  • Step B Int-10b (310 mg, 0.68 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1.49 g, 13.07 mmol, 1 mL) was added. The reaction was carried out at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-10 (210 mg, crude product), which did not require further purification. ESI-MS (m/z): 358.3 [M+H] + .
  • Step A Ethyl cyanoacetate (179 g, 1585.11 mmol) was dissolved in methanol (800 mL), ammonium acetate (4.07 g, 52.84 mmol) was added, followed by dropwise addition of Int-11a (100 g, 528.37 mmol), and finally ammonia water (75 mL). The mixture was stirred at 25 °C for 24 hours. After the reaction was complete, 100 mL of concentrated hydrochloric acid was added, and a solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate to obtain Int-11b (94 g, yield 55.19%). ESI-MS (m/z): 323.1 [M+H] + .
  • Step B Sulfuric acid (500 mL) and water (330 mL) were mixed, and Int-11b (94 g, 291.59 mmol) was added in portions. The mixture was gradually heated to 130 °C and stirred for 24 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. It was then dissolved in ethanol (900 mL) and reacted at 120 °C for 20 hours. After the reaction was complete again, the mixture was cooled. Sodium bicarbonate (122.5 g, 1457.95 mmol) was then added under ice bath conditions. Water was added, and the mixture was extracted with dichloromethane.
  • Step C Compound Int-11c (100 g, 287.8 mmol) was dissolved in tetrahydrofuran (1000 mL). Under nitrogen protection, lithium aluminum hydride (21.87 g, 575.6 mmol) was added in portions at 0 °C, and the mixture was stirred overnight at 25 °C. LC/MS showed that the reaction was complete. The reaction was quenched by the slow addition of sodium sulfate decahydrate with stirring, filtered, washed with tetrahydrofuran, and concentrated to give compound Int-11d (70 g, crude product). ESI-MS (m/z): 264.2 [M+H] + .
  • Step E Compound Int-11e (48 g, 175.58 mmol) was dissolved in dichloromethane (5000 mL), cooled to 0 °C, and triethylamine (71.07 g, 702.32 mmol, 97.62 mL) and methanesulfonic anhydride (61.17 g, 351.16 mmol) were added. The mixture was stirred for 1 hour. The reaction solution was quenched with water slowly, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound Int-11e (69 g, crude product).
  • Step F Compound Int-11e (69 g, 160.64 mmol) was dissolved in N,N-dimethylformamide (800 mL), and sodium sulfide nonahydrate (18.52 g, 192.77 mmol) was added. The mixture was stirred at 50 °C for 16 hours. LC/MS showed that the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated.
  • Step A Int-12a (2 g, 5.93 mmol) and Int-11 (1.79 g, 5.93 mmol) were dissolved in 1,4-dioxane (30 mL). Under nitrogen protection, t-BuXPhos-Pd-G3 (471.3 mg, 0.59 mmol), t-BuXPhos (251.9 mg, 0.59 mmol), and cesium carbonate (5.79 g, 17.8 mmol) were added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The solution was extracted with dichloromethane, and the organic phases were combined.
  • Step B Int-12b (2.75 g, 4.92 mmol) was dissolved in dichloromethane (20 mL), and then HCl (4.0 M 1,4-dioxane solution, 10 mL) was added at 0 °C. The reaction was allowed to proceed at room temperature for 4 hours, and a white product precipitated. LC/MS showed that the reaction was complete. After filtration and vacuum drying, a white solid Int-12 (2.8 g, crude product) was obtained. No further purification was required. ESI-MS (m/z): 390.17 [M+H] + .
  • Step A Under nitrogen atmosphere, pinacol diborate (3.14 g, 12.38 mmol), Int-13a (2 g, 6.19 mmol), potassium acetate (1.82 g, 18.57 mmol), and DPPF palladium dichloride (226.43 mg, 0.309 mmol) were dissolved in 1,4-dioxane (25 mL), and the mixture was stirred at 100 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction solution was cooled, and 30 mL of petroleum ether was added and stirred for 10 minutes. A solid was formed, filtered, and dried to give Int-13b (1.6 g, yield 69.83%), ESI-MS (m/z): 371.2 [M+H] + .
  • Step B Ammonium acetate (3.33 g, 43.22 mmol), sodium periodate (924.41 mg, 4.32 mmol), and Int-13b (1.6 g, 4.32 mmol) were dissolved in a mixed solvent of acetonitrile (20 mL) and water (10 mL). The mixture was stirred at 50 °C for 16 hours, and LC/MS showed that the reaction was complete. A large amount of solid was produced. The reaction solution was filtered, washed with water, and dried to give a white solid Int-13c (1.1 g, yield 88.35%), ESI-MS (m/z): 290.1 [M+H] + .
  • Step C Int-13c (500 mg, 1.74 mmol), Int-2c (406.71 mg, 1.74 mmol), triethylamine (1.05 g, 10.41 mmol, 1.45 mL), and copper acetate (690.82 mg, 3.47 mmol) were dissolved in N,N-dimethylformamide (6 mL). The mixture was stirred at 40 °C for 16 hours, and LC/MS showed that the reaction was complete.
  • Step D Int-13d (340 mg, 0.713 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1.49 g, 13.07 mmol, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain Int-3 (0.26 g, crude product), ESI-MS (m/z): 377.3 [M+H] + .
  • Step A Int-14a (2 g, 7.46 mmol) and Int-11 (2.26 g, 7.46 mmol) were dissolved in dimethyl sulfoxide (3 mL). Under nitrogen protection, t-BuXPhos-Pd-G3 (592.58 mg, 0.75 mmol), t-BuXPhos (316.77 mg, 0.75 mmol), and cesium carbonate (7.29 g, 22.38 mmol) were added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The solution was extracted with dichloromethane, and the organic phases were combined.
  • Step B Int-14b (2.8 g, 5.76 mmol) was dissolved in dichloromethane (30 mL), and then HCl (4.0 M 1,4-dioxane solution, 10 mL) was added at 0 °C. The reaction was allowed to proceed at room temperature for 4 hours, during which a white product precipitated. LC/MS showed that the reaction was complete. After filtration and vacuum drying, a white solid Int-14 (2 g, crude product) was obtained. No further purification was required. ESI-MS (m/z): 390.17 [M+H] + .
  • Step A Int-10a (2 g, 6.58 mmol) and Int-11 (1.59 g, 5.26 mmol) were dissolved in 1,4-dioxane (15 mL) and N,N-dimethylformamide (15 mL). Under nitrogen protection, t-BuXPhos-Pd-G3 (156 mg, 0.197 mmol), t-BuXPhos (279 mg, 0.658 mmol), and cesium carbonate (4.29 g, 13.15 mmol) were added to the reaction solution. The reaction was carried out at 80 °C for 16 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added.
  • Step B Int-14b (2.5 g, 4.76 mmol) was dissolved in dichloromethane (20 mL), and then HCl (4.0 M 1,4-dioxane solution, 10 mL) was added at 0 °C. The reaction was allowed to proceed at room temperature for 4 hours, and a white product precipitated. LC/MS showed that the reaction was complete. After filtration and vacuum drying, a white solid Int-15 (2.1 g, crude product) was obtained. No further purification was required. ESI-MS (m/z): 425.4 [M+H] + .
  • Step A Int-16a (3 g, 14.53 mmol) and acrylic acid (1.15 g, 15.98 mmol) were dissolved in acetic acid (10 mL) and water (40 mL). The reaction was carried out at 100 °C for 12 hours, and LC/MS showed that the reaction was complete. After concentration under reduced pressure, a pale yellow solid Int-16b (4.0 g, crude product) was obtained. No further purification was required. ESI-MS (m/z): 280.0 [M+H] + .
  • Step B Int-16b (4.0 g, 14.36 mmol) and ammonia (5.03 g, 143.6 mmol, 5.59 mL) were dissolved in N,N-dimethylformamide (30 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (5.46 g, 14.36 mmol) was added, and the reaction was carried out at room temperature for 12 hours. LC/MS showed that the reaction was complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step C Int-16c (3.1 g, 11.17 mmol) was dissolved in acetonitrile (60 mL). N,N'-carbonyldiimidazole (2.17 g, 13.40 mmol), triethylamine (1.86 mL, 13.40 mmol), and 4-dimethylaminopyridine (136.4 mg, 1.12 mmol) were added to the reaction solution. The reaction was carried out at 90 °C for 48 hours, and LC/MS showed that the reaction was complete. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step D Int-16d (1.0 g, 3.29 mmol) and Int-2c (771.9 mg, 3.29 mmol) were dissolved in 1,4-dioxane (8 mL) and N,N-dimethylformamide (8 mL). Under nitrogen protection, t-BuXPhos-Pd-G3 (78 mg, 0.099 mmol), t-BuXPhos (139 mg, 0.329 mmol), and cesium carbonate (2.15 g, 6.59 mmol) were added to the reaction solution. The reaction was carried out at 80 °C for 16 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added.
  • Step E Int-16e (1.2 g, 2.63 mmol) was dissolved in dichloromethane (10 mL), and then HCl (4.0 M 1,4-dioxane solution, 5 mL) was added at 0 °C. The reaction was allowed to proceed at room temperature for 2 hours, and a white product precipitated out. LC/MS showed that the reaction was complete. After filtration and vacuum drying, a white solid Int-16 (980 mg, crude product) was obtained. No further purification was required. ESI-MS (m/z): 357.2 [M+H] + .
  • Step A Compounds Int-17a (2 g, 10.04 mmol), Int-17b (3.25 g, 12.04 mmol), and N,N-diisopropylethylamine (3.89 g, 30.12 mmol) were dissolved in dimethyl sulfoxide (50 mL). The reaction was carried out at 120 °C for 5 hours, and LC/MS showed that the reaction was complete. The reaction was cooled to room temperature, and the mixture was extracted twice with dichloromethane by adding saturated ammonium chloride aqueous solution. The organic phases were combined. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B Dissolve Int-17c (3g, 6.69mmol) in dichloromethane (50mL), cool to 0°C in an ice bath, and add dropwise HCl (4.0M 1,4-dioxane solution, 9mL) to the reaction solution. React at room temperature for 4 hours; a white product precipitates, and LC/MS shows the reaction is complete. Filter, wash the filter cake with DCM, and vacuum dry to obtain a white solid Int-17 (2g, yield 85.82%). LC/MS (ESI + ) m/z: 349.2 [M+H] + .
  • Example 1 was prepared by the following steps:
  • Step A At room temperature, Int-2 (270 mg, 0.63 mmol, C) and Int-3 (217.81 mg, 0.63 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C in an ice bath, 3 drops of acetic acid were added dropwise, and sodium triacetoxyborohydride (268.11 mg, 1.27 mmol) was added in portions. The reaction was carried out at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction was quenched by adding water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 2 was prepared by the following steps:
  • Step A Dissolve 1b (60 mg, 0.087 mmol) and Int-4 (46.72 mg, 0.11 mmol) in N,N-dimethylformamide (1.2 mL), add p-toluenesulfonic acid (45.00 mg, 0.26 mmol), and react at 100 °C for 16 hours. LC/MS showed the reaction was complete. Cool to room temperature, pour the reaction solution into sodium bicarbonate solution, the product precipitated, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give pale yellow solid 2 (41.0 mg, yield 43.76%).
  • Example 3 was prepared by the following steps:
  • Step A At room temperature, Int-3 (187.88 mg, 0.54 mmol) and Int-5 (205.38 mg, 0.54 mmol) were dissolved in dichloromethane (4 mL), cooled to 0 °C in an ice bath, 3 drops of acetic acid were added dropwise, and sodium triacetoxyborohydride (231.27 mg, 1.09 mmol) was added in portions. The reaction was carried out at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction was quenched by adding water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step C Dissolve 3b (50 mg, 0.74 mmol), Int-1 (35.62 mg, 0.89 mmol), and p-toluenesulfonic acid (38.28 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL). Stir the mixture at 100 °C for 16 hours. LC/MS showed the reaction was complete. After cooling to room temperature, add an aqueous sodium bicarbonate solution to the reaction mixture. The product precipitates, is filtered, and evaporated to dryness. The residue is purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a pale yellow solid 3 (8 mg, yield 10.08%).
  • Example 4 was prepared by the following steps:
  • Step A At room temperature, 1b (80 mg, 0.11 mmol) and Int-6 (50.31 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (60.00 mg, 0.35 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC-MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, and the product precipitated. The product was filtered and evaporated to dryness.
  • Example 5 was prepared by the following steps:
