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WO2024217481A1 - Agent de dégradation d'egfr, composition pharmaceutique et utilisation associées - Google Patents

Agent de dégradation d'egfr, composition pharmaceutique et utilisation associées Download PDF

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Publication number
WO2024217481A1
WO2024217481A1 PCT/CN2024/088489 CN2024088489W WO2024217481A1 WO 2024217481 A1 WO2024217481 A1 WO 2024217481A1 CN 2024088489 W CN2024088489 W CN 2024088489W WO 2024217481 A1 WO2024217481 A1 WO 2024217481A1
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Prior art keywords
pharmaceutically acceptable
mmol
stereoisomer
acceptable salt
amino
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PCT/CN2024/088489
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English (en)
Chinese (zh)
Inventor
潘建峰
孙大庆
石谷沁
孙维梅
夏婷婷
韦韦
方滟佳
陶维康
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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Priority to CN202480026096.0A priority Critical patent/CN121013856A/zh
Publication of WO2024217481A1 publication Critical patent/WO2024217481A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07D401/14—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
    • 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
    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present disclosure belongs to the field of pharmaceutical chemistry, and specifically relates to a novel bifunctional compound capable of degrading EGFR, a pharmaceutical composition containing the compound, a preparation method thereof, and a method of using the disclosed compound and the composition thereof to treat EGFR-mediated cancer.
  • PROTAC technology Proteolysis Targeting Chimeria
  • UPS ubiquitin-proteasome system
  • PROTAC is a bifunctional small molecule triplet compound, which can be divided into three parts: target protein ligand, linker, and E3 ligase ligand (degradation determinant).
  • target protein Protein of Interest, POI
  • POI Protein of Interest
  • the target protein ligand in its structure can specifically bind to the corresponding target protein, while the other end can recruit E3 ligase to form a POI-Linker-E3 ligase ternary complex, in which E3 ligase can mediate ubiquitination of POI by ubiquitin-binding enzyme E2.
  • POI tagged with ubiquitin is recognized and degraded by the proteasome.
  • PROTAC is an event-driven pharmacological action mode. This process does not require the target protein ligand to occupy the binding site for a long time. Only the brief formation of the ternary complex is required to instantaneously complete the ubiquitination of the target protein, and the PROTAC molecule can be recycled multiple times in the cell. Therefore, compared with traditional small molecule inhibitors and large molecule antibodies, PROTAC has obvious advantages and is expected to target those difficult-to-drug proteins for drug development. It may also have the advantages of small dosage, low toxicity, independence from affinity, high selectivity, and overcoming drug resistance caused by target protein mutations/overexpression.
  • VEGFR vascular endothelial growth factor receptor
  • VEGFR-1 vascular endothelial growth factor receptor
  • VEGFR-2 vascular endothelial growth factor receptor
  • the present disclosure aims to develop a bifunctional small molecule triplet compound that can specifically degrade EGFR protein.
  • the targeting ligand can specifically bind to the target protein, such as EGFR and/or mutated EGFR, and is connected to the linker through a covalent bond in the triplet compound;
  • the linker is a connecting group between the targeting ligand and the degradation determinant, one end of which is covalently bound to the targeting ligand and the other end is covalently bound to the degradation determinant;
  • the degradation determinant can bind to the ubiquitin ligase, such as E3 ubiquitin ligase, and is covalently bound to the linker.
  • Ring A is selected from 5-6 membered heterocycloalkyl, which may be optionally substituted by 1-3 groups selected from the following groups: halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl;
  • R1 is selected from substituted or unsubstituted 5-6 membered heteroaryl
  • R 2 is selected from C 2-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, 2, m2 is selected from 0, 1, 2, and C 2-6 alkoxy may be optionally substituted by 1, 2, or 3 halogens;
  • R3 is selected from halogen, C1-4 alkyl, C1-4 haloalkyl
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl;
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form a C 6-10 aryl, a 5-6 membered heterocycloalkyl, or a 5-6 membered heteroaryl, wherein the C 6-10 aryl, the 5-6 membered heterocycloalkyl, or the 5-6 membered heteroaryl may each independently be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy, and q is selected from 1, 2, or 3;
  • Z is selected from N or CH
  • the linker is selected from a saturated or unsaturated, linear or branched C1-10 alkylene chain, wherein 1-5 methylene units in the C1-10 alkylene chain can be optionally and independently replaced by the following groups: -O-, -S-, -C(O)-, -C(R L1 )(R L2 )-, -N(R L3 )-, -Cy-, wherein R L1 , R L2 , and R L3 are each independently selected from hydrogen, C1-4 alkyl, and Cy is selected from C4-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 7-11 membered spiroheterocyclyl, wherein the C4-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 7-11 membered spiroheterocyclyl can each independently and optionally be substituted by 1-3 of the following groups: halogen, C1-4 alkyl, C1-4 haloalky
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from:
  • Ring A is selected from 5-6 membered heterocycloalkyl, which may be optionally substituted by 1-3 groups selected from the following groups: halogen, hydroxyl, C 1-4 alkane C 1-4 alkoxy, C 1-4 haloalkyl;
  • R1 is selected from substituted or unsubstituted 5-6 membered heteroaryl
  • R 2 is selected from C 3-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, 2, and m2 is selected from 0, 1, 2;
  • R3 is selected from halogen, C1-4 alkyl, C1-4 haloalkyl
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl;
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form a C 6-10 aryl, a 5-6 membered heterocycloalkyl, or a 5-6 membered heteroaryl, wherein the C 6-10 aryl, the 5-6 membered heterocycloalkyl, or the 5-6 membered heteroaryl may each independently be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy, and q is selected from 1, 2, or 3;
  • Z is selected from N or CH
  • the linker is selected from a saturated or unsaturated, linear or branched C1-10 alkylene chain, wherein 1-5 methylene units in the C1-10 alkylene chain can be optionally and independently replaced by the following groups: -O-, -S-, -C(O)-, -C(R L1 )(R L2 )-, -N(R L3 )-, -Cy-, wherein R L1 , R L2 , and R L3 are each independently selected from hydrogen, C1-4 alkyl, and Cy is selected from C4-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 7-11 membered spiroheterocyclyl, wherein the C4-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 7-11 membered spiroheterocyclyl can each independently and optionally be substituted by 1-3 of the following groups: halogen, C1-4 alkyl, C1-4 haloalky
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from 5-6 membered heterocycloalkyl groups containing 1-2 nitrogen atoms;
  • R 1 is selected from Wherein, R 1a is selected from C 1-4 alkyl, C 1-4 haloalkyl;
  • R 2 is selected from C 2-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, m2 is selected from 0, 1, and C 2-6 alkoxy may be optionally substituted by 1, 2, or 3 halogens;
  • R3 is selected from halogen
  • R5 is selected from hydrogen
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl may be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and q is selected from 1, 2, 3;
  • Z is selected from N or CH
  • the linker is selected from a saturated or unsaturated, linear or branched C 1-6 alkylene chain, wherein 1-3 methylene units in the C 1-6 alkylene chain may be optionally independently replaced by the following groups: -C(O)-, -N(R L3 )-, -Cy-, wherein R L3 is selected from hydrogen, C 1-4 alkyl, Cy is selected from 4-6 membered heterocycloalkyl, 7-11 membered spiroheterocyclyl, wherein the 4-6 membered heterocycloalkyl, 7-11 membered spiroheterocyclyl may be optionally substituted by 1-3 groups selected from the following groups: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy;
  • a degron is a moiety that is capable of binding to an E3 ubiquitin ligase.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from 5-6 membered heterocycloalkyl containing 1-2 nitrogen atoms
  • R 1 is selected from Wherein, R 1a is selected from C 1-4 alkyl, C 1-4 haloalkyl;
  • R 2 is selected from C 3-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, and m2 is selected from 0, 1;
  • R3 is selected from halogen
  • R5 is selected from hydrogen
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl may be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and q is selected from 1, 2, 3;
  • Z is selected from N or CH
  • the linker is selected from a saturated or unsaturated, linear or branched C 1-6 alkylene chain, wherein 1-3 methylene units in the C 1-6 alkylene chain may be optionally independently replaced by the following groups: -C(O)-, -N(R L3 )-, -Cy-, wherein R L3 is selected from hydrogen, C 1-4 alkyl, Cy is selected from 4-6 membered heterocycloalkyl, 7-11 membered spiroheterocyclyl, wherein the 4-6 membered heterocycloalkyl, 7-11 membered spiroheterocyclyl may be optionally substituted by 1-3 groups selected from the following groups: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy;
  • a degron is a moiety that is capable of binding to an E3 ubiquitin ligase.
  • the bifunctional compound described in the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen and methyl, and R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, and phenyl.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen, and R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, and phenyl.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen, and R 6 is selected from fluorine, methyl, ethyl, cyclopropyl, and phenyl.
  • R 5 is selected from methyl
  • R 6 is selected from chlorine. In some embodiments, R 6 is fluorine.
  • the bifunctional compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, wherein R 5 , R 6 and the atoms to which they are connected are cyclized to form q and R 6a are as defined above.
  • the bifunctional compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof wherein the structural unit Selected from In some embodiments, the structural unit Selected from
  • the bifunctional compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof wherein the linker is selected from -(AK) n1- (Cy) n2- (AK) n3- (Cy) n4- (AK) n5- , wherein the AK is selected from a C1-3 alkylene chain, any methylene unit of which is optionally replaced by - C(O)-, -NH-; Cy is selected from the following divalent rings: 4-6 membered heterocycloalkyl, 7-11 membered spiroheterocyclyl, wherein the Cy may be optionally substituted by 1-3 groups independently selected from the following groups: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy; n 1 , n 2 , n 3 , n 4 , n 5 are each independently selected from 0, 1.
  • the bifunctional compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof wherein the linker is selected from -(AK) n1- (Cy) n2- , -(Cy) n2- (AK) n3- (Cy ) n4-, -(Cy) n4- (AK) n5- , -(AK)n1-(Cy) n2- (Cy) n4- , -(Cy) n2- (Cy) n4- .
  • the linker is selected from -(AK) n1- (Cy) n2- , -(Cy) n2- (AK) n3- ( Cy ) n4- , - ( Cy) n4- (AK)n5-, -(AK)n1-(Cy) n2- (Cy) n4- .
  • L 1 is a bond or NH
  • Ring C is selected from C 6-10 aryl, 5-6 membered heteroaryl, 8-10 membered fused heterocyclic group;
  • R c is selected from halogen, C 1-4 alkyl
  • R c-1 is selected from hydrogen or deuterium
  • p-1 is selected from 0, 1, 2, 3 or 4;
  • p is selected from 0, 1, 2 or 3.
