WO2025131111A1 - Dérivé cyclique hétéroaromatique fusionné bicyclique, composition pharmaceutique et utilisation associées - Google Patents

Dérivé cyclique hétéroaromatique fusionné bicyclique, composition pharmaceutique et utilisation associées Download PDF

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Publication number
WO2025131111A1
WO2025131111A1 PCT/CN2024/141290 CN2024141290W WO2025131111A1 WO 2025131111 A1 WO2025131111 A1 WO 2025131111A1 CN 2024141290 W CN2024141290 W CN 2024141290W WO 2025131111 A1 WO2025131111 A1 WO 2025131111A1
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alkyl
ring
alkoxy
halogenated
compound
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Chinese (zh)
Inventor
李鑫
朱卫星
江斌
王如伟
许峰
王海龙
华默嘉
席宝信
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medical technology, and in particular to a bicyclic fused heteroaromatic ring derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and its medical use.
  • the Polycomb group (PcG) protein Polycomb repressive complex 2 plays the core function of transcriptional repression in the body, and achieves gene silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27me3); in tumors, it can promote the occurrence and development of tumors by inhibiting the expression of tumor suppressor genes.
  • the catalytic subunit EZH2 of PRC2 is an important representative of the third generation epidemic genetic regulation precision therapy targets. Compared with the first and second generation pan epigenetic regulation targets, current therapeutic targets can target tumors with specific mutation types, and the efficacy and safety have been greatly improved.
  • EZH2 is an ideal target for directly shutting down the abnormal activity of PRC2, as a complex protein, the function and activity of PRC2 is highly dependent on the regulation of the skeleton and another core subunit EED.
  • the methyltransferase activity of the PRC2 complex can also be inhibited by interfering with the protein-protein interaction (PPI) between EZH2 and EED.
  • PPI protein-protein interaction
  • TPD targeted protein degradation
  • PROTACs proteolysis targeting chimeras
  • Protein degraders can target "undruggable" targets, improve the selectivity and inhibitory activity of targets, prolong the duration of drug action and drug-resistant mutations; they are particularly suitable for drug development against traditionally undruggable targets (such as transcription factors and scaffold proteins), targets that are prone to acquired drug-resistant mutations during tumor targeted therapy, targets with gene amplification and/or protein overexpression, targets with different protein subtypes, scaffold proteins, protein polymers, etc.
  • small molecule inhibitors targeting EZH2 have been approved for marketing, and the feasibility of PRC2 as an anti-tumor drug target has been verified clinically, but the effect of EZH2 small molecule inhibitors in solid tumors is still limited, and multiple small molecule inhibitors of EZH2 and EED are still under clinical research.
  • the use of protein degradation technology for drug development of this target may bring new directions and breakthroughs to drug development of this target.
  • the purpose of the present application is to provide a PROTAC compound, which can degrade and/or inhibit EED protein, has excellent degradation/inhibition effect on EED protein and excellent tumor cell proliferation inhibition effect, and has excellent pharmacokinetic characteristics, small toxic and side effects, good safety, and is more suitable for treating diseases or conditions with abnormal EED protein activity (such as proliferative diseases such as cancer).
  • n0 is 0.
  • POI is a structure represented by formula (A-1) or an isomer thereof:
  • the A1 ring is a 5- to 20-membered heterocycloalkyl ring (preferably a 5- to 6-membered heterocycloalkyl ring, preferably a 15- to 20-membered heterocycloalkyl ring, more preferably a 15- to 18-membered heterocycloalkyl ring, and further preferably an 18-membered heterocycloalkyl ring) or a 5- to 10-membered heteroaryl ring (preferably an 8- to 10-membered heteroaryl ring, more preferably a 9-membered heteroaryl ring, and more preferably a 10-membered heteroaryl ring);
  • the A2 ring is absent, a 3- to 15-membered heterocycloalkyl ring, a C 3-10 cycloalkyl ring, a 5- to 15-membered heteroaryl ring (preferably a 5- to 12-membered heteroaryl ring, more preferably a 5- to 10-membered heteroaryl ring, and further preferably a 5- to 6-membered heteroaryl ring), or a C 6-10 aryl ring (preferably a benzene ring or a naphthalene ring);
  • R 1 n1 represents that the hydrogen on the 2,3-dihydrobenzofuran ring is replaced by n1 R 1s , n1 is 0, 1 or 2, each R 1 is the same or different and is independently selected from hydrogen, deuterium, halogen (preferably fluorine, chlorine or bromine), oxo, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -COC 1-8 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -OCOC 1-8 alkyl (preferably -COC
  • R 2 n2 represents that the hydrogen on the A1 ring is replaced by n2 R 2 , n2 is 0, 1 or 2, each R 2 is the same or different and is independently selected from X 1 , hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -NHC 1-8 alkyl (preferably -NHC 1-6 alkyl, more preferably -NHC 1-3 alkyl), -N(C 1-8 alkyl) 2 (preferably
  • R 1 , R 2 , and the carbon atoms connected thereto together form a 6- to 15-membered heterocycloalkyl ring;
  • the 6- to 15-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, nitro, formyl, sulfonic acid, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -COC 1-6 alkyl, -OCOC 1-6 alkyl, -COOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -PO(C 1-6 alkyl) 2 , -SOC 1-6 alky
  • the A1 ring is a 9-membered nitrogen-containing heteroaryl ring or a 10-membered nitrogen-containing heteroaryl ring.
  • the A2 ring is selected from absent, a 4- to 8-membered heterocycloalkyl ring, a saturated C4-8 cycloalkyl ring, a 5- to 10-membered heteroaryl ring, a partially unsaturated 10- to 15-membered heterocycloalkyl ring, and a benzene ring.
  • the A2 ring is selected from the group consisting of: absent, cyclobutane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, pyrazolidine ring, imidazolidine ring, piperidine ring, hexahydropyridazine ring, hexahydropyrimidine ring, piperazine ring, benzene ring, pyrazole ring, oxazole ring, imidazole ring, triazole ring, tetrazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indolizine ring, pyrazolopyridine, imidazopyridine, triazolopyridine, tetrazolopyridine, pyrrolopyridazine, pyrazolopyridine, imidazo
  • the A2 ring is selected from absent, a saturated 6-membered heterocycloalkyl ring, a partially unsaturated 12-membered heterocycloalkyl ring, a cyclohexane ring, a 5- to 6-membered heteroaryl ring, a 9-membered heteroaryl ring, and a benzene ring.
  • the A2 ring is selected from absent, a cyclohexane ring, a piperidine ring, a piperazine ring, a benzene ring, a pyridine ring, a pyrazole ring, a triazolopyridine ring, and 2,3-dihydrospiro[indene-1,4'-piperidine].
  • the A2 ring is selected from a benzene ring, a pyridine ring, and a pyrazole ring.
  • the structure Select from the following structures:
  • n1 is 0.
  • n1 is 1 or 2.
  • n1 is 1.
  • R 1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyrrolyl, pyrazolyl, pyridinyl, phenyl, pyrimidinyl, -CH 2 -cyclopropyl, -CH 2 -tetrahydropyrrolyl,
  • R1 is selected from hydrogen, deuterium, fluorine, chlorine , bromine, iodine, -CH3 , -CH2CH3, -CH( CH3 ) 2 , -CH2CH2CH3 , -CH2F , -CHF2 , -CF3 , -OCH3 , -OCH2CH3 , -OCH2CH2CH3 , -OCH ( CH3 ) 2 , -OCH2F , -OCHF2 , -OCF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -OCH2CH2F , -OCH2CHF2 , and -OCH2CF3 .
  • n1 is 1 and R1 is fluoro.
  • two R 1 and the carbon atoms to which they are attached together form a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, or a piperazine ring.
  • two R 1 s and the carbon atom to which they are attached together form a cyclopropyl ring.
  • p3 is 3, wherein one R 3 is fluorine, and the other two R 3 and the carbon atom to which they are attached form a cyclopropane ring.
  • R 2 is selected from X 1 , hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -PO(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkoxy.