  • Step A At room temperature, 1b (70 mg, 0.10 mmol) and Int-7 (58.61 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (52.50 mg, 0.31 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC-MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid.
  • Example 6 was prepared by the following steps:
  • Step A Int-3c (200 mg, 0.8 mmol) and 6a (250 mg, 0.96 mmol) were dissolved in dimethyl sulfoxide (3 mL). N,N-diisopropylethylamine (200 mg, 1.59 mmol) was added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The mixture was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • Step B Dissolve 6b (250 mg, 0.69 mmol) in dichloromethane (4 mL), and add Dysmartin oxidant (580 mg, 1.39 mmol) at 0 °C. The reaction was allowed to proceed for 4 hours at room temperature, and LC/MS showed complete reaction. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed twice with sodium thiosulfate aqueous solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • Step C Compound 6c (200 mg, 0.56 mmol) and Int-2 (120 mg, 0.28 mmol) were dissolved in N,N-dimethylformamide (2 mL), two drops of glacial acetic acid were added, the mixture was cooled to 0 °C, and sodium triacetoxyborohydride (120 mg, 0.56 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered, the filter cake was washed with water, and then dried under vacuum to give a yellow solid 6d (200 mg, yield 97.09%). ESI-MS (m/z): 733.3 [M+H] + .
  • Example 7 was prepared by the following steps:
  • Step A Int-3c (1.0 g, 3.98 mmol) and 7a (621.88 mg, 4.78 mmol) were dissolved in dimethyl sulfoxide (20 mL), and N,N-diisopropylethylamine (1.0 g, 7.96 mmol) was added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • Step B Under nitrogen protection, oxalyl chloride (210 mg, 1.66 mmol) was dissolved in anhydrous dichloromethane (3 mL). The mixture was cooled to -78 °C, and dimethyl sulfoxide (194.57 mg, 2.49 mmol) was slowly added dropwise. The mixture was stirred at -78 °C for 1 hour, and then 7b (200 mg, 0.69 mmol) in dichloromethane (2 mL) was added dropwise. The reaction was continued at -78 ° C for 2 hours. Triethylamine (560 mg, 5.53 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. LC/MS showed that the reaction was complete.
  • Step C Compound 7c (150 mg, 0.4 mmol) and Int-2 (83 mg, 0.2 mmol) were dissolved in N,N-dimethylformamide (2 mL), and two drops of glacial acetic acid were added dropwise. Under ice bath conditions, sodium triacetoxyborohydride (90 mg, 0.4 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 2 hours, and LC/MS showed complete reaction. The reaction solution was poured into water, and a yellow solid precipitated. The mixture was filtered, the filter cake was washed with water, and then dried under vacuum to obtain yellow solid 7d (150 mg, yield 96.15%). ESI-MS (m/z): 734.3 [M+H] + .
  • Example 8 was prepared by the following steps:
  • Example 9 was prepared by the following steps:
  • Example 10 was prepared by the following steps:
  • Step A Int-3c (1 g, 3.98 mmol) and 10a (688 mg, 4.78 mmol) were dissolved in dimethyl sulfoxide (20 mL), and N,N-diisopropylethylamine (1 g, 7.96 mmol) was added to the reaction solution. The reaction was carried out at 110 °C for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The mixture was extracted with dichloromethane, and the organic phases were combined. After washing with saturated brine, the mixture was dried over anhydrous sodium sulfate and filtered to dryness.
  • Step B Under nitrogen protection, oxalyl chloride (676.2 mg, 1.07 mmol) was dissolved in anhydrous dichloromethane (10 mL), cooled to -78 °C, and dimethyl sulfoxide (416.23 mg, 5.33 mmol) was slowly added dropwise. The mixture was stirred at -78 °C for 1 hour. A solution of 10b (400 mg, 1.07 mmol) in dichloromethane (3 mL) was added dropwise to the reaction mixture, and the reaction was carried out at -78 °C for 2 hours. Triethylamine (1.08 g, 10.65 mmol) was added, and the reaction was carried out at room temperature for 30 minutes. LC/MS showed that the reaction was complete.
  • Step C Compound 10c (300 mg, 0.80 mmol) and Int-2 (170 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL), and two drops of glacial acetic acid were added dropwise. Under ice bath conditions, sodium triacetoxyborohydride (168.81 mg, 0.8 mmol) was added in portions. The reaction was carried out at room temperature for 2 hours, and LC/MS showed complete reaction. The reaction solution was poured into water, and a yellow solid precipitated.
  • Example 11 was prepared by the following steps:
  • Example 12 was prepared by the following steps:
  • Step B At room temperature, 12b (510 mg, 0.89 mmol) was dissolved in DCM (4 mL), and hydrochloric acid/dioxane solution (4 M, 3 mL) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. LC/MS showed that the reaction was complete. The solvent was removed from the reaction solution under reduced pressure to obtain crude product 12c (360 mg). No further purification was required; it was used directly in the next reaction. ESI-MS (m/z): 474.3 [M+H] + .
  • Step E 12e (30 mg, 0.039 mmol) and Int-4 (22.45 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (20.08 mg, 0.11 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid.
  • Example 13 was prepared by the following steps:
  • Step B At room temperature, 13b (525 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid/dioxane solution (4 M, 4 mL) was added at 0 °C. The mixture was stirred at room temperature for 2 hours. LC/MS showed that the reaction was complete. The solvent was removed from the reaction solution under reduced pressure to obtain crude product 13c (365 mg). No further purification was required for use in the next step. ESI-MS (m/z): 474.3 [M+H] + .
  • Step C At room temperature, 13c (360 mg, 0.71 mmol, C) and Int-3 (291.69 mg, 0.85 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C in an ice bath, and catalytically added acetic acid (4 drops). Sodium triacetoxyborohydride (448.81 mg, 2.12 mmol) was added in portions, and the reaction was carried out at room temperature for approximately 2 hours. LC/MS showed that the reaction was complete.
  • Step E 13e (50 mg, 0.065 mmol) and Int-F (34.74 mg, 0.084 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (33.46 mg, 0.19 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid.
  • Example 14 was prepared by the following steps:
  • Step A 12e (30 mg, 0.039 mmol) and Int-1 (21.80 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (20.08 mg, 0.11 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a yellow solid 14 (10.6 mg, yield: 22.23%).
  • Example 15 was prepared by the following steps:
  • Step A 13e (50 mg, 0.65 mmol) and Int-1 (33.74 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (33.46 mg, 0.19 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a yellow solid 15 (10.5 mg, yield 14.13%).
  • Example 16 was prepared by the following steps:
  • Step A At room temperature, Int-2 (500 mg, 1.17 mmol) and 16a (260.34 mg, 1.41 mmol) were dissolved in dichloromethane (10 mL), and a catalytic amount of acetic acid (3 drops) was added. Under ice bath conditions, sodium triacetylborohydride (1.24 g, 5.86 mmol) was added in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 16b (550 mg, 0.99 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise to the system under ice bath conditions. The reaction was allowed to proceed at room temperature for 2 hours. LC/MS showed that the reaction was complete. Methyl tert-butyl ether was added to the system, and a large amount of solid precipitated. After filtration and drying, a white solid 16c (535 mg, yield 95%) was obtained. ESI-MS (m/z): 449.63 [M+H] + .
  • Step C 16c (610 mg, 1.06 mmol) and Int-3 (439.51 mg, 1.28 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, a catalytic amount of acetic acid (3 drops) was added to the reaction solution, followed by the addition of sodium triacetylborohydride (1.13 g, 5.32 mmol) in portions. The reaction was carried out at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D 16d (630 mg, 0.79 mmol) was dissolved in ethanol (8 mL) and water (1.6 mL). Iron powder (220.6 mg, 3.95 mmol) and ammonium chloride (211.28 mg, 3.95 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step E At room temperature, 16e (100 mg, 0.13 mmol), Int-4 (65.33 mg, 0.16 mmol), and p-toluenesulfonic acid (68.16 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and reacted at 100 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid.
  • Example 17 was prepared by the following steps:
  • Step A At room temperature, 16e (100 mg, 0.13 mmol) and 17a (65.33 mg, 0.16 mmol) were dissolved in dioxane (1.5 mL), followed by the addition of BrettPhos (14.16 mg, 0.026 mmol), BrettPhos Pd G3 (11.96 mg, 0.013 mmol), and cesium carbonate (128.97 mg, 0.39 mmol). The reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, washed with saturated brine, extracted with dichloromethane, and the organic phases were combined.
  • Example 18 was prepared by the following steps:
  • Step A At room temperature, 18a (1.64 g, 11.94 mmol) and potassium carbonate (4.95 g, 35.83 mmol) were added to 15 mL of dimethyl sulfoxide (DMSO) containing Int-3c (1.5 g, 5.97 mmol). The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • DMSO dimethyl sulfoxide
  • Step B At room temperature, 18b (1.0 g, 3.01 mmol) was dissolved in dichloromethane (15 mL). Under ice bath conditions, Desmartin oxidant (1.91 g, 4.51 mmol) was added to the reaction system. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. Saturated sodium bicarbonate solution was added to the system, followed by extraction with dichloromethane and washing with sodium thiosulfate solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 18c (760 mg, crude product). ESI-MS (m/z): 330.34 [M+H] + .
  • Step C At room temperature, 18c (420 mg, 1.51 mmol) and Int-2 (700 mg, 1.51 mmol) were dissolved in N,N-dimethylformamide (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (1.6 g, 7.55 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 18d (100 mg, 0.15 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL). Iron powder (42.78 mg, 0.77 mmol) and ammonium chloride (40.97 mg, 0.77 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step E At room temperature, 18e (50 mg, 0.074 mmol), Int-4 (36.69 mg, 0.089 mmol), and p-toluenesulfonic acid (38.28 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. After cooling the reaction solution to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added, and a yellow solid precipitated.
  • Example 19 was prepared by the following steps:
  • Step A At room temperature, 19b (1.38 g, 10.04 mmol) and potassium carbonate (4.16 g, 30.12 mmol) were added to 15 mL of dimethyl sulfoxide (1.0 g, 5.02 mmol) of 19a. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 19c (1.0 g, 3.57 mmol) was dissolved in tetrahydrofuran (15 mL). Desmartin oxidant (2.27 g, 5.36 mmol) was added to the reaction system, and the reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with sodium thiosulfate solution, and the two phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 19d (900 mg, crude product). No further purification was required. ESI-MS (m/z): 278.30 [M+H] + .
  • Step C At room temperature, 19d (700 mg, 1.51 mmol) and Int-2 (700 mg, 1.51 mmol) were dissolved in N,N-dimethylformamide (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (1.6 g, 7.55 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 19e (100 mg, 0.15 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL). Iron powder (42.78 mg, 0.77 mmol) and ammonium chloride (40.97 mg, 0.77 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step E At room temperature, 19f (50 mg, 0.08 mmol), Int-4 (49.69 mg, 0.12 mmol), and p-toluenesulfonic acid (41.48 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. After cooling the reaction solution to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added, and a yellow solid precipitated. After filtration, the crude product was obtained and purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain a white solid 19 (2.6 mg, yield 3.24%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% ammonia system