  • L 1 is a bond or NH
  • Ring C is selected from C 6-10 aryl, 5-6 membered heteroaryl, 8-10 membered fused heterocyclic group;
  • R c is selected from halogen, C 1-4 alkyl
  • p is selected from 0, 1, 2 or 3.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IA), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 , Linker and Degron are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IB), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 , Linker and Degron are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IC), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 , Linker and Degron are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IA), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 , Linker and Degron are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IA-1), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 and Linker are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IA-1), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 and Linker are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IB-1), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 and Linker are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IC-1), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, R 2 and Linker are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (ID), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IE), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IF), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IG), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IH), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IJ), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the bifunctional compound of formula (IK), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • Ring A, Linker, Degron, R 3 , R 4 , R 5 , R 6 , and Z are as defined above.
  • the present disclosure also provides a compound described by formula (TL), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 5-6 membered heterocycloalkyl, which may be optionally substituted by 1-3 groups selected from the following groups: halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl;
  • R1 is selected from substituted or unsubstituted 5-6 membered heteroaryl
  • R 2 is selected from C 2-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, 2, m2 is selected from 0, 1, 2, and C 2-6 alkoxy may be optionally substituted by 1, 2, or 3 halogens;
  • R3 is selected from halogen, C1-4 alkyl, C1-4 haloalkyl
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl;
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form a C 6-10 aryl, a 5-6 membered heterocycloalkyl, or a 5-6 membered heteroaryl, wherein the C 6-10 aryl, the 5-6 membered heterocycloalkyl, or the 5-6 membered heteroaryl may each independently be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy, and q is selected from 1, 2, or 3;
  • Z is selected from N or CH.
  • the compound of formula (TL), its stereoisomer or a pharmaceutically acceptable salt thereof wherein:
  • Ring A is selected from 5-6 membered heterocycloalkyl, which may be optionally substituted by 1-3 groups selected from the following groups: halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl;
  • R1 is selected from substituted or unsubstituted 5-6 membered heteroaryl
  • R 2 is selected from C 3-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, 2, and m2 is selected from 0, 1, 2;
  • R3 is selected from halogen, C1-4 alkyl, C1-4 haloalkyl
  • R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl;
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form a C 6-10 aryl, a 5-6 membered heterocycloalkyl, or a 5-6 membered heteroaryl, wherein the C 6-10 aryl, the 5-6 membered heterocycloalkyl, or the 5-6 membered heteroaryl may each independently be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy, and q is selected from 1, 2, or 3;
  • Z is selected from N or CH.
  • Ring A is selected from 5-6 membered heterocycloalkyl containing 1-2 nitrogen atoms
  • R 1 is selected from Wherein, R 1a is selected from C 1-4 alkyl, C 1-4 haloalkyl;
  • R 2 is selected from C 2-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, m2 is selected from 0, 1, and C 2-6 alkoxy may be optionally substituted by 1, 2, or 3 halogens;
  • R3 is selected from halogen
  • R5 is selected from hydrogen
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl may be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and q is selected from 1, 2, 3;
  • Z is selected from N or CH.
  • Ring A is selected from 5-6 membered heterocycloalkyl groups containing 1-2 nitrogen atoms;
  • R 1 is selected from Wherein, R 1a is selected from C 1-4 alkyl, C 1-4 haloalkyl;
  • R 2 is selected from C 3-6 alkoxy, C 3-6 cycloalkyl-(CH 2 ) m1 -O-, 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, wherein m1 is selected from 0, 1, and m2 is selected from 0, 1;
  • R3 is selected from halogen
  • R5 is selected from hydrogen
  • R6 is selected from hydrogen, halogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl;
  • R 5 , R 6 and the atoms to which they are attached are cyclized together to form phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl may be optionally substituted by q R 6a groups, each R 6a is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and q is selected from 1, 2, 3;
  • Z is selected from N or CH.
  • R 3 is selected from bromine.
  • the bifunctional compound described in the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen and methyl, and R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, and phenyl.
  • the bifunctional compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen, and R 6 is selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, and phenyl.
  • the compound of the above formula (TL), its stereoisomer or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen, and R 6 is selected from fluorine, methyl, ethyl, cyclopropyl, and phenyl.
  • R 5 is selected from methyl.
  • R 6 in the compound of formula (TL), its stereoisomer or pharmaceutically acceptable salt thereof, R 6 is selected from chlorine. In some embodiments, R 6 is fluorine.
  • the compound of the above formula (TL), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 and the atoms to which they are connected are cyclized together to form phenyl, pyrazine, 1,4-dioxane, pyridine, pyrimidine, wherein the benzene ring, pyrazine, 1,4-dioxane, pyridine,
  • the pyrimidine may be optionally substituted with q R 6a groups, each independently, wherein q and R 6a are as defined above.
  • the present disclosure also provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • the present disclosure also provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • the present disclosure also provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • the present disclosure also provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • R2 is selected from
  • R2 is selected from
  • R2 is selected from
  • R2 is selected from In some embodiments of the present disclosure, R2 is selected from
  • R2 is selected from
  • R2 is selected from
  • the present disclosure also provides a bifunctional compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from:
  • the present disclosure also provides the following bifunctional compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which are selected from:
  • the present disclosure also provides the following bifunctional compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which are selected from:
  • the present disclosure also provides the use of the above-mentioned compounds, bifunctional compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof in the preparation of EGFR degraders. In some embodiments, the present disclosure also provides the use of the above-mentioned compounds, bifunctional compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof in the preparation of EGFR degraders.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound, bifunctional compound, stereoisomers thereof or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers.
  • the present disclosure also provides use of the above-mentioned compound, bifunctional compound, stereoisomer thereof, pharmaceutically acceptable salt thereof or the above-mentioned composition in preparing a drug for treating EGFR-mediated related cancers.
  • the present disclosure also provides the above-mentioned compound, bifunctional compound, stereoisomer thereof, pharmaceutically acceptable salt thereof or the above-mentioned composition for degrading EGFR.
  • the present disclosure also provides the above-mentioned compound, bifunctional compound, stereoisomer thereof, pharmaceutically acceptable salt thereof or the above-mentioned composition for treating EGFR-mediated related cancers.
  • the present disclosure also provides use of the above-mentioned compound, bifunctional compound, stereoisomer thereof, pharmaceutically acceptable salt thereof or the above-mentioned composition in degrading EGFR.
  • the present disclosure also provides use of the above-mentioned compound, bifunctional compound, stereoisomer thereof, pharmaceutically acceptable salt thereof or the above-mentioned composition in treating EGFR-mediated related cancers.
  • the present disclosure also provides a method for treating cancer, comprising administering an effective therapeutic amount of the above-mentioned compound, bifunctional compound, stereoisomer thereof, pharmaceutically acceptable salt thereof or the above-mentioned composition to a patient in need thereof.
  • the above-mentioned cancer is selected from lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), bile duct cancer, kidney cancer, thyroid cancer, mesothelioma, multiple myeloma, and melanoma.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer.
  • the present disclosure also provides intermediate compounds, stereoisomers or pharmaceutically acceptable salts thereof as shown in formula (INT-1), (INT-2):
  • R 7 and R 8 are each independently selected from H or a common protecting group for amino, and Z, R 2 , R 5 and R 6 are as defined above.
  • R 7 and R 8 are each independently selected from H, a Boc protecting group, and CF 3 C(O)-.
  • the intermediate compound, stereoisomer or pharmaceutically acceptable salt thereof represented by formula (INT-1) is selected from the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
  • the intermediate compound, stereoisomer or pharmaceutically acceptable salt thereof represented by formula (INT-1) is selected from the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
  • the intermediate compound, stereoisomer or pharmaceutically acceptable salt thereof represented by formula (INT-1) is selected from the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
  • R 2 is selected from C 2-6 alkoxy, wherein the C 2-6 alkoxy may be optionally substituted by 1, 2, or 3 halogens; preferably, R 2 is selected from Preferably, R2 is selected from Preferably, R2 is selected from
  • R 2 is selected from C 3-6 cycloalkyl-(CH 2 ) m1 -O-, preferably, R 2 is selected from Preferably, R2 is selected from Preferably, R2 is selected from
  • R 2 is selected from 3-6 membered heterocycloalkyl-(CH 2 ) m2 -O-, preferably, R 2 is selected from
  • the intermediate compound, stereoisomer or pharmaceutically acceptable salt thereof represented by formula (INT-2) is selected from the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
  • the intermediate compound, stereoisomer or pharmaceutically acceptable salt thereof represented by formula (INT-2) is selected from the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
  • the intermediate compound, stereoisomer or pharmaceutically acceptable salt thereof represented by formula (INT-2) is selected from the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:
  • the linker (also called a connector) and the targeting ligand can be first connected by a chemical reaction, and then the degron is added to prepare the triplet compound of the present disclosure; or as shown in General Scheme 2, the linker and the degron are first connected by a chemical reaction, and then the targeting ligand is added to prepare the triplet compound of the present disclosure;
  • the two parts can be prepared separately and then connected, or they can be connected first and then the synthesis of each part can be completed.
  • the targeting ligand and the linker part can be connected, and the prepared targeting ligand and the linker can be connected, or a part of the targeting ligand can be connected to the linker first, and then the preparation of the targeting ligand itself can be completed after the connection is completed.
  • connection of the two parts in the triplet compound is prepared by conventional chemical reactions, such as steps 1 and 2 in general schemes 1 and 2, which can be achieved by reactions such as nucleophilic substitution, condensation or coupling.
  • the triplet compound in the present disclosure can be prepared by the following method:
  • the targeting ligand is connected to the linker, it is then connected to the degradation determinant to obtain:
  • the linker After the linker is connected to the degradation determinant, it is then connected to the targeting ligand to obtain:
  • targeting ligand, linker, and degradation determinant are as defined above.
  • the disclosed compounds have a good inhibitory effect on the cell proliferation of EGFR triple mutation, double mutation and single mutation cell lines. At the same time, the disclosed compounds have a weaker inhibitory effect on the cell proliferation of normal vascular endothelial cells that depend on VEGFR for growth, indicating that the disclosed compounds have good selectivity.
  • the disclosed compounds have good degradation effects on triple-mutated, double-mutated and single-mutated EGFR proteins; and the disclosed compounds have good oral absorption performance in mice; at the same time, the disclosed compounds show very good in vivo pharmacodynamic effects on triple-mutated and double-mutated EGFR tumor models
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for delivering biologically active agents to animals, especially mammals, and includes, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.
  • adjuvants such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.
  • Pharmaceutically acceptable carriers are within the purview of those of ordinary skill in the art and can be selected and formulated based on a number of factors. They include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition and the target therapeutic indication, etc. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers may include many different ingredients and additives (e.g., stabilized active agents, adhesives, etc.), and it is well known to those of ordinary skill in the art to include additional ingredients in a prescription for a variety of reasons.