  • R 2 is selected from X 1 , hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -COC 1-3 alkyl, -COOC 1-3 alkyl, -OCOC 1-3 alkyl, -PO(C 1-3 alkyl) 2 , -SOC 1-3 alkyl, -SO 2 C 1-3 alkyl, -OSO 2 C 1-3 alkyl, -SC 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, halo-substituted C 1-3 alkyl, halo-substituted C 1-3 alkoxy.
  • R2 is selected from Xi , hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, amino, oxo, -NHCH3 , -N( CH3 ) 2 , -CONH2 , -CONHCH3, -CON(CH3) 2 , -COCH3 , -COC( CH3 ) 3 , -COOCH3 , -COOCH2CH3, -COOC(CH3)3 , -OCOCH3 , -OCOCH2CH3 , -OCOC ( CH3 ) 3 , -PO( CH3 ) 2 , -PO( CH2CH3 ) 2 , -SOCH3, -SOCH2CH3 , -SOC ( CH3 ) 3 , -SO2CH3 , -SO2CH2CH3 , -SO 2 C(CH 3 ) 3 , -OSO 2 CH 3 , -OSO 2 CH 3 ,
  • R 2 is selected from Xi , hydrogen, halogen, cyano, -SO 2 C 1-6 alkyl, -OSO 2 C 1-6 alkyl.
  • R 2 is selected from Xi , hydrogen, halogen, cyano, -SO 2 C 1-3 alkyl, -OSO 2 C 1-3 alkyl.
  • R 2 is selected from Xi , hydrogen, fluoro, chloro, bromo, iodo, cyano, -SO 2 CH 3 , -OSO 2 CH 3 .
  • R 2 is selected from cyano, fluoro, chloro, bromo, iodo, -CH 3 , -CF 3 , -SO 2 CH 3 , hydrogen, -PO(CH 3 ) 2 .
  • R 2 is selected from cyano, chloro, bromo, -SO 2 CH 3 , hydrogen.
  • n2 is 1, and R2 is selected from Xi , hydrogen, fluorine, chlorine, bromine, iodine, -CH3 , cyano , -SO2CH3 , -OSO2CH3 , -PO( CH3 ) 2 .
  • n2 is 1, and R2 is selected from cyano, fluoro, chloro, bromo, iodo, -CH3 , -CF3 , -SO2CH3 , hydrogen, -PO( CH3 ) 2 .
  • n2 is 1, and R2 is selected from cyano, chloro, bromo, -SO2CH3 , hydrogen .
  • the structure Selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM.
  • the structure Selected from the following structures or isomers thereof: Where X1 is the connection point with L or ULM.
  • the structure Selected from the following structures or isomers thereof: X1 is the connection point with L or ULM.
  • X1 is the connection point with L or ULM.
  • Each occurrence of L a is independently selected from a chemical bond, -C(O)-, -C(O)NR L1 -, -NR L1 -, -O-, -S-, C 1-10 alkylene (preferably C 1-8 alkylene, more preferably C 1-6 alkylene, and further preferably C 1-3 alkylene), C 1-10 alkyleneoxy (preferably C 1-8 alkylene, more preferably C 1-6 alkyleneoxy, and further preferably C 1-3 alkyleneoxy), C 2-10 alkenylene (preferably C 2-8 alkenylene, more preferably C 2-6 alkenylene, and further preferably C 2-4 alkenylene), C 2-10 alkynylene (preferably C 2-8 alkynylene, more preferably C 2-6 alkynylene, and further preferably C 2-4 alkynylene), C 3-15 cycloalkylene ring (preferably C 3-10 cycloalkylene ring, more preferably C 3-8 cycloalkylene ring, and
  • each occurrence of R L1 is independently selected from hydrogen, methyl, ethyl, difluoromethyl, and monofluoromethyl.
  • each RL is independently selected from deuterium, halogen (preferably fluorine, chlorine or bromine), hydroxyl, cyano, amino, carboxyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, difluoromethyl, monofluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
  • each RL2 is independently selected from deuterium, -F, -Cl , -Br , -OH , -CN , -CHO, -COOH, -NH2 , -CH2OH , -CH2CH2OH , -CH3 , -CH2CH3 , -CH2F, -CHF2 , -CF3 , -CH2CH2F, -CH2CHF2 , -CH2CF3 , -OCH3 , -OCH2CH3, -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2, -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl , cyclopropyl , -CONH2 , -COOCH3 , -OCOCH3, -CONHCH3 , -
  • each RL2 is independently selected from deuterium, -F, -Cl , -Br , -OH , -CN , -COOH , -NH2, -CH2OH , -CH2CH2OH, -CH3 , -CH2CH3 , -CH2F , -CHF2 , -CF3, -CH2CH2F, -CH2CHF2 , -CH2CF3 , -OCH3 , -OCH2CH3 , -OCH2F , -OCHF2 , -OCF3 , -OCH2CH2F , -OCH2CHF2 , -OCH2CF3 , -COCH3 , -CH2 - cyclopropyl, cyclopropyl , and -CONH2 .
  • R L2 are each independently selected from fluoro, chloro, bromo, hydroxy, and hydroxymethyl.
  • the La is each independently selected from the following structures or isomers thereof: -C(O)-, -C(O)NH-, -O-, -S-, -NH-, C1-10 alkylene, C1-10 alkyleneoxy, C3-12 cycloalkylene ring, 4 to 12 membered heterocycloalkylene ring, 5 to 6 membered heteroarylene ring and phenylene ring; the C3-12 cycloalkylene ring, 4 to 12 membered heterocycloalkylene ring, 5 to 6 membered heteroarylene ring and phenylene ring are unsubstituted or substituted with 1, 2, 3 or 4 RL2 , and the RL2 is selected from fluorine, hydroxyl and hydroxymethyl.
  • the La is independently selected from the following structures or isomers thereof: -O-, -S-, -NH-, -C(O)-, -C(O)NH-, -(CH 2 ) m2 -, -O(CH 2 ) m2 -, -(CH 2 ) m2 O-, or a subunit form selected from the following cyclic groups: cyclopropane ring, cyclobutane ring, bicyclopentane ring, cyclopentane ring, cyclohexane ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, hydroxy-substituted piperidine ring, hydroxy-substituted piperazine ring, hydroxymethyl-substituted piperidine ring, hydroxymethyl-substituted piperazine ring, 3,3,5,5-tetramethylpiperidine
  • the La is independently selected from the following structures or isomers thereof: -( CH2 )-, -( CH2 ) 2- , -(CH2) 5- , -C(O ) -, -( CH2 ) 3- , -C(O)NH-, -( CH2 ) 8- , -O-, -NH-,
  • the La is independently selected from the following structures or isomers thereof: -(CH 2 )-,
  • L is selected from the following structures or isomers thereof: -( CH2 ) m3- , -C(O)-( CH2 ) m3- , -C(O)NH-(CH2) m3- , -C(O)NH-( CH2 ) m3 -O-, -CyO-, -NH- CyO- , -CyO -NH-( CH2 )m3-, -CyO- (CH2)m3-NH-, -CyO-( CH2 ) m3 - O- , -C(O) NH -CyO-, -( CH2 )m3 - C( O )NH-(CH2) m3 -O-CyO-O-(CH2) m3- , -CyO-CyO-, -( CH2 ) m3 -C( O)NH-(CH2) m3 -O-CyO-O-
  • Cy O is each independently selected from a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a bicyclopentane ring, a cyclohexane ring, an azetidine ring, a hydroxy-substituted azetidine ring, a tetrahydropyrrole ring, a piperidine ring, a hydroxy-substituted piperidine ring, a hydroxymethyl-substituted piperidine ring, a 4-fluoropiperidine ring, a 3,3-difluoropiperidine, a 3,3,5,5-tetramethylpiperidine, a piperazine ring, a 2-azaspiro[3.3]heptane ring, a 6-azaspiro[3.4]octane ring, a 7-azaspiro[3.5]nonane ring, a 2,6-
  • azaspiro[3.3]heptane ring a 2,6-diazaspiro[3.4]octane ring, a 2,7-diazaspiro[3.5]nonane ring, a 2-azaspiro[3.5]nonane ring, a spiro[3.3]heptane ring, a spiro[3.4]octane ring, a spiro[3.5]nonane ring, a 3,9-diazaspiro[5.5]undecane ring, a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, a thiophene ring, a furan ring, a pyrrole ring, a thiazole ring, an oxazole ring, a pyrazole ring,
  • the Cy O is each independently selected from a cyclobutane ring, a bicyclopentane ring, a benzene ring, an azetidine ring, a piperidine ring, a piperazine ring, and 3,9-diazaspiro[5.5]undecane.