  • Example 20 was prepared by the following steps:
  • Step A At room temperature, 18e (100 mg, 0.15 mmol), Int-8 (78.19 mg, 0.18 mmol), and p-toluenesulfonic acid (76.56 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give a white solid 20 (6 mg, yield 3.72%).
  • Example 21 was prepared by the following steps:
  • Step A At room temperature, 21a (2.16 g, 7.96 mmol) and potassium carbonate (3.3 g, 23.88 mmol) were added to 15 mL of dimethyl sulfoxide (DMSO) containing Int-3c (1.0 g, 3.95 mmol). The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • DMSO dimethyl sulfoxide
  • Step B At room temperature, 21b (1.0 g, 2.33 mmol) was dissolved in tetrahydrofuran (15 mL). Desmartin oxidant (1.48 g, 3.49 mmol) was added to the reaction system, and the reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with sodium thiosulfate solution, and the two phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 21c (737 mg, crude product). No further purification was required. ESI-MS (m/z): 427.5 [M+H] + .
  • Step C At room temperature, 21c (700 mg, 1.63 mmol) and Int-2 (958.88 mg, 2.45 mmol) were dissolved in N,N-dimethylformamide (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (1.04 g, 4.89 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 21d (1.0 g, 1.25 mmol) was dissolved in ethanol (10 mL) and water (2 mL). Iron powder (349.01 mg, 6.25 mmol) and ammonium chloride (334.31 mg, 6.25 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step E At room temperature, 21e (50 mg, 0.065 mmol), Int-4 (32.07 mg, 0.078 mmol), and p-toluenesulfonic acid (33.46 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. After cooling the reaction solution to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added, and a yellow solid precipitated. After filtration, the crude product was obtained and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give a white solid 20 (6.1 mg, yield 8.2%).
  • Example 22 was prepared by the following steps:
  • Step A At room temperature, 22b (1.99 g, 10.04 mmol) and potassium carbonate (4.16 g, 30.12 mmol) were added to 15 mL of dimethyl sulfoxide (DMSO) containing 22a (1.0 g, 5.02 mmol). The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. Saturated brine was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • DMSO dimethyl sulfoxide
  • Step B At room temperature, 22c (1.0 g, 2.65 mmol) was dissolved in tetrahydrofuran (15 mL). Desmartin oxidant (1.68 g, 3.97 mmol) was added to the reaction system, and the reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with sodium thiosulfate solution, and the two phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 22d (850 mg, crude product). No further purification was required. ESI-MS (m/z): 375.46 [M+H] + .
  • Step C At room temperature, 22d (850 mg, 2.27 mmol) and Int-2 (700 mg, 1.51 mmol) were dissolved in N,N-dimethylformamide (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (1.6 g, 7.55 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 22e (500 mg, 0.67 mmol) was dissolved in ethanol (10 mL) and water (2 mL). Iron powder (187.1 mg, 3.35 mmol) and ammonium chloride (179.19 mg, 3.35 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step E At room temperature, 22f (50 mg, 0.069 mmol), Int-4 (34.39 mg, 0.083 mmol), and p-toluenesulfonic acid (35.88 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give a white solid 22 (13.8 mg, yield 18.13%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% ammonia system
  • Example 23 was prepared by the following steps:
  • Step A At room temperature, 21e (100 mg, 0.13 mmol), Int-8 (68.35 mg, 0.15 mmol), and p-toluenesulfonic acid (66.92 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain yellow solid 23 (5.2 mg, yield 3.38%).
  • Example 24 was prepared by the following steps:
  • Step A At room temperature, 21e (50 mg, 0.065 mmol), Int-9 (34.25 mg, 0.078 mmol), and p-toluenesulfonic acid (33.46 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide solution (1.5 mL). The reaction was carried out at 100 °C for 16 h. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, and a yellow solid precipitated. After filtration, the crude product was obtained and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain yellow solid 24 (1.3 mg, yield 1.69%).
  • Example 25 was prepared by the following steps:
  • Step A At room temperature, 22f (100 mg, 0.14 mmol), Int-8 (73.29 mg, 0.17 mmol), and p-toluenesulfonic acid (71.76 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain a yellow solid 25 (6.0 mg, yield 3.81%).
  • Example 26 was prepared by the following steps:
  • Step A At room temperature, 22f (50 mg, 0.069 mmol), Int-9 (36.73 mg, 0.083 mmol), and p-toluenesulfonic acid (35.88 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain a yellow solid 26 (1.9 mg, yield 2.41%).
  • Example 27 was prepared by the following steps:
  • Step A At room temperature, 3b (100 mg, 0.15 mmol), 27a (56.22 mg, 0.18 mmol), and p-toluenesulfonic acid (76.55 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain a yellow solid 27 (50 mg, yield 34.64%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% ammonia system
  • Example 28 was prepared by the following steps:
  • Step A At room temperature, 3b (70 mg, 0.10 mmol), Int-4 (51.36 mg, 0.12 mmol), and p-toluenesulfonic acid (53.58 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at 100 °C for 16 hours, and LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and a saturated sodium bicarbonate aqueous solution was added. A solid precipitated out. After filtration, the crude product was obtained and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 28 (8.0 mg, yield 7.19%).
  • Example 29 was prepared by the following steps:
  • Step A At room temperature, Int-10 (210 mg, 0.59 mmol, C) and Int-3 (202.35 mg, 0.59 mmol) were dissolved in dichloromethane (5 mL). The mixture was cooled to 0 °C in an ice bath, and 3 drops of acetic acid were added dropwise. Sodium triacetoxyborohydride (186.81 mg, 0.88 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction was quenched by adding water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid 29a (310 mg, crude product). ESI-MS (m/z): 686.4 [M+H] + .
  • Step B At room temperature, 29a (200 mg, 0.29 mmol), iron powder (48.87 mg, 0.87 mmol), and ammonium chloride (46.80 mg, 0.87 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 30 was prepared by the following steps:
  • Step A At room temperature, 30b (3.47 g, 30.12 mmol) and potassium carbonate (20.45 g, 62.76 mmol) were added to 75 mL of dimethyl sulfoxide (DMSO) containing 5.0 g (25.10 mmol) of 30a. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction mixture was washed with saturated brine, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • DMSO dimethyl sulfoxide
  • Step D Under nitrogen protection, oxalyl chloride (1.17 g, 13.9 mmol) was dissolved in anhydrous dichloromethane (10 mL), and the mixture was cooled to -78 °C. Dimethyl sulfoxide (1.09 g, 13.92 mmol) was slowly added dropwise to the reaction solution, and the mixture was stirred for 1 hour. Then, 30e (1 g, 1.39 mmol) of dichloromethane (10 mL) solution was added dropwise, and the reaction was continued at -78 °C for 2 hours. Triethylamine (2.82 g, 27.83 mmol) was added, and the reaction was carried out at room temperature for 30 minutes. LC/MS showed that the reaction was complete.
  • Step E Compounds Int-5 (20 mg, 0.05 mmol) and 30f (57.82 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (1 mL). Under ice bath conditions, two drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (22.58 mg, 0.1 mmol) in portions. The reaction was carried out at room temperature for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered, and the filter cake was washed with water and dried under vacuum.
  • Example 31 was prepared by the following steps:
  • Step A At room temperature, Int-12 (300 mg, 0.65 mmol, C) and Int-3 (397.67 mg, 1.15 mmol) were dissolved in dichloromethane (10 mL). The mixture was cooled to 0 °C in an ice bath, and 3 drops of acetic acid were added dropwise. Sodium triacetoxyborohydride (407.91 mg, 1.92 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step B At room temperature, 31a (500 mg, 0.64 mmol), iron powder (212.91 mg, 3.81 mmol), and ammonium chloride (203.93 mg, 3.81 mmol) were dissolved in ethanol (10.00 mL) and water (2.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 32 was prepared by the following steps:
  • Example 33 was prepared by the following steps:
  • Step A Dissolve 33a (2.0 g, 7.46 mmol) and Int-11 (2.26 g, 7.46 mmol) in dimethyl sulfoxide (3 mL) under nitrogen protection. Add t-BuXPhos-Pd-G3 (592.58 mg, 0.75 mmol), t-BuXPhos (316.77 mg, 0.75 mmol), and cesium carbonate (7.29 g, 22.38 mmol) to the reaction solution. React at 110 °C for 4 hours. LC/MS showed that the reaction was complete. Cool the reaction solution to room temperature, add saturated ammonium chloride aqueous solution, extract with dichloromethane, and combine the organic phases.
  • Step B Dissolve 33b (2.8 g, 5.76 mmol) in dichloromethane (20 mL). Under ice bath conditions, add HCl (4.0 M, 1,4-dioxane) (10 mL) dropwise to the reaction solution. React at room temperature for 4 hours. A white product precipitates, and LC/MS shows that the reaction is complete. Filter and vacuum dry to give a pale white solid 33c (2 g, yield 80.10%). No further purification is required. ESI-MS (m/z): 390.17 [M+H] + .
  • Step C Compounds Int-3 (678.66 mg, 1.74 mmol) and 33c (500 mg, 1.45 mmol) were dissolved in N,N-dimethylformamide (10 mL). Under ice bath conditions, two drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (615 mg, 2.90 mmol) in portions. The reaction was carried out at room temperature for 2 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated out. The product was filtered and dried under vacuum to give a yellow solid 33d (700 mg, yield 67.16%). ESI-MS (m/z): 718.33 [M+H] + .
  • Step D At room temperature, 33d (700 mg, 0.98 mmol), iron powder (272.3 mg, 4.88 mmol), and ammonium chloride (260.8 mg, 4.88 mmol) were dissolved in ethanol (10.00 mL) and water (2.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 34 was prepared by the following steps:
  • Step A At room temperature, 33e (50 mg, 0.073 mmol) and Int-9 (32.03 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (37.54 mg, 0.22 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 35 was prepared by the following steps:
  • Step A At room temperature, 30c (1.0 g, 3.40 mmol) was dissolved in tetrahydrofuran (15 mL). Under ice bath conditions, Desmartin oxidant (2.16 g, 5.10 mmol) was added to the reaction system. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 35a (980 mg, crude product), requiring no further purification. ESI-MS (m/z): 292.33 [M+H] + .
  • Step B Compound 35a (400 mg, 1.37 mmol) and Int-5 (564.97 mg, 1.37 mmol) were dissolved in N,N-dimethylformamide (10 mL). Under ice bath conditions, three drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (1.45 g, 6.84 mmol) in portions. The reaction was carried out at room temperature for 2 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated out. The product was filtered and dried under vacuum to give a yellow solid 35b (300 mg, yield 33.59%). ESI-MS (m/z): 652.76 [M+H] + .
  • Step C At room temperature, 35b (300 mg, 0.46 mmol), iron powder (128.34 mg, 2.30 mmol), and ammonium chloride (122.92 mg, 2.30 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Step D At room temperature, 35c (100 mg, 0.16 mmol) and 35d (60.91 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (82.95 mg, 0.48 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 36 was prepared by the following steps:
  • Step A Compound 30f (50 mg, 0.078 mmol) and Int-13 (52 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 mL). Under ice bath conditions, two drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol) in portions. The reaction was carried out at room temperature for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered, the filter cake was washed with water, and then dried under vacuum.