  • an effective preventive or therapeutic amount refers to a sufficient amount of the compound of the present disclosure or its stereoisomers, tautomers or pharmaceutically acceptable salts to treat the disorder at a reasonable effect/risk ratio applicable to any medical treatment and/or prevention.
  • the total daily dosage of the compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts and compositions disclosed herein must be determined by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used; and similar factors known in the medical field.
  • the practice in the art is to start the dose of the compound from a level lower than that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
  • pharmaceutically acceptable salt refers to a derivative of the disclosed compound prepared with a relatively non-toxic acid or base. These salts can be prepared during the synthesis, separation, and purification of the compound, or the purified free form of the compound can be used alone to react with a suitable acid or base.
  • the compound contains a relatively acidic functional group, it reacts with an alkali metal, alkaline earth metal hydroxide or an organic amine to obtain a base addition salt, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations, and also covers amino acid salts.
  • the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to obtain an acid addition salt.
  • the term "patient” includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • non-human mammals include, but are not limited to, birds and fish, etc.
  • the mammal is a human.
  • the compounds disclosed herein exist in geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which fall within the scope of the present disclosure.
  • stereoisomer includes “enantiomers” and “diastereomers”.
  • Enantiomers refer to stereoisomers that are mirror images of each other, and “diastereomers” refer to stereoisomers that have two or more chiral centers and are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter.
  • Stereoisomers of the disclosed compounds can be prepared by chiral synthesis or chiral reagents or other conventional techniques.
  • one enantiomer of a compound of the disclosed compounds can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology.
  • a compound of a single stereo configuration can be obtained from a mixture by chiral resolution technology.
  • it can be prepared directly using chiral starting materials.
  • the separation of optically pure compounds in the disclosed compounds is usually accomplished by preparative chromatography, using a chiral chromatographic column to achieve the purpose of separating chiral compounds.
  • the absolute stereo configuration of the compound can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction can also be used to confirm the absolute configuration of the compound by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis.
  • the stereo configuration is determined by comparing it with the product with determined absolute configuration.
  • the compounds marked as "absolute configuration unknown" herein are usually separated into single isomers by chiral preparative SFC from racemic compounds, and then characterized and tested.
  • the linker is selected from -(AK) n1- (Cy)n2-(AK) n3- (Cy) n4- ( AK ) n5- , and AK and Cy are independent choices at each occurrence.
  • substituent R When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that the substituent R can be substituted at any position on the benzene ring.
  • ring refers to saturated, partially saturated or unsaturated monocyclic and polycyclic rings, and “polycyclic rings” include spirocyclic, fused or bridged rings.
  • Representative “rings” include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • hetero refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, also known as heteroatomic groups, wherein the heteroatoms are generally selected from N, O, S, and the oxidized forms generally include NO, SO, S(O) 2.
  • the nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein); the number of atoms on the ring is generally defined as the number of ring members, for example, "3-6 membered heterocycloalkyl” refers to a ring formed by 3-6 atoms arranged around each ring, each ring optionally containing 1 to 3 heteroatoms, i.e., N, O, S, NO, SO, S(O) 2 or NR, each ring optionally substituted by an R group, and R is a group defined herein.
  • cycloalkyl refers to a saturated monocyclic or polycyclic hydrocarbon group.
  • the cycloalkyl group is preferably a C 3-8 monocyclic alkyl group, more preferably a C 3-6 monocyclic alkyl group, and examples of these monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • heterocycloalkyl refers to mono-heterocycloalkyl and poly-heterocycloalkyl containing a certain number of heteroatoms or heteroatomic groups in the ring, wherein the heteroatoms are generally selected from N, O, S, NO, SO, S(O) 2 and NR.
  • the heterocycloalkyl is preferably a 3-6 membered mono-heterocycloalkyl, more preferably a 5-6 membered mono-heterocycloalkyl, and more preferably a 5-6 membered mono-heterocycloalkyl.
  • Preferred are 5-6 membered monoheterocyclic alkyl groups containing nitrogen atoms. Examples of these monoheterocyclic alkyl groups include, but are not limited to: wait.
  • cycloalkyl and heterocycloalkyl groups in the present disclosure may be fused with a benzene ring, for example
  • R 5 , R 6 and the atoms to which they are connected are cyclized to form 1,4-dioxane, which can form structure.
  • a "5-6 membered heterocycloalkyl group containing 1-2 nitrogen atoms” refers to a heterocycloalkyl group in which the heteroatom is the only nitrogen atom, other heteroatoms are not included, and the number of nitrogen atoms is 1 or 2.
  • aryl refers to an unsaturated, usually aromatic hydrocarbon group, which may be a single ring or multiple rings fused together.
  • C 6-10 aryl most preferably a monocyclic C 5-6 aryl; examples of aryl include, but are not limited to, phenyl and naphthyl.
  • heteroaryl means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom or heteroatom group (N, O, S, NO, SO, S(O) 2 or NR). Preferably, a 5-membered or 6-membered monocyclic heteroaryl.
  • heteroaryl include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl.
  • the "fused heterocyclic group” or “heterocyclic group” described in the present disclosure refers to a cyclic group formed by two or more cyclic structures sharing two adjacent atoms, at least one ring atom is a heteroatom or a heteroatom group, and its ring carbon atoms are optionally oxidized, that is, C is oxidized to form C(O);
  • the "8-10 membered fused heterocyclic group” described in the present disclosure includes a saturated 8-10 membered fused heterocyclic group, a partially saturated 8-10 membered fused heterocyclic group and an aromatic 8-10 membered fused heterocyclic group, and the fusion mode includes a 6-membered ring and a 6-membered ring, a 5-membered ring and a 6-membered ring, and a 5-membered ring and a 5-membered ring.
  • the "8-10 membered fused heterocyclic group" described in the present disclosure refers to a benzo 5-6 membered heterocyclic group, wherein the "heterocyclic group” refers to a non-aromatic monocyclic or polycyclic ring containing a certain number of heteroatoms and/or heteroatom groups in the ring, and the ring may be saturated or partially saturated.
  • 8-10 membered fused heterocyclic groups include, but are not limited to
  • alkylene chain refers to a group derived from a branched or straight-chain alkane, alkene, or alkyne with a specified number of carbon atoms by removing two hydrogen atoms, including “alkylene”, “alkenylene”, and “alkynylene”, and the alkylene group may be further substituted by other groups;
  • alkenylene and alkynylene refer to a hydrocarbon chain containing at least one double bond or triple bond, respectively, and is an unsaturated hydrocarbon chain.
  • alkylene group described in the present disclosure includes “C 1-10 alkylene group”, preferably “C 1-6 alkylene group”, “C 2-10 alkylene group”, “C 5-7 alkynylene group”, “C 7-10 alkylene group”, “C 5-7 alkenylene group”, “C 1-6 alkylene group”, “C 1-3 alkylene group”, “C 2-6 alkynylene group” and the like.
  • the “alkylene group” described in the present disclosure is preferably a “straight chain alkylene group”; specific examples of the alkylene chain include but are not limited to: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 2 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 2 )CH 2 CH 2 -, -CH(CH 2 CH 2 )CH 2 -, -C(CH 2 )(CH 2 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • any methylene unit is optionally replaced” described in the present disclosure, such as any methylene unit in "-CH 2 CH 2 CH 2 -" is replaced by -C(O)-, which may form but is not limited to the following structure -C(O)CH 2 CH 2 -, -CH 2 C(O)CH 2 -, -CH 2 CH 2 C(O)-, -C(O)CH 2 C(O)-, etc.
  • alkyl is used to represent a straight or branched saturated hydrocarbon group.
  • the alkyl group is C 1-6 , and more preferably, the alkyl group is C 1-4 .
  • Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, and the like.
  • alkoxy refers to an alkyl group connected via an oxygen bridge, i.e., a group obtained by replacing a hydrogen atom in a hydroxyl group with an alkyl group.
  • C 1-6 alkoxy is used, and more preferably C 1-4 alkoxy is used.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, and n-hexyloxy.
  • halogen means a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms.
  • C 1-6 haloalkyl is used, and more preferably C 1-4 haloalkyl is used.
  • haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.
  • the left side of a divalent group is connected to the left side group by default, and the right side of a divalent group is connected to the right side group by default.
  • the linker is selected from , it means that the carbonyl end is connected to the left targeting ligand; the hexahydropyridine ring is connected to the right degradation determinant; the linker is selected from When , it means that the tetrahydropyrrole ring is connected to the right-hand degron, and the piperazine is connected to the left-hand targeting ligand; for another example, Cy in -(AK) n1- (Cy) n2- (AK) n3 is selected from , it means that the N atom end of the ring is connected to the AK on the left, and the carbon atom end of the ring is connected to the AK on the right.
  • the naming of the title compound is converted from the compound structure with the aid of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by combining relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structure shall prevail.
  • the preparation methods of some compounds in the present disclosure refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.
  • NMR nuclear magnetic resonance
  • mass spectroscopy The structures of the compounds disclosed herein are determined by nuclear magnetic resonance (NMR) and mass spectroscopy. NMR chemical shifts ( ⁇ ) are expressed in parts per million (ppm). The units are given. NMR measurements were performed using a Bruker Ascend 400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), and heavy water (D 2 O) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • Ultra-high performance liquid chromatography-mass spectrometry was performed using a Waters UPLC H-class SQD2 mass spectrometer.
  • HPLC determination was performed using Waters e2695-2998.
  • Preparative HPLC used Waters 2555-2489 (10 ⁇ m, ODS 250 cm ⁇ 5 cm).
  • the thin layer chromatography silica gel plate used was HSGF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd.
  • the specification used for TLC was 0.20 mm ⁇ 0.03 mm, and the preparative type was 20 x 20 cm.
  • the column chromatography used 200-300 mesh silica gel from Qingdao Hailang Silica Gel Desiccant Co., Ltd. as the carrier.
  • the starting materials in the embodiments of the present disclosure are known and commercially available, or can be synthesized using or according to methods known in the art.
  • Step A Dissolve 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.0 g, 4.0 mmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (1.3 g, 4.8 mmol) in DMF (15 mL), add potassium carbonate (1.1 g, 8.0 mmol), heat to 60 ° C and stir to react overnight.
  • TLC monitors the reaction of the raw materials, cool, add water (50 mL), extract the mixture twice with ethyl acetate (100 mL), and combine the organic phases. The organic phase is washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated.