  • the Cy O is each independently selected from a cyclobutane ring, an azetidine ring, a benzene ring, and a piperidine ring.
  • the Cy O is each independently selected from the following structures or isomers thereof:
  • L is selected from the following structures or isomers thereof:
  • X 00 is the connection point between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Among them, X 00 is the connection point between L and ULM or POI.
  • L is selected from the following structures or isomers thereof:
  • X 00 is the connection point between L and ULM or POI.
  • L is selected from the following structures or isomers thereof:
  • X 00 is the connection point between L and ULM or POI.
  • L is selected from the following structures or isomers thereof:
  • X 00 is the connection point between L and ULM or POI.
  • L is selected from the following structures or isomers thereof: Among them, X 00 is the connection point between L and ULM or POI.
  • L is selected from the following structures or isomers thereof:
  • X10 is the connection point between L and POI
  • X20 is the connection point between L and ULM.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection point between L and POI, and X20 is the connection point between L and ULM.
  • L is selected from the following structures or isomers thereof:
  • X10 is the connection point between L and POI
  • X20 is the connection point between L and ULM.
  • L is selected from the following structures or isomers thereof:
  • X10 is the connection point between L and POI
  • X20 is the connection point between L and ULM.
  • L is selected from the following structures or isomers thereof:
  • X10 is the connection point between L and POI
  • X20 is the connection point between L and ULM.
  • L is selected from the following structures or isomers thereof:
  • X10 is the connection point between L and POI
  • X20 is the connection point between L and ULM.
  • L is selected from the following structures or isomers thereof: Among them, X10 is the connection point between L and POI, and X20 is the connection point between L and ULM.
  • ULM is a compound represented by formula (U-1) or an isomer thereof:
  • U 0 is a chemical bond, -N(R U0 )-, -CON(R U0 )-, -CH 2 - or -(CH 2 ) 2 -;
  • R U0 is independently hydrogen or C 1-3 alkyl
  • the B ring is selected from the group consisting of absent, a 5- to 15-membered heteroaryl ring (preferably a 6- to 12-membered heteroaryl ring, more preferably a 6- to 10-membered heteroaryl ring), a 3- to 15-membered heterocycloalkyl ring (preferably a 5- to 12-membered heterocycloalkyl ring, more preferably a 5- to 10-membered heterocycloalkyl ring), a C 3-15 cycloalkyl ring, and a C 6-10 aromatic ring (preferably a benzene ring);
  • a 5- to 15-membered heteroaryl ring preferably a 6- to 12-membered heteroaryl ring, more preferably a 6- to 10-membered heteroaryl ring
  • a 3- to 15-membered heterocycloalkyl ring preferably a 5- to 12-membered heterocycloalkyl ring, more preferably a 5- to 10-membered heterocycloalkyl
  • S 2 and S 4 are each independently selected from -N-, -NH-, -CH- and -CH 2 -;
  • S 6 is selected from C, -CH- and N;
  • R B1 b1 represents that the hydrogen on the B ring is replaced by b1 R B1s , b1 is 0, 1, 2 or 3, each R B1 is the same or different and is independently selected from X 2 , deuterium, halogen (preferably fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, nitro, -NR a1 R b1 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -SOC 1-8 alkyl (preferably -SOC 1-6 alkyl, more preferably -SOC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl),
  • S6 is -CH-.
  • r1 is 0, 1, or 2;
  • the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 3-10 cycloalkyl ring (preferably a C 3-8 cycloalkyl ring, more preferably a C 3-6 cycloalkyl ring) and a 3- to 10-membered heterocycloalkyl ring (preferably a 3- to 8-membered heterocycloalkyl ring, more preferably a 3- to 6-membered heterocycloalkyl ring);
  • R U2 r2 represents that the hydrogen on the D ring is replaced by r2 R U2 , r2 is 0, 1, 2 or 3, each R U2 is the same or different and is independently selected from X 2 , hydrogen, deuterium, halogen (preferably fluorine, chlorine), nitro, cyano, carboxyl, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkyl substituted with hydroxyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR a3 R b3 , -COC 1-6 alkyl, -COOC 1-6 alkyl, -OCOC 1-6 alkyl, -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -SOC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SC
  • halogen preferably fluor
  • RU1 is -C ( RU3RU4 ) -U1 ;
  • U 1 is selected from the following structures or isomers thereof: X 2 , -NHCO-X 2 , -NHCOCH 3 , 5- to 6-membered heteroaryl ring, The 5- to 6-membered heteroaryl ring, is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of X 2 , halogen, hydroxy, cyano, amino, carboxyl, C 1-6 alkyl (preferably methyl, ethyl, isopropyl), C 1-6 alkoxy (preferably methoxy, ethoxy, isopropoxy), halogenated C 1-6 alkyl (preferably trifluoromethyl), halogenated C 1-6 alkoxy (preferably trifluoromethoxy), -COC 1-6 alkyl (preferably -COCH 3 ), -COOC 1-6 alkyl (preferably -COOCH 3 ), -CONH 2 , -CONHC 1-6 alkyl (preferably -CONHCH 3 ),
  • R Ua is selected from hydrogen, halogen (preferably fluorine, chlorine or bromine), cyano, hydroxyl, carboxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -COC 1-6 alkyl, -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, -NHC 1-6 alkyl and -N(C 1-6 alkyl) 2 ;
  • R U3 and R U4 are each independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably C 1-3 alkoxy), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy) and -SC 1-6 alkyl (preferably -SC 1-3 alkyl); or R U3 and R U4 together with the carbon atom to which they are attached form a C 3-7 cycloalkyl (preferably C 3-6 cycloalkyl) and a 3 to 7 membered heterocycloalkyl (preferably 4 to 6 membered heterocycloalkyl); the C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -SC 1-6 alkyl, C 3-7 -membered
  • R U5 and R U6 are each independently selected from X 2 , hydrogen, deuterium, halogen, amino, cyano, carboxyl, hydroxyl, C 1-6 alkyl (preferably C 1-3 alkyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), halogenated C 1-6 alkoxy (halogenated C 1-3 alkoxy), -SC 1-6 alkyl (preferably -SC 1-3 alkyl), C 1-6 alkyl substituted by CONHC 1-6 alkyl, C 1-6 alkyl substituted by CON(C 1-6 alkyl) 2 , C 1-6 alkyl substituted by carboxyl, and C 1-6 alkyl substituted by COOC 1-6 alkyl;
  • R U8 is selected from hydroxy, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkoxy, halogenated C 1-6 alkoxy and -OCOC 1-6 alkyl;
  • X2 in RU2 , RU1 , RU5 and RU6 is a connection point between ULM and L or POI, and at least one of RU1 , RU5 , RU6 and RU2 is X2 .
  • r1 is 2.
  • the D ring is selected from a benzene ring, a 5- to 6-membered heteroaryl ring, a C 5-9 cycloalkyl ring, and a 5- to 9-membered heterocycloalkyl ring.
  • Ring D is selected from 2,3-dihydro-1H-indene.
  • the D ring is selected from a benzene ring and a 5- to 6-membered heteroaryl ring.
  • the D ring is selected from a benzene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a piperidine ring, a piperazine ring and a tetrahydropyrrole ring.
  • r1 is 0, and Ring D is 2,3-dihydro-1H-indene.
  • r1 is 1, and the D ring is a benzene ring.
  • r2 is 1.
  • r2 is 2.
  • R U2 is a 5- to 6-membered heteroaryl or phenyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine), cyano, carboxyl, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -NH 2 , -NHCOC 1-3 alkyl, -COC 1-3 alkyl, -COOC 1-3 alkyl, -OCOC 1-3 alkyl, -CONH 2 , -NHCONH 2 , -CONHC 1-3 alkyl, -NHCONHC 1-3 alkyl, -SOC 1-3 alkyl, -SO 2 C 1-3 alkyl and -SC 1-3 alkyl.