  • Example 37 was prepared by the following steps:
  • Step A Compound 30f (52.7 mg, 0.082 mmol) and Int-13 (20 mg, 0.048 mmol) were dissolved in N,N-dimethylformamide (1 mL). Under ice bath conditions, two drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol) in portions. The reaction was carried out at room temperature for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered, and the filter cake was washed with water and dried under vacuum.
  • Example 38 was prepared by the following steps:
  • Step A At room temperature, 33e (50 mg, 0.073 mmol) and Int-7 (32.25 mg, 0.073 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (37.54 mg, 0.22 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 39 was prepared by the following steps:
  • Example 40 was prepared by the following steps:
  • Example 41 was prepared by the following steps:
  • Step B At room temperature, 41a (52 mg, 0.067 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (18.79 mg, 0.34 mmol) and ammonium chloride (17.99 mg, 0.34 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step C 41b (30 mg, 0.040 mmol) and Int-7 (23.29 mg, 0.052 mmol) were dissolved in N,N-dimethylformamide (0.7 mL), and p-toluenesulfonic acid (13.91 mg, 0.081 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid.
  • Example 42 was prepared by the following steps:
  • Step A 29b (100 mg, 0.152 mmol), Int-4 (62.92 mg, 0.152 mmol), and p-toluenesulfonic acid (78.78 mg, 0.457 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 90 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a pale yellow solid 42 (51 mg, yield 30.79%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 43 was prepared by the following steps:
  • Example 44 was prepared by the following steps:
  • Step A Dissolve 1b (60 mg, 0.087 mmol) and Int-4 (46.72 mg, 0.11 mmol) in N,N-dimethylformamide (1.2 mL), add p-toluenesulfonic acid (45.00 mg, 0.26 mmol), and react at 100 °C for 16 hours. LC/MS showed the reaction was complete. Cool to room temperature, pour the reaction solution into sodium bicarbonate solution, the product precipitated, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give pale yellow solid 2 (41.0 mg, yield 43.76%).
  • Example 45 was prepared by the following steps:
  • Step A Int-3c (1.13 g, 4.51 mmol) was dissolved in dimethyl sulfoxide (60 mL), and 45a (600 mg, 4.51 mmol) and sodium bicarbonate (1.89 g, 22.53 mmol) were added. The mixture was stirred overnight at 120 °C, and the reaction was complete as shown by LC/MS. After cooling to room temperature, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 45b (300 mg, 0.82 mmol) was dissolved in DCM (15 mL). Under ice bath conditions, Desmond-Martin oxidant (523.8 mg, 1.24 mmol) was added to the reaction solution. The reaction was allowed to proceed for approximately 2 hours at room temperature, and LC-MS showed complete reaction. Sodium carbonate solution was added to the reaction solution, and the organic layer was washed twice with sodium thiosulfate solution. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain crude product 45c (310 mg, crude product), which was used directly in the next step. ESI-MS (m/z): 363.2 [M+H] + .
  • Step C At room temperature, 45c (100 mg, 0.27 mmol) and Int-3 (107.74 mg, 0.27 mmol) were dissolved in dichloromethane (5 mL), and catalytic amount of acetic acid (3 drops) was added. The reaction was carried out at room temperature for 1 hour. The mixture was cooled to 0 °C in an ice bath, and sodium triacetoxyborohydride (116.98 mg, 0.55 mmol) was added in portions. The reaction was carried out at room temperature for approximately 2 hours. LC/MS showed that the reaction was complete.
  • Step E 45e (53 mg, 0.075 mmol) and Int-4 (43.32 mg, 0.105 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (38.74 mg, 0.22 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid.
  • Example 46 was prepared by the following steps:
  • Example 47 was prepared by the following steps:
  • Example 48 was prepared by the following steps:
  • Step A Compounds Int-12 (226 mg, 0.49 mmol) and 35a (292 mg, 0.68 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, three drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (322 mg, 1.52 mmol) in portions. The reaction was carried out at room temperature for 2 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • Step B At room temperature, 48a (170 mg, 0.23 mmol), iron powder (64.59 mg, 1.16 mmol), and ammonium chloride (61.87 mg, 1.16 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Step C At room temperature, 48b (65 mg, 0.092 mmol) and Int-4 (53.27 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (47.64 mg, 0.27 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 49 was prepared by the following steps:
  • Step A At room temperature, 48b (65 mg, 0.092 mmol) and 49a (40.81 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (47.64 mg, 0.27 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 50 was prepared by the following steps:
  • Step A Compounds Int-14 (200 mg, 0.51 mmol) and 35a (195 mg, 0.67 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, three drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (217 mg, 1.03 mmol) in portions. The reaction was carried out at room temperature for 2 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • Step B At room temperature, 50a (100 mg, 0.15 mmol), iron powder (41.94 mg, 0.75 mmol), and ammonium chloride (40.17 mg, 0.75 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Step C At room temperature, 50b (50 mg, 0.078 mmol) and Int-4 (45.42 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (40.62 mg, 0.27 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 51 was prepared by the following steps:
  • Step A Compounds Int-15 (200 mg, 0.47 mmol) and 35a (178 mg, 0.61 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, three drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (199 mg, 0.94 mmol) in portions. The reaction was carried out at room temperature for 2 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • Step B At room temperature, 51a (120 mg, 0.17 mmol), iron powder (47.74 mg, 0.85 mmol), and ammonium chloride (45.73 mg, 0.85 mmol) were dissolved in ethanol (5.00 mL) and water (1.0 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Step C At room temperature, 51b (60 mg, 0.089 mmol) and Int-4 (51.59 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (46.14 mg, 0.27 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 52 was prepared by the following steps:
  • Step A Int-18 (300 mg, 0.84 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-pyrazole (209 mg, 1.01 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL).
  • Step B 52a (220 mg, 0.56 mmol) and triethylamine (165 mg, 1.64 mmol) were dissolved in dichloromethane (4 mL). Methanesulfonic anhydride (114 mg, 0.65 mmol) was added in portions to the solution at 0 °C. The reaction was carried out under nitrogen atmosphere at 25 °C with stirring for 1 hour. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain 52b (230 mg, crude product), which was used directly in the next step. ESI-MS (m/z): 482.3 [M+H] + .
  • Step C Int-14 (180 mg, 0.46 mmol) and 52b (223 mg, 0.46 mmol) were dissolved in acetonitrile (5 mL). Triethylamine (467.62 mg, 4.62 mmol) and potassium iodide (77 mg, 0.46 mmol) were added to the solution at 25 °C, and the reaction was stirred at 80 °C for 16 hours under a nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction system was cooled to room temperature, and water was added to the reaction solution. Extraction was performed with ethyl acetate. The combined organic phases were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered.
  • Step D 52c (100 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL) and methanol (0.5 mL), and p-toluenesulfonic acid (111 mg, 0.65 mmol) was added at 0 °C. The reaction was stirred at 25 °C for 4 hours. LC-MS showed that the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure to obtain 52d (100 mg, crude product), which was used directly in the next step. ESI-MS (m/z): 675.7 [M+H] + .
  • Step E Dissolve 52d (100 mg, 0.15 mmol) and 17a (52 mg, 0.16 mmol) in 1,4-dioxane (3 mL).
  • cesium carbonate 145 mg, 0.45 mmol
  • 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (16 mg, 0.03 mmol)
  • methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.015 mmol).
  • Example 53 was prepared by the following steps:
  • Example 54 was prepared by the following steps:
  • Step C Dissolve 54c (50 mg, 0.14 mmol) in dichloromethane (2 mL), and add Dysmart oxidant (91 mg, 0.21 mmol) under ice bath conditions. The reaction was carried out at 25 °C for 2 hours, and LC-MS showed that the reaction was complete. Add an aqueous sodium thiosulfate solution to the reaction mixture, extract with dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated brine, combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate the crude product 54d (50.0 mg, crude product), which was directly used in the next step of the reaction.
  • Step D At room temperature, 54d (50 mg, 0.14 mmol) and Int-17 (55 mg, 0.16 mmol) were dissolved in dichloromethane (63 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (61 mg, 0.29 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step E At room temperature, 54e (30 mg, 0.044 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (12 mg, 0.22 mmol) and ammonium chloride (12 mg, 0.22 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 54f (28 mg, crude product). ESI-MS (m/z): 651.4 [M+H] + .
  • Step F At room temperature, 54f (28 mg, 0.043 mmol), Int-4 (18 mg, 0.043 mmol), and p-toluenesulfonic acid (15 mg, 0.086 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 54 (8.5 mg, yield 13.31%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 55 was prepared by the following steps:
  • Step A Int-16 (500 mg, 1.40 mmol) and Int-3 (482 mg, 1.40 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, a catalytic amount of acetic acid (3 drops) was added to the reaction solution, followed by the addition of sodium triacetylborohydride (594 mg, 2.80 mmol) in portions. The reaction was carried out at room temperature for 2 hours. After LC/MS showed that the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step C At room temperature, 55b (80 mg, 0.12 mmol), Int-1 (49 mg, 0.12 mmol), and p-toluenesulfonic acid (63 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and reacted at 100 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 55 (31.0 mg, yield 25%).
  • Example 56 was prepared by the following steps:
  • Step A At room temperature, 55b (80 mg, 0.12 mmol), 17a (39 mg, 0.12 mmol), and p-toluenesulfonic acid (63 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and reacted at 100 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 56 (68.0 mg, yield 58.98%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 57 was prepared by the following steps:
  • Step A At room temperature, 55b (100 mg, 0.15 mmol), Int-4 (63 mg, 0.15 mmol), and p-toluenesulfonic acid (79 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and reacted at 100 °C for 16 hours. LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to the reaction solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 57 (57.0 mg, yield 35.85%).
  • Example 58 was prepared by the following steps:
  • Step A At room temperature, 22b (440.7 mg, 1.17 mmol) and Int-14 (500 mg, 1.17 mmol) were dissolved in dichloromethane (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (1.24 g, 5.87 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 58a (330 mg, 0.44 mmol) was dissolved in ethanol (5 mL) and water (1 mL). Iron powder (123 mg, 2.20 mmol) and ammonium chloride (118 mg, 2.20 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the resulting solution was concentrated under reduced pressure to obtain the crude product.