  • Step B Dissolve tert-butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.3 g, 2.6 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.09 g, 5.2 mmol) in 1,4-dioxane (18 mL) and water (6 mL). Replace with nitrogen 3-4 times, then add sodium carbonate (0.83 g, 7.8 mmol) and Pd(dppf)Cl 2 (0.19 g, 0.3 mmol), heat to 80°C and stir overnight.
  • Step C Dissolve tert-butyl 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.44 g, 2.9 mmol) in ethanol (30 mL) and water (12 mL), add ammonium chloride (1.85 g, 34.4 mmol), reduced iron powder (0.93 g, 16.7 mmol) and diatomaceous earth (2 g, 100-200 mesh) in sequence, and heat to 80°C and stir for 3 hours. TLC monitoring shows that the raw material reacts completely, cool to room temperature, filter, and concentrate to remove most of the ethanol.
  • Step A Dissolve tert-butyl 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (3.4 g, 6.79 mmol) in DCM (25 mL), add trifluoroacetic acid (5 mL), and react at 25 °C for 3 hours. After LC-MS monitoring showed that the starting material disappeared, the reaction solution was directly concentrated under reduced pressure to obtain 2.72 g 1-(1-(5-methoxy-2-(1-methylpyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine.
  • Step B 1-(1-(5-methoxy-2-(1-methylpyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine (2.72 g, 6.79 mmol) was dissolved in dichloromethane (40 mL), and DMAP (2.49 g, 20.37 mmol) and trifluoroacetic anhydride (2.14 g, 10.19 mmol) were added in sequence, and the mixture was reacted at room temperature for 1 hour. After LC-MS monitoring showed that the starting material disappeared, the reaction solution was poured into water (100 mL), extracted with dichloromethane (100 mL) 3 times, and the organic phases were combined.
  • Step C 2,2,2-trifluoro-1-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)ethane-1-one (3.20 g, 6.45 mmol) was dissolved in methanol (30 mL) at room temperature, 10% palladium carbon (800 mg) was added, hydrogen was replaced three times, and the reaction system was stirred at 25° C. for 2 hours.
  • Step A Dissolve 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (7.79 g, 31.0 mmol) and cyclopropanol (1.8 g, 31.0 mmol) in DMSO (70 mL), add potassium carbonate (8.56 g, 62.0 mmol), heat to 70 ° C and stir to react overnight.
  • TLC monitors the complete reaction of the raw materials, cool, pour the reaction solution into water (150 mL), and extract twice with ethyl acetate.
  • Step B 1-bromo-2-chloro-4-cyclopropyloxy-5-nitrobenzene (6.5 g, 22.3 mmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (7.18 g, 26.7 mmol) were dissolved in DMF (100 mL), potassium carbonate (6.14 g, 44.5 mmol) was added, and the temperature was raised to 90 ° C and stirred to react overnight. TLC monitored that the raw material reaction was complete, cooled, and the reaction solution was poured into water (200 mL), and extracted with ethyl acetate three times.
  • Step C Dissolve tert-butyl 4-(1-(2-bromo-5-cyclopropyloxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (8.3 g, 15.8 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.28 g, 22.5 mmol) in 1,4-dioxane (100 mL) and water (20 mL), and add sodium carbonate (3.35 g, 31.6 mmol).
  • Step D Dissolve tert-butyl 4-(1-(5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (5.26 g, 10.0 mmol) in ethanol (50 mL) and water (20 mL), add iron powder (36.5 g, 56.2 mmol), ammonium chloride (6.4 g, 120.0 mmol) and diatomaceous earth (7.9 g, 100-200 mesh) in sequence, heat to 80°C and stir to react for 4 hours.
  • TLC monitors the reaction of the raw materials, cool, pour the reaction solution into water (100 mL), and extract with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 3.2 g of tert-butyl 4-(1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step A tert-Butyl 4-(1-(5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.40 g, 2.66 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, and the reaction system was stirred at room temperature for 2 hours.
  • Step B 1-(1-(5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine trifluoroacetate (1.40 g, 2.59 mmol) was dissolved in dichloromethane (20 mL), DMAP (0.95 g, 7.77 mmol) and trifluoroacetic anhydride (0.82 g, 3.88 mmol) were added in sequence, and the reaction system was heated to 30 ° C and stirred for 3 hours.
  • Step C 1-(4-(1-(5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (1.48 g, 2.83 mmol) was dissolved in methanol (20 mL), 10% palladium carbon (300 mg) was added, and the air was evacuated under vacuum to replace the hydrogen for 3-4 times. The reaction system was heated to 30 ° C and stirred for 2 hours.
  • Step A Dissolve 4-bromo-5-fluoro-2-nitrophenol (2g, 8.74mmol) in N,N-dimethylformamide (30mL), add cesium carbonate (5.5g, 16.94mmol) and bromomethylcyclopropane (2.3g, 16.94mmol) in turn, and stir to 80°C for 16 hours under nitrogen protection.
  • TLC monitors the complete reaction of the raw materials, and the reaction solution is added to water (50mL), extracted twice with ethyl acetate, and the organic phases are combined.
  • Step B 1-bromo-4-(cyclopropylmethoxy)-2-fluoro-5-nitrobenzene (2.4 g, 9.03 mmol) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (2.5 g, 18.06 mmol), 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (3.8 g, 13.60 mmol) were added in sequence, and the mixture was heated to 75 °C and stirred for 16 hours under nitrogen protection. TLC monitored that the raw material reaction was complete, the reaction solution was added to water (100 mL), extracted twice with ethyl acetate, and the organic phases were combined.
  • Step C Dissolve tert-butyl 4-(1-(2-bromo-5-(cyclopropylmethoxy)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.1 g, 3.9 mmol) in 1,4-dioxane (20 mL) and water (5 mL), add potassium carbonate (1.6 g, 11.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (978 mg, 5.33 mmol) and Pd(dppf)Cl 2 (142 mg, 0.191 mmol) in sequence, replace with nitrogen three times, raise to 80°C and stir for 16 hours.
  • TLC monitoring shows that the raw material is completely reacted, concentrate under reduced pressure, pour the remaining mixture into ice water, extract twice with ethyl acetate, and combine the organic phases.
  • the organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate and concentrated.
  • the residue was purified by silica gel column chromatography to give 2 g of tert-butyl 4-(1-(5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step D Dissolve tert-butyl 4-(1-(5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2 g, 3.5 mmol) in methanol (40 mL), add 10% palladium carbon (140 mg), and hydrogenate under normal pressure for 3 hours. TLC monitoring shows that the reaction of the raw materials is complete, and the palladium carbon is removed by diatomaceous earth filtration.
  • Step A 4-bromo-5-fluoro-2-nitrophenol (4 g, 62.0 mmol) was dissolved in N,N-dimethylformamide (60 mL), and tetrabutylammonium iodide (4.7 g, 34.74 mmol), cesium carbonate (5.7 g, 17.37 mmol) and bromocyclobutane (4.7 g, 34.74 mmol) were added respectively, and the temperature was raised to 75 ° C under nitrogen protection and stirred for 16 hours. The reaction solution was added to water (100 mL), extracted twice with ethyl acetate, and the organic phases were combined.
  • Step B 1-bromo-4-cyclobutoxy-2-fluoro-5-nitrobenzene (2.7 g, 9.03 mmol) and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (3.7 g, 13.55 mmol) were dissolved in DMF (60 mL), potassium carbonate (2.5 g, 18.06 mmol) was added, and the temperature was raised to 75 ° C and stirred to react overnight.
  • Step C Dissolve tert-butyl 4-(1-(2-bromo-5-cyclobutoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.2 g, 4.1 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.3 mmol) in 1,4-dioxane (60 mL) and water (20 mL), add potassium carbonate (1.7 g, 12.3 mmol), introduce N 2 for replacement 3 times, add Pd(dppf)Cl 2 (0.15 g, 0.02 mmol), raise the temperature to 80°C and stir to react overnight.
  • the reaction of the raw materials was completed after TLC monitoring.
  • the reaction mixture was cooled and poured into water (100 mL).
  • the mixture was extracted with ethyl acetate three times.
  • the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the residue was purified by silica gel column chromatography to obtain 1.4 g of tert-butyl 4-(1-(5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step D Dissolve tert-butyl 4-(1-(5-cyclobutyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (1.4 g, 2.59 mmol) in methanol (40 mL), add 10% palladium carbon (140 mg), and react under normal pressure for 3 hours.
  • Step A Dissolve tert-butyl 4-(1-(5-cyclobutyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2.80 g, 5.18 mmol) in dichloromethane (27 mL), add trifluoroacetic acid (9 mL), and react at 25°C for 1 hour.
  • Step B 1-(1-(5-cyclobutyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine (2.27 g, 5.15 mmol) was dissolved in dichloromethane (25 mL), 4-dimethylaminopyridine (1.89 g, 15.45 mmol) and trifluoroacetic anhydride (3.24 g, 15.45 mmol) were added, and the mixture was reacted at room temperature for 1 hour. LC-MS monitoring showed that the starting material disappeared, and the reaction solution was poured into water (40 mL), extracted 3 times with dichloromethane (50 mL), and the organic phases were combined.
  • Step C 1-(4-(1-(5-cyclobutyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (1.65 g, 3.08 mmol) was dissolved in methanol (30 mL) at room temperature, 10% palladium on carbon (330 mg) was added, hydrogen was replaced three times, and the mixture was stirred at 35°C for 2 hours. LC-MS monitoring showed that the starting material disappeared, and the mixture was filtered through diatomaceous earth.
  • Step A 2-(3,5-difluorophenyl)ethan-1-ol (15.0 g, 94.9 mmol) and imidazole (13.0 g, 191.2 mmol) were dissolved in DCM (150 mL), TBSCl (22.0 g, 146.7 mmol) was added in batches, and the mixture was stirred at room temperature overnight. TLC monitored the complete reaction of the raw materials, and the reaction solution was poured into water (200 mL), separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 24.0 g of tert-butyl (3,5-difluorophenoxy) dimethylsilane.
  • Step B Dissolve tert-butyl (3,5-difluorophenoxy) dimethylsilane (24.0 g, 88.2 mmol) in anhydrous tetrahydrofuran (200 mL), cool to -78°C in a dry ice acetone bath, slowly drop n-butyl lithium (2.5 M, 40.0 mL, 100.0 mmol), stir and react at -78°C for 1 hour after the addition is complete, then drop I 2 (25.0 g, 98.0 mmol) in tetrahydrofuran (80 mL), stir and react at -78°C for 1 hour after the addition is complete, heat to 0°C for 1 hour, then heat to room temperature for stirring and react overnight.