  • halogen preferably fluorine, chlorine
  • cyano carboxyl, hydroxyl, C 1-3 alkyl,
  • the 5- to 6-membered heteroaryl is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazolyl.
  • the 5- to 6-membered heteroaryl is selected from
  • the 5- to 6-membered heteroaryl is N-(2-membered heteroaryl)
  • the 5- to 6-membered heteroaryl ring is selected from a thiazole ring, an oxazole ring, a pyrazole ring, an imidazole ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a tetrazole ring, and a triazole ring.
  • R U2 is cyano
  • R a3 and R b3 are each independently selected from hydrogen, 5- to 6-membered heteroaryl and phenyl; the 5- to 6-membered heteroaryl is thiazolyl, oxazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, pyrrolyl, triazolyl and tetrazolyl; the 5- to 6-membered heteroaryl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, -COCH 3 and -CONH 2 .
  • R U2 is -NHR a3 , wherein R a3 is a 5- to 6-membered heteroaryl or phenyl group, wherein the 5- to 6-membered heteroaryl group is selected from thiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl and pyrimidinyl; and the 5- to 6-membered heteroaryl or phenyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkyl, halo C 1-3 alkyl, -SC 1-3 alkyl and -OCOC 1-3 alkyl.
  • R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl is substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy and trifluoroethoxy.
  • R U2 is -NHR a3 , wherein R a3 is thiazolyl; said thiazolyl being substituted with 1, 2 or 3 substituents selected from the group consisting of methyl, ethyl, propyl and isopropyl.
  • R U2 is selected from the following structures: cyano,
  • R2 is 1, R U2 is selected from cyano,
  • the compound represented by formula (I) is represented by formula (IA),
  • Alkyleneoxy refers to a divalent alkoxy group. In certain embodiments, it is preferably a C 1-10 alkyleneoxy group, more preferably a C 1-8 alkyleneoxy group, further preferably a C 1-6 alkyleneoxy group, and most preferably a C 1-3 alkyleneoxy group. In certain embodiments, the alkyleneoxy group may be -OCH 2 -, -OCH(CH 3 )CH 2 -, -OCH 2 CH 2 O-, -CH 2 CH 2 O-, and the like.
  • heterocycloalkyl examples include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran- 2(3H)-one, pyrrolidine-2-one, pyrrolidine-2,5-dione, dihydrofuran-2,5-dione, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazine-2-one, morpholin-3-one, 2,3
  • Heterocycloalkylene and “heterocycloalkylene ring” are used interchangeably and are both divalent, requiring two bonding partners.
  • the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.
  • Aryl and “aromatic ring” are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 or 14 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms.
  • the aromatic ring may be optionally substituted.
  • C 6-14 aryl refers to an aryl having 6 to 14 ring carbon atoms.
  • C 6-10 aryl refers to an aryl having 6 to 10 ring carbon atoms. Non-limiting examples include phenyl, naphthyl, anthracenyl.
  • Arylene and arylene ring are used interchangeably and are both divalent, requiring two bonding partners.
  • the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 or 14 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • the heteroaryl ring may be optionally substituted.
  • 5 to 15-membered heteroaryl refers to a monocyclic heteroaryl having 5 to 15 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • 5 to 6-membered heteroaryl refers to a monocyclic heteroaryl having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • Non-limiting examples include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, isoquinolyl, benzopyrrolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, benz
  • Heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings.
  • Heteroarylene and “heteroarylene ring” are used interchangeably and are both divalent, requiring two bonding partners.
  • the second valency is generated by removing a hydrogen atom from a cycloalkyl group, e.g.
  • Halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • Halo means that one or more (eg, 1, 2, 3 or all) hydrogen atoms in a group are replaced by halogen.
  • Haloalkyl refers to an alkyl group substituted with one or more (e.g., 1, 2, 3 or all) halogens, wherein the definition of alkyl is as described above. Preferably, it is a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, and more preferably a halogenated C 1-3 alkyl group.
  • haloalkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
  • Alkoxy refers to -O-alkyl, wherein alkyl is as defined above. Preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, most preferably C 1-3 alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • Alkoxyalkyl refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above . Preferably , it is C1-6alkoxyC1-6alkyl , more preferably C1-3alkoxyC1-3alkyl .
  • alkoxyalkyl include -CH2OCH3 , -CH2OCH2CH3 , -CH2CH2OCH3 , etc.
  • Cycloalkylalkyl refers to an alkyl group substituted by one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group are as defined above. Preferably, it is C 3-6 cycloalkylC 1-6 alkyl, and more preferably, it is C 3-6 cycloalkylC 1-3 alkyl.
  • Non-limiting examples of cycloalkylalkyl include -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclobutyl, and the like.
  • Alkenylalkyl refers to an alkyl group substituted with one or more alkenyl groups, wherein the definitions of alkyl and alkenyl are as described above. Preferably, it is C2-8 alkenyl C1-10 alkyl, more preferably C2-8 alkenyl C1-8 alkyl, further preferably C2-8 alkenyl C1-6 alkyl, further preferably C2-8 alkenyl C1-3 alkyl.
  • Alkynylalkyl refers to an alkyl group substituted by one or more alkynyl groups, wherein the definitions of alkyl and alkynyl are as described above. Preferably, it is C 2-8 alkynyl C 1-10 alkyl, more preferably C 2-8 alkynyl C 1-8 alkyl, further preferably C 2-8 alkynyl C 1-6 alkyl, further preferably C 2-8 alkynyl C 1-3 alkyl.
  • Non-limiting examples of cycloalkylalkyl include -H 2 CC ⁇ CH, -CH 2 CH 2 -C ⁇ CH, wait.
  • Heterocycloalkylalkyl refers to an alkyl group substituted by one or more heterocycloalkyl groups, wherein alkyl and heterocycloalkyl are as defined above.
  • it is a 4- to 10-membered heterocycloalkylC 1-6 alkyl group, more preferably a 4- to 8-membered heterocycloalkylC 1-3 alkyl group, further preferably a 3- to 6-membered heterocycloalkylC 1-3 alkyl group, further preferably a 4- to 6 - membered heterocycloalkylC 1-3 alkyl group.
  • heterocycloalkylalkyl groups include -CH 2 -tetrahydropyrrolyl, -CH 2 -azetidinyl, -CH 2 -piperidinyl, -CH 2 -piperazinyl, and the like.
  • “Hydroxy-substituted alkyl” refers to an alkyl group substituted with one or more hydroxy groups, wherein the definition of alkyl is as described above. Preferably, it is a C 1-10 alkyl group substituted with hydroxy groups, more preferably a C 1-8 alkyl group substituted with hydroxy groups, further preferably a C 1-6 alkyl group substituted with hydroxy groups, and more preferably a C 1-3 alkyl group substituted with hydroxy groups.
  • Non-limiting examples of "hydroxy-substituted alkyl group” include -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , and the like.
  • Cyano-substituted alkyl refers to an alkyl group substituted with one or more cyano groups, wherein the definition of alkyl is as described above. Preferably, it is a cyano-substituted C 1-10 alkyl group, more preferably a cyano-substituted C 1-8 alkyl group, further preferably a cyano-substituted C 1-6 alkyl group, further preferably a cyano-substituted C 1-3 alkyl group.
  • Non-limiting examples of "cyano-substituted alkyl” include -CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , and the like.
  • Step 4 Dissolve Z11-c (25 mg, 0.05 mmol) in DMSO (2 mL), then add CuI (17.14 mg, 0.09 mmol), sodium methanesulfinate (8.82 mg, 0.09 mmol), and microwave for 20 minutes at 120 ° C, and then microwave for 3 hours at 100 ° C. After the reaction is completed, pour the reaction solution into water, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain Z11-d (18 mg, light yellow solid, crude product), which is used in the next step without further purification. MS m/z (ESI): 647.3 [M + H] + .
  • Step 5 Dissolve Z11-d (50 mg, 0.08 mmol) in ethyl acetate (2 mL), add hydrochloric acid ethyl acetate solution (4 mol/L, 2 mL), and stir at 25°C for 18 hours. After the reaction is completed, filter, wash the filter cake twice with ethyl acetate, and dry the filter cake to obtain intermediate Z11 (36 mg, white solid), yield: 96.4%. MS m/z (ESI): 447.2 [M+H] + .