  • Step C At room temperature, 58b (100 mg, 0.14 mmol), Int-4 (69 mg, 0.17 mmol), and p-toluenesulfonic acid (72 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 58 (23.4 mg, yield 15.36%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 59 was prepared by the following steps:
  • Step A Compounds Int-3 (372 mg, 1.08 mmol) and Int-14 (500 mg, 1.08 mmol) were dissolved in dichloromethane (10 mL). Under ice bath conditions, two drops of glacial acetic acid were added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (1.15 g, 5.41 mmol) in portions. The reaction was allowed to proceed at room temperature for 2 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered and dried under vacuum to give a yellow solid 59a (137 mg, yield 16.79%). ESI-MS (m/z): 754.4 [M+H] + .
  • Step B At room temperature, 59a (137 mg, 0.18 mmol), iron powder (51 mg, 0.91 mmol), and ammonium chloride (49 mg, 0.91 mmol) were dissolved in ethanol (2.5 mL) and water (0.5 mL), and reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 60 was prepared by the following steps:
  • Example 61 was prepared by the following steps:
  • Step A At room temperature, 22b (191 mg, 0.51 mmol) and Int-10 (200 mg, 0.51 mmol) were dissolved in dichloromethane (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (538 mg, 2.54 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 61a (80 mg, 0.11 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (31 mg, 0.56 mmol) and ammonium chloride (30 mg, 0.56 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 61b (75 mg, crude product). ESI-MS (m/z): 687.5 [M+H] + .
  • Step E At room temperature, 61b (75 mg, 0.11 mmol), Int-4 (54 mg, 0.13 mmol), and p-toluenesulfonic acid (56 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 61 (22.3 mg, yield 19.02%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 62 was prepared by the following steps:
  • Step A At room temperature, 22b (203 mg, 0.54 mmol) and Int-13 (200 mg, 0.45 mmol) were dissolved in dichloromethane (10 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (477 mg, 2.25 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 62a (80 mg, 0.11 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (31 mg, 0.56 mmol) and ammonium chloride (30 mg, 0.56 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 62b (75 mg, crude product). ESI-MS (m/z): 387.9 [M+2H] 2+ /2.
  • Step E At room temperature, 62b (50 mg, 0.065 mmol), Int-4 (32 mg, 0.077 mmol), and p-toluenesulfonic acid (33 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 62 (3.9 mg, yield 5.25%).
  • Example 63 was prepared by the following steps:
  • Step A At room temperature, 41b (50 mg, 0.067 mmol), Int-4 (33 mg, 0.081 mmol), and p-toluenesulfonic acid (35 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 63 (11.3 mg, yield 14.85%).
  • Example 64 was prepared by the following steps:
  • Step A At room temperature, 41b (50 mg, 0.067 mmol), Int-1 (32 mg, 0.081 mmol), and p-toluenesulfonic acid (35 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 64 (6.5 mg, yield 8.64%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 65 was prepared by the following steps:
  • Example 66 was prepared by the following steps:
  • Step A At room temperature, 22b (159 mg, 0.42 mmol) and Int-15 (150 mg, 0.35 mmol) were dissolved in dichloromethane (6 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (149 mg, 0.71 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 66a (45 mg, 0.057 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (16 mg, 0.29 mmol) and ammonium chloride (15 mg, 0.29 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 66b (40 mg, crude product). ESI-MS (m/z): 378.7 [M-100+H] + /2.
  • Step C At room temperature, 66b (40 mg, 0.053 mmol), Int-4 (26 mg, 0.064 mmol), and p-toluenesulfonic acid (27 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 66 (3.3 mg, yield 5.45%).
  • Example 67 was prepared by the following steps:
  • Step B Dissolve 67b (200 mg, 0.36 mmol) in dichloromethane (5 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1 mL) and react at room temperature for 2 hours. A white solid is produced. LC/MS shows the reaction is complete. Concentrate the reaction solution to give crude product 67c (170 mg, crude product), which requires no further purification. ESI-MS (m/z): 460.19 [M+H] + .
  • Step C At room temperature, 67d (170 mg, 0.34 mmol) and Int-3 (191 mg, 0.55 mmol) were dissolved in dichloromethane (6 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (157 mg, 0.74 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 67d (32 mg, 0.04 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (12 mg, 0.2 mmol) and ammonium chloride (11 mg, 0.2 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 67e (30 mg, crude product). ESI-MS (m/z): 758.37 [M+H] + .
  • Step E At room temperature, 67e (30 mg, 0.039 mmol), 67f (15 mg, 0.05 mmol), and p-toluenesulfonic acid (14 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 67 (13.0 mg, yield 31.34%).
  • Example 68 was prepared by the following steps:
  • Step B Dissolve 68b (200 mg, 0.36 mmol) in dichloromethane (5 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1 mL) and react at room temperature for 2 hours. A white solid is produced. LC/MS shows the reaction is complete. Concentrate the reaction solution to give crude product 68c (172 mg, crude product), which requires no further purification. ESI-MS (m/z): 460.2 [M+H] + .
  • Step C At room temperature, 68d (172 mg, 0.34 mmol) and Int-3 (191 mg, 0.55 mmol) were dissolved in dichloromethane (6 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (157 mg, 0.74 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 68d (100 mg, 0.13 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL). Iron powder (36 mg, 0.63 mmol) and ammonium chloride (34 mg, 0.63 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 68e (80 mg, crude product). ESI-MS (m/z): 758.4 [M+H] + .
  • Step E At room temperature, 68e (80 mg, 0.10 mmol), 68f (40 mg, 0.12 mmol), and p-toluenesulfonic acid (36 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a yellow solid 68 (25.0 mg, yield 22.6%).
  • Example 69 was prepared by the following steps:
  • Step B Dissolve 69a (100 mg, 0.26 mmol) in dichloromethane (2 mL), and add Dysmart oxidant (164 mg, 0.39 mmol) under ice bath conditions. The reaction was carried out at 25 °C for 2 hours, and LC-MS showed that the reaction was complete. Add an aqueous sodium thiosulfate solution to the reaction mixture, extract with dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated brine, combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude 69b (84.5 mg, crude product), which was directly used in the next step of the reaction.
  • Step C At room temperature, 69b (50 mg, 0.13 mmol) and Int-17 (50 mg, 0.14 mmol) were dissolved in dichloromethane (6 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (61 mg, 0.29 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 69c (40 mg, 0.056 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (12 mg, 0.22 mmol) and ammonium chloride (12 mg, 0.22 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 69d (30 mg, crude product). ESI-MS (m/z): 687.4 [M+H] + .
  • Step E At room temperature, 69d (30 mg, 0.044 mmol), Int-4 (27 mg, 0.065 mmol), and p-toluenesulfonic acid (15 mg, 0.087 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 69 (10.0 mg, yield 21.32%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 70 3-(4-((4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphospho)phenyl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-1-hydroxytetrahydro-2H- 1 ⁇ 6 -thiaran-1-ylidene)amino)-2,6-difluorophenyl)piperidin-2,6-dione
  • Example 70 was prepared by the following steps:
  • Step A At room temperature, Int-17 (300 mg, 0.78 mmol) and 70a (136 mg, 1.17 mmol) were dissolved in dichloromethane (5 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (330 mg, 1.56 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC-MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 70d (150 mg, 0.21 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL). Iron powder (60 mg, 1.07 mmol) and ammonium chloride (57 mg, 1.07 mmol) were added to the reaction solution, and the mixture was reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 70e (120 mg, crude product). ESI-MS (m/z): 673.3 [M+H] + .
  • Step F At room temperature, 70e (40 mg, 0.059 mmol), Int-17a (28 mg, 0.089 mmol), and p-toluenesulfonic acid (20 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 70 (25 mg, yield 43.71%).
  • Example 71 was prepared by the following steps:
  • Step A At room temperature, 70e (40.0 mg, 0.059 mmol), Int-4 (37 mg, 0.089 mmol), and p-toluenesulfonic acid (20 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 71 (25 mg, yield 37.28%).
  • Example 72 was prepared by the following steps:
  • Step A At room temperature, 70e (40.0 mg, 0.059 mmol), Int-7 (40 mg, 0.089 mmol), and p-toluenesulfonic acid (20 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 72 (25 mg, yield 34.26%).
  • Example 73 was prepared by the following steps:
  • Step A At -65°C, lithium diisopropylamino (2.0 M tetrahydrofuran solution) (11.93 mL) was added dropwise to a solution of 73a (5 g, 21.69 mmol) in tetrahydrofuran (60 mL). The reaction solution was stirred at this temperature for 1 hour, and then ethyl 3-bromopropionate (4.71 g, 26.03 mmol) in tetrahydrofuran (15 mL) was added dropwise over 10 min. The resulting solution was stirred at -65°C for 30 min and allowed to rise naturally to room temperature. LCMS showed that the reaction was complete.
  • Step B Lithium hydroxide (1.02 g, 42.65 mmol) was added to a solution of 73b (4.7 g, 14.22 mmol) in tetrahydrofuran (60 mL) and water (20 mL), and the mixture was stirred at room temperature for 16 hours.
  • LCMS showed that the reaction was complete.
  • the reaction solution was diluted with water, extracted twice with EA, the pH of the aqueous phase was adjusted to 4-5 with 1N HCl, and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, filtered, and concentrated to give 73c (4.1 g, yield 95.32%), a colorless oily liquid.
  • Step C Dissolve 73c (4 g, 13.22 mmol) in toluene (50 mL), then add concentrated sulfuric acid (98% (AR)) (1.30 g, 13.22 mmol, 0.7 mL), and stir at 100 °C for 3 hours.
  • LC-MS showed the reaction was complete.
  • the reaction solution was concentrated, and the crude product was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was concentrated to give crude product 73d (2.3 g, yield 57.50%).
  • Step D 73d (1.2 g, 3.97 mmol), Int-2c (929.36 mg, 3.97 mmol), cesium carbonate (2.58 g, 7.93 mmol), t-BuXphos (168.17 mg, 0.39 mmol), and t-BuXPhos-Pd-G3 (94.48 mg, 0.11 mmol) were dissolved in a mixed solvent of dioxane (6 mL) and N,N-dimethylformamide (6 mL). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen atmosphere. LC-MS monitoring showed product formation.
  • Step E Dissolve 73e (1.2 g, 2.63 mmol) in dichloromethane (20 mL), then add HCl (4.0 M 1,4-dioxane solution, 10 mL) at 0 °C. React at room temperature for 4 hours; a white product precipitates, and LC/MS shows the reaction is complete. Filter and vacuum dry to obtain a pale yellow solid 73f (0.7 g, crude product). No further purification is required. ESI-MS (m/z): 356.8 [M+H] + .
  • Step F At room temperature, 73f (0.5 g, 1.41 mmol, C) and Int-3 (483.88 mg, 1.41 mmol) were dissolved in dichloromethane (8 mL), cooled to 0 °C in an ice bath, 3 drops of acetic acid were added dropwise, and sodium triacetoxyborohydride (595.61 mg, 2.81 mmol) was added in portions. The reaction was carried out at room temperature for 2 hours. LC/MS showed that the reaction was complete. The reaction was quenched by water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step H 73h (100 mg, 0.15 mmol) and Int-7 (67.81 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and p-toluenesulfonic acid (78.96 mg, 0.46 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was poured into sodium bicarbonate solution, and the product precipitated. After filtration and drying, the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a pale yellow solid 73 (7.0 mg, yield 4.19%).
  • Example 74 was prepared by the following steps:
  • Step A At room temperature, 73h (100 mg, 0.15 mmol), 17a (48.32 mg, 0.15 mmol), and p-toluenesulfonic acid (78.96 mg, 0.46 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. After cooling the reaction solution to room temperature, 10 mL of saturated sodium bicarbonate aqueous solution was added, and a yellow solid precipitated. After filtration, the crude product was obtained and purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to obtain yellow solid 74 (19 mg, yield 12.91%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% ammonia system
  • Example 75 3- ⁇ 4-[(4- ⁇ [1-(4- ⁇ [5-chloro-4-( ⁇ 2-[dimethyl(oxylidene)- ⁇ 5 - methphospho]phenyl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]methyl ⁇ -1-oxylidene- 1 ⁇ 6-1,4 -thiazacyclohexane-1-yl)amino]-2,6-difluorophenyl ⁇ hexahydropyridin-2,6-dione
  • Example 75 was prepared by the following steps:
  • Step A At room temperature, 35a (245.40 mg, 0.84 mmol) and Int-10 (200 mg, 0.56 mmol) were dissolved in dichloromethane (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added, followed by the addition of sodium triacetylborohydride (237.22 mg, 1.12 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC-MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 75a (100 mg, 0.16 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL). Iron powder (44.06 mg, 0.79 mmol) and ammonium chloride (42.21 mg, 0.79 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 75b (120 mg, crude product). ESI-MS (m/z): 604.2 [M+H] + .
  • Step C At room temperature, 75b (40 mg, 0.066 mmol), 17a (31.42 mg, 0.099 mmol), and p-toluenesulfonic acid (22.82 mg, 0.13 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 75 (19.3 mg, yield 31.33%).
  • Example 76 was prepared by the following steps:
  • Step A At room temperature, 76a (3.0 g, 12.86 mmol) was dissolved in dichloromethane (30 mL). Desmartin oxidant (8.18 g, 19.29 mmol) was added to the reaction system, and the reaction was allowed to proceed for 4 hours at room temperature. LC-MS indicated completion. The reaction was then quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was washed with sodium thiosulfate solution, and the two phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily product, 76b (2.8 g, crude product), which required no further purification.
  • Step B At room temperature, 76b (300 mg, 0.65 mmol) was dissolved in dichloromethane (5 mL). Under ice bath conditions, N,N-diisopropylethylamine (84.56 mg, 0.65 mmol, 0.11 mL) was added. After 5 minutes, a catalytic equivalent of glacial acetic acid (39.29 mg, 0.70 mmol) was added dropwise. 76b (302.61 mg, 1.31 mmol) was then added to the reaction solution. The reaction was allowed to proceed for approximately 1 hour. The temperature was then lowered to 0°C, and sodium triacetylborohydride (416.00 mg, 1.96 mmol) was added in portions.
  • Step C At room temperature, 76d (250 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 °C in an ice bath, and then hydrochloric acid/dioxane solution (4.0 M, 2 mL) was added. The reaction was carried out at room temperature for approximately 2 hours. The product was visualized by LCMS. Directly evaporated to dryness under reduced pressure to give a pale yellow solid 76d (200 mg, crude product). No further purification was required. ESI-MS (m/z): 574.4 [M+H] + .
  • Step E At room temperature, 76e (50 mg, 0.066 mmol), iron powder (18.54 mg, 0.33 mmol), and ammonium chloride (17.76 mg, 0.33 mmol) were dissolved in ethanol (2.0 mL) and water (0.4 mL), and reacted at 80 °C for 1 hour. LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 77 was prepared by the following steps:
  • Step A Compound 19c (343.39 mg, 1.23 mmol) and Int-15 (350 mg, 0.82 mmol) were dissolved in N,N-dimethylformamide (2 mL), and two drops of glacial acetic acid were added. The mixture was cooled to 0 °C, and sodium triacetoxyborohydride (871.69 mg, 4.11 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 4 hours, and LC/MS showed that the reaction was complete. The reaction solution was poured into water, and a yellow product precipitated. The product was filtered, the filter cake was washed with water, and then dried under vacuum to give a yellow solid 77a (87 mg, yield 15.38%). ESI-MS (m/z): 687.8 [M+H] + .
  • Step C 77b (20 mg, 0.030 mmol), Int-4 (15.05 mg, 0.036 mmol), and p-toluenesulfonic acid (15.71 mg, 0.090 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was carried out at 100 °C for 16 hours, and LC-MS showed complete reaction. After cooling to room temperature, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a yellow solid 77 (2.8 mg, yield 8.82%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 78 3-[4-( ⁇ 9-[1-(4- ⁇ [5-chloro-4-( ⁇ 2-[dimethyl(oxylidene) - ⁇ 5 -methphospho]phenyl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]-3-oxylidene- 3 ⁇ 6-9 -aza-3-thiaspiro[5.5]undecane-3-yl ⁇ amino)-2,6-difluorophenyl]hexahydropyridin-2,6-dione
  • Example 78 was prepared by the following steps:
  • Step A 77b (20 mg, 0.030 mmol), 17a (11.53 mg, 0.036 mmol), and p-toluenesulfonic acid (15.71 mg, 0.090 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was carried out at 100 °C for 16 hours, and LC-MS showed complete reaction. After cooling to room temperature, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution, producing a large amount of solid. The residue obtained after filtration was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give yellow solid 78 (2.7 mg, yield 9.38%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 79 was prepared by the following steps:
  • Step A At room temperature, 68c (200 mg, 0.41 mmol) and 35a (176.8 mg, 0.60 mmol) were dissolved in dichloromethane (6 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (427.28 mg, 2.02 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 79a (80 mg, 0.18 mmol) was dissolved in ethanol (1.5 mL) and water (0.3 mL). Iron powder (30.36 mg, 0.54 mmol) and ammonium chloride (29.07 mg, 0.54 mmol) were added to the reaction solution, and the mixture was reacted at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 79b (75 mg, crude product). ESI-MS (m/z): 706.91 [M+H] + .
  • Step C At room temperature, 79b (75 mg, 0.11 mmol), Int-4 (52.61 mg, 0.13 mmol), and p-toluenesulfonic acid (54.89 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 79 (1.8 mg, yield 1.55%).
  • Example 80 3- ⁇ 4-[(9- ⁇ [1-(4- ⁇ [5-bromo-4-( ⁇ 5-[dimethyl(oxylidene)- ⁇ 5 - methphospho]quinoxalin-6-yl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]methyl ⁇ -3-oxylidene-3 ⁇ 6-9-aza- 3 -thiaspiro[5.5]undecane-3-yl)amino]-3-methyl-2-oxylidene[d]imidazol-1-yl ⁇ hexahydropyridin-2,6-dione
  • Example 80 was prepared by the following steps:
  • Step A At room temperature, 67c (200 mg, 0.41 mmol) and 35a (176.8 mg, 0.61 mmol) were dissolved in dichloromethane (6 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (427.28 mg, 2.02 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step B At room temperature, 80a (106 mg, 0.14 mmol) was dissolved in ethanol (1.5 mL) and water (0.3 mL). Iron powder (40.22 mg, 0.72 mmol) and ammonium chloride (38.52 mg, 0.72 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 80b (100 mg, crude product). ESI-MS (m/z): 706.5 [M+H] + .
  • Step C At room temperature, 80b (100 mg, 0.11 mmol), Int-4 (69.8 mg, 0.17 mmol), and p-toluenesulfonic acid (73.18 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 80 (3.3 mg, yield 2.16%).
  • Example 81 9- ⁇ [1-(4- ⁇ [5-bromo-4-( ⁇ 5-[dimethyl(oxylidene)- ⁇ 5 - methphospho]quinoxalin-6-yl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]methyl ⁇ -3- ⁇ [3-(2,4-dioxylidenehexahydropyrimidin-1-yl)-1-methylindazole-6-yl]aza-ylidene ⁇ -3 ⁇ 6-9 -aza-3-thiaspiro[5.5]undecane-3-one
  • Example 81 was prepared by the following steps:
  • Step A 81a (500 mg, 1.55 mmol), Int-11 (375.51 mg, 1.24 mmol), cesium carbonate (1.01 g, 3.10 mmol), t-BuXPhos (65.91 mg, 0.15 mmol), and t-BuXPhos Pd G3 (61.64 mg, 0.077 mmol) were dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 100 °C for 4 hours under nitrogen atmosphere. LC/MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure to obtain the crude product.
  • Step B Dissolve 81b (200 mg, 0.37 mmol) in dichloromethane (3 mL), then add hydrochloric acid (4.0 M in 1,4-dioxane solution) (1.5 mL) and react at room temperature for 2 hours. A yellow solid is produced. LC/MS shows the reaction is complete. Concentrate the reaction solution to give crude product 81c (200 mg, crude product), which requires no further purification. ESI-MS (m/z): 444.68 [M+H] + .
  • Step C At room temperature, 81c (200 mg, 0.42 mmol) and 35a (182.7 mg, 0.63 mmol) were dissolved in dichloromethane (5 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (441.52 mg, 2.08 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 81d (110 mg, 0.15 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (42.67 mg, 0.76 mmol) and ammonium chloride (40.87 mg, 0.76 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 81e (100 mg, crude product). ESI-MS (m/z): 690.91 [M+H] + .
  • Step E At room temperature, 81e (100 mg, 0.15 mmol), Int-4 (71.77 mg, 0.17 mmol), and p-toluenesulfonic acid (74.88 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 81 (10.7 mg, yield 6.68%).
  • Example 82 was prepared by the following steps:
  • Step A At room temperature, 69d (37 mg, 0.054 mmol), Int-7 (35.85 mg, 0.081 mmol), and p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 82 (15.8 mg, yield 26.54%).
  • Example 83 was prepared by the following steps:
  • Step A At room temperature, 69d (37 mg, 0.054 mmol), Int-8 (35.53 mg, 0.081 mmol), and p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 83 (15.4 mg, yield 25.96%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 84 3-(4- ⁇ [4-( ⁇ 4-[1-(4- ⁇ [5-bromo-4-( ⁇ 5-[dimethyl(oxylidene)- ⁇ 5-methphospho] -2 -ethylquinazolin-6-yl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]piperazin-1-yl ⁇ methyl)-1-oxylidene- 1 ⁇ 6 -thiocyclohexane-1-yl]amino ⁇ -2,6-difluorophenyl)hexahydropyridin-2,6-dione
  • Example 84 was prepared by the following steps:
  • Step A At room temperature, 69d (37.00 mg, 0.054 mmol), Int-9 (35.61 mg, 0.081 mmol), and p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain yellow solid 84 (11.3 mg, yield 19.03%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 85 was prepared by the following steps:
  • Step A At room temperature, 69d (37.00 mg, 0.054 mmol), Int-1 (32.37 mg, 0.081 mmol), and p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 85 (14.7 mg, yield 25.7%) of yellow solid.
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 86 was prepared by the following steps:
  • Step A At room temperature, 69d (37.00 mg, 0.054 mmol), 17a (25.54 mg, 0.081 mmol), and p-toluenesulfonic acid (18.55 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a white solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 86 (21.3 mg, yield 40.50%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 87 was prepared by the following steps:
  • Step A At room temperature, Int-15 (700 mg, 1.65 mmol) was dissolved in dichloromethane (5 mL). Under ice bath conditions, N,N-diisopropylethylamine (212.62 mg, 1.65 mmol, 0.30 mL) was added. After 5 minutes, a catalytic equivalent of glacial acetic acid (98.79 mg, 1.65 mmol) was added dropwise. 76b (760.93 mg, 3.29 mmol) was added to the reaction solution. The reaction was allowed to proceed for approximately 1 hour. The temperature was then lowered to 0°C, and sodium triacetylborohydride (697.35 mg, 3.29 mmol) was added in portions.
  • Step B At room temperature, 87a (430 mg, 0.67 mmol) was dissolved in dichloromethane (4 mL), cooled to 0 °C in an ice bath, and hydrochloric acid/dioxane solution (4.0 M, 2 mL) was added. The reaction was carried out at room temperature for approximately 2 hours. The product was visualized by LC-MS. Directly evaporated to dryness under reduced pressure to give a pale yellow solid 87b (320 mg, crude product). No further purification was required. ESI-MS (m/z): 541.4 [M+H] + .