  • n-butyl lithium 2.5 M, 40.0 mL, 100.0 mmol
  • Step C Dissolve tert-butyl (3,5-difluoro-4-iodophenethoxy) dimethylsilane (4.0 g, 9.6 mmol) and 2,6-bis (benzyloxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (3.0 g, 7.38 mmol) in 1,4-dioxane (60 mL) and water (12 mL), add potassium carbonate (2.55 g, 18.0 mmol) and Pd (dppf) Cl 2 (0.81 g, 1.1 mmol), replace with nitrogen 3-4 times, heat to 100 ° C and stir overnight.
  • Step D 2,6-bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,6-difluorophenyl)pyridine (3.0 g, 5.4 mmol) was dissolved in tetrahydrofuran (30 mL), TBAF.3H 2 O (2.02 g, 6.4 mmol) was added at 0°C, and the mixture was reacted at room temperature for 1 hour. TLC monitoring showed that the starting material disappeared, saturated sodium bicarbonate solution (50 mL) was added, and ethyl acetate (100 mL) was used for extraction 3 times, and the organic phases were combined.
  • Step E 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)ethan-1-ol (0.8 g, 1.79 mmol) was dissolved in dichloromethane (18 mL), trifluoroacetic acid (6 mL) was added at 0°C, and the reaction system was reacted at room temperature for 16 hours. TLC monitoring showed that the starting material disappeared, and the residue was concentrated under reduced pressure. The residue was dissolved in methanol (25 mL), 10% Pd/C (120 mg) was added, and the reaction was carried out at room temperature under 1 atm hydrogen pressure for 48 hours. Celite was filtered off.
  • Step F The obtained 2.8g 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione was separated by chiral HPLC to obtain 1.37g compound INT-8-P1 (peak time 4.46min) and 1.33g compound INT-8-P2 (peak time 5.82min). Separation conditions: Superchiral R-AD 2.1cm I.D.*25cm Length, 5um; mobile phase: acetonitrile; flow rate: 15ml/min; gradient: 100% acetonitrile within 15 minutes; detection wavelength: 220nm.
  • Step A (R)-pyrrolidine-3-carboxylic acid methyl ester hydrochloride (1.2 g, 6.97 mmol), 2-bromo-1,3-difluoro-5-iodobenzene (1.78 g, 5.58 mmol), potassium phosphate (2.96 g, 13.94 mmol) and L-proline (0.16 g, 1.39 mmol) were dissolved in DMSO (10 mL), cuprous iodide (0.27 g, 1.39 mmol) was added, nitrogen was replaced three times, and the temperature was raised to 90°C for 10 hours. TLC monitoring showed that the raw material disappeared, and the reaction solution was cooled to room temperature and poured into water (30 mL) for quenching.
  • Step B (R)-1-(4-bromo-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (0.85 g, 2.39 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (synthesis can refer to patent WO2022/261250A1, 1.50 g, 3.58 mmol) and potassium phosphate (1.01 g, 4.78 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL), replaced with nitrogen three times, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.39 g, 0.48 mmol) was added, and the reaction was stirred at 85 ° C for 3 hours under nitrogen protection.
  • Step C Dissolve (R)-1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (0.485 g, 0.91 mmol) in tetrahydrofuran Hydrofuran (2 mL), lithium hydroxide (0.22 g, 9.1 mmol) and water (0.5 mL) were added, and the reaction was stirred at 25 ° C for 2 hours. LC-MS monitoring showed that the raw material disappeared, and the reaction solution was adjusted to pH 5 with 1 mol/L hydrochloric acid, extracted with ethyl acetate (10 mL) 3 times, and the organic phases were combined.
  • Step D (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (0.24 g, 0.46 mmol) was dissolved in methanol (12 mL) and dichloromethane (2 mL), 10% palladium carbon (0.10 g) was added, hydrogen was replaced three times, and the reaction was stirred at 30°C for 20 hours. LC-MS monitoring showed that the raw material disappeared, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain 0.15 g of (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid.
  • Step A Slowly drop a toluene (10 mL) solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (460 mg, 0.76 mmol) at 50°C, and then stir to react for 2 hours. LC-MS monitoring showed that the raw material disappeared. 1 equivalent of water was added to the reaction solution at 50°C, and stirring was continued for half an hour. The reaction solution was cooled to room temperature and diluted with petroleum ether, and solids precipitated.
  • Step B Dissolve (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid tert-butyl ester (200 mg, 0.34 mmol) in methanol (12 mL) and dichloromethane (2 mL), add 10% palladium carbon (100 mg), replace with hydrogen three times, and stir at 30°C for 20 hours.
  • Step C The obtained (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid tert-butyl ester (280 mg, 0.71 mmol) was separated by chiral HPLC to obtain 128 mg (R)-1-(4-((R or S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid tert-butyl ester (peak time 4.63 min) and 120 mg of tert-butyl (R)-1-(4-((S or R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate (peak time 5.20 min).
  • Step D (R)-1-(4-((R or S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid tert-butyl ester (peak time 4.63 min, 128 mg, 0.32 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step E (R)-1-(4-((S or R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid tert-butyl ester (peak time 5.20 min, 120 mg, 0.30 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 16 hours.
  • Step A 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (4.30 g, 16.90 mmol) and cyclopropanol (1.47 g, 25.35 mmol) were dissolved in DMSO (50 mL), potassium carbonate (5.84 g, 42.25 mmol) was added, and the nitrogen was replaced by vacuum for 3-4 times.
  • the reaction system was heated to 70 ° C and refluxed for 16 hours. TLC monitored the complete reaction of the raw materials, the reaction solution was cooled to room temperature, poured into an aqueous solution of ammonium chloride (200 mL), extracted with ethyl acetate (100 mL) 3 times, and the organic phases were combined.
  • Step B 1-bromo-2-chloro-4-cyclopropyloxy-5-nitrobenzene (2.0 g, 6.84 mmol), piperidin-4-ylmethanol (1.18 g, 10.26 mmol) and potassium carbonate (1.89 g, 13.68 mmol) were added to acetonitrile (50 mL) in sequence, and the reaction system was heated to 90° C. and stirred for 48 hours. TLC monitored that the raw materials were basically reacted completely, and the reaction solution was poured into water (20 mL) after cooling, extracted 3 times with dichloromethane (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.0 g (1-(2-bromo-5-cyclopropyloxy-4-nitrophenyl) piperidin-4-yl)methanol.
  • Step C (1-(2-bromo-5-cyclopropyloxy-4-nitrophenyl)piperidin-4-yl)methanol (2.0 g, 5.39 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.68 g, 8.08 mmol) and potassium phosphate (3.43 g, 16.17 mmol) were added to a mixed solution of 1,4-dioxane/water (40 mL/10 mL).
  • Step D (1-(5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methanol (1.4 g, 3.73 mmol) was dissolved in methanol (30 mL), and palladium carbon (40 mg, 10% wt) was added after replacing the hydrogen, and then replaced with hydrogen 2-3 times, and the reaction system was stirred at room temperature overnight. TLC monitored that the raw material was basically reacted completely, the reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was collected. The filtrate was concentrated under pressure to obtain about 1.4 g of (1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanol.
  • Step A Methyl 2-cyano-5-fluorobenzoate (1.5 g, 8.37 mmol), tert-butyl 2,7-diazaspiro[3,5]nonane-7-carboxylate (2.27 g, 10.04 mmol) and DIEA (3.25 g, 25.11 mmol) were dissolved in DMSO (20 mL), and the reaction system was heated to 85 °C and stirred for 4 hours. TLC monitored the complete reaction of the raw materials. After cooling, the reaction solution was poured into ice water (200 mL), extracted with ethyl acetate (100 mL) three times, and the organic phases were combined.
  • Step B tert-butyl 2-(4-cyano-3-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3,5]nonane-7-carboxylate (3.0 g, 7.78 mmol), disodium hydrogen phosphate (11.04 g, 10.42 mmol) and acetic acid (5.25 g, 87.43 mmol) were dissolved in a mixed solution of pyridine (10 mL) and water (5 mL), and then Raney nickel (1.83 g) was added, and the hydrogen was replaced by vacuum 3-4 times. The reaction system was heated to 50°C and stirred for 24 hours. LC-MS monitoring showed that the raw materials were completely reacted.
  • reaction solution was poured into ice water (100 mL), extracted twice with dichloromethane (80 mL), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.0 g of tert-butyl 2-(4-formyl-3-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3,5]nonane-7-carboxylate.
  • Step C tert-butyl 2-(4-formyl-3-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3,5]nonane-7-carboxylate (1.0 g, 2.57 mmol), 3-amino-2,6-piperidindione hydrochloride (630 mg, 3.85 mmol) and DIEA (1.00 g, 7.71 mmol) were dissolved in DMF (20 mL), stirred at room temperature overnight, then acetic acid (1.54 g, 25.7 mmol) and sodium triacetoxyborohydride (1.63 g, 7.71 mmol) were added, and the reaction system was stirred at room temperature for 4 hours.
  • Step D Dissolve tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.15 g, 0.42 mmol) in hydrogen chloride/1,4-dioxane solution (20 mL) and stir at room temperature for 2 hours.
  • Step A 2-bromo-1,3-difluoro-5-iodobenzene (600 mg, 1.91 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (480 mg, 2.10 mmol), potassium phosphate (1.22 g, 5.73 mmol), L-proline (88 mg, 0.76 mmol) and cuprous iodide (73 mg, 0.38 mmol) were added to DMSO (10 mL) in sequence, and the reaction system was heated to 90 ° C. and stirred overnight under a nitrogen atmosphere.
  • reaction was completed by LC-MS monitoring, and the reaction solution was slowly poured into water (20 mL) after cooling, extracted 3 times with ethyl acetate (50 mL), and the organic phases were combined. The organic phase was washed three times with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 600 mg of tert-butyl 2-(4-bromo-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.
  • Step B tert-Butyl 2-(4-bromo-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (500 mg, 1.20 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (750 mg, 1.80 mmol) and potassium phosphate (760 mg, 3.60 mmol) were added sequentially to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and the atmosphere was replaced with nitrogen 3-4 times.
  • Step C Dissolve tert-butyl 2-(4-(2,6-bis(benzyloxypyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (500 mg, 0.80 mmol) in methanol (20 mL), add 10% palladium on carbon (85 mg), replace with hydrogen 3-4 times, and heat the reaction system to 30 ° C and stir for 3 days.
  • Step D Dissolve tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (150 mg, 0.33 mmol) in DCM (6 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 2 hours.
  • Step A Dissolve 4-bromo-2,6-difluorobenzeneacetonitrile (22.0 g, 94.8 mmol) in anhydrous THF (200 mL), cool to -70 °C, slowly add LDA (104.3 mL, 104.3 mmol, 1.0 mol/L), react at -70 °C for 1 hour, then add 3-bromopropionic acid ethyl ester (20.6 g, 113.8 mmol) in THF (50 mL), naturally warm to room temperature and react for 0.5 hours.