  • Step 1 Dissolve 3-bromo-6-chloro-2-fluoropyridine (8.8 g, 41.82 mmol) in ethanol (40 mL), add hydrazine hydrate (2.96 g, 50.18 mmol, purity 85%), heat to 80°C and stir overnight at 80°C. After the reaction is completed, concentrate the reaction solution to obtain Z12-a (9.3 g), yield: 99.96%. Used directly in the next step. MS m/z (ESI): 221.9 [M+H] + .
  • Step 3 Z12-b (2 g, 8.60 mmol), (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (3.31 g, 19.79 mmol) and ethanol (1 mL) were mixed and stirred at 85°C for 20 hours. After the reaction was completed, the reaction solution was concentrated and purified by CombiFlash (0-10% MeOH/DCM) to obtain intermediate Z12 (1.2 g, yellow solid) with a yield of 38.40%. MS m/z (ESI): 365.0 [M+2H] + .
  • Step 1 To a solution of 8-bromo-5-(((5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl)amino)imidazo[4,3-f]pyrimidine (100 mg, 0.28 mmol) in ethylene glycol dimethyl ether (2 mL) and water (0.2 mL) were added methyl 5-bromo-6-methylpyridine-2-carboxylate (126 mg, 0.55 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,-5-tetramethyl-1,3,2-dioxaborosilanan-2-yl)-1,3,2-dioxaborolane (174 mg, 0.69 mmol), n-butyldi(1-adamantyl)phosphine (39 mg, 0.11 mmol), K2CO3 ( 152 mg, 1.10 mmol) and Pd(OAC) 2 (12 mg, 0.06 mmol), the mixture was stirred at 70 ° C
  • Step 2 At 0°C, under nitrogen atmosphere, NIS (22 mg, 0.10 mmol) was added to a DMF (1.5 mL) solution of Z13-a (25 mg, 0.06 mmol), and the mixture was stirred at 0°C under nitrogen atmosphere for 30 minutes.
  • the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give Z13-b (20 mg, yellow liquid, crude product), yield: 43.3%.
  • Step 3 Lithium hydroxide monohydrate (10 mg, 0.43 mmol) was added to a solution of Z13-b (20 mg, 0.03 mmol) in methanol (1 mL) and water (0.2 mL), and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain intermediate Z13 (22 mg, yellow solid), yield: 96.7%. MS m/z (ESI): 546.0 [M+H] + .
  • Step 2 Dissolve Z15-a (45 mg, 90.31 ⁇ mol) in MeOH (5 mL), add a solution of NaOH (3.61 mg, 90.31 ⁇ mol) in methanol/water (5 mL/0.5 mL) under stirring at room temperature, and stir at room temperature for 3 hours. After the reaction is completed, adjust the pH value of the reaction solution to 4-5 with concentrated hydrochloric acid under ice bath conditions, and concentrate to obtain intermediate Z15 (43.73 mg, yellow solid, crude product), yield: 100.00%. MS m/z (ESI): 484 [M+H] + .
  • Step 1 Dissolve the intermediate Z9 (170 mg, 419.36 ⁇ mol) in DMF (10 mL), and slowly add NCS (56.00 mg, 419.36 ⁇ mol) in batches under an ice bath. After the reaction is completed, add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the intermediate Z16 (150 mg, yellow solid), yield: 81.3%. MS m/z (ESI): 440.1 [M+H] + .
  • Step 1 Dissolve Z10-a (323 mg, 0.77 mmol) in ultra-dry DCM (15 mL), add select-Fluor (409 mg, 1.16 mmol), and stir at room temperature for 20 hours. After the reaction is completed, pour the reaction solution into water, extract with dichloromethane (30 mL ⁇ 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by CombiFlash (0-10% MeOH/DCM) to obtain Z17-a (35 mg, yellow solid), yield: 10.39%. MS m/z (ESI): 438.1 [M+H] + .
  • Step 4 Dissolve compound Z21-1 (200 mg, 346.00 ⁇ mol) in ethyl acetate (10 mL), add Pd/C (42.02 mg, 346.00 ⁇ mol), and stir at room temperature for 2 hours under hydrogen protection. LC-MS detection. The reaction solution was filtered and concentrated under reduced pressure to obtain a colorless oil compound Z21-2 (190 mg, 327.56 ⁇ mol, 94.67% yield). MS m/z (ESI): 524.2 [M-56+H] + .
  • Step 5 Z45-d (500 mg, 1.24 mmol) and tert-butyl 4-oxopiperidin-1-carboxylate (1.49 g, 7.47 mmol) were dissolved in DMSO (9 mL) and EtOH (3 mL), and then NaBH 3 CN (781.88 mg, 12.44 mmol) and AcOH (373.58 mg, 6.22 mmol) were added thereto, and the reaction was stirred for 0.7 hours under microwave conditions at 85°C.
  • Step 3 Dissolve the compound 8-ethynyl-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (65 mg, 0.2 mmol) and tert-butyl 4-azidopiperidine-1-carboxylate (130 mg, 0.58 mmol) in t-BuOH (5 mL) and water (1 mL), add sodium ascorbate (12 mg, 70 ⁇ mol) and CuSO 4 5H 2 O (7 mg, 29 ⁇ mol), replace the mixed solution with argon and stir at 70°C for 12 hours.
  • Step 1 Dissolve 4,5-dibromo-2H-triazole (5 g, 22.04 mmol) and 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (6.46 g, 23.14 mmol) in DMF (110 mL), add Cs 2 CO 3 (21.54 g, 66.12 mmol). The reaction solution was stirred at 100°C overnight. The reaction solution was poured into water, extracted with ethyl acetate (30 ml ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 Dissolve tert-butyl 4-(4-bromotriazol-2-yl)piperidin-1-carboxylate (490 mg, 1.48 mmol) in THF (20 mL), cool to -78 °C, and slowly drop n-BuLi (2.5 M, 769.30 ⁇ L). Stir the reaction solution at -78 °C for 0.5 h, then add 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (551 mg, 2.96 mmol). Slowly warm the reaction solution to room temperature and continue stirring for 2 hours. Cool the reaction solution to 0 °C, and drop saturated NH 4 Cl solution to quench the reaction.
  • Step 4 8-Bromo-1-chloro-N-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]imidazo[1,5-c]pyrimidin-5-amine (100 mg, 251.49 ⁇ mol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)triazol-2-yl]piperidine-1-carboxylate (114.16 mg, 301.79 ⁇ mol) were dissolved in dioxane (12 mL) and water (2 mL), and PdCl 2 (dppf) (18.40 mg, 25.15 ⁇ mol) and potassium carbonate (69.51 mg, 502.98 ⁇ mol) were added.
  • Step 5 Dissolve tert-butyl 4-[4-[1-chloro-5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]triazol-2-yl]piperidine-1-carboxylate (22 mg, 38.66 ⁇ mol) in dichloromethane (10 mL) and add trifluoroacetic acid (3 mL). The reaction solution was stirred at room temperature for 2 hours.
  • Step 1 Compound 8-bromo-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (570 mg, 1.5 mmol), n-butyldi(1-adamantyl)phosphine (214 mg, 598 umol), diacetoxypalladium (67 mg, 300 ⁇ mol), K 2 CO 3 (620 mg, 4.48 mmol) and (Pin) 2 B 2 (1140 mg, 4.48 mmol) were added sequentially to a mixed solution of DME (100 mL) and water (10 mL). After nitrogen replacement three times, the reaction solution was reacted at 70° C.
  • Step 2 Dissolve Z58-a (198.72 mg, 603.85 ⁇ mol) and tert-butyl 4-(3-bromo-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate (200 mg, 603.85 ⁇ mol) in dioxane (8 mL) and water (1 mL), and add Pd(dppf)Cl 2 (44.18 mg, 60.38 ⁇ mol) and K 2 CO 3 (166.92 mg, 1.21 mmol) under argon protection. Heat to 120°C and stir for 2 hours.