  • Step C At room temperature, 87b (320 mg, 0.60 mmol) and Int-17a (120.00 mg, 0.60 mmol) were dissolved in dimethyl sulfoxide (5 mL). N,N-diisopropylethylamine (778.6 mg, 6.02 mmol, 1.05 mL) was added to the reaction solution, and the mixture was stirred at 120 °C for 8 hours. LC-MS showed that some of the starting materials were not completely reacted. Water was added to the reaction solution, and the mixture was extracted with dichloromethane/methanol (15/1).
  • Step D At room temperature, 87c (150 mg, 0.21 mmol), iron powder (58.19 mg, 1.04 mmol), and ammonium chloride (55.73 mg, 1.04 mmol) were dissolved in ethanol (4.0 mL) and water (0.8 mL), and reacted at 80 °C for 1 hour. LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 88 3-[4-( ⁇ 4-[9-(4- ⁇ [5-bromo-4-( ⁇ 5-[dimethyl(oxylidene)- ⁇ 5 - methphospho]-3-fluoro-2-methylquinoline-6-yl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-yl]-1-oxylidene- 1 ⁇ 6 -thiacyclohexane-1-yl ⁇ amino)-2,6-difluorophenyl]hexahydropyridine-2,6-dione
  • Example 88 was prepared by the following steps:
  • Step A At room temperature, 88a (1.5 g, 5.16 mmol, C) and 19a (1.03 g, 5.16 mmol) were dissolved in dimethyl sulfoxide (20 mL). Cesium carbonate (5.04 g, 15.47 mmol) was added to the reaction solution, and the mixture was stirred at 110 °C for 3 hours. LC-MS showed that the reaction was complete. Water was added to the reaction solution, and a large amount of solid was produced.
  • Step B At room temperature, 88b (1.6 g, 3.69 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C in an ice bath, and hydrochloric acid/dioxane solution (4.0 M, 10 mL) was added. The reaction was carried out at room temperature for approximately 2 hours. The product was visualized by LC-MS. Directly evaporated to dryness under reduced pressure to give a pale yellow solid, 88c (1.1 g, crude). No further purification was required. ESI-MS (m/z): 334.2 [M+H] + .
  • Step C At room temperature, 88c (350 mg, 0.95 mmol) was dissolved in dichloromethane (5 mL). Under ice bath conditions, N,N-diisopropylethylamine (122.29 mg, 0.95 mmol, 0.16 mL) was added. After 5 minutes, a catalytic equivalent of glacial acetic acid (56.82 mg, 0.95 mmol) was added dropwise. 70a (186.89 mg, 1.61 mmol) was added to the reaction solution. The reaction was allowed to proceed for approximately 1 hour. The temperature was then lowered to 0°C, and sodium triacetylborohydride (401.09 mg, 1.89 mmol) was added in portions.
  • Step E 88e (152.79 mg, 0.33 mmol), Int-10a (100 mg, 0.33 mmol), cesium carbonate (214.29 mg, 0.66 mmol), t-BuXPhos (13.96 mg, 0.033 mmol), and t-BuXPhos Pd G3 (13.06 mg, 0.016 mmol) were dissolved in 1,4-dioxane (3 mL) and N,N-dimethylformamide (3 mL). The mixture was stirred at 80 °C for 6 hours under nitrogen atmosphere. LC/MS showed that the reaction was complete.
  • Step F At room temperature, 88f (110 mg, 0.16 mmol), iron powder (44.66 mg, 0.80 mmol), and ammonium chloride (42.77 mg, 0.80 mmol) were dissolved in ethanol (2.0 mL) and water (0.4 mL), and reacted at 80 °C for 1 hour. LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was evaporated to dryness, dissolved in dichloromethane/methanol (15/1), filtered through diatomaceous earth, and the solvent was removed by vacuum distillation to obtain the crude product.
  • Example 89 was prepared by the following steps:
  • Step A At room temperature, 61b (50 mg, 0.073 mmol), 17a (34.52 mg, 0.11 mmol), and p-toluenesulfonic acid (37.61 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a white solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give white solid 89 (22.2 mg, yield 31.24%).
  • Example 90 was prepared by the following steps:
  • Step E At room temperature, 61b (50 mg, 0.073 mmol), 90a (26.8 mg, 0.073 mmol), and p-toluenesulfonic acid (37.61 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a white solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 90 (39.9 mg, yield 53.27%).
  • Example 91 was prepared by the following steps:
  • Step E At room temperature, 61b (50 mg, 0.073 mmol), Int-9 (48.12 mg, 0.11 mmol), and p-toluenesulfonic acid (37.61 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a white solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a white solid 91 (4.2 mg, yield 5.24%).
  • Example 92 was prepared by the following steps:
  • Step A 68a (300 mg, 0.89 mmol), Int-2c (311.81 mg, 1.33 mmol), cesium carbonate (578.11 mg, 1.77 mmol), t-BuXPhos (37.67 mg, 0.089 mmol), and t-BuXPhos Pd G3 (35.24 mg, 0.044 mmol) were dissolved in 1,4-dioxane (3 mL) and N,N-dimethylformamide (3 mL). The mixture was stirred at 110 °C for 4 hours under nitrogen atmosphere. LC/MS showed that the reaction was complete.
  • Step B Dissolve 92a (300 mg, 0.61 mmol) in dichloromethane (3 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1.5 mL) and react at room temperature for 2 hours. A yellow solid is produced. LC/MS shows the reaction is complete. Concentrate the reaction solution to give crude product 92b (250 mg, crude product), which requires no further purification. ESI-MS (m/z): 491.6 [M+H] + .
  • Step C At room temperature, 92b (150 mg, 0.38 mmol) and 35a (172.65 mg, 0.46 mmol) were dissolved in dichloromethane (5 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (406.07 mg, 1.92 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 92c (45 mg, 0.60 mmol) was dissolved in ethanol (1.5 mL) and water (0.3 mL). Iron powder (16.73 mg, 0.30 mmol) and ammonium chloride (16.03 mg, 0.30 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 92d (42 mg, crude product). ESI-MS (m/z): 721.92 [M+H] + .
  • Step E At room temperature, 92d (40 mg, 0.055 mmol) and Int-4 (34.34 mg, 0.083 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), and p-toluenesulfonic acid (28.66 mg, 0.17 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 93 was prepared by the following steps:
  • Step A At room temperature, 67a (300 mg, 0.89 mmol), Int-2c (311.81 mg, 1.33 mmol), cesium carbonate (578.11 mg, 1.77 mmol), t-BuXPhos (37.67 mg, 0.089 mmol), and t-BuXPhos Pd G3 (35.24 mg, 0.044 mmol) were dissolved in 1,4-dioxane (3 mL) and N,N-dimethylformamide (3 mL). The mixture was stirred at 110 °C for 4 hours under nitrogen atmosphere. LC/MS showed that the reaction was complete.
  • Step B Dissolve 93a (297 mg, 0.61 mmol) in dichloromethane (3 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1.5 mL) and react at room temperature for 2 hours. A yellow solid is produced. LC/MS shows the reaction is complete. Concentrate the reaction solution to give crude product 93b (260 mg, crude product), which requires no further purification. ESI-MS (m/z): 491.6 [M+H] + .
  • Step C At room temperature, 93b (150 mg, 0.38 mmol) and 35a (172.65 mg, 0.46 mmol) were dissolved in dichloromethane (5 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (406.07 mg, 1.92 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step E At room temperature, 93d (100 mg, 0.14 mmol) and Int-4 (85.85 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and p-toluenesulfonic acid (71.66 mg, 0.42 mmol) was added. The reaction was carried out at 100 °C for 16 hours. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was added dropwise to sodium bicarbonate solution, and a large amount of solid precipitated out. The solid was filtered and dried under vacuum.
  • Example 94 was prepared by the following steps:
  • Step B Dissolve 94b (300 mg, 0.55 mmol) in dichloromethane (2 mL), then add HCl (4.0 M in 1,4-dioxane solution) (1 mL) and react at room temperature for 2 hours. A white solid is produced. LC/MS shows the reaction is complete. Concentrate the reaction solution to give crude product 94c (240 mg, crude product), no further purification required. ESI-MS (m/z): 445.3 [M+H] + .
  • Step C At room temperature, 94c (230 mg, 0.52 mmol) and 35a (151.25 mg, 0.52 mmol) were dissolved in dichloromethane (4 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (164.48 mg, 0.78 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 94d (210 mg, 0.29 mmol) was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (48.81 mg, 0.87 mmol) and ammonium chloride (46.75 mg, 0.87 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 94e (140 mg, crude product). ESI-MS (m/z): 691.5 [M+H] + .
  • Step E At room temperature, 94e (100 mg, 0.15 mmol), Int-4 (59.72 mg, 0.15 mmol), and p-toluenesulfonic acid (74.77 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 94 (24 mg, yield 15.23%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 95 was prepared by the following steps:
  • Step A At room temperature, 94e (100 mg, 0.15 mmol), Int-7 (64.21 mg, 0.15 mmol), and p-toluenesulfonic acid (74.77 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (1.2 mL). The mixture was reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a yellow solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a yellow solid 95 (17 mg, yield 9.95%).
  • mobile phase A acetonitrile
  • mobile phase B 0.1% formic acid system
  • Example 96 1-(6- ⁇ [4-( ⁇ 4-[1-(4- ⁇ [5-bromo-4-( ⁇ 5-[dimethyl(oxylidene)- ⁇ 5 - methphospho]quinoxalin-6-yl ⁇ amino)pyrimidin-2-yl]amino ⁇ -2-ethyl-5-methoxyphenyl)hexahydropyridin-4-yl]piperazin-1-yl ⁇ methyl)-1-oxylidene- 1 ⁇ 6 -thiocyclohexyl-1-yl]amino ⁇ -1-methylindazole-3-yl)-2-oxylidene hexahydropyrimidin-4-one
  • Example 96 was prepared by the following steps:
  • Step B Dissolve 96a (150 mg, 0.38 mmol) in dichloromethane (3 mL), and add Dysmart oxidant (251.67 mg, 0.59 mmol) under ice bath conditions. The reaction was carried out at 25 °C for 2 hours, and LC-MS showed that the reaction was complete. Add an aqueous sodium thiosulfate solution to the reaction mixture, extract with dichloromethane, wash the organic phase with saturated sodium bicarbonate solution and saturated brine, combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate the crude product 96b (150 mg, crude product), which was directly used in the next step of the reaction.
  • Step C At room temperature, 96b (150 mg, 0.37 mmol) and Int-17 (143.45 mg, 0.41 mmol) were dissolved in N,N-dimethylformamide (3 mL). Acetic acid (3 drops) was added in an ice bath, followed by the addition of sodium triacetylborohydride (118.49 mg, 0.56 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC/MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step D At room temperature, 96c (110 mg, 0.15 mmol) was dissolved in ethanol (4 mL) and water (0.8 mL). Iron powder (41.79 mg, 0.75 mmol) and ammonium chloride (40.03 mg, 0.75 mmol) were added to the reaction solution, and the reaction was carried out at 80 °C for 1 hour. LC/MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was concentrated, dissolved in dichloromethane/methanol (15/1), and concentrated under reduced pressure to obtain crude product 96d (88.0 mg, crude product). ESI-MS (m/z): 706.4 [M+H] + .
  • Step E At room temperature, 96d (88.0 mg, 0.13 mmol), Int-4 (77.26 mg, 0.19 mmol), and p-toluenesulfonic acid (42.99 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 100 °C for 16 hours. After cooling the reaction solution to room temperature, a saturated sodium bicarbonate aqueous solution was added, resulting in the precipitation of a white solid. The crude product was obtained by filtration and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a white solid 96 (58 mg, yield 42.51%).
  • Example 97 was prepared by the following steps:
  • Step A Dissolve 3 (70 mg, 0.067 mmol) and potassium carbonate (11.17 mg, 0.081 mmol) in N,N-dimethylformamide (1.5 mL), then add iodomethane (11.48 mg, 0.081 mmol), and stir at room temperature for 16 hours.
  • LCMS showed the reaction was complete.
  • the filtrate was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 97 (34 mg, yield 46.97%).
  • ESI-MS (m/z): 526.9 [M+2H] 2+ /2.
  • Example 98 was prepared by the following steps:
  • Step A 51b (65 mg, 0.097 mmol), 17a (45.88 mg, 0.15 mmol), and p-toluenesulfonic acid (49.98 mg, 0.29 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), purged three times with nitrogen, and the reaction mixture was stirred at 90 °C for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid 98 (32 mg, yield 34.07%).