  • LDA 104.3 mL, 104.3 mmol, 1.0 mol/L
  • 3-bromopropionic acid ethyl ester 20.6 g, 113.8 mmol
  • Step B Dissolve 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyric acid ethyl ester (29.3 g, 88.2 mmol) in THF (210 mL) and water (70 mL), add lithium hydroxide monohydrate (6.35 g, 265.0 mmol), and stir at room temperature for 3 hours. TLC monitoring shows that the raw material is completely reacted, the reaction solution is adjusted to pH 3 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (200 mL) 3 times.
  • Step C 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyric acid (27.4 g, 90 mmol) was dissolved in toluene (270 mL) at room temperature, and concentrated sulfuric acid (9.7 g, 99 mmol) was added. The reaction system was heated to 100 ° C and stirred for 3 hours. LCMS monitoring showed that the raw material reaction was complete. The reaction solution was cooled to room temperature and poured into a saturated sodium bicarbonate aqueous solution (300 mL) in batches, and extracted with ethyl acetate (200 mL) 3 times.
  • Step D 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (20 g, 65.8 mmol) was dissolved in DMF (200 mL) and water (40 mL), and 1-ethoxyethylene-2-boronic acid pinacol ester (15.6 g, 79 mmol), CsF (20 g, 131.5 mmol) and Pd(dtbpf)Cl 2 (2.12 g, 3.3 mmol) were added. Nitrogen was replaced 3-4 times, and the reaction system was heated to 80°C and stirred for 2 hours. LCMS monitoring showed that the raw material was completely reacted.
  • Step E The obtained 10g (E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione was separated by chiral HPLC to obtain 4.6g of compound INT-14-P1 (peak time 4.36min) and 4.5g of compound INT-14-P2 (peak time 6.49min). Separation conditions: Superchiral R-AD (Chiralway Biotech Co., Ltd.), 2.1cm I.D.*25cm Length, 5um; mobile phase: methanol; flow rate: 15ml/min; gradient: 100% methanol within 15 minutes; detection wavelength: 220nm.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P 1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added at 0°C, and the reaction system was reacted at 0°C for 2 hours. TLC monitoring showed that the starting material disappeared, saturated sodium bicarbonate solution (20 mL) was added, ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (380 mg, 0.93 mmol) and 5-bromo-2-chloro-N-(1-(dimethylphosphoryl)naphthalene-2-yl)pyrimidine-4-amine (synthesis can refer to patent WO2022/268229A1, 311 mg, 0.93 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (1.1 g, 9.3 mmol) was added, and the temperature was raised to 98 ° C and stirred overnight.
  • Step C tert-Butyl 4-(1-(4-((5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (342 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 4 hours.
  • Step D (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (134 mg, 0.172 mmol) was dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (66.6 mg, 0.51 mmol), (R or S)-4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenethyl methanesulfonate (80 mg, 0.21 mmol) and sodium iodide (7.8 mg, 0.052 mmol) were added.
  • the reaction system was heated to 80°C under nitrogen protection and refluxed with stirring for 16 hours.
  • LC-MS monitoring showed that the raw material disappeared, and the reaction solution was cooled, and water (20 mL) was added to the reaction solution, and ethyl acetate (30 mL) was used for extraction twice, and the organic phases were combined.
  • the organic phase was washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step A (S or R)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P2, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and the mixture was stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (134 mg, 0.172 mmol) was dissolved in acetonitrile (5 mL), N,N-diisopropylethylamine (66.6 mg, 0.51 mmol), (S or R)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenylethyl methanesulfonate (70 mg, 0.21 mmol) and sodium iodide (7.8 mg, 0.052 mmol) were added, and the reaction system was heated to 80°C under nitrogen protection and refluxed for 16 hours.
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and the mixture was stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B Dissolve tert-butyl 4-(1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (571 mg, 1.22 mmol) and (3-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide (synthesis can refer to patent WO2022/171123A1, 500 mg, 1.22 mmol) in n-butanol (10 mL), add trifluoroacetic acid (1.39 g, 12.2 mmol), warm to 98 ° C and stir to react overnight.
  • the crude product was purified by silica gel column chromatography to obtain 480 mg of tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (480 mg, 0.57 mmol) in dichloromethane (5 mL), add 5N hydrochloric acid-dioxane solution (5 mL), and stir at room temperature for 16 hours. The disappearance of the starting material was monitored by TLC, and tert-butyl methyl ether (10 mL) was added.
  • Step D (3-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide hydrochloride (202 mg, 0.26 mmol) was dissolved in acetonitrile (10 mL), and (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (90 mg, 0.26 mmol), DIEA (101 mg, 0.79 mmol) and sodium iodide (4 mg, 0.02 mmol) were added in sequence, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Step A (S or R)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P 2, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and the mixture was stirred at 0°C for 2 hours. TLC monitoring showed that the starting material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted three times, and the organic phases were combined.
  • Step B (3-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide hydrochloride (225 mg, 0.29 mmol) was dissolved in acetonitrile (10 mL), (S or R)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (100 mg, 0.29 mmol), DIEA (112 mg, 0.86 mmol) and sodium iodide (4 mg, 0.03 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in DCM (10 mL), triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added at 0°C, and the reaction system was reacted at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (800 mg, 1.56 mmol) and 5-bromo-2-chloro-N-(1-(dimethylphosphoryl)naphthalen-2-yl)pyrimidin-4-amine (530 mg, 1.3 mmol) were dissolved in n-butanol (20 mL), trifluoroacetic acid (0.85 g, 13.1 mmol) was added, and the mixture was heated to 98°C and stirred overnight.
  • the crude product was purified by isopropyl ether/ethyl acetate beating to obtain 600 mg of 4-(1-(4-((5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (600 mg, 0.68 mmol) in ethyl acetate (2 mL) and 1,4-dioxane (2 mL), add 5N hydrogen chloride-1,4-dioxane solution (5 mL) under ice bath, and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-cyclobutoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide hydrochloride (153 mg, 0.20 mmol) was dissolved in acetonitrile (6 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (80 mg, 0.23 mmol), DIEA (76 mg, 0.58 mmol) and sodium iodide (5 mg, 0.04 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Step A (S or R)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P2, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and the mixture was stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B (2-((5-bromo-2-((2-cyclobutoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide hydrochloride (150 mg, 0.20 mmol) was dissolved in acetonitrile (6 mL), (S or R)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (80 mg, 0.23 mmol), DIEA (75 mg, 0.58 mmol) and sodium iodide (5 mg, 0.04 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in DCM (10 mL), triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added at 0°C, and the reaction system was reacted at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (500 mg, 1.3 mmol) and (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (synthesis can refer to patent CN114728994A, 311 mg, 0.93 mmol) were dissolved in n-butanol (8 mL), trifluoroacetic acid (1.5 g, 13.2 mmol) was added, and the temperature was raised to 98°C and stirred to react overnight.
  • Step C tert-Butyl 4-(1-(4-((5-bromo-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (540 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 4 hours.
  • Step D (2-((5-bromo-2-((2-cyclobutyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl) (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenylethyl methanesulfonate (81 mg, 0.23 mmol), DIEA (76 mg, 0.58 mmol) and sodium iodide (6 mg, 0.04 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Step A (S or R)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P2, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and the mixture was stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B (2-((5-bromo-2-((2-cyclobutoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (134 mg, 0.17 mmol) was dissolved in acetonitrile (6 mL), and N,N-diisopropylethylamine (66 mg, 0.51 mmol), (S or R)-4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenethyl methanesulfonate (70 mg, 0.21 mmol) and sodium iodide (12.8 mg, 0.09 mmol) were added, and the reaction system was heated to 80°C under nitrogen protection and refluxed with stirring for 16 hours.
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in DCM (10 mL), triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added at 0°C, and the reaction system was reacted at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B Dissolve tert-butyl 4-(1-(4-amino-5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (750 mg, 1.22 mmol) and (2-((5-bromo-2-chloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (500 mg, 1.47 mmol) in n-butanol (10 mL), add trifluoroacetic acid (1.39 g, 12.2 mmol), heat to 80°C and stir to react overnight.
  • the crude product was purified by isopropyl ether/ethyl acetate beating to obtain 600 mg of 4-(1-(4-(5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step C Dissolve tert-butyl 4-(1-(4-(5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (600 mg, 0.68 mmol) in 1,4-dioxane (4 mL), add 5N hydrogen chloride-1,4-dioxane solution (5 mL) under ice bath, and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (150 mg, 0.18 mmol) was dissolved in acetonitrile (6 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (75 mg, 0.23 mmol), DIEA (76 mg, 0.58 mmol) and sodium iodide (6 mg, 0.04 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Step A (S or R)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P2, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and the mixture was stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B (2-((5-bromo-2-((2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (153 mg, 0.20 mmol) was dissolved in acetonitrile (6 mL), (S or R)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (80 mg, 0.23 mmol), DIEA (76 mg, 0.58 mmol) and sodium iodide (6 mg, 0.04 mmol) were added, and the temperature was raised.
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B Dissolve tert-butyl 4-(1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (314 mg, 0.63 mmol) and 5-bromo-2-chloro-N-(4-(dimethylphosphoryl)quinolin-3-yl)pyrimidin-4-amine (200 mg, 1.3 mmol) in n-butanol (10 mL), add trifluoroacetic acid (554 mg, 4.8 mmol), heat to 98°C and stir to react overnight.
  • trifluoroacetic acid 554 mg, 4.8 mmol
  • the crude product was purified by isopropyl ether/ethyl acetate beating to obtain 276 mg of 4-(1-(4- Tert-butyl ((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (276 mg, 0.32 mmol) in dichloromethane (3 mL), add 5N hydrogen chloride-1,4-dioxane solution (5 mL) under ice bath, and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-1-yl)dimethylphosphine oxide (111 mg, 0.14 mmol) was dissolved in acetonitrile (8 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (60 mg, 0.17 mmol), DIEA (56 mg, 0.43 mmol) and sodium iodide (2 mg, 0.01 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (200 mg, 0.49 mmol) and 5-bromo-2-chloro-N-(4-(dimethylphosphoryl)quinolin-3-yl)pyrimidin-4-amine (200 mg, 1.3 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (557 mg, 4.9 mmol) was added, and the mixture was heated to 98°C and stirred overnight.