  • Step 2 Dissolve Z62-a (2.2 g, 8.49 mmol) and diboronic acid pinacol ester (3.23 g, 12.74 mmol) in dioxane (30 mL), add potassium acetate (2.50 g, 25.47 mmol) and Pd(dppf)Cl 2 (621.29 mg, 849.09 ⁇ mol) under argon protection. Heat to 95 °C and stir overnight. Filter off the solid and concentrate under reduced pressure to obtain a crude product. The residue was separated by CombiFlash column (20 g, 0-30% EA/PE) to obtain Z62-b (2.4 g, 7.84 mmol, 92.32% yield) as a light yellow solid. MS m/z (ESI): 307.2 [M+H] + .
  • Step 4 Dissolve Z62-c (0.3 g, 603.72 ⁇ mol) in THF (10 mL), cool to -78 °C under argon protection, and slowly add DIBAL-H (1 M, 2.41 mL). Stir at low temperature for 3 hours. Add saturated aqueous ammonium chloride solution at low temperature to quench the reaction, add a large amount of anhydrous sodium sulfate and ethyl acetate, filter out the solid, and concentrate the mother liquor under reduced pressure to obtain a crude product. The residue was separated by CombiFlash column (4 g, 0-60% EA/PE) to obtain Z62 (0.2 g, 456.77 ⁇ mol, 75.66% yield), a light yellow solid. MS m/z (ESI): 438.1 [M+H] + .
  • Step 1 Under argon protection, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (1g, 2.75mmol) was dissolved in THF (50mL) and n-BuLi (2.5M, 5.49mL) was added dropwise at -78°C. After reacting at -78°C for 1 hour, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane was slowly added dropwise, and then reacted at -78°C for 1 hour.
  • Step 2 6-bromo-3-iodo-2-methylpyridine (1 g, 3.36 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.04 g, 3.36 mmol) were dissolved in 1,4-dioxane (20 mL), water (4 mL), and DMSO (2 mL), and then Pd(dppf)Cl 2 (245.60 mg, 335.66 ⁇ mol) and K 2 CO 3 (927.84 mg, 6.71 mmol) were added. The reaction was stirred at 65° C. for 3 hours.
  • Step 3 Under argon protection, Z64-b (153.50 mg, 434.53 ⁇ mol), Z64-a (110 mg, 334.25 ⁇ mol), Pd(dppf)Cl 2 (43.17 mg, 66.85 ⁇ mol), K 2 CO 3 (115.49 mg, 835.63 ⁇ mol), 1,4-dioxane (10 mL), and water (0.5 mL) were mixed and heated at 100°C for 3 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated, washed with saturated brine, and concentrated to obtain a crude product.
  • Step 4 Z64-c (70 mg, 125.53 ⁇ mol), platinum dioxide (2.85 mg, 12.55 ⁇ mol), methanol (2 mL) and EA (2 mL) were stirred at room temperature for 6 hours under hydrogen atmosphere. The reaction solution was filtered and concentrated to obtain Z64-d (70 mg, 125.08 ⁇ mol, yield 99.64%), a yellow solid oil. The crude product was directly used in the next step. MS m/z (ESI): 560.3 [M+H] + .
  • Step 1 4-(tert-Butyloxycarbonyl)amino)butyric acid (502.84 mg, 2.47 mmol) and (2S,4R)-1-((S)-2-amino-3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1 g, 2.25 mmol) were dissolved in DMF (25 mL), and DIPEA (872.09 mg, 6.75 mmol, 1.18 mL) and HATU (1.27 g, 3.37 mmol) were added. The reaction was stirred at room temperature for 1 hour, and the reaction solution was then dried under reduced pressure.
  • Step 2 Z67-a (0.8 g, 1.27 mmol) was dissolved in DCM (20 mL), and then HCl (4 M in EA, 5 mL) was added. The reaction was stirred at room temperature for 1 hour, and then the reaction solution was concentrated to obtain a yellow solid product Z67-b (719 mg, 1.27 mmol, 99.98% yield, HCl). MS m/z (ESI): 530.3 [M+H] + .
  • Step 3 Dissolve 5-bromo-4-chloro-2-(methylthio)pyrimidine (9.66 g, 43.84 mmol) in DMF (120 mL), lower the temperature to 0°C, then add NaH (3.19 g, 83.34 mmol, 60% purity) in batches, and stir the reaction at 0°C for 1 hour. Then, add a solution of 5-bromo-4-chloro-2-methylaminopyrimidine (10 g, 41.75 mmol) in DMF (120 mL) dropwise into the reaction solution, warm the temperature to room temperature and stir for 2 hours.
  • Step 4 Add HCl (3M, 30 mL) aqueous solution to Z67-c (15 g, 35.43 mmol) in THF (200 mL) at 0°C, stir the reaction solution at room temperature for 1 hour, then concentrate the reaction solution, alkalize to pH 8-9 with Na 2 CO 3 aqueous solution, extract with DCM (500 mL ⁇ 2), wash with saturated brine (100 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to successfully obtain a red oily product Z67-d (8.5 g, 32.80 mmol, 92.57% yield).
  • Step 5 A mixture of formic acid (39 g, 720.26 mmol, 31.97 mL, 85% purity) and acetic anhydride (34.8 g, 328.21 mmol, 32.01 mL) was heated at 50 ° C for 1 hour, and then the reaction mixture was cooled to room temperature and added to a DCM (100 mL) solution of Z67-d (8.5 g, 32.80 mmol), and the reaction solution was stirred at room temperature for 2 hours.
  • formic acid 39 g, 720.26 mmol, 31.97 mL, 85% purity
  • acetic anhydride 34.8 g, 328.21 mmol, 32.01 mL
  • Step 2 Dissolve 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]imidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylic acid methyl ester (323 mg, 0.77 mmol) in tetrahydrofuran (10 mL), cool to 0°C, add N-iodosuccinimide (173 mg, 0.77 mmol), and stir the reaction solution at 0°C for 1 hour. The reaction solution was poured into water, extracted with DCM (100 ml ⁇ 3), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • Step 3 Dissolve 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-1-iodoimidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylic acid methyl ester (350 mg, 0.64 mmol) in DMF (15 mL), add CuI (1.22 g, 6.42 mmol), PdCl 2 (dppf) (47 mg, 0.064 mmol) and methyl 2,2-difluoro-2-fluorosulfonylacetate (1.23 g, 6.42 mmol). The reaction solution was stirred at 90° C. overnight under argon protection.
  • Step 4 Dissolve 5-[5-[(5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamino]-1-(trifluoromethyl)imidazo[1,5-c]pyrimidin-8-yl]pyridine-2-carboxylic acid methyl ester (100 mg, 0.21 mmol) in tetrahydrofuran (15 mL) and add potassium trimethylsilanol (40 mg, 0.31 mmol). The reaction solution was stirred at room temperature for 4 hours. The reaction solution was separated by CombiFlash (0-80% MeOH/DCM) to obtain a yellow solid product Z68 (50 mg, 51.48% yield). MS m/z (ESI): 474.1 [M+H] + .
  • Step 1 Add the compound 8-bromo-1-fluoro-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (760 mg, 2 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (754 mg, 2 mmol), potassium carbonate (828 mg, 6 mmol) and catalyst 1,1-bis(diphenylphosphine)diferroni palladium dichloride (146 mg, 0.2 mmol) to a mixed solvent of 5 ml 1,4-dioxane and 1 ml water, replace with nitrogen three times, then heat at 100° C.
  • Step 2 Compound H159-a (552 mg, 1 mmol) was added to a mixed solvent of 5 ml dichloromethane and 1 ml trifluoroacetic acid, stirred at room temperature for 1 hour, and then concentrated to dryness by oil pump to obtain compound H159-b (451 mg, 1 mmol). Yield: 100%. MS m/z (ESI): 452 [M+H] + .
  • Step 1 Under argon protection, 1-bromo-4-iodobenzene (8.20 g, 28.98 mmol), 3-aminocyclobutanecarboxylic acid methyl ester hydrochloride (4 g, 24.15 mmol), L-proline (1.11 g, 9.66 mmol), cuprous iodide (919.95 mg, 4.83 mmol), potassium carbonate (6.68 g, 48.30 mmol), and DMSO (40 mL) were mixed and heated to 80 ° C for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate (20 mL ⁇ 2), and the organic layers were combined, washed, and concentrated to obtain a crude product.