Landscapes

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

Abstract

La présente invention concerne un agent de dégradation contenant un lieur de sulfoximine, un intermédiaire de celui-ci et une utilisation associée. L'agent de dégradation contenant un lieur de sulfoximine selon la présente invention est un composé tel que représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci. L'agent de dégradation de la présente invention présente une forte activité de dégradation des protéines cibles, une efficacité pharmacologique favorable et de bonnes perspectives de pharmacopotentialité.
PCT/CN2025/098244 2024-06-03 2025-05-30 Agent de dégradation contenant un lieur de sulfoximine, intermédiaire de celui-ci et son utilisation Pending WO2025252011A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202410709717 2024-06-03
CN202410709717.7 2024-06-03
CN202411424158 2024-10-12
CN202411424158.1 2024-10-12

Publications (1)

Publication Number Publication Date
WO2025252011A1 true WO2025252011A1 (fr) 2025-12-11

Family

ID=97960061

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/098244 Pending WO2025252011A1 (fr) 2024-06-03 2025-05-30 Agent de dégradation contenant un lieur de sulfoximine, intermédiaire de celui-ci et son utilisation

Country Status (1)

Country Link
WO (1) WO2025252011A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210016103A (ko) * 2019-07-31 2021-02-15 주식회사 온코빅스 Alk 단백질의 분해를 유도하는 신규 화합물 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물
CN113423431A (zh) * 2019-01-03 2021-09-21 尹图赛利有限公司 包含可裂解接头的化合物及其用途
WO2021202600A1 (fr) * 2020-03-30 2021-10-07 The Scripps Research Institute Inhibiteurs à petites molécules de l'hémagglutinine de la grippe
WO2024032600A1 (fr) * 2022-08-08 2024-02-15 西藏海思科制药有限公司 Dérivé hétérocyclique, et composition à base de celui-ci et utilisation pharmaceutique associée
WO2024039901A2 (fr) * 2022-08-19 2024-02-22 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et utilisations associées
WO2024072178A1 (fr) * 2022-09-30 2024-04-04 (주)사이러스테라퓨틱스 Composé pour la dégradation ciblée de protéines et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113423431A (zh) * 2019-01-03 2021-09-21 尹图赛利有限公司 包含可裂解接头的化合物及其用途
KR20210016103A (ko) * 2019-07-31 2021-02-15 주식회사 온코빅스 Alk 단백질의 분해를 유도하는 신규 화합물 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물
WO2021202600A1 (fr) * 2020-03-30 2021-10-07 The Scripps Research Institute Inhibiteurs à petites molécules de l'hémagglutinine de la grippe
WO2024032600A1 (fr) * 2022-08-08 2024-02-15 西藏海思科制药有限公司 Dérivé hétérocyclique, et composition à base de celui-ci et utilisation pharmaceutique associée
WO2024039901A2 (fr) * 2022-08-19 2024-02-22 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et utilisations associées
WO2024072178A1 (fr) * 2022-09-30 2024-04-04 (주)사이러스테라퓨틱스 Composé pour la dégradation ciblée de protéines et son utilisation

Similar Documents

Publication Publication Date Title
TWI752580B (zh) Kras突變蛋白抑制劑
JP7840517B2 (ja) 二環式複素環誘導体およびオレキシン－２受容体アゴニストとしてのそれらの使用
CN110582495B (zh) 作为tnf活性的调节剂的稠合五环咪唑衍生物
CN110248939B (zh) 作为rho-激酶抑制剂的酪氨酸酰胺衍生物
CN105899490B (zh) 嘧啶fgfr4抑制剂
CN106061976B (zh) 多氟化合物作为布鲁顿酪氨酸激酶抑制剂
CN115626919A (zh) 哒嗪基噻唑甲酰胺类化合物
CN109890820B (zh) 用作神经营养因子酪氨酸激酶受体抑制剂的氨基吡唑并嘧啶化合物
WO2024083256A1 (fr) Agent de dégradation pan-kras, son procédé de préparation et son utilisation
US9890168B2 (en) 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof
AU2017201873A1 (en) PDE9i with imidazo pyrazinone backbone
WO2021023233A1 (fr) Agent de dégradation de la protéine egfr et application antitumorale de celui-ci
TW201443023A (zh) 作爲ｒｏｃｋ抑制劑之酞□酮及異喹啉酮
JP6531167B2 (ja) ブロモドメイン阻害剤としてのテトラヒドロキノリン誘導体
US20200299265A1 (en) Aminopyridine derivatives and their use as selective alk-2 inhibitors
IL268565A (en) History of pyrazole as bromodomain inhibitors
WO2023274280A1 (fr) Forme cristalline d'un inhibiteur de dérivé de biphényle et son procédé de préparation
WO2024217481A1 (fr) Agent de dégradation d'egfr, composition pharmaceutique et utilisation associées
CN114981270B (zh) Mll1抑制剂和抗癌剂
WO2022171118A1 (fr) Composé ayant une activité antitumorale et son utilisation
CN108017633A (zh) N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-2-氟代丙烯酰胺衍生物及应用
US10849897B2 (en) Pyridyl derivatives as bromodomain inhibitors
HK40085586B (zh) 哒嗪基噻唑甲酰胺类化合物
HK40084227B (zh) 哒嗪基噻唑甲醯胺类化合物
HK40059656B (zh) 哒嗪基噻唑甲酰胺类化合物

Legal Events

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

Ref document number: 25819128

Country of ref document: EP

Kind code of ref document: A1