  • the crude product was purified by isopropyl ether/ethyl acetate beating to obtain 240 mg of 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (240 mg, 0.27 mmol) in dichloromethane (2 mL), add 5N hydrogen chloride-1,4-dioxane solution (5 mL) under ice bath, and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-cyclobutoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-1-yl)dimethylphosphine oxide hydrochloride (150 mg, 0.19 mmol) was dissolved in acetonitrile (6 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (80 mg, 0.23 mmol), DIEA (74 mg, 0.57 mmol) and sodium iodide (5 mg, 0.04 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 13 is a diagrammatic representation of Embodiment 13:
  • Step A Dissolve 1-(4-(1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (700 mg, 1.38 mmol) and (2-((5-bromo-2-chloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (570 mg, 1.38 mmol) in n-butanol (15 mL) at room temperature, add trifluoroacetic acid (1.57 g, 13.80 mmol), heat to 100°C and stir for 16 hours.
  • Step B 1-(4-(1-(4-((5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (660 mg, 0.75 mmol) was dissolved in methanol (16 mL) at room temperature, and water (4 mL) and potassium hydroxide (420 mg, 7.50 mmol) were added in sequence, and the mixture was heated to 60°C and stirred for 0.5 hours.
  • Step C (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (0.05 g, 0.15 mmol) and (2-((5-bromo-2-((2-cyclobutyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (0.12 g, 0.15 mmol) were dissolved in DMF (2 mL) at room temperature.
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • Step A 1-(4-(1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (100 mg, 0.20 mmol) and (2-((5-bromo-2-chloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (82 mg, 0.20 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (230 mg, 2.01 mmol) was added, and the air was evacuated and replaced with nitrogen 3-4 times in vacuo.
  • reaction system was heated to 100° C., refluxed and stirred for 16 hours. LC-MS monitoring showed that the starting material disappeared.
  • the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 65 mg of 1-(4-(1-(4-((5-bromo-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one.
  • Step B 1-(4-(1-(4-((5-bromo-4-((1-(dimethylphosphoryl)naphthalene-2-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-yl)-2,2,2-trifluoroethane-1-one (65 mg, 0.075 mmol) was dissolved in methanol/water (8 mL/2 mL), potassium hydroxide (42 mg, 0.75 mmol) was added, and the nitrogen was replaced by air under vacuum 3-4 times.
  • the reaction system was heated to 60 ° C and refluxed and stirred for 2 hours.
  • LC-MS monitoring showed that the raw material disappeared, water (50 mL) was added to the reaction solution, and it was extracted 3 times with ethyl acetate (50 mL), and the organic phase was combined.
  • Step C (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (57 mg, 0.074 mmol) and (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (25 mg, 0.074 mmol) were dissolved in DMF (5 mL), and DIEA (19 mg, 0.15 mmol) and HATU (42 mg, 0.11 mmol) were added in sequence, and the air was replaced with nitrogen 3-4 times under vacuum, and the reaction system was stirred at room temperature for 10 minutes.
  • DMF 5 mL
  • DIEA (19 mg,
  • Embodiment 15 is a diagrammatic representation of Embodiment 15:
  • Step A 1-(4-(1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (100 mg, 0.20 mmol) and (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (76 mg, 0.20 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (230 mg, 2.01 mmol) was added, and the air was evacuated and replaced with nitrogen 3-4 times in vacuo.
  • reaction system was heated to 100° C. and refluxed and stirred for 16 hours. LC-MS monitoring showed that the starting material disappeared.
  • the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 100 mg of 1-(4-(1-(4-((5-bromo-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one.
  • Step B 1-(4-(1-(4-((5-bromo-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-yl)-2,2,2-trifluoroethane-1-one (100 mg, 0.12 mmol) was dissolved in methanol/water (8 mL/2 mL), potassium hydroxide (67 mg, 0.12 mmol) was added, and the nitrogen was replaced by air under vacuum 3-4 times.
  • the reaction system was heated to 60 ° C and refluxed and stirred for 2 hours.
  • LC-MS monitoring showed that the raw material disappeared, and water (50 mL) was added to the reaction solution to quench, and the mixed solution was extracted 3 times with ethyl acetate (50 mL), and the organic phases were combined.
  • Step C (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (80 mg, 0.11 mmol) and (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (37 mg, 0.11 mmol) were dissolved in DMF (5 mL), DIEA (28 mg, 0.22 mmol) and HATU (63 mg, 0.17 mmol) were added in sequence, and the air was evacuated and replaced with nitrogen 3-4 times.
  • DMF 5 mL
  • DIEA 28 mg, 0.22 mmol
  • HATU 63 mg, 0.
  • Embodiment 16 is a diagrammatic representation of Embodiment 16:
  • Step A (R)-1-(4-((R or S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (INT-10-P1, 37 mg, 0.11 mmol) and (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (80 mg, 0.11 mmol) were dissolved in DMF (3 mL) at room temperature, DIEA (71 mg, 0.55 mmol) was added slowly, stirred for 5 minutes, and HATU (63 mg, 0.17 mmol) was added in batches, and stirred at room temperature for 10 minutes.
  • DIEA 71 mg, 0.
  • Embodiment 17 is a diagrammatic representation of Embodiment 17:
  • Step A (R)-1-(4-((S or R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (INT-10-P2, 37 mg, 0.11 mmol) and (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (80 mg, 0.11 mmol) were dissolved in DMF (3 mL) at room temperature, DIEA (71 mg, 0.55 mmol) was added slowly, stirred for 5 minutes, and HATU (63 mg, 0.17 mmol) was added in batches, and stirred at room temperature for 10 minutes.
  • DIEA 71 mg, 0.
  • Embodiment 18 is a diagrammatic representation of Embodiment 18:
  • Step A Dissolve (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (300 mg, 0.79 mmol) and 1-(4-(1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (370 mg, 0.79 mmol) in n-butanol (2 mL), add trifluoroacetic acid (900 mg, 7.9 mmol), heat to 100 °C and stir overnight. LC-MS monitoring showed that the starting material disappeared.
  • Step B 1-(4-(1-(4-((5-bromo-4-((2-(dimethylphosphoryl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-yl)-2,2,2-trifluoroethane-1-one (274 mg, 0.32 mmol) was dissolved in methanol (4 mL), water (1 mL) and potassium hydroxide (180 mg, 3.2 mmol) were added in sequence, and the temperature was raised to 60 ° C for 1 hour.
  • Step C (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (28 mg, 0.084 mmol) and (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (60 mg, 0.084 mmol) were dissolved in DMF (1 mL) at room temperature, DIEA (33 mg, 0.25 mmol) was added, and HATU (48 mg, 0.13 mmol) was added in batches after stirring for 5 minutes, and stirred at room temperature for 10 minutes.
  • Embodiment 19 is a diagrammatic representation of Embodiment 19:
  • Step A (3-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide (200 mg, 0.49 mmol) and 1-(4-(1-(4-amino-5- Cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (230 mg, 0.49 mmol) was dissolved in n-butanol (8 mL), trifluoroacetic acid (560 mg, 4.9 mmol) was added, and the air was evacuated and replaced with nitrogen 3-4 times.
  • Step B 1-(4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (110 mg, 0.13 mmol) was dissolved in methanol/water (8 mL/2 mL), potassium hydroxide (73 mg, 1.3 mmol) was added, and the reaction system was heated to 60 ° C. and refluxed and stirred for 2 hours.
  • Step C (3-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide (80 mg, 0.10 mmol) and (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (34 mg, 0.10 mmol) were dissolved in DMF (5 mL), DIEA (26 mg, 0.20 mmol) and HATU (57 mg, 0.15 mmol) were added successively, and the reaction system was stirred at room temperature for 10 minutes.
  • DMF 5 mL
  • DIEA 26 mg, 0.20 mmol
  • HATU 57 mg, 0.15
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • Step A (1-(4-(1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1- Ketone (150 mg, 0.31 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)dimethylphosphine oxide (synthesis can refer to patent WO2022/127807A1, 130 mg, 0.31 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (350 mg, 3.10 mmol) was added, and the air was evacuated and replaced with nitrogen 3-4 times in vacuo.
  • Step B 1-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)pyrimidin-2-yl)amino]-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (120 mg, 0.14 mmol) was dissolved in methanol/water (8 mL/2 mL), sodium hydroxide (56 mg, 1.40 mmol) was slowly added, and the air was evacuated and replaced with nitrogen 3-4 times.
  • sodium hydroxide 56 mg, 1.40 mmol
  • the reaction system was heated to 65 ° C and then heated to 40 ° C. Flow and stir for 2 hours. LC-MS monitoring shows that the raw material disappears. Water (50 mL) is added to the reaction solution to quench. The mixed solution is extracted 3 times with dichloromethane (50 mL), and the organic phase is combined.
  • Step C (6-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)dimethylphosphine oxide (70 mg, 0.10 mmol) and (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (41 mg, 0.12 mmol) were dissolved in DMF (5 mL), DIEA (40 mg, 0.30 mmol) and HATU (57 mg, 0.15 mmol) were added, and the air was evacuated and replaced with nitrogen 3-4 times.
  • DMF 5 mL
  • DIEA 40
  • Embodiment 21 is a diagrammatic representation of Embodiment 21.
  • Step A Dissolve (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (synthesis can refer to patent WO2022/12622A1, 210 mg, 0.49 mmol) and 1-(4-(1-(4-amino-5-cyclopropyloxy-2-(1-methylpyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-yl)-2,2,2-trifluoroethane-1-one (241 mg, 0.49 mmol) in n-butanol (8 mL) at room temperature, add trifluoroacetic acid (558 mg, 0.49 mmol), heat to 100°C and stir for 16 hours.
  • Step B 1-(4-(1-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinoline-6-amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methylpyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-yl)-2,2,2-trifluoroethane-1-one (260 mg, 0.29 mmol) was dissolved in methanol (8 mL) at room temperature, water (2 mL) and potassium hydroxide (163 mg, 0.29 mmol) were added in sequence, and the mixture was heated to 40° C. and stirred for 30 minutes.
  • Step C (3R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (18 mg, 0.051 mmol) and (6-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (40 mg, 0.051 mmol) were dissolved in DMF (3 mL) at room temperature, DIEA (20 mg, 0.15 mmol) and HATU (29 mg, 0.076 mmol) were added, and the reaction system was stirred at room temperature for 10 minutes.
  • Embodiment 22 is a diagrammatic representation of Embodiment 22.
  • Step A (3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (20 mg, 0.059 mmol) and (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (44 mg, 0.059 mmol) were dissolved in DMF (2 mL), DIEA (38 mg, 0.29 mmol) was added, HATU (34 mg, 0.088 mmol) was added after stirring for 5 minutes, and the reaction system was stirred at room temperature for 10 minutes.