  • Step 2 Under argon protection, H80-a (730 mg, 2.01 mmol), 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine (628.25 mg, 2.21 mmol), palladium acetate (90.25 mg, 402.00 ⁇ mol), n-butyldi(1-adamantyl)phosphine (144.13 mg, 402.00 ⁇ mol), potassium carbonate (1.11 g, 8.04 mmol), biboronic acid pinacol ester (1.02 g, 4.02 mmol), DME (20 mL), water (2 mL) were mixed and heated at 70 ° C for 16 hours.
  • Step 3 Mix H80-b (490 mg, 804.06 ⁇ mol), THF (20 mL), and TFA (2 mL) and stir at room temperature for 5 minutes, then cool to -15 °C and add N-iodosuccinimide (180.90 mg, 804.06 ⁇ mol), and react at -15 °C for 15 minutes. Pour the reaction solution into ice water, add protective sodium bicarbonate solution to adjust pH>7, and then extract with ethyl acetate (10 mL ⁇ 2), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product.
  • Step 4 Add lithium hydroxide (5.86 mg, 244.53 ⁇ mol) to a solution of H80-c (50 mg, 81.51 ⁇ mol) and THF (2 mL) and water (0.5 mL) at room temperature, and react at room temperature for 1 hour. Concentrate the reaction solution and add 1N HCl to adjust the pH to ⁇ 3. The aqueous phase is lyophilized to obtain H80-d (48 mg, 80.08 ⁇ mol, yield 98.25%) as a white solid. MS m/z (ESI): 600.2 [M+H] + .
  • Step 1 Under argon protection, 1-bromo-4-iodobenzene (13.33 g, 47.10 mmol), 4-(dimethoxymethyl)piperidine (5 g, 31.40 mmol), L-proline (1.45 g, 12.56 mmol), cuprous iodide (1.20 g, 6.28 mmol), potassium carbonate (8.68 g, 62.80 mmol), and DMSO (50 mL) were mixed and heated to 80°C for 16 hours.
  • Step 2 Add TFA (5 mL) to a DCM (10 mL) solution of H87-a (6.1 g, 19.41 mmol) at room temperature, and react at room temperature for 1 hour. Concentrate the reaction solution to obtain a crude product, dissolve the crude product in dichloromethane, add saturated sodium bicarbonate solution and wash once, wash once with saturated brine, dry with anhydrous sodium sulfate and concentrate to obtain H87-b (5 g, 18.65 mmol, yield 96.05%), a yellow liquid. The crude product is directly used in the next step. MS m/z (ESI): 268.1 [M+H] + .
  • Step 3 Add NaBH(OAC) 3 (13.66 g, 64.43 mmol) to a solution of tert-butyl piperazine-1-carboxylate (3 g, 16.11 mmol), H87-b (4.75 g, 17.72 mmol), DCM (50 mL) and AcOH (0.5 mL), and react at room temperature for 3 hours. Pour the reaction solution into water, extract with dichloromethane (10 mL ⁇ 2), combine the organic layers, wash with saturated brine and concentrate to obtain a crude product.
  • Step 4 Add TFA (10 mL) to a solution of H87-c (4.8 g, 10.95 mmol) in DCM (20 mL) at room temperature, and react at room temperature for 1 hour. Concentrate the reaction solution and then add dichloromethane. Add saturated sodium bicarbonate solution to adjust pH>8. Collect the organic phase, dry it over anhydrous sodium sulfate, and concentrate to obtain H87-d (4 g, 8.84 mmol, 80.77% yield, TFA), a yellow solid. The crude product is directly used in the next step. MS m/z (ESI): 338.2 [M+H] + .
  • Step 5 Mix H87-d (4 g, 8.84 mmol), methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (6.38 g, 13.27 mmol), DIPEA (3.43 g, 26.53 mmol, 4.62 mL), and DMSO (50 mL) and heat to 110 ° C for 16 hours. Pour the reaction solution into ice water, extract with ethyl acetate (30 mL ⁇ 2), wash the combined organic layers with water three times, wash once with saturated brine, and then dry with anhydrous sodium sulfate and concentrate to obtain a crude product.
  • Step 6 H87-e (1 g, 1.93 mmol) and biboronic acid pinacol ester (1.47 g, 5.78 mmol) were dissolved in 1,4-dioxane (20 mL), and Pd(dba) 2 (218.28 mg, 385.01 ⁇ mol) and PCy3 (259.12 mg, 924.01 ⁇ mol) were added under argon protection, and the temperature was raised to 120°C and stirred for 24 hours. The reaction solution was filtered and the filtrate was concentrated to obtain a crude product.
  • Step 7 Under argon protection, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (400 mg, 1.10 mmol), H87-f (684.50 mg, 1.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (80.37 mg, 109.84 ⁇ mol), potassium carbonate (455.41 mg, 3.30 mmol), 1,4-dioxane (20 mL) and DMSO (1 mL) were mixed and heated at 100°C for 2 hours.
  • Step 1 Dissolve dibromohydroxycarbonate (25g, 123.25mmol) in EA (250mL) and water (25mL), add 3-butyn-1-ol (34.56g, 493.02mmol), NaHCO 3 (31.80g, 369.76mmol) and react at room temperature for 3 hours. Filter the reaction solution, add water to the filtrate and separate the layers, extract with ethyl acetate twice, wash once with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry to obtain a crude product.
  • Step 2 Dissolve 2-(3-bromoisoxazol-5-yl)ethanol-1-ol (18 g, 93.74 mmol) in acetone (150 mL) at 0°C, add Jones reagent (100 mL), and react at room temperature for 16 hours. The reaction solution was slowly poured into ice water, extracted twice with ethyl acetate, and the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2-(3-bromoisoxazol-5-yl)acetic acid (16.8 g, 81.56 mmol, yield 87.00%), a brown liquid, and the crude product was directly used in the next step. MS m/z (ESI): 203.7 [M+H] + .
  • Step 3 Dissolve 2-(3-bromoisoxazol-5-yl)acetic acid (16 g, 77.67 mmol) in methanol (100 mL) and add concentrated sulfuric acid (2 mL) at 70 ° C for 1 hour. After the reaction solution is concentrated to a small volume, water is added, extracted with dichloromethane (50 mL ⁇ 2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • Step 4 Dissolve 2-(3-bromoisoxazol-5-yl)acetic acid methyl ester (14g, 63.63mmol) in THF (150mL) under ice bath, add potassium tert-butoxide (10.69g, 95.27mmol), stir for 10min, slowly add 2-iodopropane (14.06g, 82.72mmol, 8.26mL), react at room temperature for 16 hours.
  • Step 5 Add 2-(3-bromoisoxazol-5-yl)-3-methylbutyric acid methyl ester (8g, 30.52mmol), potassium hydroxide (8.56g, 152.61mmol), methanol (45mL), and water (5mL) into a pressure autoclave and react at 110°C for 16 hours.
  • Step 6 Heat 2-(3-methoxyisoxazol-5-yl)-3-methylbutyric acid (5 g, 25.10 mmol) and HBr/AcOH (20 mL) at 80°C for 0.5 hours. Concentrate the reaction solution to obtain 2-(3-hydroxyisoxazol-5-yl)-3-methylbutyric acid (4.6 g, 24.84 mmol, yield 98.97%), a yellow liquid, and the crude product is directly used in the next step. MS m/z (ESI): 186.1 [M+H] + .
  • Step 7 Add thionyl chloride (13.30 g, 111.78 mmol, 8.12 mL) dropwise to a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methylbutyric acid (4.6 g, 24.84 mmol) in methanol (50 mL), and react at room temperature for 2 hours. After the reaction solution is concentrated to dryness, water is added and extracted with ethyl acetate (20 mL ⁇ 2). The combined organic layers are washed with saturated brine and concentrated to obtain a crude product.