  • DIEA 38 mg, 0.29 mmol
  • HATU 34 mg, 0.088
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • Step A (2-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (70 mg, 0.095 mmol) and 1-(4-(2,6-dioxopiperidin-3-yl(-3,5-difluorophenyl)azetidine-3-carboxylic acid (34 mg, 0.095 mmol) were dissolved in DMF (1.5 mL), DIEA (37 mg, 0.29 mmol) and HATU (54 mg, 0.14 mmol) were added sequentially.
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • Step A (3-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide (50 mg, 0.065 mmol) and 1-(4-(2,6-dioxopiperidin-3-yl(-3,5-difluorophenyl)azetidine-3-carboxylic acid (22 mg, 0.068 mmol) were dissolved in DMF (1.5 mL), DIEA (25 mg, 0.20 mmol) and HATU (37 mg, 0.098 mmol) were added, and the mixture was stirred under vacuum.
  • DMF 1.5 mL
  • DIEA 25 mg, 0.20 mmol
  • HATU 37 mg, 0.098 mmol
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (250 mg, 0.5 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (synthesis can refer to patent WO2022/12622A1, 230 mg, 0.52 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (670 mg, 5 mmol) was added, and the temperature was raised to 98 ° C.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropyloxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (280 mg, 0.31 mmol) in dichloromethane (5 mL), add 5N hydrogen chloride/1,4-dioxane solution (1 mL) under ice bath and stir at room temperature for 2 hours. TLC monitoring showed that the starting material disappeared.
  • Step D (6-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide hydrochloride (110 mg, 0.13 mmol) was dissolved in acetonitrile (10 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (52 mg, 0.15 mmol), DIEA (52 mg, 0.40 mmol) and sodium iodide (2 mg, 0.01 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 26 is a diagrammatic representation of Embodiment 26.
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B Dissolve tert-butyl 4-(1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (298 mg, 0.58 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (300 mg, 1.12 mmol) in n-butanol (10 mL), add trifluoroacetic acid (1.34 g, 11.8 mmol), heat to 98°C and stir to react overnight.
  • TLC monitoring shows that the starting material disappears, cool to room temperature, and concentrate the reaction solution under reduced pressure.
  • the residue is dissolved in tetrahydrofuran (10 mL), triethylamine (176 mg, 1.74 mmol) is added, and di-tert-butyl dicarbonate (230 mg, 1.1 mmol) is added after stirring for 10 minutes, and stirred at room temperature for 4 hours.
  • Water (50 mL) was added to the reaction solution to quench, and ethyl acetate (50 mL) was used for extraction 3 times, and the organic phases were combined.
  • the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography to obtain 300 mg of 4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (300 mg, 0.33 mmol) in dichloromethane (10 mL) and add under ice-cooling. Trifluoroacetic acid (10 mL) was added and stirred at room temperature for 2 hours. TLC monitoring showed that the raw material disappeared, and the reaction solution was concentrated under reduced pressure.
  • Step D (6-((5-bromo-2-((2-cyclobutoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (85 mg, 0.11 mmol) was dissolved in acetonitrile (10 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (44 mg, 0.13 mmol), DIEA (41 mg, 0.32 mmol) and sodium iodide (2 mg, 0.01 mmol) were added, and the mixture was stirred at 80°C for 16 hours.
  • Embodiment 27 is a diagrammatic representation of Embodiment 27.
  • Step A (6-((5-bromo-2-((2-cyclopropyloxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (65 mg, 0.083 mmol) and 1-(4-(2,6-dioxopiperidin-3-yl(-3,5-difluorophenyl)azetidine-3-carboxylic acid (30 mg, 0.083 mmol) were dissolved in DMF (1.5 mL), DIEA (32 mg, 0.25 mmol) and HATU (47 mg, 0.12 mmol) were added, and nitrogen was added.
  • DMF 1.5 mL
  • DIEA 32 mg, 0.25 mmol
  • HATU 47 mg, 0.12 mmol
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-cyclopropylmethoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (248 mg, 0.49 mmol) and 5-bromo-2-chloro-N-(4-(dimethylphosphoryl)quinolin-3-yl)pyrimidin-4-amine (200 mg, 0.49 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (554 mg, 4.86 mmol) was added, and the mixture was heated to 75°C and stirred overnight.
  • trifluoroacetic acid 554 mg, 4.86 mmol
  • the crude product was purified by silica gel column chromatography to obtain 70 mg of tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropylmethoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropylmethoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (70 mg, 0.08 mmol) in dichloromethane (3 mL), add 6N hydrogen chloride/1,4-dioxane solution (5 mL) under ice bath and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-cyclopropylmethoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-1-yl)dimethylphosphine oxide hydrochloride (65 mg, 0.08 mmol) was dissolved in N'N-dimethylformamide (3 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (33 mg, 0.10 mmol), DIEA (30 mg, 0.24 mmol) and sodium iodide (2 mg, 0.01 mmol) were added, and the temperature was raised to 80°C and stirred for 16 hours.
  • N'N-dimethylformamide 3 mL
  • R or S -4
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added, and stirred at 0°C for 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, and ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-isopropoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (200 mg, 0.49 mmol) and 5-bromo-2-chloro-N-(4-(dimethylphosphoryl)quinolin-3-yl)pyrimidin-4-amine (292 mg, 0.59 mmol) were dissolved in n-butanol (5 mL), trifluoroacetic acid (556 mg, 4.88 mmol) was added, and the mixture was heated to 98°C and stirred overnight.
  • Step C Dissolve tert-butyl 4-(1-(4-((5-bromo-4-((4-(dimethylphosphoryl)quinolin-3-yl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (370 mg, 0.24 mmol) in dichloromethane (3 mL), add 5N hydrogen chloride/1,4-dioxane solution (5 mL) under ice bath and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-isopropoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-1-yl)dimethylphosphine oxide hydrochloride (130 mg, 0.16 mmol) was dissolved in acetonitrile (8 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (65 mg, 0.19 mmol), DIEA (62 mg, 0.48 mmol) and sodium iodide (2 mg, 0.01 mmol) were added, and the temperature was raised to 80°C and stirred for 16 hours.
  • Embodiment 30 is a diagrammatic representation of Embodiment 30.
  • Step A (R or S)-3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (INT-8-P1, 100 mg, 0.38 mmol) was dissolved in DCM (10 mL), triethylamine (116 mg, 1.12 mmol) and methanesulfonyl chloride (64 mg, 0.56 mmol) were added at 0°C, and the reaction system was reacted at 0°C. 2 hours. TLC monitoring showed that the raw material disappeared, saturated sodium bicarbonate solution (20 mL) was added, ethyl acetate (50 mL) was extracted 3 times, and the organic phases were combined.
  • Step B tert-butyl 4-(1-(4-amino-5-cyclopropylmethoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (270 mg, 0.53 mmol) and 5-bromo-2-chloro-N-(2-(dimethylphosphoryl)-4-fluorophenyl)pyrimidin-4-amine (200 mg, 0.53 mmol) were dissolved in n-butanol (10 mL), trifluoroacetic acid (602 mg, 5.28 mmol) was added, and the mixture was heated to 75°C and stirred overnight.
  • the crude product was purified by silica gel column chromatography to obtain 250 mg of tert-butyl 4-(1-(4-(5-bromo-4-(2-(dimethylphosphoryl)-4-fluorophenylamino)pyrimidine-2-amino)-5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate.
  • Step C Dissolve tert-butyl 4-(1-(4-(5-bromo-4-(2-(dimethylphosphoryl)-4-fluorophenylamino)pyrimidine-2-amino)-5-(cyclopropylmethoxy)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazine-1-carboxylate (250 mg, 0.29 mmol) in dichloromethane (5 mL), add 6N hydrogen chloride/1,4-dioxane solution (5 mL) under ice bath and stir at room temperature for 2 hours.
  • Step D (2-((5-bromo-2-((2-(cyclopropylmethoxy)-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide hydrochloride (100 mg, 0.13 mmol) was dissolved in N'N-dimethylformamide (3 mL), (R or S)-4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenylethyl methanesulfonate (66 mg, 0.19 mmol), DIEA (49 mg, 0.38 mmol) and sodium iodide (5 mg, 0.03 mmol) were added, and the temperature was raised to 80°C and stirred for 16 hours.
  • N'N-dimethylformamide 3 mL

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Abstract

La présente divulgation concerne un nouveau composé bifonctionnel capable de dégrader l'EGFR, une composition pharmaceutique contenant le composé, son procédé de préparation et l'utilisation du composé selon la présente invention dans le traitement de maladies prolifératives cellulaires, telles que le cancer.
PCT/CN2024/088489 2023-04-19 2024-04-18 Agent de dégradation d'egfr, composition pharmaceutique et utilisation associées Pending WO2024217481A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021190417A1 (fr) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Nouvel inhibiteur aminopyrimidine d'egfr
WO2022171123A1 (fr) * 2021-02-10 2022-08-18 Beigene, Ltd. Agents de dégradation d'egfr et procédés d'utilisation
TW202237597A (zh) * 2021-03-19 2022-10-01 大陸商上海齊魯製藥研究中心有限公司 新型egfr降解劑
WO2022228547A1 (fr) * 2021-04-30 2022-11-03 四川海思科制药有限公司 Dérivé de phosphonyle, et composition et application pharmaceutique de celui-ci
WO2022228556A1 (fr) * 2021-04-30 2022-11-03 Beigene, Ltd. Agents de dégradation d'egfr et méthodes d'utilisation associées
WO2022268229A1 (fr) * 2021-06-25 2022-12-29 和径医药科技（上海）有限公司 Inhibiteur de protéine ou agent de dégradation, composition pharmaceutique le contenant et utilisation pharmaceutique
CN116891502A (zh) * 2022-03-29 2023-10-17 上海齐鲁制药研究中心有限公司 Egfr降解剂

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021190417A1 (fr) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Nouvel inhibiteur aminopyrimidine d'egfr
WO2022171123A1 (fr) * 2021-02-10 2022-08-18 Beigene, Ltd. Agents de dégradation d'egfr et procédés d'utilisation
TW202237597A (zh) * 2021-03-19 2022-10-01 大陸商上海齊魯製藥研究中心有限公司 新型egfr降解劑
WO2022228547A1 (fr) * 2021-04-30 2022-11-03 四川海思科制药有限公司 Dérivé de phosphonyle, et composition et application pharmaceutique de celui-ci
WO2022228556A1 (fr) * 2021-04-30 2022-11-03 Beigene, Ltd. Agents de dégradation d'egfr et méthodes d'utilisation associées
WO2022268229A1 (fr) * 2021-06-25 2022-12-29 和径医药科技（上海）有限公司 Inhibiteur de protéine ou agent de dégradation, composition pharmaceutique le contenant et utilisation pharmaceutique
CN116891502A (zh) * 2022-03-29 2023-10-17 上海齐鲁制药研究中心有限公司 Egfr降解剂

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