  • Step 2 Add HCl/1,4-dioxane (15 mL) to a solution of H64-c (5.1 g, 16.02 mmol) and DCM (30 mL) at room temperature, and react at room temperature for 2 hours. Filter the reaction solution and collect the solid to obtain H64-d (4 g, 15.70 mmol, 98.03% yield, HCl) as a yellow solid. MS m/z (ESI): 219.1 [M+H] + .
  • Step 3 At room temperature, H64-d (4.34 g, 18.76 mmol), HATU (7.81 g, 20.54 mmol), DIPEA (6.93 g, 53.59 mmol, 9.33 mL), and DMF (50 mL) were mixed and then rac-(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethylamine (3.9 g, 17.86 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water, and the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 2).
  • Step 4 H64-e (1 g, 2.32 mmol) was dissolved in HCl/1,4-dioxane (4 M) (20 mL) and stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure to obtain crude product H64-f (720 mg, 2.17 mmol, 93.75% yield) as a pink solid. The crude product was directly reacted in the next step. MS m/z (ESI): 332.2 [M+H] + .
  • Step 1 Under argon protection, 1-bromo-4-iodobenzene (6.40 g, 22.61 mmol), 4-(dimethoxymethyl)piperidine (3 g, 18.84 mmol, HCl), L-proline (867.68 mg, 7.54 mmol), cuprous iodide (717.66 mg, 3.77 mmol), potassium carbonate (5.21 g, 37.68 mmol), and DMSO (40 mL) were mixed and heated to 80 ° C for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate (20 mL ⁇ 2), and the combined organic layers were washed with saturated brine and concentrated to obtain a crude product.
  • Step 2 Under argon protection, 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (500 mg, 1.37 mmol), H65-a (474.55 mg, 1.51 mmol), palladium acetate (61.65 mg, 274.60 ⁇ mol), n-butyldi(1-adamantyl)phosphine (98.45 mg, 274.60 ⁇ mol), potassium carbonate (759.01 mg, 5.49 mmol), biboronic acid pinacol ester (697.30 mg, 2.75 mmol), DME (20 mL), and water (2 mL) were mixed and heated to 85° C.
  • Step 6 At room temperature, H65-e (80 mg, 226.36 ⁇ mol), H64-f (75.02 mg, 226.36 ⁇ mol), DIPEA (87.77 mg, 679.09 ⁇ mol, 118.29 ⁇ L), and DMF (5 mL) were mixed and HATU (102.48 mg, 271.64 ⁇ mol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was added with ice water and extracted with ethyl acetate (15 mL ⁇ 2). The organic layers were combined, washed with saturated brine, and concentrated to obtain a crude product.
  • Step 5 Dissolve the compound 5',7'-dioxaspiro[indane-1,8'-pyrido[4,3-c]pyridazine]-5-carboxylic acid tert-butyl ester (226.03 mg, 618.62 ⁇ mol) in acetonitrile (10 mL), add phosphorus oxychloride (474.27 mg, 3.09 mmol) and diisopropylethylamine (799.52 mg, 6.19 mmol, 1.08 mL) under argon protection, heat to 80 degrees and stir for 25 minutes, cool to room temperature, add (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (517.10 mg, 3.09 mmol), and stir at room temperature for 2 hours.
  • Step 1 Compound 3-(hydroxymethyl)azetidine-1-carboxylic acid benzyl ester (5.0 g, 22.60 mmol) was dissolved in dichloromethane (60 mL), and (1,1-diacetoxy-3-oxo-1,2-benzoiodine-1-yl) acetate (14.38 g, 33.90 mmol) was added with stirring at room temperature, and stirred at room temperature for 2 hours.
  • Step 2 Compound 3-formylazetidine-1-carboxylic acid benzyl ester (5.0 g, 22.81 mmol) was dissolved in methanol (100 mL), trimethyl orthoformate (12.10 g, 114.03 mmol) and 4-methylbenzenesulfonic acid (196.37 mg, 1.14 mmol) were added under stirring at room temperature, and stirred overnight at room temperature. LC-MS detection.
  • Step 3 Compound 3-(dimethoxymethyl)azetidine-1-carboxylic acid benzyl ester (668.62 mg, 2.52 mmol) was dissolved in methanol (20 mL), palladium carbon (576.39 mg, 541.62 ⁇ mol, 10% purity) was added, and stirred at room temperature for 2 hours under hydrogen protection. LC-MS detection. The reaction solution was filtered and concentrated under reduced pressure to obtain a colorless oil 3-(dimethoxymethyl)azetidine (330 mg, 2.52 mmol, 99.82% yield). MS m/z (ESI): 132 [M+H] + .
  • Step 5 3-(2,6-dibenzyloxy-3-pyridyl)-6-[3-(dimethoxymethyl)azetidin-1-yl]-1-methylindazole (0.8 g, 1.45 mmol) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), and palladium carbon (154.61 mg, 145.28 ⁇ mol, 10% purity) was added. Hydrogen was replaced three times and stirred at room temperature overnight under a hydrogen atmosphere. The hydrogen was replaced again, heated to 40 degrees and stirred for 4 hours. LCMS showed that the product was generated.
  • Step 3 [1-(4-amino-2-fluorophenyl) hexahydropyridin-4-yl] dimethoxymethane (1.6 g, 5.22 mmol), 2,6-bis(benzyloxyalkyl)-3-bromopyridine (1.93 g, 5.22 mmol), 2-(2-aminophenyl) 1-benzenesulfonate palladium, ⁇ 2-[2,6-bis(propan-2-yloxyalkyl)phenyl]phenyl ⁇ dicyclohexylphosphine (0.44 g, 0.52 mmol), cesium carbonate (5.10 g, 15.65 mmol) were dissolved in 1,4-dioxane (50 mL), and the mixture was stirred at 100 ° C.
  • Step 1 (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid (1.2 g, 5.57 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2 g, 4.65 mmol) were added to DMF (2 mL), followed by HATU (2.12 g, 5.57 mmol) and DIPEA (2 mL), and stirred at room temperature for 10 minutes.
  • Step 2 H5-a (320 mg, 678.71 ⁇ mol) was dissolved in THF (9 mL) and water (5 mL), LiOH (211.30 mg, 8.82 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the pH was neutralized with dilute hydrochloric acid (2 mol/L) to pH 3-4, and the mixture was concentrated to obtain H5-b (300 mg, light yellow solid), yield: 96.62%. MS m/z (ESI): 458.1 [M+H] + .
  • Step 3 Dissolve 2-(4-(2-((tert-butoxycarbonyl)amino)ethoxy)phenoxy)acetic acid (560 mg, 1.8 mmol) in DMF (3 mL), add (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (774 mg, 1.8 mmol), HATU (683 mg, 1.8 mol) and DIPEA (230 mg, 0.44 mmol) and stir at room temperature for 18 hours.
  • Step 5 H5-b (150 mg, 327.90 ⁇ mol) and H5-d (245.44 mg, 393.48 ⁇ mol) were dissolved in DMF (6 mL), and DIPEA (127.14 mg, 983.70 ⁇ mol, 171.34 ⁇ L) and HATU (185.56 mg, 491.85 ⁇ mol) were added, and stirred at room temperature for 18 hours.

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Abstract

La présente demande concerne un composé bifonctionnel tel que représenté dans la formule (I). De plus, un sel pharmaceutiquement acceptable ou un stéréo-isomère, une composition pharmaceutique et l'utilisation du composé sont en outre divulgués dans la présente demande. Le composé de la présente demande a un bon effet de dégradation sur l'EED, a un bon effet d'inhibition sur la prolifération cellulaire de cellules tumorales, et a un effet de traitement potentiel sur les tumeurs. POI—(L) n0—ULM (I).
PCT/CN2024/141290 2023-12-22 2024-12-23 Dérivé cyclique hétéroaromatique fusionné bicyclique, composition pharmaceutique et utilisation associées Pending WO2025131111A1 (fr)

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Cited By (2)

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WO2026012504A1 (fr) * 2024-07-12 2026-01-15 杭州普罗提奥医药科技有限公司 Composé de liaison à crbn pour dégrader une protéine cible et utilisation d'un composé
CN121735952A (zh) * 2026-02-26 2026-03-27 山东齐都药业有限公司 维立西呱的制备方法及其中间产物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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